saralasin and Hypertension

Chronic activation of the renin-angiotensin system (RAS) plays a crucial role in the development of various cardiovascular diseases (CVD). Thus, effective RAS inhibition has been a major achievement to improve the treatment of patients at risk for CVDs, such as myocardial infarction, heart failure and stroke. Three substance classes that block RAS-activation are currently available, angiotensin converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor blockade (ARB) and renin inhibitors. Although the overall goal of these drugs remains the blockade of RAS activation, their individual targets in this system vary and may substantially influence the clinical benefit derived from the long term use of these substances. Here, we summarize the evidence available for the use of ARBs in different cardiovascular pathologies and the impact of this evidence on current treatment guidelines for patients at risk for CVD. Today, ARBs represent a good alternative in case of ACE-inhibitor intolerance due to their outstanding tolerability. ARBs in comparison to ACE-inhibitors have been proven to exert similar effective in the treatment of systolic heart failure, primary prevention of stroke, new onset of diabetes mellitus (DM) type 2 and DM type 2 dependent macroalbuminuria. ARBs should be considered as alternatives to ACE-inhibitors in subjects post-myocardial infarction. Overall however, there is no profound proof for a specific cardiovascular protection by blockade of the angiotensin II Type 1 (AT1) receptor that exceeds the impact of ACE-inhibition or synergises with ACE-blockade. In fact, combination of ARBs and ACE-inhibitor result in an increased rate of adverse effects and, therefore, this combination should not be encouraged. To summarize, the initial hope for a more specific impact on cardiovascular diseases by inhibition of the AT1-receptor in comparison to ACE-inhibition has not come true. However, ARBs have been proven to be equally effective as ACE-blockade in a large variety of clinical settings.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Diseases; Consensus; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Hypertension; Hypertrophy, Left Ventricular; Middle Aged; Practice Guidelines as Topic; Primary Prevention; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Risk Factors; Saralasin; Secondary Prevention; Stroke; Tetrazoles; Time Factors; Treatment Outcome; Valine; Valsartan

This is a personal historical account relating the events that led to the first application of angiotensin inhibition (either by ACE inhibitors or by angiotensin receptor blockade) to the investigation of the pathogenesis and treatment of hypertension, ischemic heart disease, and heart failure. Included are animal experiments, clinical observations, and the earliest clinical experimental studies that helped define some of the detrimental effects of angiotensin II and the beneficial hemodynamic results of its inhibition, which have been subsequently corroborated and amplified by large randomized outcome trials.

Topics: Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Antihypertensive Agents; Captopril; Clinical Trials as Topic; Coronary Circulation; Heart Failure; Hemodynamics; Humans; Hypertension; Male; Myocardial Ischemia; Renin; Renin-Angiotensin System; Saralasin; Teprotide

Topics: Amino Acid Sequence; Angiotensin II; Angiotensin Receptor Antagonists; Antihypertensive Agents; Biphenyl Compounds; Hemodynamics; Humans; Hypertension; Imidazoles; Losartan; Molecular Sequence Data; Pyridines; Receptors, Angiotensin; Renin-Angiotensin System; Saralasin; Tetrazoles

Milestones in understanding the renin-angiotensin system (RAS) until the development of angiotensin II antagonists are described briefly. Sites at which the RAS might be blocked are outlined.. Saralasin-like compounds were used in numerous experimental and clinical situations and clarified the role of the RAS. Some of these situations are described (e.g. hypertension and cardiac failure) particularly in regard to the control of arterial pressure and aldosterone secretion by the RAS. Saralasin and its analogues allowed visualization, for the first time, of complete angiotensin II/effector (especially blood pressure) dose-response curves.. The clinical usefulness of ACE inhibitors in hypertension, cardiac failure, diabetes mellitus and after acute myocardial infarction is emphasized. In particular, ACE inhibitors have actions beyond blockade of angiotensin II formation, necessitating cautious interpretation of data from their use.. Experience with renin inhibitors in documenting and confirming the role of the RAS is outlined. NON-PEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS: Characteristics of losartan-like compounds are discussed in brief, and the results of their limited use in clinical medicine are outlined.. Blocking agents have led to great advances in knowledge of the RAS and its physiological and pathophysiological functions. ACE inhibitors are used regularly in a number of clinical disorders and, in theory, have therapeutic potential beyond alternative antihypertensive drugs in the prevention of cardiovascular complications in essential hypertension. The place of renin inhibitors and angiotensin II receptor antagonists in clinical practice, however, remains to be determined.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; History, 19th Century; History, 20th Century; Humans; Hypertension; Renin; Renin-Angiotensin System; Saralasin

Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve hemodynamics in some patients with congestive heart failure. It is now possible to antagonize chronically angiotensin II at its receptor using the non-peptide angiotensin II inhibitor losartan (DuP 753, MK 954). When administered by mouth, this compound induces a dose-dependent inhibition of the pressor response to exogenous angiotensin II. This effect is closely related to circulating levels of the active metabolite E3174. Preliminary studies performed in hypertensive patients suggest that losartan has a blood pressure lowering action equivalent to that of an ACE inhibitor. Whether this compound will compare favorably with ACE inhibitors requires however further investigation.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Humans; Hypertension; Imidazoles; Losartan; Reference Values; Renin-Angiotensin System; Saralasin; Tetrazoles

Through the multiple actions of angiotensin II (AII), the renin-angiotensin system (RAS) participates in cardiovascular homeostasis. Angiotensin II acts by binding to specific membrane-bound receptors, which are coupled to one of several signal transduction pathways. These AII receptors exhibit heterogeneity, represented by AT1 and AT2 receptor subtypes. The AT1 receptor mediates the major cardiovascular action of the RAS. This receptor has been cloned from multiple species, disclosing features consistent with a transmembrane, G-protein-linked receptor. Further AII receptor heterogeneity is evident by the cloning of isotypes of the AT1 receptor. Blocking the interaction of AII with its receptor is the most direct site to inhibit the actions of the RAS. Many AII receptor antagonists, including peptide analogs of AII and antibodies directed against AII, possess unfavorable properties that have limited their clinical utility. The discovery and further development of imidazole compounds with AII antagonist properties and favorable characteristics, however, has promise for clinical utility. The leader in this field is a selective AT1 receptor antagonist losartan (previously known as DuP 753 or MK-954). Losartan was demonstrated to be an effective antagonist of many AII-induced actions and an effective antihypertensive agent in many animal models of hypertension (HTN). Losartan also demonstrated secondary benefits in preventing stroke, treating congestive heart failure (CHF), and delaying the progression of renal disease in animal models. Clinical studies confirm the AII antagonist action of losartan and suggest that losartan will be effective in the treatment of essential HTN. AII antagonism is likely to provide useful treatment in essential HTN and CHF, conditions in which the RAS is known to play a major role. The utility of AII antagonism may extend beyond that of HTN and CHF, as suggested by the potential usefulness of angiotensin-converting enzyme (ACE) inhibition in the treatment or prevention of many other diseases. The key advantage AII antagonists provide over ACE inhibitors is that they may avoid unwanted side effects, related to bradykinin potentiation with the latter drugs. The AII antagonists will help determine the role of the RAS in physiologic regulation and in the pathophysiology of various disease states.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Cardiovascular Diseases; Heart Failure; Homeostasis; Humans; Hypertension; Imidazoles; Losartan; Receptors, Angiotensin; Renin-Angiotensin System; Saralasin; Tetrazoles

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Humans; Hypertension; Imidazoles; Kidney; Losartan; Receptors, Angiotensin; Saralasin; Tetrazoles

The acute blockade of the renin-angiotensin system has been made it possible to investigate its role in the maintenance of blood pressure and aldosterone secretion in normotensive and hypertensive subjects. The administration of saralasin or captopril and, in the near future, of renin inhibitors induces a fall in blood pressure that is variable from one subject to the other according to the sodium balance and the level of activation of the system. These blockers also decrease the angiotensin II-dependent aldosterone production and increase renin secretion according to the circulating level of angiotensin II and the functional state of adrenal and juxtaglomerular receptors. In practice the definition of an abnormal response to renin-angiotensin blockade is difficult to define precisely, but the hypotensive effect has been tentatively used for the diagnosis of renin-dependent hypertension, especially renovascular hypertension and primary hyperaldosteronism. In renal artery stenosis the most convincing results mainly concern the lateralization of an abnormal unilateral renin secretion, which is potentiated by an acute blockade of the renin-angiotensin system. The acute administration of converting enzyme inhibitor is also useful to detect the absence of decrease in plasma aldosterone, which is characteristic of a solitary tumor or of other anatomical and functional disorders of the adrenal glands.

Topics: Aldosterone; Blood Pressure; Captopril; Humans; Hypertension; Renin; Renin-Angiotensin System; Saralasin; Sodium

Topics: 1-Sarcosine-8-Isoleucine Angiotensin II; Angiotensin II; Blood Pressure; Humans; Hypertension; Hypertension, Renovascular; Saralasin; Structure-Activity Relationship

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Humans; Hypertension; Proline; Renin-Angiotensin System; Saralasin

Topics: Animals; Antihypertensive Agents; Blood Pressure; Captopril; Crotalid Venoms; History, 20th Century; Humans; Hypertension; Propranolol; Renin; Renin-Angiotensin System; Saralasin; Snakes

Topics: Animals; Captopril; Cats; Humans; Hypertension; Hypertension, Renovascular; Proline; Rabbits; Rats; Saralasin

Topics: Blood Pressure; Captopril; Depression, Chemical; Humans; Hypertension; Prognosis; Renin; Renin-Angiotensin System; Saralasin

Topics: Animals; Blood Pressure; Captopril; Disease Models, Animal; Disease Susceptibility; Dogs; Humans; Hypertension; Injections, Intraventricular; Oligopeptides; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Saralasin; Stress, Psychological

Topics: Adrenergic beta-Antagonists; Age Factors; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Cardiovascular Diseases; Humans; Hypertension; Posture; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Saralasin; Sodium

Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocorticotropic Hormone; Angiotensinogen; Body Fluids; Captopril; Cushing Syndrome; Glucocorticoids; Humans; Hypertension; Pituitary Gland; Potassium; Renin-Angiotensin System; Saralasin; Sodium; Tomography, X-Ray Computed

In the present paper, the involvement of the renal kallikrein-kinin system in the pathogenic mechanism of essential hypertension is discussed in the larger framework of the complex hormonal actions of prostaglandins (PGs), catecholamines, renin and angiotensins in the long-term control of arterial blood pressure and sodium metabolism. An attempt is also made to emphasize the role of the cerebral renin-angiotensin system in this pathogenic mechanism. To better understand the problems raised in this paper, the concomitant consultation of two previously published papers [88], [89] is recommended.

Topics: 18-Hydroxydesoxycorticosterone; Angiotensin II; Animals; Blood Pressure; Hypertension; Kallikreins; Kinins; Prostaglandins; Rats; Renin; Saralasin; Sodium; Water

Topics: Acromegaly; Adult; Age Factors; Animals; Arteriosclerosis; Blood Volume; Cardiovascular Diseases; Child; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Disease Models, Animal; Humans; Hypercalcemia; Hypertension; Natriuresis; Renin-Angiotensin System; Risk; Saralasin; Sympathetic Nervous System; Thyroid Diseases

Topics: Adrenal Glands; Adrenergic beta-Antagonists; Aldosterone; Angiotensin II; Angiotensins; Animals; Blood Pressure; Disease Models, Animal; Humans; Hydrocortisone; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Kidney; Renin; Saralasin; Teprotide

Recent research has shown that the renin-angiotensin-aldosterone system plays a role in maintaining or causing high blood pressure in the majority of patients and it has demonstrated that renin-sodium profiling defines this involvement. Plasma renin activity measurements reveal the degree of renin-mediated vasoconstriction supporting the blood pressure, and the urinary sodium value indicates the appropriateness of the renin activity to the volume status. Together with determination of serum potassium levels, this test is basic for screening and for definitive diagnosis of the surgically curable forms of renovascular and adrenocortical hypertension. For the remaining majority of patients with other forms of hypertension, renin profiling, used in the context of the vaso-constriction-volume analytical model, helps to reveal the relative participation of vasoconstriction and volume factors and it thereby guides simpler, more specific, and more predictable treatments using either antirenin or antivolume agents. In particular, renin profiling allows the physician to select those patients who should first receive a beta-blocker or a newer anti-renin drug instead of a diuretic. The vasoconstriction-volume analysis also can provide useful baseline information about the pace, severity, and prognosis of the disease in individual patients. For medical practice the new approach enables treatment with one drug instead of two for major subgroups, and the likelihood of more specific physiologic corrections. More research within this framework promises even better treatments as we near final solutions.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antihypertensive Agents; Blood Pressure; Diagnosis, Differential; Diuretics; Hemodynamics; Humans; Hypertension; Hypertension, Renovascular; Potassium; Propranolol; Renin; Saralasin; Sodium

Topics: Adult; Aged; Angiotensin II; Creatinine; Electrolytes; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Middle Aged; Prognosis; Renin; Renin-Angiotensin System; Saralasin

Saralasin is a highly soluble and stable AII antagonist with a relatively short half-life; therefore, its effects are rapidly reversible when administered i.v. Acute and subacute studies have shown only transient toxicosis with no significant pathology or teratology. Saralasin's angiotensin receptor affinity has been correlated with its biologic acitivity. Observations from the pharmacodynamic investigations have shown that saralasin is a specific competitive antagonist of the vascular, renal, adrenal, cardiac, and central nervous system actions of AII. In addition, these studies further support the utility of saralasin as a diagnostic and therapeutic agent for patients whose hypertension is due directly to AII.

Topics: Adrenal Glands; Angiotensin II; Animals; Binding, Competitive; Biopharmaceutics; Cattle; Dogs; Half-Life; Haplorhini; Humans; Hypertension; In Vitro Techniques; Kidney; Macaca mulatta; Male; Mice; Muscle, Smooth; Rabbits; Rats; Reproduction; Saralasin

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Dogs; Humans; Hypertension; Hypertension, Renovascular; Infusions, Parenteral; Oligopeptides; Proline; Rabbits; Rats; Saralasin; Teprotide

Topics: Adrenal Glands; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensins; Animals; Blood Pressure; Central Nervous System; Dogs; Glomerular Filtration Rate; Hemodynamics; Hypertension; Norepinephrine; Rabbits; Rats; Receptors, Angiotensin; Renin; Saralasin; Sodium

Topics: Adrenal Glands; Aldosterone; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Cardiovascular System; Diet; False Positive Reactions; Humans; Hypertension; Hypertension, Renal; Kidney; Posture; Rabbits; Receptors, Angiotensin; Renin; Saralasin; Sodium; Teprotide

Topics: Adenoma; Adrenal Gland Neoplasms; Adrenocortical Hyperfunction; Catecholamines; Contraceptives, Oral, Hormonal; Estrogens; Female; Humans; Hyperaldosteronism; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Male; Pheochromocytoma; Renin; Saralasin; Sodium

Topics: Amino Acid Sequence; Angiotensin II; Angiotensins; Animals; Antibodies; Blood Pressure; Chemistry; Fluorescent Antibody Technique; Goats; History, 19th Century; History, 20th Century; Humans; Hypertension; Kidney; Peptidyl-Dipeptidase A; Rabbits; Renin; Saralasin; Sodium; Teprotide

Topics: Aldosterone; Angiotensin II; Aortic Valve Stenosis; Bartter Syndrome; Binding, Competitive; Blood Pressure; Contraceptives, Oral; Humans; Hypertension; Hypertension, Renal; Renin; Saralasin

Topics: Adult; Angiotensin II; Diagnosis, Differential; Female; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renovascular; Male; Middle Aged; Renin; Saralasin

Topics: Adrenergic beta-Antagonists; Angiotensin II; Blood Pressure; Diagnosis, Differential; Diuretics; Ferricyanides; Furosemide; Humans; Hyperaldosteronism; Hypertension; Hypertension, Renal; Nitroprusside; Oligopeptides; Pheochromocytoma; Propranolol; Renal Veins; Renin; Saralasin; Stimulation, Chemical; Teprotide

Topics: Aldosterone; Blood Volume; Female; Humans; Hyperaldosteronism; Hypertension; Hypertension, Malignant; Hypertension, Renal; Middle Aged; Propranolol; Renal Veins; Renin; Saralasin; Sodium; Teprotide; Vasoconstriction

Topics: Angiotensin II; Humans; Hypertension; Juxtaglomerular Apparatus; Renin; Saralasin

Angiotensin antagonists have become useful tools in studying pharmacologic and pathophysiologic roles of the renin-angiotensin axis. Several of these uses are described herein. Their value as t-ols in the diagnosis of renal artery stenosis is yet to be determined.

Topics: Aldosterone; Angiotensin II; Blood Pressure; Humans; Hypertension; Kidney; Kinetics; Propranolol; Renal Artery Obstruction; Renal Veins; Renin; Saralasin; Vasodilator Agents; Water-Electrolyte Balance

Topics: Aldosterone; Angiotensin II; Animals; Blood Pressure; Calcium; Dogs; Hypertension; Hypertension, Renal; Kidney; Norepinephrine; Propranolol; Rabbits; Rats; Renin; Saralasin; Sodium

The effect of acebutolol as an antihypertensive beta receptor-blocking drug was evaluated in 15 patients that remained hypertensive while on diuretics. Observations were made in a small randomized double-blind trial in which the drug was compared to placebo and subsequently during a single-blind phase when the drug was given to those who had not responded to placebo. The dose range for acebutolol was 200 to 600 mg twice daily. Pretreatment plasma renin activity (PRA) and the response to intravenous saralasin infusion were assessed as predictors of the antihypertensive effect of acebutolol. None of six patients receiving placebo had a response of goal blood pressure or below; six of nine receiving acebutolol did respond (P less than 0.01). Acebutolol treatment induced reduction in diastolic pressure, heart rate, and PRA pooled from both phases of the study. There were no significant correlations between acebutolol therapy. Our data indicate that acebutolol is effective in diuretic-resistant hypertensive patients and that indices of the renin-angiotensin system are not predictors of the therapeutic response.

Topics: Acebutolol; Adrenergic beta-Antagonists; Adult; Aged; Blood Pressure; Clinical Trials as Topic; Diuretics; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Random Allocation; Renin; Saralasin

1 Patients with borderline (group I) and sustained hypertension (group II) were treated with beta-blocking drugs, diuretics and the combination of both. In the two groups of patients the antihypertensive effectiveness of both short-term intravenous or chronically oral propranolol was directly related to the extent to which the drug produced an absolute reduction in plasma renin activity (PRA). No such a correlation could be obtained with pindolol. In group I following beta-blockade, day-night profiles of PRA were similar to those observed in group II before treatment. Thus, in this latter subgroup, low renin profiles might reflect reduced beta-adrenergic activity. 2 When the chronically beta-blockaded patients were changed to chronic diuretic therapy it became evident that young hypertensive patients of group II showed a more pronounced BP response than the patients of group I. In those patients of group II in whom pressure was not controlled by the diuretic alone, combination with a beta-blocker led to pressure normalization. 3 The beta-blocking drug induced reduction in pressure was greater in the 25-35 yr olds, than in those older than 55. In contrast, the antihypertensive effect of the diuretic was more pronounced in the 55-70 yr olds than in those younger than 40. 4 It is concluded that sympathetic nervous system activity mainly determined PRA as well as antihypertensive effectiveness of both the beta-blockers and the diuretics. As to outpatient management it is proposed that with exception of young borderline hypertensives who seem to respond best to beta-blockers, initial antihypertensive drug therapy may consist of a diuretic agent. If the antihypertensive effect of the diuretic is insufficient, combination with a beta-blocking drug could be used to achieve the best effect.

Topics: Adrenergic beta-Antagonists; Adult; Age Factors; Aged; Blood Pressure; Drug Therapy, Combination; Female; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Pindolol; Propanolamines; Propranolol; Renin; Saralasin; Spironolactone

1. The haemodynamic response to antagonistic (10 microgram min-1 kg-1) and agonistic (40 microgram min-1 kg-1) doses of saralasin was studied in young essential hypertensive patients. Blood pressure behaviour alone was thought to be inadequate to describe the response pattern. 2. Pre-saralasin setting of the renin-angiotensin axis was varied with salt intake (15 and 290 mmol of Na+/day) each for 10 days. This failed to influence blood pressure or plasma volume. 3. Antagonist blockade after low salt lowered blood pressure in three patients with the highest plasma renin values. Cardiac output rose in two of these, but it dropped in all others. 4. Decreases in cardiac output occurred with both doses of saralasin and even with suppression of the renin-angiotensin axis. This response is therefore unlikely to be due to removal of myocardial or venous angiotensin effects. 5. The renin-angiotensin system played a part in maintenance of blood pressure only with severe salt restriction and in a small proportion of cases. 6. No heart rate effect was seen with sarcalasin. 7. Blood pressure and total peripheral resistance responses were dependent on pre-(antagonist/agonist) setting, but heart rate and cardiac output were not influenced by this factor.

Topics: Adult; Angiotensin II; Angiotensins; Blood Pressure; Cardiac Output; Heart Rate; Humans; Hypertension; Male; Renin; Saralasin

1. Captopril (25 mg) reduced plasma angiotensin II (ANG II) by 53% (P less than 0.001) and mean brachial artery pressure (MBAP) by 18.7 mmHg (P less than 0.001) within 75 min in 26 hypertensive patients. After 2 months (on 150-600 mg/day) MBAP had decreased by 27.1 mmHg (n = 18) with no further change of plasma ANG II. delta MBAP was significantly related to control log plasm renin (PRA) and log ANG II in both conditions. 2. The acute depressor response to captopril was 11.2 mmHg greater (P less than 0.001) than delta MBAP during saralasin infusion (n = 12). 3. Heart rate slightly increased after acute administration of captopril (+3.3 beats/min; P less than 0.005), but cardiac output was not significantly affected; systemic vascular resistance decreased by 10% (P less than 0.01) with unchanged pulmonary vascular resistance. 4. During chronic administration, oxygen consumption, cardiac output and stroke volume increased by 15% (P less than 0.01), with unchanged heart rate; systemic vascular resistance had dropped by 30% (P less than 0.001). 5. Plasma ANG II and plasma aldosterone decreased, and PRA and ANG I increased acutely, with no further changes during chronic treatment.

Topics: Aldosterone; Angiotensin II; Blood Pressure; Captopril; Cardiac Output; Clinical Trials as Topic; Heart Rate; Humans; Hypertension; Oxygen Consumption; Placebos; Proline; Renin; Saralasin; Stroke Volume; Vascular Resistance

Topics: Angiotensin II; Angiotensins; Blood Pressure; Captopril; Humans; Hypertension; Male; Proline; Propranolol; Reference Values; Renin; Saralasin

The effect of a 4-hour infusion of the angiotensin II analogue sar1 ala8 angiotensin II (saralasin) on plasma aldosterone concentration (PAC) was assessed in relation to plasma renin activity (PRA) in 12 patients, both on normal sodium intake and after marked sodium depletion. On normal sodium intake the response of PAC to saralasin was variable; following sodium depletion saralasin induced a marked decrease in PAC in 11 of 12 patients. The extent of the change in PAC induced by saralasin correlated closely with log PRA. The data indicate that saralasin is also a competitive antagonist of the effect of the endogenous renin-angiotensin system (RAS) on the adrenal cortex, with agonistic activity appearing at low levels of PRA. The effect of sodium depletion on AC appears to be mediated to a major degree by the RAS.

Topics: Adrenal Cortex; Adult; Aldosterone; Angiotensin II; Female; Humans; Hypertension; Hypertension, Renovascular; Infusions, Parenteral; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Potassium; Renin; Saralasin; Sodium

In order to elucidate the involvement of the brain renin-angiotensin system (RAS) in cadmium intracerebroventricular (ICV) hypertension, we evaluated the effects of a pretreatment with different drugs: clonidine, an alpha(2) adrenergic agonist, enalapril and captopril, both ACE inhibitors, and saralasin, a competitive nonselective AT(1) and AT(2) receptor antagonist. We used a rat strain with low levels of kallikrein (LKR) that was more sensitive to ICV cadmium hypertension, compared with normal kallikrein rats (NKRs), the control strain. The interplay between the kallikrein-kinin system and the RAS in the LKR strain caused various hemodynamic alterations, which we believe were the result of elevated RAS activity in these animals. Moreover, we suggest that the defective kallikrein-kinin system in LKR may also cause an alteration in the activation of brain RAS in these animals. The LKR displayed elevated concentrations of plasma AII, hypertrophy of the myocardium, and initial alterations in the renal glomerulotubular system. With the exception of clonidine, all of the other drugs showed greater antihypertensive effects of differing statistical significance in LKR, compared with NKR. Both ACE inhibitors were able to significantly reduce pressor response to cadmium ICV in LKR throughout the experiment, whereas in NKR, they were only able to reduce the hypertensive peak of cadmium. A significant protective effect was also observed in LKR pretreated with saralasin, while no effect was observed in NKR. These findings confirm the presence of brain RAS activation in LKR and its contribution to the central control of pressor response to cadmium ICV.

Topics: Adrenergic alpha-Agonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Brain; Cadmium; Captopril; Clonidine; Enalapril; Heart; Histocytochemistry; Hypertension; Kallikrein-Kinin System; Kallikreins; Kidney; Male; Rats; Rats, Wistar; Renin-Angiotensin System; Saralasin

Previous findings have shown that some of the neurons in the median preoptic nucleus (MnPO) receive both catecholaminergic inputs from the brainstem and angiotensinergic inputs from the subfornical organ (SFO), and that alterations in the function of the brain renin-ANG system are implicated in hypertension, especially in spontaneous hypertensive rats (SHR). In an attempt to clarify the action of these inputs on MnPO neurons and to find the difference in the action between normotensive Wistar-Kyoto (WKY) rats and SHR, we used microdialysis to investigate the effects of injections of saralasin (Sar), an angiotensin II (ANG II) antagonist, into the third ventricle (3V) on monoamine release in the MnPO area of awake WKY and SHR. The content of noradrenaline (NA) in the MnPO area was significantly higher in SHR. No significant differences were observed between WKY and SHR in the concentrations of dopamine (DA) and of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). In both WKY and SHR, Sar (Sar, 5 microg in 1 microl, three injections at 2-h intervals) injected into the 3V significantly decreased the extracellular concentrations of NA, DOPAC and HVA in the MnPO area. The decreases were much greater in SHR than in WKY rats. Similar injections of saline vehicle had no significant effect on the extracellular levels of NA, DA and the metabolites. These results suggest that central angiotensinergic circuits may serve to increase NA and DA release in the MnPO area, and support that a disorder in the ANG system may contribute, in part, to the elevated blood pressure of SHR.

Topics: Angiotensin II; Animals; Biogenic Monoamines; Hypertension; Injections, Intraventricular; Male; Microdialysis; Neural Pathways; Neurons; Preoptic Area; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Saralasin; Subfornical Organ

We investigated, in mesenteric arteries from hypertensive rats (SHR), the possible changes in neurogenic nitric oxide (NO) release produced by angiotensin II (AII), and the possible mechanisms involved in this process. In deendothelialized segments the NO synthase inhibitor N(G)-nitro-L-arginine (L-NAME, 10 microM) increased the contractions caused by electrical field stimulation (EFS, 200 mA, 0.3 ms, 1-16 Hz, for 30 s). AII (0.1 nM) enhanced the response to EFS, which was unmodified by the subsequent addition of L-NAME. The AII antagonist receptor saralasine (0.1 microM) prevented the effect of AII, and the subsequent addition of L-NAME restored the contractile response. SOD (25 u/ml) decreased the reponse to EFS and the subsequent addition of L-NAME increased this response. AII did not modify the decrease in EFS response induced by SOD, and the addition of L-NAME increased the response. None of these drugs altered the response to exogenous noradrenaline (NA) or basal tone except SOD, which increased the basal tone, an effect blocked by phentolamine (1 microM). In arteries pre-incubated with [3H]-NA, AII did not modify the tritium efflux evoked by EFS, which was diminished by SOD. AII did not alter basal tritium efflux while SOD significantly increased it. These results suggest that EFS of SHR mesenteric arteries releases neurogenic NO, the metabolism of which is increased in the presence of AII by the generation of superoxide anions.

Topics: Angiotensin II; Animals; Electric Stimulation; Hypertension; Male; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Inbred SHR; Saralasin; Superoxide Dismutase; Superoxides

Spontaneously hypertensive rats (SHR) have an activated brain angiotensin system. We hypothesized 1) that ventilation (V) would be greater in conscious SHR than in control Wistar-Kyoto (WKY) rats and 2) that intravenous infusion of the ANG II-receptor blocker saralasin would depress respiration in SHR, but not in WKY. Respiration and oxygen consumption (VO(2)) were measured in conscious aged-matched groups (n = 16) of adult female SHR and WKY. For protocol 1, rats were habituated to a plethysmograph and measurements obtained over 60-75 min. After installation of chronic intravenous catheters, protocol 2 consisted of 30 min of saline infusion ( approximately 14 microliter. kg(-1). min(-1)) followed by 40 min of saralasin (1.3 microgram. kg(-1). min(-1)). V, tidal volume (VT), inspiratory flow [VT/inspiratory time (TI)], breath expiratory time, and VO(2) were higher, and breath TI was lower in "continuously quiet" SHR. In SHR, but not in WKY rats, ANG II-receptor block decreased V, VT, and VT/TI and increased breath TI. During ANG II-receptor block, an average decrease in VO(2) in SHR was not significant. About one-half of the higher V in SHR appears to be accounted for by an ANG II mechanism acting either via peripheral arterial receptors or circumventricular organs.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Female; Hypertension; Inspiratory Capacity; Oxygen Consumption; Pulmonary Ventilation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Respiration; Saralasin; Tidal Volume

Stress-induced hypertension (SIH) was performed by electric shock on hind paw in rats. Habenula(Hb) lesion decreased the degree of SIH. After stress, the Ang II concentration in blood plasma and in Hb were increased. BP was elevated after icv or MHb administration of Ang II, and decreased after microinjection of saralasin into MHb. The BP changes induced by Ang II and saralasin were more prominent in SIH than in normotensive rats. Iontophoresis of AngII (or saralasin) into Hb increased (or decreased) the discharges of the excitatory neurons related to cardiovascular activity. Ang II could inhibit the activity of Ik channel. Using the same methods, the actions of L-NNA and SNP were investigated. From above, it is suggested that Hb is involved in the development of SIH. Stress stimulus strengthened the sensitivity of Hb, especially MHb to AngII, and also induced in increase of AngII. These changes would promote the response of sensitized Hb in the development of SIH.

Topics: Angiotensin II; Animals; Electric Stimulation; Habenula; Hypertension; Neurons; Rats; Saralasin; Stress, Physiological

To study the relationship between the enhanced proliferation and renin-angiotensin system (RAS) of aortic smooth muscle cells (ASMC) from SHR rats.. To measure the effects of angiotensin II (Ang), captopril (Cap), saralasin (Sar) on proliferation, Ang and angiotensin converting enzyme (ACE) levels in cultured ASMC from WKY and SHR rats.. Ang was a bifunctional growth factor, which induced SHR ASMC hyperplasia in 2% FCS-RPMI 1640 medium, but not in serum free (SF)-medium. SHR ASMC had stronger proliferative ability compared with WKY while SHR ASMC RAS was activated. Enhanced proliferation of SHR ASMC and ACE activity were obviously inhibited by long-term treatment (4-wk) of both Cap and Sar, while Ang content decreased in Cap treatment group and increased in Sar treatment group. The antiproliferative effect of Cap and Sar on SHR ASMC was stronger than that on WKY. SHR, WKY ASMC RAS were not influenced by short-term (24 h) treatment of Cap.. Long-term treatment of Cap and Sar suppressed SHR ASMC growth through inhibition of Ang generation or blockade of Ang binding to its receptor.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Captopril; Cell Division; Cells, Cultured; Culture Media, Serum-Free; Hypertension; Male; Muscle, Smooth, Vascular; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; Saralasin

When an approximately 30 centiMorgan (cM) region of chromosome 13 containing the renin gene from the Dahl salt-resistant rat (R) was introgressed into the Dahl salt-sensitive rat (S), the resulting congenic rat (designated S.R-Ren) had a systolic blood pressure on a 2% (w/w) salt diet that was 24 mmHg lower than that of its S counterpart. Due to the large size of the transferred segment (over 30 million bp), the question remained as to whether or not the renin gene was the cause of the blood-pressure difference between the strains. We evaluated the role of the renin-angiotensin system in S.R-Ren and S rats fed a 0.05% salt diet by examining differences between strains in (1) expression of renin in three tissue types, (2) the blood-pressure response to blockade of both angiotensin-converting enzyme and angiotensin II receptors, and (3) pressure natriuresis. No differences were found in renin levels in plasma, kidney or adrenal gland between strains. The blood-pressure responses to the angiotensin-converting-enzyme inhibitor captopril and to the angiotensin II-receptor blocker saralasin in conscious S and S.R-Ren rats were similar. Furthermore, renal function, evaluated by a pressure-natriuresis index that took into account both the time and the arterial pressure needed to excrete an acute salt load, did not differ between strains. Our findings therefore fail to demonstrate a role for the renin gene in conferring lower blood pressure in the congenic rat and suggest that there is an unknown arterial-pressure-regulating locus in this 30 cM region of chromosome 13.

Topics: Adrenal Glands; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Enzyme Inhibitors; Hypertension; Kidney; Natriuresis; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; RNA, Messenger; Saralasin; Sodium

Previous studies have suggested that angiotensin (ANG) synthesis, receptor activation, or both, in the median preoptic nucleus (MnPO) are responsible for initiating ANG-related salt appetite in normotensive rats. The present study was designed to test whether treatment with saralasin (Sar), an ANG II antagonist, in the MnPO area causes changes in saline (0.3 M NaCl solution) and water intakes in the spontaneously hypertensive rat (SHR), which is known to show greater salt appetite compared to normotensive Wistar-Kyoto (WKY) rats. Treatment with Sar in the MnPO area produced significantly attenuated saline intake, but had no effect on water intake. The results may support the importance of the ANG system in the MnPO area for salt appetite, and suggest that a disorder in the system may cause abnormal salt intake in SHR.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Appetite; Drinking; Hypertension; Injections; Male; Preoptic Area; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Saralasin; Sodium, Dietary

We examined the effects of U-97018, an AT1 receptor antagonist, on the pressor response to intracerebroventricularly (i.c.v.) administered angiotensin II (AII) in conscious normotensive rats in comparison to losartan, EXP 3174, EXP 655, and saralasin. In an i.c.v. study, U-97018, losartan, and EXP 3174 reduced the pressor response. EXP 655, an AT2 selective antagonist, also inhibited the pressor response to i.c.v. AII. U-97018 combined with EXP 655 did not fully eliminate the pressor response to i.c.v. AII. Moreover, saralasin, a nonselective peptide AII antagonist, also failed to abolish the pressor response to i.c.v. AII. Therefore, both AT1- and AT2-receptors probably are functional in inhibiting the pressor response to i.c.v. AII and that a part of the i.c.v. AII-induced pressor response occurs through non-AT1- and non-AT2-receptors. In an intravenous (i.v.) study, U-97018, losartan, and EXP 3174 reduced the pressor response to i.c.v. AII. At 10 mg/kg orally (p.o.), which is an antihypertensive dose in spontaneously hypertensive rats (SHR), neither U-97018 nor losartan reduced the pressor response to i.c.v. AII even at 180 min after administration. This result indicates that neither U-97018 nor losartan, at the oral antihypertensive dose, reaches the brain in sufficient amount to affect the pressor response to i.c.v. AII.

Topics: Administration, Oral; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Imidazoles; Injections, Intravenous; Injections, Intraventricular; Losartan; Male; Pyridazines; Pyridines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Saralasin; Tetrazoles

We investigated the genesis of the hypertensive response to acute (45 min) aortic constriction in two models of chronic vasopressin (AVP) deficiency, i.e., Brattleboro strain and median eminence lesioned (MEL) Wistar rats. The same degree of partial aortic constriction, with a pneumatic cuff placed around the abdominal aorta, yielded a sudden and maintained increase in carotid pressure to the same extent in Brattleboro, MEL and sham-MEL rats. Blockage of AVP V1 receptors with d(CH2)5Tyr[Me]AVP did not affect the hypertensive response of Brattleboro or MEL rats, but gradually blunted the response of sham-MEL rats. Blockage of angiotensin II receptors with saralasin blunted the hypertensive response of the AVP-deficient subjects throughout the experiment, but only delayed (5-15 min) the onset of hypertension in sham-MEL rats. Simultaneous blockage of AVP and angiotensin II blunted the hypertensive response of sham-MEL and AVP-deficient rats throughout the experiment. These data demonstrate that when one vasoactive system is chronically absent, as is the case for AVP in Brattleboro and MEL rats, the renin-angiotensin system plays the major role in the pathophysiology of acute aortic coarctation hypertension.

Topics: Angiotensin Receptor Antagonists; Animals; Antidiuretic Hormone Receptor Antagonists; Aortic Coarctation; Arginine Vasopressin; Blood Pressure; Chronic Disease; Female; Hormone Antagonists; Hypertension; Male; Median Eminence; Rats; Rats, Brattleboro; Rats, Wistar; Renin-Angiotensin System; Saralasin

Angiotensin II (Ang II) potentiates sympathetic neurotransmission by presynaptic facilitation of norepinephrine release. We investigated whether endogenous Ang II modulates peripheral sympathetic activity in sodium-depleted essential hypertensive patients. We evaluated the effect of intrabrachial infusion of saralasin, an Ang II antagonist (5 micrograms/100 mL forearm tissue per minute), and benazeprilat, an angiotensin-converting enzyme inhibitor (2 micrograms/100 mL forearm tissue per minute), on forearm vasoconstriction (measured by strain-gauge venous plethysmography) induced by the application of lower body negative pressure (-10 mm Hg for 5 minutes). Both saralasin and benazeprilat (n = 6 for each group) blunted the vasoconstrictor action of lower body negative pressure, suggesting that circulating Ang II modulates peripheral sympathetic activity. In addition, since beta-adrenoceptor stimulation can activate the production of vascular Ang II, the effect of saralasin and benazeprilat on lower body negative pressure application was evaluated in the presence of isoproterenol (0.09 microgram/100 mL forearm tissue per minute) and propranolol (10 micrograms/100 mL forearm tissue per minute). In two other groups of hypertensive patients, isoproterenol infusion increased the release of Ang II in the forearm vasculature (arteriovenous values measured by radioimmunoassay). Furthermore, isoproterenol potentiated lower body negative pressure-induced vasoconstriction. This facilitating effect was abolished by either saralasin or benazeprilat (n = 6 for each group). In contrast, in two further groups of patients (n = 6 for each group), in the presence of the beta-blocker propranolol saralasin and benazeprilat did not alter the vasoconstrictor action of the endogenous sympathetic stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Pressure; Diet, Sodium-Restricted; Female; Forearm; Humans; Hypertension; Isoproterenol; Male; Middle Aged; Norepinephrine; Plethysmography; Propranolol; Saralasin; Sympathetic Nervous System; Vasoconstriction

The present study was designed to investigate the effect of a lack of vasopressin resulting from electrolytic lesion of the median eminence of the hypothalamus on the acute 45-min aortic coarctation hypertension elicited in conscious rats by means of a pneumatic cuff placed around the aorta above the renal arteries. Forty-eight hours after lesion, aortic constriction elicited a prompt (5-min) rise in mean carotid pressure from 115 +/- 2 to 149 +/- 2 mmHg, followed by a gradual decline to 129 +/- 2 mmHg. In contrast, sham-lesioned rats exhibited a prompt hypertensive response from 118 +/- 2 to 157 +/- 2 mmHg that leveled off throughout the experiment. Lesioned rats treated with saralasin presented a blunted hypertensive response (within 125 +/- 2 to 130 +/- 2 mmHg), whereas sham-lesioned rats showed only a delay in the onset of hypertension. The hypertensive response of lesioned rats was unaffected by the vasopressin antagonist [d(CH2)5Tyr(Me)]AVP, whereas sham-lesioned rats submitted to this treatment presented a prompt rise in pressure followed by a gradual decline at the end of the experiment. Lesioned and sham-lesioned rats treated with saralasin plus vasopressin antagonist showed a blunted hypertensive response throughout the experiment. These data demonstrate that the integrity of the median eminence plays a pivotal role in the maintenance (30-45 min) of acute aortic coarctation hypertension, presumably involving the release of vasopressin from the neurohypophysis, whereas angiotensin II mainly accounts for the prompt (5-15 min) rise in pressure.

Topics: Acute Disease; Animals; Aortic Coarctation; Arginine Vasopressin; Blood Pressure; Hypertension; Male; Median Eminence; Rats; Rats, Wistar; Saralasin; Vasopressins

The aims of this study were to determine the relations between platelet free calcium concentrations ([Ca2+]i), intracellular pH (pHi), and aggregation and to assess the effects of angiotensin II (Ang II) and endothelin-1 on these platelet parameters in normotensive subjects and hypertensive patients. Seventeen normotensive subjects, 25 untreated hypertensive patients, and 34 treated hypertensive patients were studied. Platelet cytosolic free [Ca2+]i and pHi were measured spectrofluorometrically using specific fluorescent probes (fura 2-AM and BCECF-AM, respectively) in unstimulated and Ang II- and endothelin-1-stimulated platelets. Aggregation was measured by a turbidometric technique. Basal [Ca2+]i (141 +/- 11 nmol/L) and pH (7.16 +/- 0.01) were higher (P < .05) in the untreated hypertensive group compared with the normotensive (118 +/- 9 nmol/L, 7.11 +/- 0.01, respectively) and treated hypertensive (121 +/- 11 nmol/L, 7.12 +/- 0.01, respectively) groups. In the combined normotensive and hypertensive groups, there were significant correlations between [Ca2+]i and mean arterial pressure (r = .75, P < .01), pHi and mean arterial pressure (r = .72, P < .01), [Ca2+]i and pHi (r = .71, P < .01), [Ca2+]i and aggregation (r = .69, P < .02), and pHi and aggregation (r = .56, P < .05). Ang II stimulation significantly increased [Ca2+]i and pHi in the untreated hypertensive and normotensive groups. The net change in [Ca2+]i induced by Ang II was significantly higher (P < .05) in the untreated hypertensive group compared with the other groups (67 +/- 6 nmol/L for the untreated hypertensive group versus 54 +/- 5 and 29 +/- 8 nmol/L for the normotensive and treated hypertensive groups, respectively). In the presence of Ang II, thrombin-induced aggregatory responses were increased in all three groups, but the maximal response was significantly higher in the untreated hypertensive group compared with the other groups (P < .05). Endothelin-1 increased pHi through endothelin A-receptors (effect blocked by the specific antagonist BQ-123) but had no significant effect on [Ca2+]i or aggregation. However, endothelin-1 blunted thrombin-induced platelet aggregation in normotensive subjects but not in hypertensive patients. In conclusion, increased Ang II-stimulated [Ca2+]i and pHi in platelets of essential hypertensive patients may be associated with increased aggregatory responses. The stimulatory effect of endothelin-1 on pHi but not on [Ca2+]i or aggregation suggests that i

Topics: Adult; Aged; Amiloride; Analysis of Variance; Angiotensin II; Blood Platelets; Calcium; Cytosol; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelins; Female; Humans; Hydrogen-Ion Concentration; Hypertension; In Vitro Techniques; Male; Middle Aged; Peptides, Cyclic; Platelet Aggregation; Receptor, Endothelin A; Receptors, Endothelin; Regression Analysis; Saralasin

To obtain direct evidence for and evaluate functional aspects of the vascular tissue renin-angiotensin system.. The local release of renin and angiotensin II was studied in forearm and coronary vascular beds of hypertensive hospitalized patients. The interaction between the vascular tissue renin-angiotensin system and sympathetic neurotransmission was also evaluated.. Local beta-adrenoceptor stimulation released active and inactive renin and angiotensin II from forearm vessels, indicating the presence of a vascular tissue renin-angiotensin system in essential hypertensives. Local production of active renin and angiotensin II was closely correlated with circulating renin levels, suggesting that this vascular tissue renin-angiotensin system is at least partly dependent on uptake of renin from the circulating renin-angiotensin system. The local active renin and angiotensin II production was rapidly exhausted; this might represent a short-term control mechanism. Locally generated angiotensin II increased sympathetic vasoconstriction through the presynaptic release of noradrenaline and this effect was mediated by beta-adrenoceptor stimulation. Infusions of adenosine promoted the release of active renin and angiotensin II from the forearm and the coronary vessels.

Topics: Adenosine; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Coronary Vessels; Forearm; Humans; Hypertension; Isoproterenol; Norepinephrine; Receptors, Adrenergic, beta; Renin; Renin-Angiotensin System; Saralasin

The hemodynamic responses and the role of renal nerves in the physiopathogenesis of acute (45 min) aortic coarctation hypertension were studied in conscious rats. The hemodynamic responses elicited by aortic constriction in intact and bilaterally nephrectomized rats were analyzed by means of miniaturized pulsed-Doppler flow probes. Anephric rats presented a smaller increase in mean carotid pressure (MCP) and calculated aortic resistance during aortic coarctation than did intact animals. Reflex bradycardia throughout the experiment did not differ significantly between the two groups. The pressor response following aortic coarctation in untreated renal-denervated rats was similar to that found in intact subjects. Renal-denervated rats previously treated with V1-vascular arginine vasopressin antagonist [d(CH2)5Tyr(Me)AVP] showed the same hypertensive response as control renal-denervated rats. Previous treatment of renal-denervated rats with saralasin (an angiotensin II antagonist) produced a significant reduction in the hypertensive response throughout the experiment when compared to untreated renal-denervated rats. Similarly, rats treated with the vasopressin antagonist plus saralasin showed a blunted hypertensive response following aortic coarctation. The results for rats previously treated with vasopressin antagonist plus saralasin did not differ from those obtained with saralasin alone. Overall, the results of aortic coarctation hypertension obtained in the present study indicate that: 1) Anephric rats showed a blunted hypertensive response due to the lack of neuro-humoral release of vasopressor substances (e.g. angiotensin II and vasopressin) triggered by the kidneys, when only the mechanical factor of constriction was present; 2) The lack of afferent feedback from the kidneys in renal-denervated rats for vasopressin release from the central nervous system allowed angiotensin II to play the major physiopathological role associated with the mechanical factor in the hypertensive response.

Topics: Animals; Aorta, Abdominal; Aortic Coarctation; Arginine Vasopressin; Denervation; Hemodynamics; Hypertension; Kidney; Male; Nephrectomy; Neurons, Afferent; Rats; Rats, Inbred Strains; Saralasin

We examined whether neural or humoral mechanisms mediate the acute versus chronic phases of angiotensin II (ANG II)-dependent hypertension in rabbits. ANG II was administered intravenously at 50 ng.kg-1.min-1 for 10 days. This dose of ANG II elevated mean arterial pressure (MAP) from 76 +/- 2 to 98 +/- 2 mmHg on day 1 and sustained the hypertension throughout the infusion period. Heart rate (226 +/- 7 beats/min) was not altered. The depressor response to ganglionic blockade (-38 +/- 2 mmHg) was significantly blunted on day 1 (-22 +/- 3 mmHg) and was significantly enhanced on days 5 (-52 +/- 4 mmHg) and 7 (-52 +/- 6 mmHg). In contrast, plasma norepinephrine (PNE) and renal sympathetic nerve activity (RSNA) levels were acutely reduced to approximately one-third of control (day 1 of ANG II) and chronically rose to an intermediate level (2-9 days of ANG II). However, the pressor effect of resetting PNE and RSNA may be magnified by an augmented pressor responsiveness to alpha-agonists after chronic ANG II. In animals with the area postrema removed, PNE, RSNA, and heart rate were acutely reduced and remained chronically depressed. In addition, area postrema lesion blocked the chronic, but not the acute hypertensive response, to infusing ANG II. Thus the direct vasoconstrictor actions of ANG II appear to acutely predominate, whereas neurogenic vasomotor tone appears to chronically predominate. This shift appears to be mediated by changes in vascular sensitivity, as well as the area postrema allowing resetting of the baroreflex.

Topics: Angiotensin II; Animals; Blood Pressure; Cerebral Ventricles; Dose-Response Relationship, Drug; Ganglionic Blockers; Heart Rate; Hypertension; Kidney; Nervous System Physiological Phenomena; Norepinephrine; Phenylephrine; Rabbits; Saralasin; Sympathetic Nervous System; Trimethaphan

1. Isolated perfused rat kidneys were used to study the effects of plasma fractions obtained by gel filtration from essential hypertensive patients (n = 40) and from normotensive subjects (n = 36) on resistance vessels. Perfusion pressure was recorded at a constant flow. 2. Plasma fractions were obtained by gel filtration and contained substances with a molecular mass in the range 1000-1500 Da. The plasma fractions from hypertensive patients used in this study had been shown to increase blood pressure after intravenous injection in rats. 3. In the isolated rat kidneys, the hypertensive fractions increased perfusion pressure by 20 +/- 17 mmHg (mean +/- SD, range 5-58 mmHg, n = 40). The analogous fractions from normotensive subjects did not change perfusion pressure significantly. 4. In Ca2(+)-free medium containing 2 mmol/l ethyleneglycol bis-(aminoethyl ether)tetra-acetate, the change in perfusion pressure induced by active plasma fractions was reduced by 95.2 +/- 6.3%. Addition of nifedipine to the perfusion medium reduced, but did not abolish, the pressure response of the kidneys. 5. In solutions containing phentolamine or saralasin, vasoconstriction was not reduced. 6. Thus in the active fractions from hypertensive plasma, a vasopressor agent with direct action on resistance vessels can be demonstrated. This substance probably acts by increasing Ca2+ influx in vascular smooth muscle cells.

Topics: Adult; Angiotensin II; Animals; Blood Pressure; Chromatography, Gel; Female; Humans; Hypertension; In Vitro Techniques; Kidney; Male; Middle Aged; Molecular Weight; Nifedipine; Norepinephrine; Phentolamine; Rats; Rats, Inbred WKY; Saralasin; Sodium-Potassium-Exchanging ATPase; Vascular Resistance

During acute angiotension II (Ang II) infusion (200 ng/kg/min i.v.) into anesthetized rats, mean arterial pressure rose from 124 +/- 1 to 154 +/- 2 mm Hg. The peptidic Ang II antagonist saralasin lowered arterial pressure in a dose-dependent manner. The maximal decrease in pressure was similar to that observed after the Ang II infusion was discontinued. The nonpeptide Ang II antagonist, 4'-[( 2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazole-1-yl] methyl) [1,1'-biphenyl] -2-carboxylic acid (SC-48742), lowered acutely elevated arterial pressure to a level similar to that on discontinuation of the angiotensin infusion. Chronic (8 days) infusion of Ang II (20 ng/kg/min i.v.) increased mean arterial pressure from 116 +/- 3 to 164 +/- 7 mm Hg, which then decreased to 121 +/- 6 mm Hg on termination of the infusion. Saralasin (10 micrograms/kg/min, a maximally effective dose during acute angiotensin infusion) decreased mean arterial pressure from 168 +/- 7 to 141 +/- 3 mm Hg, a pressure significantly higher (p less than 0.05) than the pressure observed after the angiotensin infusion was discontinued. SC-48742 decreased mean arterial pressure from 167 +/- 7 to 127 +/- 3 mm Hg, a pressure not statistically different from the minimum pressure observed after the angiotensin infusion was terminated. The mechanism of blood pressure elevation during acute high dose or chronic low dose Ang II infusion is different, the latter having a significant neural component as measured by the response to trimethaphan. The peptidic antagonist saralasin was fully effective in lowering acute angiotensin hypertension but only partially effective during chronic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Imidazoles; Infusions, Intravenous; Male; Rats; Rats, Inbred Strains; Saralasin

We used an experimental model of in situ isolated carotid arteries to clarify the participation of angiotensin II (Ang II) in the mechanical properties of the arterial wall in 12-week-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs). The effects of local incubation with saralasin ([Sar1,Thr8]Ang II, 10(-6) M) on carotid compliance were compared with the effects of endothelium removal and with those of total abolition of vasomotor tone with potassium cyanide (0.1 mg/ml). Operating carotid compliance measured for pressure values close to the mean arterial pressure of each group was (mean +/- SD) 12.6 +/- 2.9 x 10(-3) microliters/mm Hg.mm vessel in WKY rats and 8.2 +/- 1.6 x 10(-3) microliters/mm Hg.mm vessel in SHRs (p less than 0.001). With intact endothelium, local incubation with saralasin increased carotid compliance by 24% in WKY rats and 23% in SHRs relative to control values (p less than 0.05 and p less than 0.001, respectively). Endothelium removal induced significant increases in carotid compliance in WKY rats (17%, p less than 0.01) and in SHRs (33%, p less than 0.001). After endothelium removal, saralasin induced significant further carotid compliance increases in both strains (+18%, p less than 0.001, and +11%, p less than 0.01, in WKY rats and SHRs, respectively). After potassium cyanide poisoning, carotid compliance did not increase further relative to saralasin values in both strains with or without endothelium. These findings suggest that Ang II receptors play a major role in the control of the basal vasomotor tone of large arteries in both normotensive and hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Animals; Arteries; Compliance; Endothelium, Vascular; Hypertension; In Vitro Techniques; Male; Potassium Cyanide; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; Saralasin

The serial changes in systemic and renal hemodynamics, water and electrolyte balances and various vasoactive hormones were examined in 12 conscious dogs before, during (10 days) the administration of dexamethasone (DEX: 0.5 mg/kg/day) and after the cessation of DEX. In addition, during the administration of DEX, pressor responses to angiotensin II, norepinephrine, an angiotensin II analogue, saralasin, and an alpha-1-blocker, prazosin, were studied. Abrupt elevation of blood pressure to 106 +/- 5 mmHg on Day 1 (vs. 91 +/- 6 mmHg control: P less than 0.05) associated with marked increases in total peripheral resistance (P less than 0.01) was shown in DEX treated animals. Accompanied with these changes, renal blood flow increased to 146 +/- 12 ml/min (vs. 103 +/- 8 ml/min control: P less than 0.05) on Day 1 and maintained. In contrast, the results of serial alterations in hormones could not show any significant changes except significant elevations in atrial natriuretic peptide and reductions of cortisol and arginine vasopressin. Also, marked natriuresis and diuresis were observed in DEX administration dogs. Pressor response to norepinephrine was significantly increased and administration of either saralasin and prazosin significantly reduced the blood pressure of DEX treated animals. These results in DEX-treated conscious dogs confirmed our previous findings in human and rats. Glucocorticoid-induced hypertension mainly depends on the increases in total peripheral resistance but not volume factors.

Topics: Animals; Blood Pressure; Body Weight; Cardiac Output; Dexamethasone; Dogs; Heart Rate; Hemodynamics; Hormones; Hypertension; Male; Neurosecretory Systems; Norepinephrine; Prazosin; Renal Circulation; Saralasin; Vascular Resistance

Upper body arterial hypertension developed in 12 fetal lambs after chronic suprarenal aortic blood flow reduction. Sixty minutes after blood flow reduction, intravenous saralasin infusion was able to reduce upper body mean arterial blood pressure to control levels. Although saralasin infusion was able to decrease upper body arterial blood pressure after 1 day of hypertension, it was not able to return blood pressure to control levels. Three or more days later, saralasin was unable to cause a significant reduction in upper body arterial blood pressure. We conclude that, although the renin-angiotensin system has a role in maintaining the elevated blood pressure after greater than or equal to 1 day of suprarenal aortic blood flow reduction, some other mechanism also participates. We have ruled out a role for changing blood volume, and our results suggest that an elevation of plasma catecholamines is not responsible. Some other pathway for fluid regulation available to the fetus may be responsible.

Topics: Angiotensin II; Animals; Aorta; Blood Flow Velocity; Blood Gas Analysis; Blood Pressure; Blood Volume; Epinephrine; Female; Fetal Diseases; Hypertension; Norepinephrine; Pregnancy; Saralasin; Sheep; Urine

The purpose of the present study was to determine whether Ang II releases adenosine from the perfused rat lung. Rat lungs were perfused in situ with a physiological salt solution and were loaded with [3H]adenosine. The release of 3H from the perfused rat lung in response to intra-arterial injections of Ang II and other hormones was quantitated. Studies were conducted in both normal rats and in rats that had been nephrectomized before surgery to avoid exposure of the lungs to high levels of endogenous Ang II. Bolus doses of Ang II (10(-12)-10(-7) mol) increased the efflux of 3H from the lungs. Analysis of this effluent by thin-layer chromatography indicated that most of the Ang II-induced release of 3H was [3H]adenosine. The maximal response was usually obtained with 10(-9) mol, and higher doses (10(-8) and 10(-7) mol) mobilized less [3H]adenosine, which suggested tachyphylaxis. The effect of exogenous Ang II on [3H]adenosine release was greatly enhanced when activation of the endogenous renin-angiotensin system was prevented with prior nephrectomy. Infusion of the Ang II selective antagonist, (1-Sar-8-Ile)-Ang II, blocked Ang II-induced [3H]adenosine release. Neither norepinephrine, bradykinin, nor vasopressin consistently released adenosine. We conclude that (a) Ang II can induce the release of adenosine from the perfused rat lung, (b) this effect is receptor mediated, (c) this response is somewhat selective for Ang II, and (d) exposure to high levels of exogenous or endogenous Ang II causes tachyphylaxis so that Ang II-induced adenosine release is attenuated.

Topics: Adenosine; Anesthesia; Angiotensin II; Animals; Chromatography, Thin Layer; Hypertension; Lung; Male; Nephrectomy; Pulmonary Circulation; Rats; Rats, Inbred Strains; Renin; Saralasin

This study was undertaken to investigate the role played by renal functional and structural changes in the development of radiation-induced hypertension. Four groups of rats were studied: 1) left kidney radiated, 2) sham procedure, 3) uninephrectomy followed 3 weeks later by radiation of the contralateral kidney, and 4) uninephrectomy followed by sham procedure 3 weeks later. All radiated rats became hypertensive at 12 weeks (p less than 0.05) and had higher protein excretion (p less than 0.05). In the presence of an intact contralateral kidney, radiation causes mild-to-moderate histological abnormalities, and therefore, creatinine clearance and water and sodium handling do not change. Plasma renin activity increased in this group (p less than 0.05). Radiated uninephrectomized rats showed decreased creatinine clearance (p less than 0.05), but renin activity remained unchanged. These rats developed severe histological abnormalities in glomeruli, interstitia, tubuli, and vessels resulting in increased sodium and water output. The average of individual tubular and interstitial scores correlated significantly with both water intake and output but not with sodium excretion. These studies suggest that in the presence of an intact kidney, renin is an important determinant in the development or maintenance of radiation hypertension, whereas in the absence of the contralateral kidney, severe histological changes and renal failure are prominent despite increased water intake and output. The more severe glomerular sclerosis and proteinuria in the latter model could be related to diminished renal mass.

Topics: Animals; Biomechanical Phenomena; Blood Pressure; Creatine; Drinking; Glomerular Filtration Rate; Hypertension; Kidney; Kidney Glomerulus; Natriuresis; Nephrectomy; Radiation Injuries, Experimental; Rats; Rats, Inbred Strains; Renin; Saralasin; Sclerosis

1. The interaction between the vascular renin-angiotensin system and presynaptic beta-adrenoreceptors was examined in male and female normotensive and spontaneously hypertensive rats, using the in vitro perfused mesentery preparation. 2. Enhancement of the pressor response to periarterial nerve stimulation by isoprenaline was shown to be significantly greater in preparations from male and female spontaneously hypertensive rats compared to corresponding preparations from normotensive Wistar rats. 3. In preparations from normotensive and hypertensive animals, the potentiating effect of isoprenaline was prevented by pretreatment with propranolol or ICI 118 551, but not atenolol, implicating a beta 2-adrenoreceptor. 4. Angiotensin II enhanced the responses to peripheral nerve stimulation in preparation from normotensive and hypertensive animals. Enhancement was significantly greater in preparations from hypertensive animals. 5. The potentiation caused by isoprenaline was blocked by the angiotensin II receptor antagonist [Sar1-Ile8] angiotensin II, and by captopril. The potentiation following angiotensin II was unaffected by ICI 118 551. 6. These results suggest that stimulation of presynaptic beta 2-adrenoreceptors activates a localized angiotensin II system. No significant differences in this facilitatory system were observed between male and female animals, but the potentiation caused by activation of this system was considerably greater in the spontaneously hypertensive rats.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Animals; Blood Pressure; Captopril; Female; Hypertension; In Vitro Techniques; Isoproterenol; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Saralasin; Splanchnic Circulation; Sympathetic Nervous System; Synaptic Transmission

The role of vasopressin (AVP) and angiotensin II (ANG II) in the onset of acute (45 min) aortic coarctation hypertension was studied in conscious rats. Changes in mean carotid pressure (MCP) and heart rate (HR) were measured in four groups of rats. Control rats presented a hypertensive response that attained a plateau 5 min after coarctation and remained near this level throughout the experiment. Rats treated with AVP V1-vascular receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-(O-methyl)tyrosine]arginine vasopressin [d(CH2)5Tyr(Me)AVP] presented a prompt rise in MCP similar to the control rats, but in contrast to this group, the MCP started to decline progressively. Rats treated with saralasin presented a delay in the onset of hypertension right after coarctation but slowly attained values similar to those for control rats. In contrast, the rats treated with AVP antagonist plus saralasin showed a blunted MCP elevation throughout the experiment. Reflex bradycardia observed in the rats treated with saralasin or the AVP antagonist plus saralasin was similar to that observed in the control rats, whereas for the group treated only with AVP antagonist, the reflex bradycardia was more intense than for the other three groups, indicating an increased sensitivity of the baroreflex. These data demonstrate that in addition to the mechanical effect of aortic constriction, both ANG II and AVP participate in the onset of acute aortic coarctation hypertension. Moreover, the results indicate that ANG II acts on the prompt (5 min) rise in pressure, whereas AVP is responsible for the maintenance (30-45 min) of the arterial pressure elevation.

Topics: Acute Disease; Angiotensin II; Animals; Aortic Coarctation; Arginine Vasopressin; Blood Pressure; Carotid Arteries; Heart Rate; Hypertension; Male; Rats; Rats, Inbred Strains; Saralasin; Vasopressins

Endothelin, an endothelium-derived vasoconstrictor peptide, and angiotensin II were intravenously injected into the femoral vein of normotensive Wistar-Kyoto (WKY) rats that had been anesthetized with urethane. Blood pressure and heart rate were recorded from a cannula inserted into the carotid artery. All experiments were carried out after treatment with adrenergic and cholinergic antagonists. Endothelin showed a potent, dose-dependent pressor action. The dose-response relations for the increase in blood pressure of rats receiving endothelin were comparable with those of rats receiving angiotensin II. However, endothelin showed far more long-lasting effects. Endothelin-induced responses consisted of three phases: a rapid and transient depressor phase and then two phases of pressor (transient and long-lasting) response. Nicardipine (0.1 mg/kg), a dihydropyridine Ca2+ channel blocker, markedly attenuated the slow phase of the pressor response but only slightly attenuated the rapid one. The pressor action of endothelin was not inhibited by continuous infusions of saralasin, which almost abolished the angiotensin II-induced pressor response. Endothelin-induced pressor response was also not attenuated by indomethacin, a prostaglandin synthesis inhibitor. These data provide evidence that endothelin produces a unique, potent, and long-lasting pressor response, which appears to be in part related to the activation of Ca2+ channels. In 12-week-old spontaneously hypertensive rats (SHR), the maximal pressor response to endothelin was slightly but significantly greater than that in age-matched WKY rats, but the dose dependency of the response was approximately consistent with that in WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Animals; Blood Pressure; Dose-Response Relationship, Drug; Endothelins; Hypertension; Indomethacin; Nicardipine; Peptides; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Saralasin; Time Factors; Vasoconstrictor Agents

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Enalapril; Hypertension; Nitroprusside; Rats; Saralasin

The inhibition of converting enzyme (CE) activity in target tissues other than blood and lung vascular endothelium may be important for the antihypertensive action of CE inhibitors (ICE) (Unger et al 1983). In order to determine if ICE may have an effect on the transmembrane Na movements implicated in the regulation of vascular tone, we have studied the effects of trandolapril and enalapril on 22Na effluxes from the tail artery of 20 weeks old SHR. In vivo, the chronic oral treatment (14 days) with trandolapril (1.3 mg/kg/day) decreased the ouabain-sensitive 22Na efflux (controls: 0.050 +/- 0.004 min-1 (n = 8); trandolapril (1 mg/kg): 0.030 +/- 0.03 min-1 (n = 10) p less than 0.01), and the ouabain-insensitive 22Na efflux (controls: 0.088 +/- 0.0030 min-1; trandolapril (1 mg/kg): 0.080 +/- 0.003 min-1 (n = 10) p less than 0.05). Enalapril had no effect at the dose of 10 mg/kg/day (14 days). In vitro, trandolapril diacid (RU 44403) decreased the ouabain-sensitive 22Na efflux (controls: 0.045 +/- 0.002 min-1 (n = 6); RU 44403 (10(-9) M): 0.031 +/- 0.002 min-1 (n = 6) p less than 0.01), and the ouabain-insensitive efflux (controls: 0.096 +/- 0.004 min-1 (n = 6); RU 44403 (10(-9) M): 0.084 +/- 0.006 min-1 (n = 6) p less than 0.05). The effects were dose-dependent. Enalapril diacid (MK 422) also dose-dependently decreased 22Na effluxes but it was approximately 10 fold less active.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Arteries; Cell Membrane; Enalapril; Hypertension; Indoles; Male; Ouabain; Rats; Rats, Inbred SHR; Saralasin; Sodium; Sodium Radioisotopes; Tail

Control of cell calcium handling and transport may be abnormal in hypertension. We have studied calcium efflux rates in response to angiotensin II and vasopressin in cultured vascular smooth muscle cells from New Zealand genetically hypertensive rats and normotensive control rats. Calcium efflux with both peptides was time- and concentration-dependent and was significantly greater in cells from the genetically hypertensive rats (P less than 0.001, analysis of variance). In addition, mean +/- s.d. protein content (0.31 +/- 0.01 versus 0.28 +/- 0.02 mg/well, n = 48, P less than 0.001) and calculated total cell calcium (3.63 +/- 0.27 versus 2.86 +/- 0.32 nmol/mg protein, n = 16, P less than 0.005) were greater in genetically hypertensive rat cells. These data are consistent with the presence of abnormal cell calcium dynamics in hypertension in genetically hypertensive rats.

Topics: Angiotensin II; Animals; Calcium; Cells, Cultured; Hypertension; Muscle, Smooth, Vascular; Rats; Rats, Mutant Strains; Saralasin; Vasopressins

Intrarenal administration of angiotensin I converting enzyme (ACE) inhibitors carried out in norepinephrine- (NE; 2-4 micrograms/kg per min) or in angiotensin II- (ANG II; 60-90 ng/kg per min) induced acute hypertension in conscious unrestrained rabbits. Intrarenal administration of captopril (5 mg/kg) and MK-422 (1 mg/kg) caused no significant effect when injected intravenously. However, it showed a prompt and marked depressor effect in NE- but not in ANG II-induced hypertension. This effect was not observed after intrarenal infusion of saralasin (2 and 10 micrograms/kg per min) in NE-induced hypertension. While pretreatment with aprotinin or indomethacin failed to inhibit the depressor action, 2-bromoethylamine hydrobromide (BEA), which is known to induce necrosis of the renal papilla, produced complete abolition of the depressor effect of an intrarenal injection of MK-422 in NE-induced hypertension. These results indicate that the kidney plays an important role in the depressor action of ACE inhibitors in NE- but not in ANG II-induced acute hypertension, and that this effect may be related to the potentiation of antihypertensive renomedullary lipids rather than the inhibition of the renin-angiotensin system or the potentiation of bradykinin or prostaglandins.

Topics: Acute Disease; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aprotinin; Female; Heart Rate; Hypertension; Indomethacin; Kidney; Norepinephrine; Rabbits; Saralasin

Our study on intracellular effects of angiotensin II in human platelets showed that: (1) angiotensin II increases intracellular free calcium in platelets via a receptor-operated mechanism and this increase is dose-dependent; (2) the effect on platelet intracellular free calcium depends on the extracellular calcium concentration; (3) ACE inhibition leads to an increased sensitivity of intracellular free calcium to angiotensin II but does not alter epinephrine-induced calcium increase; (4) nifedipine reduces the susceptibility of platelet intracellular free calcium for angiotensin II.

Topics: Administration, Oral; Adult; Angiotensin II; Blood Platelets; Blood Pressure; Calcium; Captopril; Female; Humans; Hypertension; In Vitro Techniques; Male; Middle Aged; Nifedipine; Saralasin

The plasma levels of immunoreactive (IR)-ANF have been evaluated by radioimmunoassay in several models of experimental hypertension and in human hypertension. In all models of experimental hypertension so far studied, the plasma levels of IR-ANF are consistently increased. This is accompanied by a decrease, at certain time intervals, of the IR-ANF levels in the left atrium. In human essential hypertension, the plasma levels of IR-ANF are not increased except in the severe form (diastolic blood pressure above 110 mmHg). In renovascular hypertension, the peripheral levels of IR-ANF are not different from the normal levels but are increased above normal in aortic blood.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Female; Heart Atria; Hypertension; Hypertension, Renovascular; Male; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Saralasin; Sympathetic Nervous System

A central pressor effect of angiotensin II (ANG II) has been implicated in the pathogenesis of several forms of experimental hypertension. Therefore, the present studies were designed to investigate mechanisms that contribute to hypertension resulting from selective stimulation of brain ANG II receptors by chronic intracerebroventricular (ICV) infusion of ANG II. Specifically, the role of the sympathetic nervous system, the pressor actions of vasopressin, and the direct vasoconstrictor effect of blood-borne ANG II were investigated in rats made hypertensive by 5- to 7-day ICV ANG II infusions (6 micrograms/h). Rats were chronically instrumented with indwelling arterial and venous catheters and a lateral cerebral ventricular cannula. Acute intravenous infusion of the competitive ANG II receptor antagonist [Sar1-Ala8]ANG II during the period of ICV ANG II infusion resulted in a moderate decrease in arterial pressure, indicating that an increase in blood-borne ANG II may account for a small component of the hypertensive response to ICV ANG II. Activation of the sympathetic nervous system appeared to be the major contributor to the elevated arterial pressure, since acute ganglionic blockade and combined alpha- and beta-adrenergic blockade produced greater depressor responses in rats made hypertensive with chronic ICV ANG II infusion than in normotensive rats. Furthermore, peripheral sympathectomy delayed hypertension development. Intravenous administration of a specific antagonist of the vascular vasopressin receptor did not cause a depressor response in rats made hypertensive with chronic ICV ANG II infusions. These studies demonstrate that a major mechanism involved in the pressor response to acute ICV ANG II injections, namely vasopressin release, does not appear to contribute to hypertension produced by chronic ICV infusions of ANG II. Rather, this form of hypertension is characterized predominantly by an increase in sympathetic vasoconstrictor tone and possibly by a mechanism activated by a small increase in circulating levels of ANG II.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Arginine Vasopressin; Blood Pressure; Blood Vessels; Electric Stimulation; Ganglionic Blockers; Hexamethonium; Hexamethonium Compounds; Hypertension; Injections, Intraventricular; Male; Neurotransmitter Agents; Rats; Rats, Inbred Strains; Receptors, Angiotensin; Saralasin; Spinal Cord; Sympathectomy, Chemical

In a multicentric prospective study should be tested clinically the effectiveness and the tolerance of an angiotensin-II-antagonist (Saralasin-IWF) developed by the Institut für Wirkstofforschung der Akademie der Wissenschaften, its position in the differential-diagnostic step programme of the arterial hypertension should be analysed and with it should be performed pathogenetic investigations for hypertension after kidney transplantation. Taking into consideration international studies our results confirm that the Saralasin test, taking into account strongly standardized methodical prerequisites, is suited to objectify a participation of the RAAS in the hypertension pathogenesis, without, however, thus making an absolutely reliable evidence concerning the etiology of hypertension. The Saralasin test may represent an important diagnostic criterion for an optimization of the therapy of "volume-resistant" hypertension under the conditions of haemodialysis and in connection with selective renin determinations it possesses a high value in the screening diagnostics of the arterial stenosis after allogenic kidney transplantation.

Topics: Blood Pressure; Diagnosis, Differential; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Kidney Transplantation; Postoperative Complications; Renal Dialysis; Saralasin

Topics: Adrenal Cortex Hormones; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Aldosterone; Catecholamines; Cushing Syndrome; Diagnosis, Differential; Humans; Hyperaldosteronism; Hypertension; Pheochromocytoma; Renin; Saralasin

Rats were placed on powdered chow containing either no additives (controls), mestranol (a synthetic estrogen), norethynodrel (a synthetic progestin), or both mestranol and norethynodrel. After 6 mo on these diets, catheters were placed in the carotid artery and jugular vein of each rat. An arterial blood sample was obtained for plasma renin activity (PRA), plasma renin concentration (PRC), and plasma renin substrate concentration (PRS). Mean arterial pressure was measured in each rat. The angiotensin II (ANG II) antagonist, [Sar1-Ile8]ANG II, was infused intravenously for 30 min while blood pressure was recorded. Rats treated with mestranol and/or norethynodrel had PRA and PRC values that were not different from the control rats; however, mestranol-treated rats and rats treated with mestranol plus norethynodrel had PRS values that were substantially (P less than 0.01) higher than the controls. Arterial pressures in rats treated with mestranol and with mestranol plus norethynodrel were significantly (P less than 0.01) elevated when compared with the controls and with the rats treated with norethynodrel alone. Infusion of the ANG II antagonist failed to alter arterial pressure in any of the groups of rats. These results indicated that, in the steroid combination found in the oral contraceptive Enovid, it is the estrogenic component that results in hypertension in this rat model. Also this study found no evidence that ANG II plays a role in maintaining the elevated arterial pressure following long-term treatment with mestranol in rats.

Topics: Angiotensin II; Animals; Blood Pressure; Contraceptives, Oral; Female; Hypertension; Mestranol; Norethynodrel; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; Saralasin

Twenty-nine patients with essential hypertension were studied while on their normal diets, on the 5th day of a high sodium diet (around 350 mmol/day) and on the 5th day of a low sodium diet (10 mmol/day). The fall in mean arterial pressure on changing from the high sodium to the low sodium diet was 9.0 +/- 1.6 mmHg and the rise in the plasma renin activity in the same period was 2.52 +/- 0.41 ng/ml/h, these two variables being significantly correlated (r = -0.45; P less than 0.02). An infusion of saralasin was given on the 5th day of the low sodium diet. A highly significant negative correlation was found between the fall in blood pressure on sodium restriction and the change in blood pressure with saralasin (r = -0.52; P less than 0.005); this correlation was still significant when corrected for the severity of the hypertension (r = -0.41; P = 0.03) while it became non-significant if controlled for plasma renin activity on the low sodium diet (r = -033; NS). These results provide direct evidence that the fall in blood pressure which is seen on reducing sodium intake in many patients with essential hypertension is, at least in part, directly mediated by the reactivity of the renin angiotensin system.

Topics: Adult; Aged; Blood Pressure; Diet, Sodium-Restricted; Female; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; Saralasin

Topics: Angiotensin II; Arginine Vasopressin; Blood Pressure; Calcium; Captopril; Cold Temperature; Enzyme Precursors; Humans; Hyperaldosteronism; Hypertension; Hypertension, Malignant; Hypertension, Renal; Magnesium; Natriuretic Agents; Propranolol; Renin; Renin-Angiotensin System; Saralasin; Sodium; Teprotide

Topics: 6-Ketoprostaglandin F1 alpha; Adrenal Glands; Adult; Epoprostenol; Female; Humans; Hypertension; Male; Middle Aged; Renin-Angiotensin System; Saralasin; Sympathetic Nervous System

We have previously shown that rats housed in individual metabolism cages develop arterial hypertension and that this can be prevented by adrenalectomy. In the present work the influence of adrenalectomy on blood pressure, heart rate and on fluid and electrolyte balance was investigated in rats with established isolation-induced hypertension. Seven days after adrenalectomy, systolic blood pressure was reduced to levels similar to those seen before the induction of hypertension; the fall in blood pressure was accompanied by tachycardia. It is likely that the reduction in blood pressure was partly due to volume depletion, since adrenalectomized rats showed reductions in fluid, sodium and potassium balance during the first week after operation. Over the following 3 weeks, blood pressure and heart rate returned to pre-operative hypertensive levels, associated with increasingly positive balances for fluid and sodium. Maintenance of elevated blood pressure in isolated rats following adrenalectomy is likely to have been aided by activation of the renin-angiotensin system, since infusion of saralasin caused profound hypotension in these circumstances, whereas it had a slight pressor effect in intact rats with isolation-induced hypertension.

Topics: Adrenalectomy; Animals; Blood Pressure; Heart Rate; Hypertension; Male; Potassium; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Saralasin; Social Isolation; Sodium; Water-Electrolyte Balance

Topics: Adrenal Gland Neoplasms; Humans; Hypertension; Male; Middle Aged; Pheochromocytoma; Saralasin

The role of the renin-angiotensin system in the aetiology of perioperative hypertension was studied in 15 previously normotensive patients undergoing coronary artery surgery and anaesthetized with fentanyl. Measurements of plasma renin activity were made at intervals before and during cardiopulmonary bypass (CPB). In addition, angiotensin II blockade with saralasin was used in an attempt to treat hypertension during CPB. Nine of the patients became hypertensive (increase in systemic pressure of more than 20 per cent) before CPB and although the mean plasma renin activity was higher in this group than in the normotensive patients it was within normal limits for each group. Hypertension during CPB (mean blood pressure greater than 100 mmHg at 1.8 l X m-2 flow), occurred in seven patients but was not associated with increased renin activity and did not respond to saralasin in doses up to 20 micrograms X kg-1 X min-1. It is concluded that cardiopulmonary bypass associated hypertension is not mediated by activation of the renin-angiotensin system.

Topics: Angiotensin II; Cardiopulmonary Bypass; Female; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; Saralasin; Vascular Resistance

Topics: 1-Sarcosine-8-Isoleucine Angiotensin II; Adult; Aldosterone; Angiotensin II; Blood Pressure; Heart Rate; Humans; Hyperaldosteronism; Hypertension; Hypertension, Renovascular; Middle Aged; Renin; Saralasin

Renin release elicited by i.v. injection of loop-diuretics was used to study the effects of angiotensin II (AII) on intrarenal hemodynamics. The vasoconstrictive action of intrarenally synthesized AII predominates in the efferent glomerular arteriole. Such a vasoconstrictive effect could affect blood flow in the vasa recta which stem from efferent arterioles of juxtamedullary glomeruli. Renin secretion and renal inner medullary blood flow (tissue clearance of 133Xe) were simultaneously measured before and after frusemide-induced renin release. The relationship between renin secretion and renal inner medullary blood flow was inverse. Changes in renal medullary blood flow may be physiological determinants of medullary osmolality and renal concentration ability. The intrarenal role of AII in urinary concentration recovery after frusemide was examined. Inhibition of renin release by propranolol or AII-blockade (by saralasin or Hoe 409) delayed recovery of urinary osmolality. In the conscious rat, propranolol slowed down recovery of the cortico-papillary gradient for sodium. Its vasoconstrictive action on the efferent glomerular arteriole might enable the renin-angiotensin system to participate in the control of renal excretion of salt and water.

Topics: Angiotensin II; Animals; Dogs; Furosemide; Humans; Hypertension; Kidney Concentrating Ability; Kinetics; Male; Osmolar Concentration; Propranolol; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; Saralasin; Sodium; Urine

The pressor response to lysine vasopressin was tested in groups of male Wistar, Brattleboro, Wistar-Kyoto, and spontaneously hypertensive rats. Moreover, the influence of sodium intake, angiotensin II, saralasin, captopril, norepinephrine, and isoproterenol on vasopressin pressor responses was evaluated. The right iliac artery and one or both femoral veins of the animals were catheterized under light ether anesthesia. The experiments were carried out following a 2-h stabilization period with the rats awake and semirestrained. Pressor responsiveness was evaluated acutely on the basis of dose-response curves (0.5-4 mU). In the Wistar rats, angiotensin II (10 and 30 ng/min) and isoproterenol (10 ng/min) markedly decreased the response to vasopressin, whereas variations in sodium intake and blood pressure per se did not seem to exert any influence. Norepinephrine (250 ng/min) slightly enhanced the pressor responsiveness to the smaller doses of lysine-vasopressin. Brattleboro rats with congenital diabetes insipidus were less sensitive to vasopressin than the other animals, and neither angiotensin II nor isoproterenol induced any change. In conclusion, the pressor responsiveness to vasopressin can vary considerably depending on several factors. These must be taken into account when evaluating the possible pressor role of vasopressin in experimental and clinical settings.

Topics: Angiotensin II; Animals; Blood Pressure; Captopril; Dose-Response Relationship, Drug; Hypertension; Isoproterenol; Lypressin; Male; Norepinephrine; Proline; Rats; Rats, Inbred Strains; Saralasin; Sodium; Species Specificity

The circulatory effects of captopril, an angiotensin I-converting enzyme inhibitor, and saralasin, a competitive angiotensin II antagonist, were studied during halothane anaesthesia in spontaneously hypertensive (SH) rats. Captopril decreased blood pressure significantly in unanaesthetized rats. Pretreatment with indomethacin, a prostaglandin synthesis inhibitor, did not modify the antihypertensive action of captopril. During 1 MAC halothane anaesthesia, the mean arterial pressure (MAP) in unmedicated SH control rats was maintained at a relatively high level (16.2 +/- 0.7 kPa, mean +/- s.e. mean), while in captopril-treated rats MAP decreased to 8.8 +/- 1.1 kPa. Indomethacin somewhat inhibited MAP decrease in the captopril-medicated group. Saralasin infusion in halothane-anaesthetized rats decreased MAP in the same way as captopril alone. The tolerance to haemorrhagic shock was markedly impaired in rats receiving captopril or saralasin, compared to untreated controls. During halothane anaesthesia, the plasma renin activities in the captopril, captopril + indomethacin, and saralasin groups were significantly higher than in untreated animals. Plasma kininogen was unaffected by any of the medications. The results suggest that the renin-angiotensin system is important in maintaining blood pressure in halothane anaesthesia, and that the tolerance to haemorrhagic shock is particularly impaired by drugs inhibiting the renin-angiotensin system.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Enflurane; Halothane; Heart Rate; Hypertension; Indomethacin; Male; Proline; Rats; Renin-Angiotensin System; Saralasin; Shock, Hemorrhagic

Topics: Adult; Angiotensin II; Blood Pressure; Female; Humans; Hypertension; Injections, Intravenous; Male; Middle Aged; Renin; Saralasin; Sodium

Topics: 1-Sarcosine-8-Isoleucine Angiotensin II; Aldosterone; Angiotensin II; Blood Pressure; Humans; Hypertension; Renin; Saralasin

Vascular reactivity to noradrenaline after angiotensin II and saralasin administration has been studied in vitro on isolated arterial vessels (aorta and mesenteric artery strips) of two strains of normotensive rats and spontaneously hypertensive rats. The results showed: 1. There were no differences in the response to noradrenaline and angiotensin II when they were applied separately on isolated arterial strips of spontaneously hypertensive rats as compared to two strains of normotensive Wistar rats; 2. The potentiated effect of noradrenaline in the presence of angiotensin II is higher on isolated arterial vessels of spontaneously hypertensive rats than on isolated arterial vessels of normotensive rats; 3. The potentiated effect of noradrenaline in the presence of angiotensin II was depressed after administration of angiotensin II-blocker.

Topics: Angiotensins; Animals; Aorta; Hypertension; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Norepinephrine; Rats; Rats, Inbred Strains; Saralasin

Topics: Animals; Arginine Vasopressin; Blood Pressure; Epinephrine; Heart Rate; Hypertension; Isoquinolines; Male; Methylprednisolone; Methylprednisolone Acetate; Norepinephrine; Phenylethanolamine N-Methyltransferase; Rats; Rats, Inbred Strains; Saralasin; Tetrahydroisoquinolines; Vasoconstriction

Topics: Angiotensin II; Humans; Hypertension; Receptors, Angiotensin; Renin-Angiotensin System; Saralasin

Angiotensin-converting enzyme inhibitors, both teprotide and captopril, induce a potentiated renal vascular response in patients with essential hypertension, and with that a consistent increase in sodium excretion and occasionally an increase in glomerular filtration rate. In patients with advanced congestive heart failure resistant to other vasodilators, a similar triad occurs. It is not yet clear in which settings the renal response to angiotensin-converting enzyme inhibition reflects a reduction in angiotensin II formation--thus implicating the renin-angiotensin system in the pathogenesis--or an additional action, such as a potentiation of the local actions of bradykinin or enhanced prostaglandin formation. Under some circumstances, especially where a qualitatively and quantitatively similar response occurs to angiotensin antagonists and angiotensin-converting enzyme inhibitors or where an angiotensin antagonist prevents an additional response to a converting enzyme inhibitor, it is clear that the specific action of the converting enzyme inhibitor on angiotensin II formation is responsible. Unfortunately, for most responses in animal models and all responses in patients, such rigorous evidence is not yet available.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Captopril; Dogs; Glomerular Filtration Rate; Heart Failure; Humans; Hypertension; Kinins; Rabbits; Rats; Renal Circulation; Renin-Angiotensin System; Saralasin; Sodium; Teprotide; Water-Electrolyte Balance

The effect of angiotensin II on the pressor response of the mesenteric vascular bed to periarterial adrenergic nerve stimulation (PNS) was compared between spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Angiotensin II (1-20 ng/ml) caused a marked potentiation of the vasoconstrictor response to PNS (8 Hz, 2 msec, for 30 sec) in a concentration-dependent manner without significantly affecting the base-line perfusion pressure in either WKY or SHR. The facilitatory effect of angiotensin II was significantly greater in SHR than in WKY preparations. The effective concentration for the peptide in SHR was approximately one-third of that found in WKY. Angiotensin II also potentiated the pressor response to exogenously administered norepinephrine (NE, 50 ng) in both WKY and SHR. The degree of potentiation of the response to PNS was greater than that to NE in SHR, while this differential was found only at high concentrations of angiotensin II on the WKY. The facilitatory effect of angiotensin II on the pressor response to either PNS or NE was markedly reduced by [Sar1-Ile8]angiotensin II (200 ng/ml) in both WKY and SHR. Angiotensin II caused further potentiation of the vasoconstrictor response to PNS or NE infusion in the presence of cocaine (5 micrograms/ml), which was of a greater magnitude in SHR than in WKY. These results suggest that the presynaptic facilitatory modulation of adrenergic vascular neurotransmission, mediated by angiotensin II receptors, is enhanced in the perfused mesenteric vascular bed of SHR.

Topics: Angiotensin II; Animals; Blood Pressure; Cocaine; Drug Synergism; Electric Stimulation; Hypertension; Male; Norepinephrine; Rats; Receptors, Angiotensin; Saralasin; Sympathetic Nervous System; Synaptic Transmission

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Humans; Hypertension; Kidney; Renin; Renin-Angiotensin System; Saralasin

Screening tests for primary aldosteronism were compared in 22 patients with this disorder and 140 hypertensive controls. Adequate (93-100%) sensitivity and specificity were not provided by single tests ((1) serum K, (2) furosemide-stimulated PRA, or (3) plasma aldosterone concentration (PAC) after furosemide, or (4) after 2 liters 0.9% NaCl)), but were provided by combinations: (2) + (1) or (3); (2) + (1) or (4); and by a pressor response to saralasin + (3) or (4). Mechanism of the observed excessive rise in PAC "stimulated" by furosemide and standing for 2 h was studied in the same patients. The rise in "stimulated" PAC was (a) associated with a low PRA and not reproducible by angiotensin II infusions; (b) associated with a slight but significant rise in plasma cortisol and was reproducible by ACTH infusions. It is, therefore, attributed to the effects of slight ACTH release acting on adrenal tissue with super-sensitivity of aldosterone response to ACTH.

Topics: Aldosterone; Blood Pressure; Furosemide; Humans; Hyperaldosteronism; Hypertension; Mass Screening; Posture; Potassium; Renin; Saralasin

The significance of active and inactive renin was investigated by comparison of an in vitro assay of active, total and inactive plasma renin concentration (APRC, TPRC, IPRC) and plasma angiotensin II concentration (PA II) with an in vivo change in mean arterial pressure (MAP) produced by angiotensin antagonism with saralasin and by angiotensin converting enzyme blockade with captopril. A significant relationship between the changes in MAP during saralasin and captopril with the pre-treatment level of APRC, TPRC and PA II were found; while the pre-existing level of inactive renin was not a predictor for the hypotensive effect of saralasin and captopril. During captopril and saralasin significant increases in TPRC and APRC were found and no change in IPRC.

Topics: Adult; Angiotensin II; Blood Pressure; Captopril; Cold Temperature; Enzyme Activation; Enzyme Precursors; Female; Humans; Hypertension; Male; Renin; Saralasin

Cultured JGC contain renin, angiotensin I, angiotensin I-converting enzyme, angiotensin II, and, by implication, the entire RAS. JGC, as transplants, appear to secrete angiotensin II/III directly into the bloodstream to cause hypertension when the renal mass is reduced. There are two main phases of the hypertensive state, an angiotensin-dependent developmental phase and a non-angiotensin-dependent maintenance phase. This model may be useful in attempts to evaluate pro-hypertensive actions of angiotensin other than those due to direct systemic vasoconstriction. Certain of these actions appear to be intrarenal and include the stimulation of sodium reabsorption, a decrease in renopapillary blood flow, the stimulation of prostaglandin synthesis, and a constraint on the antihypertensive function of the RIC.

Topics: Angiotensin II; Angiotensin III; Animals; Captopril; Cells, Cultured; Hypertension; Juxtaglomerular Apparatus; Nephrectomy; Rats; Saralasin

Topics: Adult; Female; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; Saralasin

Topics: Adult; Angiotensin II; Captopril; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Proline; Renin-Angiotensin System; Saralasin

Topics: Adult; Female; Humans; Hypertension; Male; Middle Aged; Saralasin

The antihypertensive effect of captopril and its mechanism of action were studied in patients with essential and renal hypertension. In mild essential hypertension (n = 12), during monotherapy with captopril (50 to 450 mg, 4 to 12 weeks) blood pressure was normalized in seven, improved in two and remained unchanged in three patients, plasma levels of active and acid-activatable inactive renin significantly increased and angiotensin II decreased, whereas no consistent changes in urinary kallikrein excretion occurred. In severe renal (n = 14) and essential (n = 9) hypertension, blood pressure was normalized in eight (seven with renal hypertension), improved in seven and unchanged in eight patients, when captopril (50 to 450 mg, 3 to 15 months) was added to the antihypertensive medication. In one patient with stenosis in a transplanted renal artery reversible renal failure occurred during captopril therapy possibly because of a steep initial decrease in blood pressure, although a toxic effect of the drug cannot be excluded. In another series of 12 renal and 8 essential hypertensive patients, a significant correlation between the acute effect of captopril (within 90 minutes) an saralasin on blood pressure was demonstrated (r=0.71, p less than 0.001). The change in blood pressure after either drug was significantly related to the initial plasma renin concentration. In conclusion, captopril seems to be an effective antihypertensive agent in essential and renal hypertension. Renal function should be monitored during captopril therapy. Our studies suggest that captopril decreases blood pressure by inhibiting the vasopressor action of the renin-angiotensin system.

Topics: Angiotensin II; Captopril; Electrolytes; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Proline; Renin; Renin-Angiotensin System; Saralasin

Topics: Adolescent; Aldosterone; Angiotensin II; Aortic Coarctation; Child; Humans; Hypertension; Natriuresis; Postoperative Period; Renin; Renin-Angiotensin System; Saralasin

Topics: Angiotensin II; Humans; Hypertension; Hypertension, Renovascular; Renin; Saralasin

We studied the isolated blood-free perfused nonclipped kidneys from the 2-kidney Goldblatt hypertensive rat model (GHR) to evaluate intrinsic excretory responses to changes in perfusion pressure. We examined kidneys from 10 control rats (in vivo systolic BP 110 +/- 3.6 mm Hg), from 9 rats with nonmalignant hypertension (HBP) (in vivo systolic BP 158 +/- 6.5 mm Hg), and from 5 rats with malignant HBP (in vivo systolic BP 183 +/- 6.4 mm Hg). We found that at all levels of perfusion pressure, the renal vascular resistances were significantly higher and glomerular filtration rate (GFR) lower in kidneys from hypertensive rats than in kidneys from control rats. Kidneys from hypertensive rats had lower urinary excretion of sodium (UNaV) and urine flow than kidneys from control rats at all levels of pressure above 100 mm Hg. The most striking differences in all functional parameters were noted in kidneys from rats with malignant HBP. Kidneys from both hypertensive and control rats failed to show changes in vascular resistance in response to Saralasin. We conclude that the nonclipped kidney in GHR exhibits a blunted natriuresis in response to elevated perfusion pressure which occurs in the absence of angiotensin II (AII) and renin substrate. This diminished pressure natriuresis may be caused partly by the lower GFR and by reduced pressure transmission due to greater renal vascular resistance and thus may be partially responsible for the maintenance of the hypertensive state.

Topics: Animals; Blood Pressure; Constriction; Hypertension; Male; Natriuresis; Pressure; Rats; Rats, Inbred Strains; Renal Artery; Renal Circulation; Saralasin; Sodium; Urodynamics

Saralasin acetate, a competitive inhibitor of angiotensin II, was administered as a continuous infusion to two pediatric patients for 8 and 13 days, respectively, to control hypertension. Both patients had become refractory to parenterally administered antihypertensive medications and had an ileus that precluded drug treatment orally. Both patients had a reduction in blood pressure of 30% in response to intravenous infusion of saralasin as a diagnostic test. In the patient with renal failure, neither saralasin nor ultrafiltration was effective alone, but blood pressure was controlled when their use was combined. In these two patients the continuous infusion of saralasin proved to be an effective means for blood pressure control and was unassociated with any recognized adverse effects.

Topics: Angiotensin II; Child; Female; Humans; Hypertension; Infant; Infusions, Parenteral; Male; Saralasin; Ultrafiltration

Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Captopril; Central Nervous System Agents; Diuretics; Humans; Hypertension; Saralasin; Sympatholytics; Vasodilator Agents

Topics: Angiotensin II; Angiotensins; Blood Pressure; Captopril; Humans; Hypertension; Ischemia; Kidney; Peptidyl-Dipeptidase A; Posture; Renin; Saralasin; Teprotide

The response to norepinephrine (NE) of arterial smooth muscle from two types of experimental hypertensive rats was investigated. Aortic strips from one-kidney, one-clip hypertensive animals were less responsive to NE than those from their normotensive controls but strips from one-kidney, one-clip hypertensive animals showed no difference from their corresponding controls. The contractility in response to NE was the same in all groups. These results suggest that the mechanisms responsible for lesser reactivity in the one-kidney hypertensive group are not a consequence of elevated blood pressure itself but may be related to changes in the intrinsic sensitivity of aortic smooth muscle. Tonin potentiated the contraction induced by NE in aortic strips from hypertensive and normotensive rats. This effect was more pronounced in the one-kidney, one-clip hypertensive animals, so that although the aortic smooth muscle from these animals is less reactive to NE, the decreased reactivity can be more than compensated by the presence of tonin. The mechanism of potentiation is not yet clear but the fact that Saralasin did not inhibit it suggests that angiotensin II is not generated in situ.

Topics: Animals; Aorta, Thoracic; Blood Pressure; Hypertension; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nephrectomy; Norepinephrine; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Strains; Saralasin

The blood pressure response to different doses of methylprednisolone was examined in the rat. It is concluded that doses varying from 2.5 mg/kg/week to 20 mg/kg/week of this agent caused clear-cut elevations in arterial pressure. The methylprednisolone-induced arterial hypertension was accompanied by elevation in Plasma Renin Activity and administration of captopril or saralasin caused significant drops in systemic arterial pressure. Concomitant long term administration of captopril and methylprednisolone caused a delay in appearance and smaller elevations in arterial pressure. It is concluded the methylprednisolone in the rat causes arterial hypertension which is at least partially dependent upon renin angiotensin system activation. However elevated blood pressure levels were noticeable even during chronic captopril administration leading to the conclusion that other mechanism (s) may participate in the pathogenesis of this experimental model of hypertension in rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Captopril; Disease Models, Animal; Hypertension; Male; Methylprednisolone; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Saralasin

Topics: Angiotensin I; Angiotensin II; Humans; Hypertension; Kidney; Renin; Saralasin

During aetiological investigation of recently developed hypertension in a 31-year-old man, isolated dissection of the upper branch of the right renal artery was discovered. Injection, after sodium depletion, of saralasin, a competitive angiotensin II inhibitor, resulted in significant fall of the mean arterial pressure. During sodium depletion, the plasma renin activity was higher in the right renal artery (17.8 ng/ml/h) than in the left artery (9.4 ng/ml/h) and the infra-renal portion of the inferior vena cava (8.7 ng/ml/h). These figures suggested that surgical treatment of the dissection would have beneficial effects on blood pressure. Six months after resection of the pathological arterial segment and replacement by a graft from the internal saphenous vein, blood pressure had spontaneously returned to normal levels.

Topics: Adult; Aortic Dissection; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Male; Renal Artery; Renin; Saralasin

Topics: Adult; Aldosterone; Angiotensin II; Blood Pressure; Captopril; Diet, Sodium-Restricted; Female; Humans; Hypertension; Male; Middle Aged; Renin; Saralasin; Sodium

1. To examine the possible participation of the brain iso-renin-angiotensin system in the control of blood pressure, as well as in the regulation of plasma renin activity, saralasin and captopril were injected into the cerebral ventricles of three types of experimental hypertensive rats with different plasma renin profiles. 2. Injection of saralasin and captopril into the cerebral ventricles resulted in a significant decrease in blood pressure of two-kidney, one-clip Goldblatt hypertensive rats (11 +/- 2 and 9 +/- 3 mmHg respectively) and that of spontaneously hypertensive rats (13 +/- 2 and 12 +/- 2 mmHg respectively), but in deoxycorticosterone (DOC)-salt hypertensive rats injection of these two agents showed a significant increase in blood pressure (13 +/- 2 and 12 +/- 3 mmHg respectively). 3. The plasma renin activity was markedly decreased after injection of saralasin and captopril into the cerebral ventricles of two-kidney, one-clip Goldblatt hypertensive rats. Conversely, in DOC-salt hypertensive rats, the plasma renin activity was markedly increased after injection of these two agents. In spontaneously hypertensive rats these agents caused no significant change in plasma renin activity. 4. These findings suggest that the brain iso-renin-angiotensin system participates in the central regulation of blood pressure and may be responsible for modulation of the peripheral renin-angiotensin system.

Topics: Angiotensin II; Animals; Blood Pressure; Brain; Captopril; Endopeptidases; Hypertension; Hypertension, Renovascular; Male; Rats; Renin; Saralasin

Topics: Aged; Angiotensin II; Blood Pressure; Diet, Sodium-Restricted; Female; Follow-Up Studies; Furosemide; Humans; Hypertension; Male; Middle Aged; Renin; Retrospective Studies; Saralasin

Topics: Antihypertensive Agents; Captopril; Drug Evaluation; Guanfacine; Guanidines; Humans; Hypertension; Labetalol; Minoxidil; Nifedipine; Phenylacetates; Saralasin; Verapamil

Topics: Angiotensin II; Child; Humans; Hypertension; Hypertension, Renovascular; Saralasin

Conditions for Simultaneous stimulation of cerebral and renal renin-angiotension systems (RAS) are created in the examined by us model of combined cerebral and renal ischemic hypertension. As a results of interaction between them the effect o cerebral RAS predominates, since renin concentration in the medulla oblongata is elevated while the renal renin concentration remains unchanged, but the plasma renin activity is lowered. The blocking of the action of cerebral angiotension by the venously administered angiotensin antagonist saralasin does not alter substantially blood pressure, but causes elevation of the renal renin concentration in the ischemic and intact kidney and normalization of plasma renin activity, without affecting the level of sodium and potassium.

Topics: Angiotensin II; Animals; Blood Pressure; Brain; Hypertension; Injections, Intraventricular; Kidney; Male; Nerve Block; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Saralasin

Sixteen patients (11 M, 5 F), median age 41 years, with essential hypertension insufficiently controlled on hydrochlorothiazide 75 mg/day (DBP greater than or equal to 100 mmHg) were investigated. Plasma renin concentration (PRC), angiotensin II concentration (PA II), aldosterone concentration (PAC), plasma noradrenaline concentration (PNAC), plasma volume (PV) and exchangeable sodium (NaE) were determined and a saralasin-infusion (5.4 nmol/kg/min) was carried out while the patients were on thiazide alone, and in fourteen cases, repeated 3 months later after addition of a beta-blocker (propranolol 6, metoprolol 6 and atenolol 2 patients). On thiazide alone PRC, PA II and PAC was higher than normal in the group as a whole and the angiotensin II-inhibitor, saralasin, caused a significant decrease in MAP in twelve out of sixteen patients. After addition of a beta-blocker SBP and DBP decreased from 164/109 mmHg to 136/94 mmHg. PRC and PA II decreased by 40% and 58%, respectively. At this point saralasin caused no significant change in MAP. No close correlation was found between changes in BP on beta-blocker treatment and either PRC, PA II or saralasin response on thiazide treatment. PV, NaE, PAC and PNAC did not change sigificantly. It is concluded that in pts with thiazide-induced stimulation of the renin-angiotensin system (RAS) addition of a beta-blocker leads to suppression of RAS and the angiotensin II dependence of the blood pressure is nearly abolished. This mechanism might well contribute to the antihypertensive effect of beta-blockade in this particular situation. However, the pharmacological changes induced by beta-blockade are very complex, and most likely other factors are involved in the antihypertensive effect of beta-blocking drugs.

Topics: Adrenergic beta-Antagonists; Adult; Aldosterone; Angiotensin II; Drug Interactions; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Norepinephrine; Plasma Volume; Renin; Saralasin; Sodium

The present survey paper, concerning newer drugs used in the treatment of arterial hypertension, deals with the following types of agents: centrally acting drugs, such as clonidine nd alpha-methyl-DOPA; vasodilator drugs with a direct action on smooth muscle, such as minoxidil; diuretic agents, with special reference to the choice of a drug from the vast number of compounds; beta-sympatholytic drugs (beta blockers) and which drug to choose; prazosin, with special reference to its considerable theoretical interest; drugs that influence the renin-angiotensin system, such as saralasin (P 113), an angiotensin II-antagonist; and inhibitors of the converting enzyme, such as teprotide (SQ 20,881) and captopril (SQ 14,225). Finally, a general schedule for the treatment of hypertension, issued as a guideline by the Dutch Institution of General Practitioners, is presented.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Clonidine; Diuretics; Humans; Hypertension; Renin; Saralasin; Vasodilator Agents

Topics: Adult; Angiotensin II; Female; Humans; Hypertension; Renin; Saralasin; Teprotide

The effects of an angiotensin-II analog (saralasin, i.v.) and of a converting enzyme inhibitor (captopril, oral) were compared in 12 sodium-depleted patients with hypertension. The decrease of the mean intraarterial pressure (MAP) with captopril (-21.5 +/- [SEM] 4.3 mm Hg) was more pronounced (P < 0.001) than the change of MAP during saralasin (-10.5 +/- 4.0 mm Hg). The pretreatment arterial plasma renin activity (log PRA) was closely related to the change of MAP during saralasin (r = -0.94; P < 0.001) and also to the captopril-induced change of MAP (r = -0.82; P < 0.001); similar results were obtained for the log plasma angiotensin (PA) I and II levels. The change of MAP was more pronounced, however, with captopril than during saralasin at any level of pretreatment PRA, PAI or PAII. Saralasin did not affect heart rate (P > 0.4), but during captopril the heart rate increased by 5.1 beats/min (P < 0.001). Captopril produced a 70% decrease of PAII, but the change of MAP was poorly related to the changes of PAII (r = -0.57; P < 0.05); PRA and PAI rose threefold to fourfold. PRA, PAI, and PAII all increased during saralasin. These observations may suggest that the antihypertensive action of captopril is not based solely on the inhibition of AII formation, but also the agonistic effect of saralasin has to be considered.

Topics: Adult; Angiotensin I; Angiotensin II; Blood Pressure; Captopril; Female; Heart Rate; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Male; Peptidyl-Dipeptidase A; Proline; Renin; Saralasin

1. The peptide converting enzyme inhibitor captopril was given (1.25 mg/kg intravenously) to normal and nephrectomized rats and rats with renovascular and deoxycorticosterone hypertension. 2. Captopril lowered blood pressure to a small extent in normal and nephrectomized rats. Bradykinin infusion in nephrectomized animals, however, potentiated the vasodepressor action of captopril. 3. Captopril produced a major blood pressure fall in the early stages of Goldblatt two-kidney one-clip hypertension: even when hypertension had been present for more than 4 months, a substantial vasodepressor action was seen. Rats with deoxycorticosterone-induced hypertension also showed a significant blood pressure fall. 4. Captopril was given to salt-loaded and salt-depleted rats in which the renin-angiotensin system had been blocked by infusion of the competitive angiotensin II antagonist saralasin. Captopril still lowered blood pressure in the salt-depleted group. 5. Captopril lowers blood pressure in situations where the renin-angiotensin system is not responsible for blood pressure maintenance. Further, the fall in blood pressure produced in Goldblatt two-kidney one-clip hypertension is greater than would be predicted on the basis of renin-angiotensin blockade. It is likely therefore that captopril lowers blood pressure by an action additional to angiotensin blockade. Bradykinin potentiation is one possible mechanism by which this may take place.

Topics: Angiotensin II; Animals; Blood Pressure; Bradykinin; Captopril; Disease Models, Animal; Female; Hypertension; Nephrectomy; Proline; Rats; Renin; Saralasin

Saralasin was used as a functional test of the renin-angiotensin axis in 4 renal transplant patients with hypertension. Blood pressure was recorded by an automatic recording device and plasma renin activity was measured by radioimmunoassay of angiotensin I. A positive saralasin test suggested renin-mediated hypertension despite normal peripheral renin levels in a 40-year-old man whose original kidney disease was nephrosclerosis. Since the blood pressure was refractory to intravenous sodium nitroprusside saralasin was used for 14 hours to control blood pressure before and after arteriography in the patient. Removal of the native kidneys markedly ameliorated the hypertension. A 35-year-old woman with transplant hypertension was responsive to angiotensin blockade only during a period of abrupt worsening of blood pressure associated with an acute rejection episode. Finally, 2 patients with advanced chronic rejection responded to saralasin administration. These studies confirm that 1) angiotensin blockade is a useful tool in the diagnosis of renin-dependent hypertension even when plasma renin levels are not elevated, 2) saralasin can be used to control renin-dependent forms of hypertension that are refractory to intravenous sodium nitroprusside therapy and 3) transplant hypertension associated with acute and chronic rejection appears to be renin-dependent.

Topics: Adult; Angiotensin II; Blood Pressure; Female; Graft Rejection; Humans; Hypertension; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Renin; Saralasin; Transplantation, Homologous

Topics: Adolescent; Adult; Aldosterone; Angiotensin II; Bartter Syndrome; Child; Diet, Sodium-Restricted; Female; Furosemide; Humans; Hydrocortisone; Hypertension; Liver Cirrhosis; Male; Middle Aged; Renin; Saralasin

To evaluate the role of the renin-angiotensin system and sodium depletion in the hypotensive response to 1-sarcosine-8-alanine-angiotensin II (saralasin), 15 male patients with essential hypertension were studied on a diet containing 120 mEq of sodium and 100 mEq of potassium per day. After a 5-day control period, all subjects had a mild pressor response to the saralasin infusion (p less than 0.01). After 5 days of the diuretic metolazone (5 mg/day), eight of the 15 patients had a vasodepressor response; these responders had a significantly greater increase in plasma renin activity and angiotensin II concentrations than did the non-responders. Sodium deficit differed markedly (p less than 0.001) between the two groups (361 +/- 121 mEq (SD) vs 52 +/- 26 mEq sodium, respectively). The addition of spironolactone (400 mg/day) for 5 days resulted in saralasin responsiveness in all but two patients, both of whom had small sodium deficits. Thus, variability in the natriuretic response to diuretics may affect saralasin testing and limit its clinical utility.

Topics: Adult; Aged; Angiotensin II; Blood Pressure; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Hypertension; Hyponatremia; Infusions, Parenteral; Male; Metolazone; Middle Aged; Renin; Saralasin; Sodium; Spironolactone

There are very few areas of clinical pharmacology being pursued as vigorously as hypertension. Numerous new drugs are being discovered and tested both in United States and overseas. The most promising new antihypertensive drugs seem to fall into the angiotensin-renin blocker group and those affecting the sodium-volume axis in hypertensive patients. We can look forward to newer agents that are efficacious as monotherapy and on a daily or twice daily dosage regimen for the treatment of the vast majority of hypertensive patients. There is further hope that preoperative evaluation with angiotensin blockers in patients with renovascular hypertension may improve the predictability of successful renal bypass surgery.

Topics: Aged; Antihypertensive Agents; Captopril; Diuretics; Humans; Hypertension; Male; Metoprolol; Middle Aged; Mineralocorticoid Receptor Antagonists; Pindolol; Saralasin; Timolol; United States; Vasoconstrictor Agents

Patients with primary hyperparathyroidism are frequently hypertensive. Studies were performed to determine whether the hypertension in this disorder could be corrected by saralasin infusion. Five patients with primary hyperparathyroidism and one patient with secondary hyperparathyroidism were salt depleted before saralasin testing by the administration of 1 mg/kg furosemide at 1700 h on the evening before testing. Blood pressure was measured every 2 min by an automatic recording device. Saralasin was given as a continuous iv infusion of 1, 3, 6, and 10 micrograms/kg . min for 30 min. Blood for measurement of PRA was drawn 4 min before, immediately before, and 4, 8, 12, 16, 22, 30, 60, and 90 min after the infusion was begun. Saralasin did not reduce blood pressure in these patients. The mean postsaralasin blood pressure (12--20 min after the start of the infusion) was 155/102 mm Hg compared to the control blood pressure of 156/101 mm Hg (blood pressure at -4 and 0 min). The inability of saralasin to effect a vasodepressor response was unexpected, since the mean PRA before saralasin infusion was elevated at 1895 ng/dl . 3 h (normal range, 409--818 ng/dl . 3 hr; 95% confidence limits). These studies suggest that the hypertension associated with hyperparathyroidism is not renin dependent.

Topics: Adult; Aged; Angiotensin II; Blood Pressure; Calcium; Creatinine; Female; Humans; Hyperparathyroidism; Hypertension; Male; Middle Aged; Parathyroid Hormone; Posture; Renin; Saralasin

Topics: Adolescent; Adult; Aldosterone; Angiotensin II; Blood Pressure; Female; Heart Rate; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Male; Middle Aged; Renin; Saralasin; Sodium

Topics: Angiotensin II; Blood Pressure; Blood Volume; Humans; Hypertension; Renal Dialysis; Renin; Saralasin

In two-kidney Goldblatt hypertensive, spontaneously hypertensive, and normotensive control rats, the activity of the renin-angiotensin system was tested during variation of sodium balance. Acute, exactly calculable and selective changes in total body sodium were achieved by haemodialysing conscious rats, using dialysates with high and low sodium contents. The activity of the renin-angiotensin system was evaluated by blood pressure response to angiogtensin II blockade (saralasin bolus injection; 25 micrograms/kg b.w., i.v.) and plasma renin activity. During sodium-depletion, blood pressure maintenance became renin-dependent; sodium-loading caused a decrease of renin-angiotensin activity in renovascular hypertension. A weak direct correlation between depressor response to saralasin and the plasma renin activity could be established in the different sodium-depleted and sodium-loaded states.

Topics: Animals; Blood Pressure; Disease Models, Animal; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Male; Rats; Renal Dialysis; Renin; Saralasin; Sodium

The biological significance of active and inactive renin was investigated by comparison of an in-vitro assay of active, total and inactive plasma renin concentration (PRC), plasma renin activity (PRA) and plasma concentrations of angiotensin I and II with an in-vivo change in mean arterial blood pressure (MAP) produced by antagonism of angiotensin with treatment with saralasin and by blockade of angiotensin-converting enzyme by treatment with captopril. A significant relationship between the changes in MAP during treatment with saralasin and captopril with the pretreatment levels of PRA, active and total PRC and angiotensin II were found; while the pre-existing level of inactive renin was not a predictor for the hypotensive effect of saralasin and captopril. During treatment with saralasin and captopril significant increases in PRA, plasma angiotensin I concentration and total and active PRC were found and no change in inactive PRC was observed.

Topics: Adult; Angiotensin I; Angiotensin II; Captopril; Female; Humans; Hypertension; Male; Renin; Saralasin

Topics: Acromegaly; Adrenal Glands; Adult; Aldosterone; Angiotensin II; Blood Pressure; Diet, Sodium-Restricted; Humans; Hypertension; Middle Aged; Posture; Potassium; Reference Values; Renin; Saralasin; Sodium

The mechanisms of hypertension in coarctation remain to be clearly defined. In other hypertensive states, abnormal plasma renin activity (PRA) has been unmasked by the depletion of extracellular volume and the use of angiotensin antagonists. In a group of patients with coarctation, preoperative and postoperative evaluations of the renin-angiotensin system have been performed. Before operation, a group of patients with coarctation and a group of normal control subjects both underwent salt restriction followed by diuresis. A standard angiotensin antagonist (saralasin) test was performed on the patients with coarctation, and they demonstrated excessive renin-angiotensin activity compared to the control subjects. Following operation, paradoxical hypertension developed in all of the patients. Repeat saralasin test in these patients again revealed excessive angiotensin activity in the same patients as preoperatively. It appears that the renin-angiotensin system plays a more active role in coarctation than previously believed.

Topics: Adolescent; Angiotensin II; Aortic Coarctation; Child; Child, Preschool; Furosemide; Humans; Hypertension; Renin; Saralasin

The number of studies in the literature on diagnostic and therapeutic uses of angiotensin antagonists has been increasing geometrically. Nearly 1,000 publishsd items deal with saralasin alone, although neither saralasin nor captopril is yet approved for general use or widely available. Reports to date represent only a fraction of the eventual situations in which these agents are likely to help the researcher and clinician. Food and Drug Administration approval of both agents is pending, and both are expected to be available soon. Consequently, the practitioner will want to become familiar with their usefulness, especially to screen for secondary forms of hypertension and to treat moderate to severe primary or secondary hypertension.

Topics: Angiotensin II; Angiotensins; Blood Pressure; Captopril; Diagnosis, Differential; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Proline; Renin; Saralasin

Topics: Adult; Angiotensin II; Blood Pressure; Humans; Hypertension; Norepinephrine; Renin; Saralasin

The Authors have studied, in a group of hypertensive subjects with low renin, the behavior of arterial blood pressure, PRA, plasma aldosterone, plasma K and Na, after intravenous load of Saralasin before and after treatment with Furosmide (40 mg orally given for 4 days). In such conditions we evidenced an agonist effect of Saralasin mainly on plasma aldosterone and less on arterial pressure. The Authors conclude that Saralasin, in given conditions (free receptor sites), can exhibit on agonist effect on aldosterone secretion; such agonist effect can be augmented by dopaminergic deficit, that sometimes in present is essential arterial hypertension.

Topics: Adult; Aldosterone; Angiotensin II; Blood Pressure; Female; Furosemide; Humans; Hypertension; Male; Middle Aged; Potassium; Renin; Saralasin; Sodium

1. To study which factors determine the balance between the antagonistic and agonistic effects of the angiotensin II analogue [Sar1,Ala8]-angiotensin II (saralasin) in man, saralasin was infused in subjects on a 'normal' sodium intake (group 1) during sodium restriction with appropriately elevated plasma angiotensin II levels (group 2) and in sodium-restricted subjects in whom plasma angiotensin II was suppressed by converting enzyme inhibition with captopril (group 3). 2. The action of saralasin was agonistic in group 3, antagonistic in group 2 and variable in group 1. 3. For groups 1 and 2 together the saralasin-induced changes of arterial pressure, of plasma aldosterone and of plasma renin were significantly related to control plasma angiotensin II but also the the 24 h urinary sodium excretion. When group 3 was included the changes remained significantly related to plasma angiotensin II but not to the urinary sodium excretion. 4. The results indicate that angiotensin II and not sodium status determines the agonistic/antagonistic balance of saralasin's actions.

Topics: Adult; Aldosterone; Angiotensin II; Blood Pressure; Captopril; Female; Humans; Hypertension; Male; Middle Aged; Renin; Saralasin; Sodium

1. Neurosecretion of peptides from superfused neurohypophyses in vitro was inhibited by dopamine. 2. This inhibition was dose-dependent. 3. Intravenous injection of the dopamine agonist, bromocriptine, lowered blood pressure in spontaneously hypertensive rats within 15 min. 4. Saralasin or captopril also lowered blood pressure of spontaneously hypertensive rats, but progressively over a period of 3 h. 5. The results suggest that dopamine and angiotensin have opposite effects on the neurosecretion of vasopressin. 6. Vasopressin appears to be involved in maintenance of blood pressure in the spontaneously hypertensive rat but is apparently not the only factor.

Topics: Angiotensin II; Animals; Bromocriptine; Captopril; Dopamine; Hypertension; In Vitro Techniques; Oxytocin; Pituitary Gland, Posterior; Proline; Rats; Saralasin; Swine; Vasopressins

Topics: Adult; Angiotensin II; Blood Pressure; Captopril; Humans; Hypertension; Male; Middle Aged; Proline; Renin; Saralasin

Topics: Adolescent; Adult; Aged; Angiotensin II; Blood Pressure; Chemical Phenomena; Chemistry; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Renin; Saralasin

Renin, aldosterone and exchangeable sodium were measured in 38 hypertensive and 56 normotensive renal transplant recipients with good renal function and without renal artery stenosis. Response to competitive blockade of angiotensin II using saralasin was studied in 20 of the hypertensive group. Hypertension was uncommon when bilateral nephrectomy had been performed. When diseased kidneys remained in situ, blood pressure after transplantation correlated well with blood pressure on dialysis. Plasma renin activity was higher in hypertensive patients despite higher exchangeable sodium levels. Urinary aldosterone was also higher and correlated well with blood pressure and plasma renin activity. Angiotensin II blockade produced a fall in blood pressure proportional to plasma renin activity. These observations suggest that hypersecretion of renin is an aetiological factor in the hypertension of renal transplant recipients. It appears to act both through the stimulation of aldosterone secretion, with resultant salt retention, and through the direct vasoconstrictor action of angiotensin II. Since renin levels were lower in patients subjected to bilateral nephrectomy the source of the excess renin is probably the host's kidneys.

Topics: Adult; Aldosterone; Blood Pressure; Humans; Hypertension; Kidney; Kidney Transplantation; Middle Aged; Postoperative Complications; Renin; Saralasin; Sodium; Transplantation, Homologous

Topics: Adolescent; Adult; Angiotensin II; Aortic Coarctation; Cardiac Catheterization; Child; Humans; Hypertension; Middle Aged; Saralasin

Two siblings are described with hypertension, hyperreninism, hyperaldosteronism and hypokalemia. Propranolol therapy lowered blood pressure markedly, but failed to normalize serum potassium. Indomethacin orally decreased blood pressure and normalized all biochemical abnormalities. We suggest that in these patients there exists a renin-dependent hypertension in combination with a state of hyperprostaglandinism. It is likely from our studies in these 2 patients, that the state of hyperprostaglandinism is secondary to a hypertension with increased sympathetic tone.

Topics: Adolescent; Adult; Angiotensin II; Drug Therapy, Combination; Female; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Indomethacin; Male; Propranolol; Prostaglandins; Renin; Saralasin; Spironolactone; Syndrome

The role of the renin--angiotensin system in the maintenance of blood pressure during halothane anesthesia and sodium nitroprusside (SNP)-induced hypotension was evaluated. Control rats received halothane anesthesia (1 MAC) for one hour, followed by SNP infusion, 40 microgram/kg/min, for 30 min, followed by a 30-min recovery period. A second group of rats was treated identically and, in addition, received an infusion of saralasin (a competitive inhibitor of angiotensin II) throughout the experimental period. In each group, SNP infusion resulted in an initial decrease in blood pressure from 86 torr and 83 torr, respectively, to 48 torr. During the SNP infusion the control animals demonstrated a progressive increase in blood pressure to 61 torr, whereas the saralasin-treated animals showed no change. Following discontinuation of SNP, blood pressure in the control animals rebounded to 94 torr, as compared with 78 torr in the saralasin-treated rats. This study indicates that with stable halothane anesthesia, the partial recovery of blood pressure during SNP infusion and the post-SNP rebound of blood pressure can be completely blocked by saralasin. This demonstrates the participation of the renin--angiotensin system in antagonizing the combined hypotensive effects of halothane and SNP.

Topics: Angiotensin II; Animals; Blood Pressure; Carbon Dioxide; Ferricyanides; Halothane; Hydrogen-Ion Concentration; Hypertension; Male; Nitroprusside; Oxygen; Rats; Renin; Saralasin; Time Factors

Determinants of glomerular ultrafiltration were studied by micropuncture in clamped (n = 11) and unclamped (n = 7) kidneys of two-kidney hypertensive rats and compared to 15 controls. Infusion of the angiotensin II antagonist and saralasin lowered the blood pressure significantly. Glomerular capillary pressure (PGC) in clamped kidneys was decreased to 56 +/- (SD) 3 vs. 61 +/- 3 mm Hg in controls. Early proximal flow rate (EPFR) was decreased to 20 +/- 1 vs. 26 +/- 2 nl/min in controls, at an unchanged single nephron filtration fraction (SNFF), indicating a reduced glomerular plasma flow (SNGPF). Preglomerular resistance (RA) was increased by 21%. In unclamped kidneys PGC was increased to 65 +/- 2 mm Hg. EPFR was increased to 32 +/- 2 nl/min, indicating, at an unchanged SNFF, an increased SNGPF. RA increased by 51%, whereas postglomerular resistance declined by 25%. The ultrafiltration coefficient was reduced by 24% in unclamped kidneys. Our results indicate that in clamped kidneys an increase of RA causes a reduction of PGC and hence a reduction of pressure at the baroreceptor site which may act as a trigger mechanism for renin release.

Topics: Animals; Disease Models, Animal; Glomerular Filtration Rate; Hypertension; Kidney; Kidney Tubules, Proximal; Rats; Renal Artery Obstruction; Saralasin

4 patients with hypertensive crisis (glomerulonephritis [n = 2], phaeochromocytoma [n = 1], reno-vascular hypertension [n = 1] combined with encephalopathy, showed a normalisation of blood-pressure up to 18 days during angiotensin-II-blockade with saralasin. Prior, blood pressure was treated insufficiently by intravenous diazoxide and Na-nitroprusside. Increased plasma-renin-activity and plasma levels of catecholamines pointed to an activation of the renin-angiotensin- and sympathico-adrenergic system. A trial of therapy with saralasin--especially, if blood-pressure response to diazoxide and sodium-nitroprusside is insufficient--could be indicated. Side-effects like pressor-reactions are excluded by very low priming doses (0,1 microgram/kg/min); rebound-hypertension at the end of the therapy is avoided by an overlapping therapy with renin suppressing drugs (beta-receptor blockers, clonidine, guanfacinum).

Topics: Adrenergic beta-Antagonists; Adult; Aged; Angiotensin II; Clonidine; Female; Furosemide; Glomerulonephritis; Humans; Hypertension; Hypertension, Renovascular; Male; Pheochromocytoma; Renin; Saralasin

Simultaneous hemodynamic and blood gas measurements were performed in 26 hypertensive adults, who were cigarette smokers, before and after a 30-minute infusion of saralasin (5 microgram/kg/min) which is a highly specific competitive antagonist of angiotensin II (AII). The arterial pressure fell in nine, rose in seven and was unchanged in ten patients. The mean cardiac index for the entire group remained unchanged. Pulmonary arterial or wedge pressure, pulmonary vascular resistance, arterial PCO2 and pH did not change. Unrelated to the hemodynamic changes, the mean arterial oxygen pressure (PaO2) increased from 68.6 +/- 2.2 mm Hg to 73.9 +/- 2.1 mm Hg (P less than 0.001). In the absence of a significant increase in alveolar ventilation as indicated by an unchanged mean PCO2 and lacking a hemodynamic explanation, the mechanism for the rise in PaO2 is speculative at this stage. The possibility of an improvement in the distribution of ventilataion by saralasin infusion is under investigation.

Topics: Adult; Aged; Angiotensin II; Carbon Dioxide; Cardiac Output; Female; Hemodynamics; Humans; Hydrogen-Ion Concentration; Hypertension; Injections, Intra-Arterial; Lung; Male; Middle Aged; Oxygen; Oxygen Consumption; Pulmonary Circulation; Saralasin; Smoking; Vascular Resistance

Topics: Adrenergic beta-Antagonists; Angiotensins; Captopril; Central Nervous System; Clonidine; Humans; Hypertension; Methyldopa; Renin; Reserpine; Saralasin; Sodium

1. The results of the Veterans Administration Co-operative Study have been extended by the subsequent clinical trials, which included patients of both sexes and with less vascular disease. The later studies confirm the effectiveness of treatment in preventing most complications except myocardial infarction and sudden death. Furthermore, the lower diastolic blood pressure in which treatment has been shown to have a significant beneficial effect has been lowered from 105 mmHg as indicated by the Veterans Study to 100 mmHg as shown by the much larger Australian trial. The possibility of reducing the incidence of sudden death and fatal myocardial infarction has been suggested by other recent control trials using beta-adrenoreceptor-blocking drugs, an approach that needs further exploration. 2. A number of interesting and useful new drugs have appeared which include tienilic acid, minoxidil, saralasin and captopril, and in addition recent controlled trials have re-emphasized the effectiveness of the old drug, reserpine, when combined with a diuretic. The art of treatment of hypertension therefore appears to be in a healthy state and we should expect more advances in the future.

Topics: Adrenergic alpha-Antagonists; Angiotensin II; Glycolates; Humans; Hydrochlorothiazide; Hypertension; Minoxidil; Pyrimidines; Reserpine; Saralasin; Ticrynafen; United States

1. The acute effects of the kallikrein inhibitor aprotinin (498 ki.u./min), and the kininase II inhibitor SQ 14,225 (250 MICROGRAM), GIVEN INTRAVEnously during saralasin-induced angiotensin blockade, were studied in conscious sham-operated rats and rats with benign and malignant two-kidney, one-clip Goldblatt hypertension during dietary sodium restriction. 2. The blood pressure of conscious sham-operated rats increased significantly in response to aprotinin. It remained unchanged after SQ 14,225 in contrast to the significant vasodepressor effect seen when SQ 14,225 was given to the same rats under surgical stress and pentobarbital anaesthesia. 3. Benignly hypertensive rats showed a consistent vasopressor response to aprotinin and a marked vasodepressor response to SQ 14,225. The effects of both inhibitors were markedly and significantly blunted in malignantly hypertensive rats. 4. Our demonstration that two agents with known opposite actions on the kallikrein-kinin system produced predictable and opposite effects on blood pressure may indicate that this system is involved in the homeostatic regulation of blood pressure. It may play an important antihypertensive role in benign two-kidney, one-clip Goldblatt hypertension, a role which might be impaired in malignant hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aprotinin; Blood Pressure; Body Weight; Captopril; Homeostasis; Hypertension; Kallikreins; Kinins; Male; Proline; Rats; Renin; Saralasin

Saralasin, 10 microgram/kg per min, caused an immediate rise in blood pressure in 52 of 57 (91.2%) hypertensive patients. The increase in diastolic pressure averaged 18.8 +/- 1.83 mm Hg (mean +/- SE) in normal renin patients on a normal salt intake. This immediate pressor response was absent in only five high renin patients and, conversely, was very large in three low renin patients. Direct arterial recordings are necessary to define the response accurately; it begins in 60--90 seconds, peaks in amplitude at 2.05 +/- 0.38 minutes, and subsides over the next 5 minutes in normal renin and high renin patients. The blood pressure elevation is inversely related to background plasma renin activity (r = -0.66, P less than 0.001), and also is directly, but weakly, related to 24-hour urinary sodium excretion (r = + 0.29). Therefore, the amplitude of the elevation is predictably diminished by the rise in plasma renin consequent to prior sodium restriction, and also by preliminary receptor exposure to low dose nonpressor infusions of saralasin itself (0.01-0.1 microgram/kg per min). Phentolamine had no effect on the response in two patients. We propose that the immediate pressor response to saralasin is related directly to the preexisting degree of vacancy of angiotensin II vascular receptors and that the initial agonistic action of the drug may prove useful in defining the angiotensin II receptor status in hypertensive diseases.

Topics: Angiotensin II; Blood Pressure; Catecholamines; Diastole; Diet, Sodium-Restricted; Humans; Hypertension; Infusions, Parenteral; Natriuresis; Phentolamine; Receptors, Angiotensin; Receptors, Cell Surface; Renin; Saralasin; Sodium; Time Factors

To determine the mechanism underlying altered adrenal responsiveness in patients with essential hypertension, the renin-angiotensin-aldosterone axis was assessed in normotensive and hypertensive subjects using three pharmacological probes: SQ 20881, a converting enzyme inhibitor; saralasin, a competitive angiotensin antagonist with prominent agonist properties; and angiotensin itself. All subjects were studied while supine and in balance on a 10 meq Na/100 meq K intake. The decrement in plasma aldosterone with SQ 20881 in 26 hypertensive subjects (15+/-3 ng/dl) was normal (13+/-4 ng/dl), suggesting that the altered adrenal responsiveness in hypertensives is not because of a change in a postreceptor event or in the relative contribution of angiotensin to the control of aldosterone secretion. Saralasin at a dose (0.1 mug/kg per min) that reduced aldosterone levels in all normals produced a normal aldosterone decrement (14+/-3 ng/dl) in 19 patients with renovascular hypertension (12+/-4 ng/dl). The same dose, however, had no net effect on plasma aldosterone levels in 70 patients with normal or high renin essential hypertension (-1+/-1 ng/dl) despite identical metabolic balance and control renin and angiotensin levels. The altered response could be explained by an agonist effect, aldosterone rising in 45 of the essential hypertensives. There were no significant differences between normal and abnormal responders in pre- and postcortisol, -potassium, -renin and -angiotensin concentrations. Angiotensin was infused (0.1-3 ng/kg per min) in 15 patients with normal renin essential hypertension, previously studied with saralasin. A probit transformation defined the dose required to induce a 50% increase in aldosterone (ED50). In the patients in whom aldosterone rose with saralasin, the dose required to induce a 50% increase was significantly greater (P < 0.001) than in those in whom aldosterone fell normally (1.02+/-0.06 [SD] vs. 0.38+/-0.07 ng/kg per min). Vascular responses were similar in the various groups. We conclude that altered adrenal responsiveness to angiotensin in some essential hypertensive patients is secondary to a change in the interaction of angiotensin with its adrenal receptor.

Topics: Adrenal Glands; Adult; Aged; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Humans; Hypertension; Hypertension, Renovascular; Middle Aged; Receptors, Angiotensin; Receptors, Cell Surface; Saralasin; Teprotide

Topics: Angiotensin-Converting Enzyme Inhibitors; Enzyme Inhibitors; Humans; Hypertension; Proline; Saralasin; Teprotide

1. Specific angiotensin II (ANGII) receptor binding was measured in regions of the brains of the New Zealand gentically hypertensive and normal rats. 2. ANGII receptor binding was consistently lower in the septum, midbrain, thalamus and posterior medulla of the genetically hypertensive rats than in normal rats. 3. Blood pressure responses to intraventricular injections of ANGII and an ANGII antagonist [Sar1,Ala8]angiotensin were studied in conscious and pentobarbitone-anaesthetized genetically hypertensive and normal rats. In conscious rats no significant difference between the two strains of rat was detected. 4. In pentobarbitone-anaesthetized rats intraventricular injection of 40 microgram of [Sar1,Ala8]angiotensin had a hypotensive effect which was three times greater in the genetically hypertensive rats than that observed in normal rats. The latency of this hypotensive effect was longer than the latency of the hypertensive effect of ANGII. 5. The drinking responses to intraventricular injections of ANGII were similar in genetically hypertensive and normal rats. 6. The physiological role of the ANGII system is discussed and it is concluded that an abnormality of this system in the brain may well be responsible for the hypertension found in the genetically hypertensive rat.

Topics: Angiotensin II; Animals; Blood Pressure; Brain; Drinking Behavior; Female; Hypertension; Male; Membranes; Phenobarbital; Rats; Receptors, Angiotensin; Receptors, Cell Surface; Saralasin

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Humans; Hypertension; Hypertension, Renovascular; Oligopeptides; Renin; Saralasin; Sodium; Teprotide

Topics: Adult; Aldosterone; Angiotensin II; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Norepinephrine; Renin; Saralasin; Sympathetic Nervous System

Topics: Aldosterone; Angiotensin II; Animals; Humans; Hypertension; Hypertension, Renal; Renin; Saralasin

Diuretic and vasodilator drugs alter the BP response to saralasin causing drug interactions. Saralasin-induced BP reduction is related directly to PRA and intravascular volume. Diuretic agents deplete intravascular volume and elevate PRA, enhancing saralasin hypotension. Vasodilating agents increase PRA and may induce angiotensin dependence of BP. Thus, with potent vasodilators, saralasin can induce hypotension. Rebound hypertension has been reported after saralasin infusion in several patients with accelerated or malignant hypertension. Theoretically, this BP elevation could be related to sustained release of renin resulting from disinhibition of an intrarenal angiotensin receptor inhibitory to renin release. Since propranolol can block saralasin-induced renin release, angiotensin and beta-blockers could constitute a beneficial drug interaction.

Topics: Angiotensin II; Angiotensins; Blood Pressure; Blood Volume; Diuretics; Drug Interactions; Humans; Hypertension; Infusions, Parenteral; Posture; Propranolol; Renin; Saralasin; Sodium; Vasodilator Agents

Topics: Adolescent; Adult; Aged; Angiotensin II; Blood Pressure; Diagnosis, Differential; Evaluation Studies as Topic; Female; Humans; Hypertension; Hypertension, Renovascular; Male; Middle Aged; Racial Groups; Radiography; Renin; Saralasin

Topics: Adolescent; Adult; Aged; Angiotensin II; Binding, Competitive; Blood Pressure; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renal; Male; Middle Aged; Natriuresis; Posture; Renin; Saralasin; Sodium; Time Factors; Vasoconstriction

Topics: Angiotensin II; Angiotensins; Binding, Competitive; Blood Pressure; Diastole; Female; Humans; Hypertension; Hypertension, Renovascular; Injections, Intravenous; Middle Aged; Posture; Radiography; Renin; Saralasin; Sodium; Stimulation, Chemical; Systole

Topics: Angiotensin II; Diastole; Furosemide; Humans; Hypertension; Hypertension, Renovascular; Infusions, Parenteral; Pressoreceptors; Renal Artery Obstruction; Renin; Saralasin; Sodium; Time Factors

Topics: Adult; Angiotensin II; Blood Pressure; Cardiac Volume; Heart Rate; Hemodynamics; Humans; Hypertension; Middle Aged; Plasma Volume; Pressoreceptors; Renal Artery Obstruction; Renin; Saralasin; Vascular Resistance

Topics: Adolescent; Angiotensin II; Blood Pressure; Child; Child, Preschool; Diagnosis, Differential; Evaluation Studies as Topic; Female; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Infusions, Parenteral; Male; Methods; Nephrectomy; Renin; Saralasin

The research environment in which saralasin was discovered has been described, and illustrations of the rationale which contributed to its synthesis, selection for development, and eventual development have been presented. As an example, the synthesis of [Sar1, Val5, Ala8]-AII (P113, saralasin) was an attempt to make an AII antagonist which would be resistant to metabolism by aminopeptidases. Subsequent evaluation, however, indicated that the substitution of sarcosine had not only protected against aminopeptidase degradation but unexpectedly also had greatly increased the octapeptide's affinity for vascular smooth muscle receptors. Finally, the laboratory demonstration of saralasin as a potential therapeutic and diagnostic entity and the clinical confirmation of use of saralasin in hypertensive patients are reviewed.

Topics: Angiotensin II; Angiotensins; Animals; Aorta; Binding Sites; Blood Pressure; Dogs; History, 20th Century; Hypertension; Muscle Contraction; Rabbits; Rats; Renin; Saralasin

Topics: Adolescent; Angiotensin II; Aortic Coarctation; Blood Pressure; Child; Child, Preschool; Humans; Hypertension; Postoperative Complications; Renin; Saralasin

1. Sixteen patients (11 male, five female), median age 41 years, with essential hypertension insufficiently controlled by hydrochlorothiazide (75 mg/day; diastolic blood pressure greater than or equal to 100 mmHg), were studied. 2. Plasma renin concentration [renin], plasma angiotensin II concentration ([ANG II]), plasma volume and exchangeable sodium (NaE) were determined, and a saralasin infusion (5.4 nmol min-1 kg-1) was carried out while the patients were on thiazide alone and, in 14 cases, 3 months after addition of a beta-adrenoreceptor blocker (propranolol, six, metoprolol, six, and atenolol, two patients). 3. On thiazide alone, saralasin caused a significant decrease in mean arterial blood pressure in 12 out of 16 patients. The saralasin response was closely related to pre-saralasin plasma [ANG II] (r = 0.73, P less than 0.01). Plasma [renin] and [ANG II] were higher than normal in the group as a whole. 4. After addition of a beta-adrenoreceptor blocker systolic and diastolic blood pressure decreased from 164/109 mmHg to 136/94 mmHg. Plasma [renin] and [ANG II] decreased by 40 and 58% respectively. At this point, saralasin caused no significant change in mean arterial pressure. No close correlation was found between plasma [renin] or [ANG II] or saralasin response on thiazide treatment and changes in blood pressure during subsequent thiazide/beta-adrenoreceptor-blocker treatment. Plasma volume and NaE did not change significantly. 5. In patients with thiazide-induced stimulation of the renin-angiotensin system, addition of a beta-adrenoreceptor blocker leads to suppression of the system and, at the same time, ANG II-dependence of blood pressure disappears. This contributes to the antihypertensive effect of beta-adrenoreceptor blockers in this particular situation.

Topics: Adult; Angiotensin II; Atenolol; Blood Pressure; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Metoprolol; Plasma Volume; Propanolamines; Propranolol; Renin; Saralasin; Sodium

Topics: Angiotensin II; Electrolytes; Female; Humans; Hypertension; Hypokalemia; Male; Renin; Saralasin

Among the newer antihypertensive agents are the beta-blocking drugs, such as propranolol. These agents are useful as second-step drugs to be used if diuretic therapy alone is not effective. In mild to moderately severe hypertension, propranolol, in does of up to 480 mg/day in combination with a thiazide diuretic, has been found to be effective in over 80% of patients on long-term therapy. This degree of response is essentially similar to that noted with a combination of reserpine and a diuretic agent. Although some observers believe that propranolol produces many fewer side effects than the other step 2 drugs (reserpine and alpha-methyldopa), there are some patients who do experience restlessness, insomnia, and depression. Clonidine may be substituted for another step 2 drug, is of moderate potency, but may not be tolerated by a large number of patients because of the severe dry mouth and drowsiness that it produces. Prazosin appears to be a suitable substitute for hydralazine as an effective vasodialator if thiazides plus propranolol or thiazides plus reserpine or alpha-methyldopa are not effective. In some instances, it many be an acceptable second-step drug because of its alpha-adrenoreceptor-blocking properties. The angiotensin II competitive inhibitors or converting enzyme inhibitors may in the future have some place in the management of hypertension.

Topics: Angiotensin II; Clonidine; Diuretics; Humans; Hypertension; Minoxidil; Prazosin; Propranolol; Saralasin; Vasodilator Agents

The development of malignant hypertension was studied in stroke-prone spontaneously hypertensive rats (SHR) kept on 1% NaCl as drinking water. Along with salt-loading, blood pressure gradually increased and reached a severe hypertensive level (greater than 230 mmHg), which was followed by increases in urinary protein (greater than 100 (mg/250 g body wt)/day) and plasma renin concentration (PRC, from 18.9 +/- 0.1 to 51.2 +/- 19.4 (ng/ml)/h, mean +/- SD). At this stage, renal small arteries and arterioles showed severe sclerosis and fibrinoid necrosis. Stroke was observed within a week after the onset of these renal abnormalities. The dose of exogenous angiotensin II (AII) producing 30 mmHg rise in blood pressure increased with the elevation of PRC, from 22 +/- 12 to 75 +/- 36 ng/kg, which was comparable to that in rats on water. The fall of blood pressure due to an AII inhibitor, [1-sarcosine, 8-alanine]AII (10(microgram/kg)/min for 40 min) became more prominent with the increase in PRC in salt-loaded rats, but was not detected in rats on water. These findings suggest that the activation of renin-angiotensin system participates in malignant hypertension of salt-loaded stroke-prone SHR rats that show stroke signs, proteinuria, hyperreninemia, and renovascular changes.

Topics: Angiotensin II; Animals; Blood Pressure; Diet; Hypertension; Hypertension, Malignant; Kidney; Male; Rats; Renin; Saralasin; Sodium Chloride; Vascular Resistance

Topics: Adolescent; Adult; Angiotensin II; Blood Pressure; Dose-Response Relationship, Drug; Humans; Hypertension; Hypertension, Renal; Middle Aged; Renin; Saralasin; Sodium

The saralasin test was performed in 68 hypertensives. A clear-cut dependence of the test results on initial plasma-renin concentration and particular sodium balance was demonstrated. Because of this dependence the saralasin test should be performed only under constant conditions. A mild stimulation of the renin-angiotension system by salt restriction to a mean sodium excretion of 50 mmol daily and 80 mg furosemide by mouth 12 hours before the test seems best. In this way essential and renovascular hypertension could be distinguished with considerable reliability (P less than 0.001). Among patients with essential hypertension one could clearly separate those with high plasma-renin concentration from those with a normal or low one. Among patients with renovascular hypertension those with haemodynamically significant renal artery stenosis could with high probability be distinguished from those with non-effective stenosis. A positive saralasin test without testing the function of the normal contralateral kidney does not provide an indication for operation.

Topics: Adult; Aged; Angiotensin II; Diagnosis, Differential; Furosemide; Humans; Hypertension; Hypertension, Renal; Middle Aged; Renin; Saralasin

Topics: Adult; Angiotensin II; Diuretics; Female; Furosemide; Humans; Hydrochlorothiazide; Hypertension; Male; Plasma Volume; Posture; Renin; Saralasin; Sodium; Sodium Chloride Symporter Inhibitors

Adrenal responsiveness to angiotensin II (AII) and the diastolic blood pressure responses to saralasin were studied in 19 patients with high renin essential hypertension (HREH) on a 10-meq Na(+)/100 meq K(+) diet. The increment in plasma renin activity (PRA) between supine and upright positions was used as an estimate of the acute stimulation of the adrenal gland by endogenous AII; the normal increment in plasma aldosterone divided by the increment in PRA was >3.8. 7 of 19 had abnormal upright posture responses with significantly greater mean PRA increments (24+/-6 ng/ml per h) and significantly smaller plasma aldosterone increments 47 +/- 16 ng/dl) (P < 0.036) compared to the increments observed in HREH patients with normal adrenal responsiveness (PRA = 15 +/- 1 ng/ml per h; plasma aldosterone = 87 +/- 17 ng/dl). When AII was infused at doses of 0.1-3 ng/kg per min, only patients with normal posture responses had normal plasma aldosterone increments; plasma aldosterone levels failed to significantly increase even at the highest infusion rate in the patients with the abnormal upright posture responses. The AII competitive inhibitor, saralasin (0.3-30 mug/kg per min) was then infused to study the occurrence of angiotensinogenic hypertension in both HREH subgroups. The mean decline in diastolic blood pressure to saralasin in the subnormal adrenal responsive patients (-15 +/- 3 mm Hg) was significantly greater than in the normal adrenal responsive group (-3 +/- 2 mm Hg) (P < 0.02).It is concluded that patients with HREH are not a homogeneous population; approximately one-third have AII-dependent hypertension. In these patients, the mechanism responsible for the elevated renin and blood pressure could be a compensatory increase secondary to decreased adrenal responsiveness to AII. In the remainder, the high PRA levels have little, if any, causal role in the pathogenesis of the hypertension but could reflect a marker of other pathophysiologic processes.

Topics: Adrenal Cortex; Adrenal Cortex Function Tests; Adult; Aldosterone; Angiotensin II; Blood Pressure; Depression, Chemical; Female; Humans; Hypertension; Male; Middle Aged; Posture; Renin; Saralasin

Topics: Acebutolol; Adolescent; Adult; Aldosterone; Angiotensin II; Blood Pressure; Diet; Heart Rate; Humans; Hypertension; Middle Aged; Natriuresis; Posture; Renal Veins; Renin; Saralasin

Topics: Adult; Age Factors; Aldosterone; Amino Acid Sequence; Angiotensin II; Angiotensins; Female; Humans; Hyperaldosteronism; Hypertension; Hypertension, Renovascular; Kinetics; Male; Middle Aged; Renin; Saralasin; Sodium

The effects on arterial pressure of saralasin and short-term (seven days) administration of the cardioselective beta-blocker atenolol were compared in 21 patients with various forms of hypertension. During saralasin administration mean arterial pressure (MAP) decreased by 8.8 +/- 2.1 per cent. Atenolol administration was associated with a MAP fall of 23.6 +/- 2.9 per cent. The change in MAP induced by atenolol was higher than that produced by saralasin (P less than 0.001) and no significant correlation (r = 0.40, P greater than 0.05) between their respective effects was found. These results suggest that the antihypertensive action of atenolol is not related to pre-treatment activity of the renin-angiotensin system as estimated by the hypotensive effect of saralasin. Other mechanisms should be sought in order to explain the effectiveness of this betablocker in hypertensive patients.

Topics: Adult; Angiotensin II; Antihypertensive Agents; Atenolol; Female; Humans; Hypertension; Male; Middle Aged; Propanolamines; Renin; Saralasin

Saralasin (S) infusion, at a dose of 10 micrograms/kg/min IV, decreased Glomerular Filtration Rate (GFR) in 18 hypertensive patients. This effect was more pronounced in those patients with angiotensinogenic hypertension due to the somation of the effects of S upon renal vasculature and systemic arterial pressure. A decrease in urinary sodium excretion was also observed being more intense in those patients whose systemic pressure also decreased during S infusion. In group II (10 hypertensive patients) infusion of S in increasing doses (0.1, 0.5, 1.0, 5.0 and 10.0 micrograms/kg/min) a progressive decrease in GFR was observed only when the arterial pressure also decreased. However urinary sodium excretion decreased progressively as S doses increased. This effect was not related to S effect upon arterial pressure. This observation indicates that S, like angiotensin II, has a direct effect upon the renal tubules evoking an increase of sodium reabsorption.

Topics: Angiotensin II; Blood Pressure; Creatinine; Glomerular Filtration Rate; Humans; Hypertension; Kidney Tubules; Potassium; Saralasin; Sodium

Topics: Angiotensin II; Blood Pressure; Humans; Hypertension; Hypertension, Renovascular; Renin; Saralasin; Sodium

The hypothesis that increased plasma-renin tends to lower blood-pressure is proposed. Binding of renin to blood-vessel walls is postulated to have some vasodilator action which would oppose the usual blood-pressure-raising action caused by generation of angiotensin. Many of the effects of saralasin and of converting-enzyme inhibitor on blood-pressure in relation to concentrations of renin in blood plasma and in the kidneys seem to support this hypothesis.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Humans; Hypertension; Kallikreins; Kidney; Mice; Rats; Renin; Saralasin; Teprotide; Vasodilator Agents

1. In plasma samples from normal subjects and patients with untreated essential hypertension, the concentration of inactive renin (as measured after acidification) was on average 4-5 times higher than the concentration of active renin (as measured without acidification).2. Plasma angiotensin II concentration was correlated to active renin but not to inactive renin. 3. A hyperacute stimulation induced by infusion of saralasin resulted in a marked rise of active renin, whereas inactive renin remained unchanged. 4. An acute stimulation induced by frusemide and ambulation led to a considerable rise in active renin and a slight, but significant, rise of inactive renin. 5. Stimulation with oral thiazide over 5 days induced a seven-fold rise of active renin, with a doubling of inactive renin. Thiazide treatment for 3 months led to a four-fold rise of active renin and a three-fold rise of inactive renin. 6. There was no difference between the concentrations of inactive renin in systemic plasma, ipsilateral and contralateral renal venous plasma in 12 patients with renovascular hypertension, neither before nor after infusion of saralasin with the associated fall in blood pressure. 7. We conclude that the time constants pertinent to secretion or release of active and inactive renin in man are of different orders of magnitude.

Topics: Benzothiadiazines; Diuretics; Enzyme Activation; Humans; Hypertension; Hypertension, Renovascular; Kidney; Renin; Saralasin; Sodium Chloride Symporter Inhibitors

Topics: Angiotensin II; Blood Pressure; Diagnosis, Differential; Diastole; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Renin; Saralasin

1. The pressor role of renin stimulated by chronic diuretic therapy has been assessed in 31 patients with essential hypertension by infusing the angiotensin II antagonist, saralasin, immediately before and at the end of 2 weeks' treatment with the diuretic, chlorthalidone. 2. Under diuretic therapy the change in blood pressure caused by saralasin was found to be correlated to plasma renin activity values, in such a way that small pressor responses were again observed in patients whose renin was mildly stimulated by the diuretic, whereas a marked depressor response occurred in patients whose renin was markedly increased. 3. On the other hand, the hypotensive effect of chlorthalidone was correlated to values of plasma renin activity under diuretic therapy in an opposite direction: indeed little or no decrease and sometimes an increase in blood pressure were observed in patients with marked renin activation by diuretic therapy. 4. It is concluded that stimulation of renin release by chronic diuretic therapy can be considered a factor limiting the hypotensive activity of diuretic drugs.

Topics: Adult; Aged; Angiotensin II; Blood Pressure; Chlorthalidone; Heart Rate; Humans; Hypertension; Middle Aged; Renin; Saralasin

Topics: Adult; Aldosterone; Angiotensin II; Benzothiadiazines; Blood Pressure; Diuretics; Female; Humans; Hypertension; Male; Renin; Saralasin; Sodium Chloride Symporter Inhibitors

To define the role of the renin-angiotensin system in post-transplantation hypertension we studied 12 hypertensive recipients of renal transplants. The patients received saralasin acetate, an angiotensin II antagonist, while on a normal sodium diet and again after seven days of sodium restriction. In six patients with only one kidney, saralasin did not lower blood pressure on either diet; salt depletion did not lower systolic or diastolic blood pressures. In six patients with more than one kidney, salt depletion also did not lower blood pressure; however, salt depletion plus saralasin lowered their systolic pressures from a mean (+/- S.E.M.) of 146 +/- 9 to 128 +/- 8 mm Hg, and mean diastolic pressures fell from 103 +/- 5 to 89 +/- 5 (P less than 0.001). In four of five patients renal-vein renin activity was greater in one or more host kidneys than in the transplant kidney (or kidneys). Although pre-transplant blood pressure was the same in both groups, post-transplantation hypertension is more likely to be angiotensin II-dependent in patients with more than one kidney.

Topics: Adolescent; Adult; Aldosterone; Angiotensin II; Blood Pressure; Diet; Female; Humans; Hypertension; Infusions, Parenteral; Kidney; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Renal Veins; Renin; Saralasin; Sodium; Transplantation, Homologous

Topics: Adult; Aged; Angiotensin II; Chlorthalidone; Diuretics; Drug Therapy, Combination; Hemodynamics; Humans; Hypertension; Middle Aged; Renin; Saralasin

Angiotensin antagonists have proved useful in elucidating the clinical role of the renin-angiotensin system; and their diagnostic and therapeutic efficacy in hypertension has been the subject of many reports but the hemodynamic effects remain unknown. Therefore, saralasin was infused intravenously (1.3 mg/min for 30 min) in 26 sodium-depleted patients with hypertension. Systemic hemodynamic alterations were determined before, during, and after infusion. On the basis of mean arterial pressure (MAP) changes, patients were classified as responders, nonresponders, or pressorresponders (MAP changes greater than or equal to 10 mm Hg). MAP fall in responders was achieved through reduced cardiac output and/or total peripheral resistance, with minimal or absent reflexive heart rate increase. In nonresponders, despite no change in MAP, output fell in parallel with stroke index and left ventricular ejection rate, In pressorresponders, saralasin increased vascular resistance. Thus, in addition to variable effects on vascular receptors, saralasin produced inhibitory cardiac effects either through altered venous return or inhibition of contractility.

Topics: Adult; Aged; Angiotensin II; Blood Pressure; Cardiac Output; Female; Heart Rate; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Saralasin; Vascular Resistance

The effect of saralasin, a clinically employed angiotensin antagonist, upon hemodynamics and plasma catecholamine concentration was compared to the infusion of noradrenaline. These studies were carried out to determine if a transient pressor effect frequently observed during saralasin infusion might be mediated by release of catecholamines from the adrenal medulla. After five minutes of saralasin infusion, mean arterial pressure rose significantly, pulse rate fell slightly, and plasma noradrenaline increased by 115 +/- 28 pg./ml. Plasma adrenaline was unchanged. After 30 minutes of saralasin infusion, mean arterial pressure was at control levels and plasma catecholamine concentrations were also no different from pre-infusion levels. Infusion of noradrenaline produced a hemodynamic pattern similar to that observed during the first five minutes of saralasin infusion. However, there was a thirteen-fold increase of plasma noradrenaline observed when compared to the first five minutes of saralasin infusion. It was concluded that the transient pressor action of saralasin could not be explained by release of catecholamines from the adrenal medulla. However, the very slight increase in plasma norepinephrine observed during the first five minutes of saralasin infusion may imply altered function of sympathetic neurons.

Topics: Angiotensin II; Blood Pressure; Epinephrine; Heart Rate; Humans; Hypertension; Norepinephrine; Saralasin; Stimulation, Chemical; Time Factors

Hypertension in patients on chronic hemodialysis is thought to be largely of two types--volume dependent or renin dependent. If renin-dependent hypertension is mediated by angiotensin II, then angiotensin II antagonism should lower blood pressure. To test this hypothesis, the angiotensin II antagonist saralasin was given to 15 hypertensive patients on chronic hemodialysis. Patients were separated into two groups by their blood pressure response. In responders blood pressure was 191/112 mm Hg and fell to 147/85 during saralasin administration (P less than 0.01). In contrast, nonresponders had blood pressures of 190/111 mm Hg before and 188/110 during saralasin administration. Five responders subsequently ahd nephrectomies with normalization of their blood pressures. Plasma renin activity averaged 70 ng/ml . 3 h of angiotensin I in responders and increased to 110 after saralasin (P less than 0.05), while nonresponders had values of 21 before and after saralasin. These results offer strong support for the hypothesis that renin-dependent hypertension is an important mechanism in certain patients on chronic hemodialysis and that such patients will respond to angiotensin II antagonism.

Topics: Adolescent; Adult; Angiotensin II; Blood Pressure; Female; Humans; Hypertension; Male; Nephrectomy; Renal Dialysis; Renin; Saralasin

A radioimmunoassay for the angiotensin II-inhibitor saralasin has been developed. The assay is based upon an exploitation of the cross-reactivity of antisera raised against angiotensin II, with radioiodinated saralasin as the tracer peptide. Performance data for the assay and results obtained in clinical infusion studies are presented.

Topics: Angiotensin II; Cross Reactions; Humans; Hypertension; Immune Sera; Infusions, Parenteral; Radioimmunoassay; Saralasin

1. Angiotensin II blockade before and after marked sodium depletion in patients with hypertension [unilateral renovascular (eight), bilateral renovascular (four) and essential (four)] was performed by intravenous administration of the angiotensin II antagonist Sar1-Ala8-angiotensin II (saralasin). 2. On normal sodium intake, saralasin decreased mean blood pressure by 8 mmHg in the unilateral renovascular group, by 6 mmHg in the bilateral renovascular group and increased it by 3 mmHg in the essential hypertensive group. After sodium depletion saralasin decreased mean blood pressure by 33 mmHg, 35 mmHg and 18 mmHg respectively. The saralasin-induced decrease in blood pressure significantly correlated with the log of the initial plasma renin activity. 3. Saralasin infusion decreased effective renal plasma flow (ERPF) in all three hypertension subgroups, both on normal sodium intake and after sodium depletion. Glomerular filtration rate decreased in direct relation to the hypotensive effect of saralasin but ERPF showed this relationship only after sodium depletion. On normal sodium intake saralasin increased filtration fraction by 17%, but decreased it by 7% after sodium depletion. 4. It is concluded that the hypotensive action of saralasin closely correlates with the value of circulating plasma renin activity, apparently independent of the aetiology of the hypertension. The decrease in ERPF during saralasin infusion in the patients on normal sodium intake seems mainly related to the agonistic activity of saralasin, but that after sodium depletion to the hypotensive effect of saralasin.

Topics: Adult; Angiotensin II; Blood Pressure; Female; Hemodynamics; Humans; Hypertension; Hyponatremia; Kidney; Male; Middle Aged; Renin; Saralasin

Topics: Blood Pressure; Diuretics; Drug Interactions; Humans; Hypertension; Polythiazide; Renin; Saralasin; Sodium Chloride Symporter Inhibitors

Topics: Adult; Aldosterone; Angiotensin II; Blood Pressure; Female; Furosemide; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Potassium; Renin; Saralasin; Sodium

Topics: Adolescent; Adult; Angiotensin II; Blood Pressure; Blood Volume; Diet; Female; Humans; Hypertension; Male; Middle Aged; Renal Dialysis; Renin; Saralasin; Sodium

Topics: Angiotensin II; Humans; Hypertension; Hypertension, Renal; Saralasin

A 10 mg bolus of the angiotensin blocker saralasin was injected 113 times in 68 subjects with essential or renovascular hypertension. Ninety percent of injections caused a transient increase in blood pressure, which correlated with plasma renin activity (PRA) (r = -0.54); Mean increase at 2 minutes was 21/13.4 mm Hg (P less than 0.001) and was independent of pre-injection control blood pressure, with a rapid decrease to or below control values thereafter. Thirty-seven subjects were studied on successive days before and after furosemide-induced sodium depletion (152 +/- 26 mEq [SE] sodium loss). In the low renin group, sodium depletion did not change PRA or the magnitude of the pressor response to saralasin, but significantly decreased control MAP by 13 mm Hg (P less than 0.01). In normal and high renin patients, MAP was unchanged after diuresis, but PRA increased significantly and the pressor response was attenuated. The net effect of sodium depletion was to reduce the pressor response to saralasin in all renin subgroups by 9 to 12 mm Hg. Saralasin bolus injection, unlike infusion, saturates available vascular receptors only briefly, eliminating prolonged pressor responses.

Topics: Adolescent; Adult; Angiotensin II; Blood Pressure; Child; Female; Humans; Hypertension; Male; Middle Aged; Pressoreceptors; Renin; Saralasin; Sodium; Time Factors

The effect of an angiotensin II antagonist (saralasin) on arterial pressure, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was assessed in seven dialysis-resistant hypertensive patients. During saralasin infusion performed before hemodialysis, mean arterial pressure fell by 8 to 18.3% in six out of the seven subjects; arterial pressure was normalized in three of them. After hemodialysis (6 subjects), a normal arterial pressure was achieved in five patients. One patient was resistant to saralasin before and after dialysis. A negative correlation (r = 0.62) was obtained between pre-infusion PRA and the change in mean arterial pressure induced by saralasin. Post-infusion PRA increased in saralasin responsive patients, the change in PRA being correlated (r = 0.82) with the pre-infusion PRA. Plasma aldosterone concentration was variably affected by saralasin; a negative correlation between pre-infusion PAC and the absolute change in PAC during saralasin was obtained (r = 0.72). The role of angiotensin II in the maintenance of a high arterial pressure in chronic dialysis patients was demonstrated. In saralasin-resistant patients, more vigorous ultrafiltration is proposed.

Topics: Adult; Aldosterone; Angiotensin II; Blood Pressure; Female; Filtration; Humans; Hypertension; Male; Middle Aged; Renal Dialysis; Renin; Saralasin

We have studied the effects of intravenous infusion of saralasin, a competitive antagonist of angiotensin II, in 27 hypertensive patients: 13 had essential hypertension, 14 had renal lesions which involved the renal artery in 9 cases. In essential hypertensives saralasin administration did not significantly lower blood pressure, even after mild salt depletion. It induced a decrease in blood pressure in 7 patients with renal abnormalities (5 with renal artery stenosis, 2 with unilateral parenchymal disease). It may be suggested that in these cases hypertension was dependent, at least partly, on the renin-angiotensin system. In agreement with other investigators, we have found a relationship between the level of plasma renin activity and the blood pressure decrease obtained by saralasin. In patients with unilateral renal artery stenosis, blood pressure decrease was related to renal vein ratio of plasma renin activity.

Topics: Adult; Angiotensin II; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Renal Artery Obstruction; Renin; Saralasin

Under inactin anesthesia, intravenous infusion of [Sar1,Thr8]angiotensin II produced a hypotensive effect in young spontaneously hypertensive rats (SHR) treated with furosemide and in mature SH rats fed a low-sodium diet. The angiotensin antagonist also lowered blood pressure of young and mature SH rats receiving a normal diet. Deoxycorticosterone acetate (DOCA) plus saline reversed the hypotensive effect of [Saru,Thr8]angiotensin II in young SH rats, but did not do so in mature SH rats. Plasma renin activity (PRA) was not significantly changed by anesthesia. Furosemide or the low-sodium diet significantly increased PRA in young and mature SH rats. In contrast, DOCA plus saline significantly reduced PRA in both young and mature SH rats. However, there was no correlation between PRA and the action of the angiotensin II antagonist. These data suggest that the renin-angiotensin system is involved in genetic hypertension.

Topics: Aging; Angiotensin II; Animals; Blood Pressure; Desoxycorticosterone; Diet, Sodium-Restricted; Hypertension; Infusions, Parenteral; Rats; Renin; Saralasin; Sodium

The angiotensin II (AII) antagonist [Sar1-Ala8]AII (Saralasin) was injected into the brain ventricles (IVT) and intravenously (IV) in five different types of hypertensive unanesthetized rats. Renal hypertension was studied 16-22 days after kidney clipping. Intravenous infusions of cumulative doses (0.1-100 microgram/kg per min) and IVT injections (5-40 microgram) of Saralasin did not change mean arterial pressure (MAP) in controls and in one-clip, one-kidney Goldblatt hypertension, whereas MAP decreased in one-clip, two-kidney Goldblatt hypertension following IV and IVT Saralasin. In two-clip, two kidney hypertensive rats, IVT Saralasin decreased MAP but was ineffective when infused IV. Both IV and IVT Saralasin increased MAP in DOC hypertension. In spontaneously hypertensive (SH) rats, IV Saralasin increased MAP; IVT injection decreased MAP. The effect of IVT Saralasin in SH rats persisted 15-20 h after nephrectomy. We conclude that plasma AII may contribute to peripheral and central mechanisms of blood pressure regulation. The dissociation of the effects of IV and IVT Saralasin and the persistance of blood pressure decrease in nephrectomized SH rats following IVT Saralasin further support a role for locally formed brain angiotensin.

Topics: Angiotensin II; Animals; Blood Pressure; Desoxycorticosterone; Female; Hypertension; Hypertension, Renal; Injections, Intravenous; Injections, Intraventricular; Male; Rats; Renin; Saralasin

Transient hypertension occurred in 3 patients shortly after blunt injury to the abdomen. Renal trauma was suspected in all 3 patients and radiological evidence for renal injury was present in 2. Plasma renin activity definitely was elevated in 1 patient and probably was elevated in another. There was a decrease in blood pressure in all 3 patients during infusion of the angiotensin II analogue--saralasin--showing that the hypertension in these patients was angiotensin-mediated. Renal function as reflected by the blood urea nitrogen, creatinine and electrolytes was not impaired significantly. Thus, acute hypertension after blunt abdominal trauma may be angiotensinogenic and is not necessarily sustained.

Topics: Adult; Angiotensin II; Blood Pressure; Humans; Hypertension; Kidney; Male; Nitroprusside; Renin; Saralasin; Wounds, Nonpenetrating

The mechanism by which the angiotensin converting enzyme inhibitor, teprotide (SQ 20881), lowers blood pressure was assessed in anesthetized normotensive and spontaneously hypertensive (SHR) rats. Teprotide always was administered at a maximally effective dose of 1 mg/kg. In six normal Wistar rats, teprotide lowered blood pressure only after sodium depletion, an effect which was abolished by bilateral nephrectomy. Saralasin infusion (5 microgram/kg/min) into salt-depleted normal rats induced a blood pressure effect similar to that of teprotide. When administered in addition to saralasin infusion, teprotide did not reduce blood pressure further in normal rats or in SHR. When blood pressure of normal rats was raised by angiotensin II infusion (200 ng/kg/min), teprotide did not affect the induced blood pressure increase. In contrast, the pressure rise induced by angiotensin I infusion (230 ng/kg/min) was reversed by saralasin, but again concomitant administration of teprotide did not induce further blood pressure reduction. Thus, under the particular conditions of the present study, teprotide did not appear to exert its hypotensive effect by any mechanism other than inhibition of the renin-angiotensin system. Furthermore, given at a maximally effective dose to the rat, it produced no greater vasodepressor effect than did saralasin.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Depression, Chemical; Drug Interactions; Female; Hypertension; Nephrectomy; Oligopeptides; Rats; Saralasin; Sodium Chloride; Teprotide

Topics: Angiotensin II; Blood Pressure; Female; Humans; Hypertension; Middle Aged; Phentolamine; Saralasin

Plasma renin activity (PRA) and concentration, measured after acid treatment of the plasma (PRC3.3), were determined on the same plasma samples in different conditions. Log PRA and log PRC3.3 were significantly (P less than 0.001) and similarly related to sodium intake, age, and plasma aldosterone concentration in normal subjects. The correlation coefficient between log PRA and log PRC3.3 was 0.49 in 80 sodium-replete and sodium-deplete normal subjects, and it was 0.84 in 84 hypertensive patients untreated or under treatment with thiazides. On the contrary, during beta adrenergic blockade, PRA decreased significantly (P less than 0.001) by 62% while the changes in PRC3.3 were not significant. At maximal exercise, PRA increased significantly by 168% while the PRC3.3 increase of 24% was not significant. In hypertensive patients with unilateral renal artery stenosis the ipsilateral renal vein/artery ratio was higher for PRA (2.46) than for PRC3.3 (1.56), whereas both ratios on the controlateral side were similar and close to one (1.14 and 1.06). The conditions in which PRA and PRC3.3 determinations are concordant or discordant are discussed.

Topics: Adult; Age Factors; Aged; Aldosterone; Angiotensin II; Diet; Diet, Sodium-Restricted; Female; Humans; Hypertension; Male; Metoprolol; Middle Aged; Physical Exertion; Renal Artery Obstruction; Renal Veins; Renin; Saralasin

Topics: Angiotensin II; Blood Pressure; Humans; Hypertension; Renin; Saralasin

Topics: Aldosterone; Angiotensin II; Blood Pressure; Diet, Sodium-Restricted; Humans; Hypertension; Renin; Saralasin

A central stimulatory effect of angiotensin II (AII) on the secretion of arginine-vasopressin (AVP) has been described. The competitive blocker of AII, saralasin (SAR) has been used for diagnostic purposes in angiotensin-dependent hypertension. In addition SAR has a partially agnoistic effect. The aim of the present study was to demonstrate whether AVP-levels can be influenced during SAR-induced renin stimulation. In 9 patients with essential hypertension blood pressure dropped significantly under SAR (10 microgram/kg/min over a 30 min period). Before and after SAR plasma renin activity (PRA) and AVP were measured by RIA, SAR evoked significantly increments of PRA in all patients and of AVP in 6 patients. The increased serum concentrations of AVP following SAR may be explained either by the depressor effect of SAR, its diminished concentration at the central receptor, or a partial AII-agonistic effect.

Topics: Adolescent; Adult; Angiotensin II; Arginine Vasopressin; Female; Humans; Hypertension; Male; Middle Aged; Renin; Saralasin; Stimulation, Chemical; Vasopressins

1-Sar-8-ala-angiotensin II did not change intra-arterial pressure in 25 sodium replete hypertensive patients, whilst the pressure changes were closely related to the plasma renin level during sodium depletion (r = -0.87; n = 32). The study indicates that arterial pressure is not dependent on angiotensin II in sodium replete patients and in sodium deplete subjects with low PRC, while it is angiotensin dependent during sodium depletion in the others. Plasma renin is unaffected in sodium replete subjects, but increases during saralasin in sodium deplete conditions. Saralasin stimulates aldosterone secretion only in sodium replete patients.

Topics: Adult; Aldosterone; Angiotensin II; Blood Pressure; Diet; Female; Humans; Hypertension; Male; Renin; Saralasin; Sodium

Topics: Adult; Aged; Aldosterone; Angiotensin II; Antihypertensive Agents; Blood Pressure; Clonidine; Female; Humans; Hypertension; Male; Middle Aged; Renin; Saralasin

Topics: Adolescent; Adult; Aldosterone; Angiotensin II; Blood Pressure; Female; Humans; Hypertension; Hypertension, Renal; Kidney; Male; Middle Aged; Receptors, Angiotensin; Renal Artery Obstruction; Renin; Saralasin

In 34 patients saralasin was infused after variable degrees of sodium depletion in order to differentiate between essential and renin-induced hypertension. After sodium-depletion of short duration mean arterial pressure dropped more than 10 mm Hg in 9 of 25 patients with essential and in 7 of 9 patients with renin-induced hypertension. After long-lasting sodium depletion the fall of mean arterial pressure exceeded 10 mm Hg in 11 of 16 patients with essential and in 8 of 9 patients with renin-induced hypertension. Thus saralasin did not discriminate essential and renin-induced hypertension. Also, plasma renin concentration before and after saralasin did not allow to differentiate between the two forms of hypertension. The changes of renin during infusion of saralasin was negatively correlated to the change of blood pressure. Renal vein renin ratio in patients with renovascular hypertension was not modified by saralasin. Renin and aldosterone changed inversely during saralasin infusion.

Topics: Aldosterone; Angiotensin II; Blood Pressure; Humans; Hypertension; Hypertension, Renal; Renin; Saralasin

Topics: Acebutolol; Adult; Aldosterone; Angiotensin II; Blood Pressure; Female; Half-Life; Humans; Hypertension; Kallikreins; Kidney Neoplasms; Renin; Saralasin

Topics: Angiotensin II; Animals; Blood Pressure; Dogs; Humans; Hypertension; Oligopeptides; Propranolol; Saralasin; Teprotide

Hemodynamic measurements were obtained before and after 30 minutes of saralasin infusion in 26 fasting adults with hypertension (25 men and 1 woman). Nine showed a depressor response with a decrease in mean intaarterial pressure greater than 20 mm Hg. Ten were nonresponders and seven had an agonistic response with an increase in mean arterial pressure of greater than 10 mm Hg. Heart rate, pulmonary arterial and wedge pressures and pulmonary vascular resistance were nearly identical in the three groups and remained unchanged. Cardiac index decreased from a mean of 2.76 +/- 0.14 (standard error of the mean) to 2.48 +/- 0.1 liters/min per m2 in the nonresponders (P less than 0.02) but remained unchanged in the groups with a depressor or an agonistic response. The mean systemic vascular resistance decreased from 2,406 +/- 303 to 1,839 +/- 265 dynes sec/cm5 in the group with a depressor response (P less than 0.001) and increased in nonresponders (less than 0.02) and those with an agonistic response (P less than 0.01). However, regardless of the response of mean arterial pressure, systemic vascular resistance decreased only in the 10 patients with a plasma renin activity greater than 5 ng/ml per hour (8 from the depressor response group and 1 each from the nonresponse and agonistic response groups). It is concluded that (1) classification based soley on the response of aterial pressure to saralasin ignores important hemodynamic changes; (2) the response of cardiac index--no change in the patients with a depressor response and a reduction in nonresponders--suggests that endogenous angiotension II supports cardiac output in these groups; (3) a decrease in systemic vascular resistance is better than a decrease in mean arteiral pressure as a predictor of the status of the plasma renin activity; and (4) lack of change in pulmonary vascular resistance suggests that endogenous angiotension II plays an insignificant role in maintaining the resistance of the pulmonary vasculature.

Topics: Adult; Aged; Angiotensin II; Blood Pressure; Cardiac Output; Evaluation Studies as Topic; Female; Heart Rate; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Pulmonary Circulation; Renin; Saralasin; Vascular Resistance

Topics: Angiotensin II; Extracellular Space; Humans; Hypertension; Middle Aged; Propranolol; Renin; Saralasin; Sodium; Vasoconstriction

This study was carried out to assess the influence of saralasin (SAR), an angiotensin II-analogue, on peripheral and central angiotensin II-receptors by measurements of plasma renin activity (PRA) and arginine-vasopressin (AVP) release. Before and during i.v. infusion of 10 microgram/kg/min of SAR over a 30 minute period, blood samples were obtained from 15 recumbent hypertensive patients (7 renovascular, 8 essential) to determine hormone activities by radioimmunoassay. In 10 patients with a decrease of blood pressure following SAR, PRA increased significantly whereas AVP levels increased significantly in only 7 of these patients. In the remaining 5 patients without a fall of blood pressure, PRA and AVP remained virtually unchanged. The results indicate that an enhanced AVP release may be due to a hypotensive stimulus induced by SAR in angiotensinogenic hypertension. A direct influence of SAR on central receptors is unlikely under the conditions studied.

Topics: Adolescent; Adult; Angiotensin II; Arginine Vasopressin; Female; Humans; Hypertension; Hypertension, Renovascular; Male; Middle Aged; Receptors, Angiotensin; Renin; Saralasin

The blood pressure response to the angiotensin II analog 1-sar-8-ala-angiotensin II, or saralasin, was studied in five patients with clinical and laboratory evidence of Cushing's syndrome. Plasma renin activity, plasma renin substrate, and plasma renin concentration were measured in all five patients. The renin system and the response to saralasin were measured after furosemide administration. Plasma aldosterone was measured after infusion of 2 liters normal saline. All patients studied showed a hypotensive response to saralasin, the mean BP changing from 163/108 mm Hg to 130/85 mm Hg (P less than 0.02). There was a significant elevation of the plasma renin activity and plasma renin concentration in the patients compared to normal subjects, although plasma renin substrate was not significantly different from normal values. There was normal suppression of plasma aldosterone after the infusion of 0.9% saline. The findings indicate that the hypertension of these patients with Cushing's syndrome was mediated in large part by angiotensin II.

Topics: Adrenal Glands; Adrenalectomy; Adult; Aldosterone; Angiotensin II; Angiotensinogen; Blood Pressure; Cushing Syndrome; Female; Humans; Hydrocortisone; Hypertension; Male; Middle Aged; Renin; Saralasin

An immediate pressor response to [Sar1-Ala8]-angiotensin II (saralasin) is described in all of 16 hypertensive subjects. Blood pressure rose within 1-3 min, peaked at 4-6 min, then returned toward baseline. Plasma norepinephrine and dopamine beta-hydroxylase activity were unchanged by saralasin, indicating that the pressor response is not mediated by saralasin-induced catecholamine release. Ten normal renin hypertensives had diastolic pressor responses of 19.4 +/- 3.3 mm Hg. After 5 weeks of diuretic therapy, the diastolic pressor responses to saralasin were decreased to 4.9 +/- 2.4 mm Hg. Six low renin hypertensives had diastolic pressor responses of 26.2 +/- 6.2 mm Hg, but 5 weeks of diuretic therapy did not decrease these pressor responses significantly. In two normal and two low renin hypertensives, the diastolic blood pressure rose to levels greater than 150 mm Hg. The amplitudes of the immediate pressor responses were inversely correlated with the base-line plasma renin activities, r = -0.46. The data support the concept that the agonist activity of saralasin occurs at the angiotensin II vascular receptor level with clinical expression mediated by sodium and/or volume changes.

Topics: Angiotensin II; Blood Pressure; Dopamine beta-Hydroxylase; Humans; Hypertension; Norepinephrine; Renin; Saralasin

Topics: Adrenergic beta-Antagonists; Adult; Age Factors; Ambulatory Care; Blood Pressure; Central Nervous System; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Pindolol; Propranolol; Renin; Saralasin; Time Factors

Saralasin, an angiotensin II inhibitor was infused in 10 hypertensive patients. A blood pressure reduction was achieved after stimulation of the renin-angiotensin-system by salt depletion. Heart rate and cardiac output failed to compensate for reduction of blood pressure. Thus circulatory reflex-mechanisms are inhibited by saralasin. A direct influence on baroreceptor mechanism and/or catecholamines is probable. Failure of the hypotensive effect of saralasin in salt-depleted patients after administration of beta-blockers supports this hypothesis.

Topics: Adrenergic beta-Antagonists; Adult; Angiotensin II; Aorta; Blood Pressure; Cardiac Output; Diet, Sodium-Restricted; Female; Heart Rate; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Renin; Saralasin; Vascular Resistance

To understand the role of the renin-angiotensin-aldosterone system in the pathogenesis of human hypertension, in serial studies we have blocked the system using three different pharmacologic probes: 1) reduction of renin secretion by administration of the beta receptor blocker, propranolol; 2) blockade of the action of angiotensin II by infusion of saralasin, a competitive antagonist of angiotensin II; and 3) blockade of the enzymatic conversion of angiotensin I to angiotensin II by infusing a nonapeptide competitive inhibitor. The depressor responses induced by either propranolol or the nonapeptide expose a significant to major involvement of excess renin--angiotensin in maintaining the hypertension of some 50 to 70% of common forms of hypertension including "essential" hypertension. This subgroup includes nearly all patients with high or "normal" renin--sodium profiles. The considerably lower estimates for a renin factor in essential hypertension suggested by saralasin testing now appear due to the partial agonism of this drug. Further studies are required to determine whether this relative or absolute excess of renin secretion is primarily involved in the hypertension and if not why it fails to shut itself off. Similar studies of normal subjects are also needed to determine whether renin support of blood pressure is proportionately greater or less than in hypertensive subjects. Meanwhile the validation provided by these three different pharmacologic probes portends a burgeoning clinical role for renin--sodium profiling not only in screening for renal and adrenal cortical hypertensions but also for characterizing the vasoconstrictor and volume elements involved in various individual patients and thus enabling more specific treatments of the various subtypes of essential hypertension.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Volume; Humans; Hypertension; Models, Biological; Natriuresis; Oligopeptides; Propranolol; Renin; Saralasin; Teprotide; Vascular Resistance

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Humans; Hypertension; Saralasin

(1) An immediate pressor response so saralasin, 10 microgram/kg/min, occurred in 52 of 57 (91%) hypertensive patients. (2) We propose that the amplitude of the immediate pressor response functions as an in vivo measure of the number of initially vacan angiotensin II vascular receptors. (3) The immediate pressor response to saralasin forecasts the subsequent sustained response, both of which are related to the renin-sodium profile. (4) The dual blood pressure responses to saralasin, immediate and sustained, make this drug useful for the pharmacological identification of high, normal, and low renin hypertensive patients as they are presently classified. (5) The ability of saralasin to elevate the BP immediately in most hypertensive patients shows the need for caution in its use. It is a safe drug from this standpoint if very small infusions (0.01-0.10 microgram/kg/min) are first tried in hypertensive patients whose PRA is unknown.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Humans; Hypertension; Kinetics; Receptors, Angiotensin; Receptors, Cell Surface; Renin; Saralasin; Teprotide

The angiotensin II antagonist 1-sar-8-ala-angiotensin II (saralasin) was infused in forty-six patients with hypertension of various aetiology (essential, renal arterial or parenchymal disease, primary hyperaldosteronism), before and/or during sodium volume depletion obtained by chlorthalidone and low sodium diet. When saralasin was infused in twenty-five patients ingesting 130 mmol of sodium per day, including patients with proven renovascular hypertension, the changes in mean arterial pressure and ranged from +10 to -7 mmHg (mean: +0.20 mmHg) and were not related to the plasma renin concentration (PRC) (r = -0.11). During sodium volume depletion, saralasin induced changes in mean arterial pressure, ranging from +21 to -76 mmHg, which were closely related to log PRC (n = 32; r = -0.87). Combined sodium depletion and antagonism of angiotensin II 'normalized' mean arterial pressure (less than or equal to 100 mmHg) in twenty-one of the thirty-two patients, while pressure remained between 106 and 147 mmHg in eleven 'poor' responders, so that pressor mechanisms other than sodium volume and angiotensin must be responsible for the remaining elevation of pressure in these patients. The study indicates that arterial pressure is not dependent on the immediate pressor effects of angiotensin II in sodium replete patients, and in sodium deplete subjects whose PRC remains low, while it is at least partly angiotensin II dependent during sodium volume depletion in the others. The results cast doubts on the clinical usefulness of saralasin in the investigation of patients with hypertension, when studied in the conditions of the present study.

Topics: Adult; Angiotensin II; Blood Pressure; Female; Humans; Hypertension; Male; Middle Aged; Renin; Saralasin; Sodium

Topics: Adrenal Cortex Hormones; Adult; Angiotensin II; Catecholamines; Female; Humans; Hypertension; Male; Middle Aged; Renin; Saralasin

Topics: Angiotensin II; Animals; Blood Pressure; Brain; Female; Hypertension; Male; Nephrectomy; Rats; Saralasin

Topics: Angiotensin II; Animals; Dogs; Humans; Hypertension; Kinins; Oligopeptides; Pindolol; Propranolol; Renin; Saralasin; Teprotide

Topics: Aldosterone; Angiotensin II; Animals; Corticosterone; Desoxycorticosterone; Extracellular Space; Hypertension; Hypertension, Renal; Hyponatremia; Rats; Renal Artery Obstruction; Renin; Saralasin; Sodium; Sodium Chloride; Teprotide

Topics: Angiotensin II; Animals; Desoxycorticosterone; Femoral Vein; Hypertension; Hypertension, Renal; Injections, Intravenous; Injections, Intraventricular; Rats; Rats, Inbred Strains; Saralasin

Topics: Angiotensin II; Blood Pressure; Humans; Hypertension; Oligopeptides; Renin; Saralasin; Sodium; Teprotide

Topics: Aldosterone; Angiotensin II; Blood Pressure; Cardiac Output; Diet, Sodium-Restricted; Heart Rate; Hemodynamics; Humans; Hypertension; Hypertension, Renal; Renin; Saralasin

Topics: Angiotensin II; Bartter Syndrome; Diagnosis, Differential; Humans; Hypertension; Hypertension, Renal; Renin; Saralasin

Topics: Adrenal Gland Neoplasms; Angiotensin II; Blood Pressure; Depression, Chemical; Humans; Hypertension; Pheochromocytoma; Saralasin

An angiotensin II (A II) analogue (1-Sar-8-Ala-angiotensin II) (saralasin) was infused into 418 untreated hypertensive subjects during a 1-day evaluation while blood pressure was recorded every 2 minutes by Arteriosonade. At 5 mug/kg per min, saralasin produced a change in mean blood pressure which correlated significantly (r=-0.54, P less than 0.001) with the stimulated plasma renin activity (PRA) (after intravenous furosemide and ambulation for 2 hours. Saralasin caused a rise inmean blood pressure of at least 7.0 mm Hg in 97 hypertensive subjects, who also had a low stimulated PRA (1.3+/-SEM, 0.1 ng/ml per hour; normal range, 1.7-8.5). On a low sodium diet, the pressor response of hypertensive subjects to saralasin continued and was an even better indicator of a low stimulated PRA. Infusion of saralasin at 10 mug/kg per min into normal subjects on an unrestricted diet, a low sodium diet, and a high sodium diet produced, respectively, no change, a fall (P less than 0.05), and a rise (P less than 0.005) in blood pressure. The same saralasin dose in six hypertensive subjects who showed a pressor response to the analogue in the 1-day study also produced a rise in blood pressure when given on a low sodium diet, and this rise was more than twice that seen in normal subjects on a high sodium diet. Hypertensive subjects who showed the pressor response had a significantly greater (P less than 0.01) pressor sensitivity to A II than did hypertensive nonresponders to saralasin and noraml subjects on an uncontrolled diet. The affinity of the vascular receptors for the analogue was greater in the hypertensive group that showed the pressor response to saralasin. In summary, the pressor response to saralasin, as defined above, occurred in 23% of a large unselected group of hypertensive subjects and was associated with salt loading, a low stimulated PRA, and increased pressor sensitivity to A II.

Topics: Adult; Angiotensin II; Blood Pressure; Blood Urea Nitrogen; Creatinine; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Regional Blood Flow; Renin; Saralasin; Sodium

Topics: Angiotensin II; Hypertension; Posture; Renin; Saralasin; Sodium; Teprotide

1. Blood pressure and plasma renin activity were studied after bilateral nephrectomy in groups of rats with hypertension caused by unilateral renal ischaemia with the opposite kidney left intact. 2. Although blood pressure showed only a small fall in the first hour after bilateral nephrectomy, plasma renin activity fell rapidly with a half-life of 10 min. 3. Infusion of converting enzyme inhibitor (SQ20881) produced a 26-1% fall in blood pressure 1 h after nephrectomy, 24-% at 2 h and 4-6% at 6 h. 4. An angiotensin antagonist (Sar1-Ala8-angiotensin II) was infused into hypertensive rats 1 h after nephrectomy; this blocked the vasodepressor action of the converting enzyme inhibitor, indicating that the fall in blood pressure produced by the inhibitor was due to its action upon the renin-angiotensin system. 5. The renin-angiotensin system maintains blood pressure in this model even after plasma renin has fallen to insignificant levels. This supports the view that vascular renin activity has a longer half-life than circulating renin and is important in the control of blood pressure.

Topics: Angiotensin II; Animals; Arteries; Blood Pressure; Female; Hypertension; Ischemia; Kidney; Nephrectomy; Oligopeptides; Rats; Renin; Saralasin; Teprotide

The purpose of this study was to determine whether increased sympathetic nervous system activity with proportionally greater stimulation to the kidney could result in sustained hypertension. This was simulated by continuous intrarenal norepinephrine infusion. Effects of chronic infusion of norepinephrine (0.285 microng/kg per min) into the renal artery and inferior vena cava were compared in uniephrectomized conscious dogs. Ten days of intrarenal norepinephrine infusion produced a sustained rise in mean arterial pressure (25 mm Hg), and a 32-mEg positive sodium balance occurred. Inferior vena caval infusion caused a transient rise, lasting 24 hours, in mean arterial pressure which was associated with a 54-mEq natriuresis. With renal artery infusion, peripheral plasma renin activity rose from 1.0 +/- 00.2 to 4.4 +/- 0.8 ng angiotensin I/ml per hour at 1 hour (P less than 0.002) and fell to 1.4 +/- 0.4 at 24 hours (not significant). Inferior vena caval infusion produced a similar result. [Sar1,ala8]angiotensin II (6 MICrong/kg per min) produced no significant change in arterial blood pressure. (alpha-Adrenergic blockade with phentolamine normalized the blood pressure. Renal plasma flow was chronically decreased by about 25% in dogs given intrarenal norepinephrine; no significant change in glomerular filtration rate occurred. The cardiac output decreased from a control of 7.2 +/- 0.6 to 4.8 +/- 0.1 liters/min (P less than 0.01) and total peripheral resistance was increased from a control of 13 +/- 1 to 26 +/- 1 resistance units (RU) (P less than 0.0005) in dogs given intrarenal norepinephrine. The data indicate that chronic intrarenal infusion of norepinephrine in uninephrectomized conscious dogs results in sustained hypertension characterized by decreased renal plasma flow, normal glomerular filtration rate, positive sodium balance, and increased total peripheral resistance due to norepinephrine-dependent vasoconstriction.

Topics: Aldosterone; Angiotensin II; Animals; Blood Pressure; Dogs; Dose-Response Relationship, Drug; Female; Hemodynamics; Hypertension; Kidney; Kidney Function Tests; Natriuresis; Norepinephrine; Phentolamine; Renin; Saralasin

Saralasin, an angiotensin II antagonist, was infused into 49 patients with renal artery stenosis, 10 patients with essential hypertension and normal renal arteriograms, and five patients with "low-renin essential hypertension." Renal venous renin and differential renal function studies were used to assess the functional significance of arterial stenoses. "Response" to saralasin, evidenced by a fall in blood pressure during infusion, occurred in no patients with "low renin" hypertension and in only 20% of patients with normal renal arteriograms. In contrast, saralasin "response" occurred in more than 80% of patients with renal artery stenosis and lateralizing functional studies and 100% of cases of "proven" renovascular hypertension (cure or improvement of hypertension after operative treatment). We suggest that saralasin infusion might be a valuable screening test for the recognition of renovascular hypertension.

Topics: Angiotensin II; Blood Pressure; Diagnosis, Differential; Humans; Hypertension; Hypertension, Renal; Nephrectomy; Renal Artery Obstruction; Renin; Saralasin

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Female; Furosemide; Hypertension; Hypertension, Renal; Rats; Rats, Inbred Strains; Renin; Saralasin; Species Specificity

Eighteen patients with advanced or malignant hypertension due to essential hypertension, systemic lupus erythematosus or chronic glomerulonephritis were infused intravenously with 1-Sar-8-Ile-Angiotensin II, a competitive antagonist of aniotensin II. The spectrum of responses was broad from a mild elevation to a marked fall in blood pressure. The changes in mean blood pressure caused by this peptide showed a significant correlation with the level of peripheral plasma renin activity immediately before the infusion (r=0.5652, p less than 0.02). This peptide infusion reduced blood pressre in 12 patients (responders), but not in 6 (non-respnders). There were no differences with age, sex and severity of hypertension except for the level of peripheral plasma renin activity between the two groups. Our retrospective study showed that in 12 responders propranolol reduced blood pressure to near the normal level, while in 6 non-responders furosemide induced similar depressor response. It is concluded that the vasodepressor effect of this peptide correlates with the levels of peripheral plasma renin activity and that the responses to this drug can be used as a guide for the selection of effective antihypertensive drugs.

Topics: Adolescent; Adult; Angiotensin II; Blood Pressure; Drug Evaluation; Female; Humans; Hypertension; Male; Middle Aged; Renin; Saralasin

Saralasin (1-sar-8-ala-angiotensin II), a competitive inhibitor of angiotensin II, was administered to 32 patients with renovascular or essential hypertension before (Day 1) and after (Day 2) they were mildly sodium depleted by furosemide (1 mg/kg body weight). A blood pressure lowering effect of saralasin was observed in 16 of 17 patients with renovascular hypertension on Day 2, but in only 10 of the 17 on Day 1. Of the 15 patients with essential hypertension, only the four with high renin levels exhibited a vasodepressor response on Day 2; three responded similarly on Day 1. The Average net sodium loss between the 2 days was greater for patients who responded to the drug on Day 2 (170 meq) than those who did not (129 meq) (P less than 0.05); however, there was no correlation between blood pressure response and either net sodium loss or urinary sodium excretion at the time of testing. Plasma renin activity correlated with saralasin responses (r=-0.74, P less than 0.01). Saralasin testing during a state of modest sodium depletion compares favorably with renin measurements in the detection of renin-mediated hypertension.

Topics: Adult; Angiotensin II; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Prospective Studies; Renin; Saralasin; Sodium; Vasomotor System

Thirty-four patients, most with a low-renin "essential" hypertension, and seven normal subjects were placed on diuretic therapy for 4 to 5 weeks. In the normal subjects, infusion of a highly specific, competitive angiotensin II analogue (1-sar-8-ala-angiotensin II, saralasin) did not significantly change recumbent blood pressure either before or after diuretic administration. In contrast, the hypertensive patients as a group had a low stimulated plasma renin activity before diuretic therapy and a rise in blood pressure during saralasin infusion. After therapy, the stimulated plasma renin activity was higher and saralasin produced a fall in blood pressure in some patients who were still hypertensive. The results suggest that short-term diuretic therapy, which is thought to act through its natriuretic effects, can convert some patients with essential hypertension, many with a low or a low-normal stimulated plasma renin activity, to individuals whose hypertension is supported by angiotensin II. The fall in blood pressure to saralsin infusion after diuretic therapy was directly proportional to the height to which diuretics elevated the stimulated plasma renin activity.

Topics: Adult; Aged; Angiotensin II; Blood Pressure; Diuretics; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Renin; Saralasin; Spironolactone; Stimulation, Chemical

The reliability of the angiotensin II (AT II)-antagonist Saralasin in the diagnosis of AT II-dependent forms of hypertension was investigated in 61 cases of hypertension of different etiology. In 14 patients, lowering of blood pressure by Saralasin suggested an AT II-dependent hypertension which could be ascertained in 8 patients (5 had undergone successful surgery) by increased levels of plasma-renin-activity (PRA), AT II, PRA-ratio in renal vein blood and by angiography. Besides, depressor reactions by Saralasin yielded additional information in three patients with renovascular hypertension but normal levels of PRA and AT II, in two patients with high renin essential hypertension and one patient with pheochromocytoma. This test seems to be valuable in the diagnosis of renin-dependent hypertension.

Topics: Angiotensin II; Blood Pressure; Diagnosis, Differential; Evaluation Studies as Topic; Female; Humans; Hypertension; Hypertension, Renal; Male; Renin; Saralasin

The hypotensive effect of acute sodium volume depletion, produced by chlorthalidone and a low sodium diet, was inversely related to the plasma renin concentration (PRC) in 13 hypertensive patients of varying aetiology (r = 0.61; p less than 0.05); weight reduction induced by this therapy was not related to PRC (r = 0.12; p greater than 0.1). The angiotensin II antagonist 1-sar-8-ala-angiotensin II failed to reduce arterial pressure when the patients ingested 130 mEq sodium per day, but pressure fell when it was infused during sodium volume depletion, except when PRC remained low; the changes in pressure were related to the plasma renin level (r = 0.78; p less than o.005). The combined hypotensive response to acute sodium volume depletion and to angiotensin II blockade during sodium volume depletion was not related to PRC (r = 0.15; p greater than 0.1). The results demonstrate that acute sodium volume depletion caused similar weight loss in patients with high and low PRC values, and it would have had similar hypotensive effects but for angiotensin-induced vasoconstriction in the high renin patients. Since 1-sar-8-ala-angiotensin II also reduced arterial pressure in 6 patients during chronic diuretic therapy, angiotensin II must still induce vasoconstriction in these circumstances.

Topics: Adult; Angiotensin II; Blood Pressure; Body Weight; Chlorthalidone; Diet, Sodium-Restricted; Female; Humans; Hypertension; Male; Renin; Saralasin; Sodium

1. The initial blood pressure response to saralasin (Sar1-Ala8-angiotensin II) infusion was examined in 15 normal subjects, eight patients with untreated essential hypertension and 65 patients established on chronic haemogialysis (including six anephric patients), and related to measurements of plasma renin activity (PRA), angiotensin II, plasma catecholamines (noradrenaline and adrenaline), blood volume and extracellular fluid volume ([35S]sulphate space or exchangeable sodium). 2. A transient rise in arterial pressure, maximum after 5-6 min, occurred in all normal subjects, patient with essential hypertension and anephric patients, and in 41 of the 59 dialysis patients with kidneys. 3. In the normal subjects, saralasin infusion resulted in a significant rise in plasma noradrenaline (mean increase 360%, P less than 0-02) without change in plasma adrenaline concentration. The change in noradrenaline was significantly related to the change in mean blood pressure (P less than 0-05) and was similar to the response to 5 min of a 40 degree head-up tilt. 4. An increase in plasma noradrenaline also occurred in dialysis patients (P less than 0-005) but the change in mean blood pressure with saralasin in this group was inversely related to PRA (P less than 0-001) and angiotensin II (P less than 0-001), directly related to blood volume (P less than 0-001), but unrelated to the change in plasma noradrenaline. 5. The pressor response to saralasin may be mediated not only by angiotensin-like action on vascular receptors but also by an action on the central or peripheral autonomic nervous system.

Topics: Adolescent; Adult; Angiotensin II; Blood Pressure; Blood Volume; Catecholamines; Extracellular Space; Female; Humans; Hypertension; Male; Middle Aged; Renal Dialysis; Renin; Saralasin

Topics: Angiotensin II; Animals; Blood Pressure; Disease Models, Animal; Dogs; Enzyme Inhibitors; Humans; Hypertension; Pindolol; Propranolol; Rats; Renal Artery Obstruction; Renin; Saralasin

Topics: Adrenergic beta-Antagonists; Diazoxide; Humans; Hypertension; Minoxidil; Nitroprusside; Prostaglandins; Saralasin

Complications of hypertension are by far the greatese preventable public health problem in many of the developed countries of the world. Pharmacologic interventions which primarily involve drug interactions are the generally available and effective means of preventing or delaying these hypertensive complications. Mechanisms of beneficial antihypertensive drug interactions involve simultaneous reduction or control of blood volume (diuretic agents) and decrease of peripheral resistance. Reduction of peripheral resistance without producing intolerable side effects has recetnly been achieved by a complex drug interaction. This interaction involves simultaneous vasodilation and inhibition by beta-adrenergic blocking agents of reflex activation of the renin-angiotensin axis. Clonidine, by effects similar to propranolol, can substitute for propranolol in some patients, or add to the beneficial effects of this important drug interaction.

Topics: Adrenergic beta-Antagonists; Clonidine; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Minoxidil; Propranolol; Saralasin; Vasodilator Agents

The effect of infusion of the angiotensin II antagonist P113 on blood-pressure (B.P.) has been studied in 10 patients with various forms of hypertension under four different conditions: before and after salt depletion and with or without propranolol treatment. The fall in B.P. after P113 infusion significantly correlated with log P.R.A. (plasma-renin activity), irrespective of diagnosis or treatment. P113 infusion caused a consistent fall in B.P. only after sodium depletion. The changes in B.P. after P113 infusion and those induced by propranolol correlated only during sodium depletion, when P.R.A. values rose. It is concluded that sodium depletion induced "renin dependency" of B.P. in all patients. The decrease in B.P. renin dependency after propranolol therapy suggests that suppression of P.R.A. is one of the antihypertensive mechanisms underlying the action of this drug.

Topics: Adolescent; Adult; Angiotensin II; Antihypertensive Agents; Blood Pressure; Brain Injuries; Diet, Sodium-Restricted; Female; Humans; Hypertension; Infusions, Parenteral; Male; Middle Aged; Propranolol; Renin; Saralasin; Sodium

The renin angiotensin system has an important role in regulating arterial blood pressure in homeostasis and disease. A reciprocal relationship exists between sodium balance and the circulating levels of renin and angiotensin II. The vascular responsiveness to angiotensin II, the major vasconstrictor component of the renal pressor system, can be impaired by numerous factors including sodium depletion or a reduction in effective plasma volume. In situations in which the renin-angiotensin system is activated, a negative relationship between the angiotensin II pressor response and the circulating angiotensin II level is observed. This effect seems to involve a change of the angiotensin II receptor interaction in the vascular smooth muscle. The prevention of angiotensin II generation by the inhibition of converting enzyme causes an immediate increase in the pressor response to angiotensin; after bilateral nephrectomy, it takes much longer to develop. In addition, the depressor response to angiotensin antagnoists and converting enzyme inhibitor is preserved after bilateral nephrectomy for much longer periods than can be accounted for by the disappearance of circulating renin. These observations support the view that the decrease in vascular response to angiotensin II during sodium deprivation or when body fluid volumes are reduced is the result of prior occupancy of the receptor sites by endogenous hormone generated both in the plasma and locally within blood vessel walls. Therefore, a change in the number or affinity of receptors consequent to a change in sodium balance or as a modulating function of the renin-angiotensin system need not be postulated to explain changes in angiotensin vascular responsiveness.

Topics: Angiotensin II; Animals; Binding, Competitive; Blood Pressure; Blood Vessels; Dogs; Humans; Hypertension; Nephrectomy; Protease Inhibitors; Rabbits; Rats; Receptors, Angiotensin; Receptors, Cell Surface; Renin; Saralasin; Sheep; Sodium

This study was designed to examine more closely the differences in blood pressure responses in hypertensive patients to two agents which block the renin-angiotensin system. Accordingly, 39 seated patients received under the same conditions both saralasin, an octapeptide competitive antagonist of angiotensin II, and the nonapeptide converting enzyme inhibitor, SQ20881, which blocks the generation of angiotensin II from angiotensin I. A second component of the study involved administration of these agents in 10 addtional studies in anephric subjects. Although both agents produced maximal responses in blood pressure that correlated well with each other (p less than 0.001) and with the pretreatment plasma renin levels (p less than 0.001), analysis of the results by renin subgroups revealed significant differences. Thus, both drugs lowered the diastolic pressures of patients with high renin levels, but but converting enzyme inhibitor produced changes of greater amplitude (p less than 0.05). In contrast, saralasin was consistently pressor in both patients with low renin levels and anephric patients in whom converting enzyme blockade preduced no significant changes in blood pressure. Another impressive disparity in the responses to the two agents occurred in the group with normal renin levels in whom saralasin produced either neutral or pressor responses (mean change was +2.0 +/- 1.5 standard error of the mean (SEM) per cent control diastolic pressure) whereas the converting enzyme inhibitor consistently induced depressor responses (mean change was -10.2 +/- 1.2 per cent, p less than 0.001). Altogether, the results suggest that converting enzyme inhibitor tests for angiotensin II-dependent blood pressure with more sensitivity than the partial agonist saralasin. Moreover, it is unlikely that the differences between the responses to the two agents were due to bradykinin accumulation, since depressor responses to converting enzyme inhibitor were not observed in the patients with low renin levels and the anephric patients.

Topics: Adolescent; Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Female; Humans; Hypertension; Hypertension, Renal; Kidney Diseases; Male; Middle Aged; Oligopeptides; Renin; Saralasin; Sodium; Teprotide

Topics: Adenoma; Adrenal Cortex Neoplasms; Adrenal Gland Diseases; Adrenocorticotropic Hormone; Cushing Syndrome; Female; Humans; Hydrocortisone; Hyperaldosteronism; Hyperplasia; Hypertension; Hypokalemia; Hypothalamo-Hypophyseal System; Methods; Middle Aged; Saralasin

Stroke index obtained by impedance cardiography was compared with values obtained by dye-dilution technique in 17 subjects in 122 determinations made within 2 min of each other. Fifty of these determinations were done after drug administration, postural change, or saline infusion. All values obtained by both methods correlated significantly, but with wide scatter (r=0.49, n = 122, P less than 0.001). The series of determinations within each subject, however, correlated only in one subject significantly; thus any changes of stroke index measured by both techniques were not commensurate. In addition, the impedance stroke index values were significantly lower than the dye-dilution technique, impedance cardiography presently does not determine reliably absolute values of stroke index and is not suitable to evaluate changes of stroke index.

Topics: Adult; Ballistocardiography; Cardiac Output; Dye Dilution Technique; Humans; Hypertension; Indocyanine Green; Posture; Saralasin

1. A P113 Saralasin infusion test was performed in 10 patients on long-term regular hemodialysis. Six patients were considered to have hypertension resistant to dialysis treatment and 4 had their arterial pressure controlled by dialysis. 2. Five out of 6 resistant and 3 out of 4 responsive patients had a positive response to Saralasin associated with a normalization of diastolic arterial pressure. 3. The value of the Saralasin infusion test to pre-select the patients for bilateral nephrectomy is discussed and it is felt that a negative test may be of more value in encouraging more aggressive ultrafiltration in hypertension apparently resistant to dialysis therapy.

Topics: Adult; Angiotensin II; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Nephrectomy; Renal Dialysis; Renin; Saralasin

The early clinical pharmacologic investigations of saralasin were facilitated by the availability of a highly sensitive and specific radioimmunoassay for this peptide. In these studies, plasma concentrations of saralasin were correlated with inhibition of angiotensin receptors in each of three organ systems: vascular smooth muscle, adrenal cortex, and the renin release control mechanism in the kidney. The biochemical half-life of plasma saralasin was 3.2 min and an infusion time-to-plateau was 12--15 min. Saralasin inhibited adrenal cortical, vascular, and intrarenal (renin release) angiotensin receptors. The time required for manifesting these blocking actions was short(3--10 min) except for the 30--60 min required to suppress plasma aldosterone. Saralasin-induced blood pressure lowering was dependent on previously elevated serum renin activity and volume depletion. Expansion of intravascular volume prevented hypotensive responses to saralasin even in high-renin patients. Saralasin-induced renin release occurred independent of hypotension and could be inhibited by propranolol, a beta-adrenergic blocking agent. Thus, saralasin is a selective angiotensin antagonist which lacks organ specificity. It is a highly useful tool in pharmacologic studies of the renin--angiotensin axis in man and shows promise as a diagnostic tool.

Topics: Aldosterone; Angiotensin II; Angiotensin Receptor Antagonists; Humans; Hypertension; Radioimmunoassay; Receptors, Angiotensin; Renin; Saralasin; Time Factors

To investigate the role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome two patients with hypercorticism were infused with 20 mg saralasin (1-sar-8-ala-angiotensin II) over a period of 30 minutes under constant blood pressue control. In addition, one patient with primary aldosteronism, an established form of mineralocorticoid hypertension, served as control. Neither in the two patients with Cushing's syndrome nor in the patient with primary aldosteronism could a blood pressure lowering effect of saralasin be observed. In the two patients with hypercoritcism both renin activity and plasma aldosterone increased during saralasin infusion. The patient with primary aldosteronism only showed a weak increase in plasma aldosterone concentration.

Topics: Aldosterone; Angiotensin II; Blood Pressure; Cushing Syndrome; Female; Humans; Hyperaldosteronism; Hypertension; Renin; Saralasin

Topics: Angiotensin II; Blood Pressure; Female; Headache; Humans; Hypertension; Male; Middle Aged; Propranolol; Renin; Saralasin; Sodium

To investigate the roles of angiotensin II and sodium in essential high-renin, normal-renin and low-renin hypertension, 14 patients received the competitive antagonist of angiotensin II, saralasin, during periods of sodium depletion and repletion. Blood-pressure response to saralasin was determined by the state of sodium balance. Patients from all three renin subgroups exhibited a fall in blood pressure when sufficiently sodium depleted, and an elevation in blood pressure when sodium replete or insufficiently depleted. However, those with low renin required loss of substantially more sodium (sufficient to elicit compensatory stimulation of renin) before depletion could be achieved. In patients with essential hypertension of all three renin subgroups, sodium balance determines the degree of participation of the renin-angiotensin system in sustaining high blood pressure. Even the low-renin type can become renin dependent with sufficient sodium depletion.

Topics: Adult; Aldosterone; Angiotensin II; Blood Pressure; Feedback; Humans; Hypertension; Kidney; Middle Aged; Renin; Saralasin; Secretory Rate; Sodium

Topics: Adult; Angiotensin II; Chlorthalidone; Humans; Hypertension; Hypotension; Male; Saralasin

Topics: Angiotensin II; Female; Humans; Hypertension; Hypotension; Saralasin; Water-Electrolyte Imbalance

Topics: Animals; Blood Pressure; Female; Homeostasis; Hypertension; Hypotension; Indomethacin; Nephrectomy; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins E; Rabbits; Regional Blood Flow; Saralasin; Sheep; Uterus; Vascular Resistance; Veins

Specific antagonists of the renin angiotensin system have been used to investigate the role of this hormonal system in blood pressure homeostasis and in different types of experimental and clinical hypertension. Using this approach it was possible to show that renin via angiotensin participates actively in blood pressure maintenace, particularly following sodium depletion. Such antagonists, if available for oral administration and taken together with a diuretic, would be useful therapeutically.

Topics: Adult; Angiotensin II; Animals; Humans; Hypertension; Hypertension, Renal; Male; Oligopeptides; Rats; Renin; Saralasin; Sodium; Teprotide

The demonstration that the components required for the generation of angiotensin II are present in the brain has led to the proposal that there is a brain renin-angiotensin system. To test this hypothesis, experiments were performed to determine if biologically active amounts of angiotensin II are formed when renin is injected into the cerebral ventricles. The effects of central administration of agents known to block the peripheral renin-angiotensin system were also investigated. It was shown that intraventricular renin increased water intake, blood pressure and ADH secretion and that these effects were blocked by saralasin. These findings indicated an interaction between injected renin, brain angiotensinogen and converting enzyme, resulting in the formation of angiotensin II in physiologically active concentrations. However, these experiments did not demonstrate a role for endogenous brain renin activity. Central administration of saralasin in normal animals did not decrease water intake, blood pressure or ADH secretion. These studies thus failed to demonstrate a physiological role for the proposed brain renin-angiotensin system in controlling water balance and blood pressure.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Brain; Dogs; Drinking; Hypertension; Rats; Renin; Saralasin; Swine; Vasopressins

1) Saralasin was administered to 9 normotensive volunteers and 13 patients with essential hypertension after sodium depletion and sodium repletion. 2) In standing normotensive volunteers, angiotensin II inhibition induced significant hypotension if previously a cumulative sodium loss of at least 160-200 mEq had been induced. 3) In patients with essential hypertension, saralasin infusion induced either blood pressure reduction, no change or even significant blood pressure increase, depending on the prevailing state of sodium balance. 4) Following vigorous and prolonged sodium depletion induced by low sodium diet, with chlorthalidone and spironolactone, blood pressure became renin-dependent even in those patients who initially had exhibited a hypertensive response to saralasin, suggesting that under appropriate conditions, renin can play an active pressure role in all patients with essential hypertension. 5) Saralasin administration to patients with essential hypertension may not only be useful for recognizing renin dependency but may also, via the slight intrinsic agonistic effect of the compound, permit identification of overactivity of the sodium factor.

Topics: Adult; Angiotensin II; Blood Pressure; Humans; Hypertension; Male; Middle Aged; Posture; Renin; Saralasin; Sodium; Time Factors

Five hypertensive haemodialysis patients have been infused with saralisin. The infusion appears to be a simple diagnostic test separating patients into two groups. First, there are those whose blood pressure does not fall with saralasin pre-dialysis, but does fall with weight removal during dialysis; the blood pressure in these patients can be controlled by a reduction in pre-dialysis weight. Second, there are those whose blood pressure does fall with saralasin either pre- or post-dialysis; their arterial pressure does not fall with weight removal, but can be controlled by anti-hypertensive drugs. In two of the patients who responded to saralasin, the mechanism of the high blood pressure appeared to change from volume dependency, partial or complete, with suppressed renin release, to angiotensin dependency, partial or complete, as weight was removed during dialysis. These patients illustrate the importance of the interaction between volume and the level of angiotensin II in the maintenance of hypertension.

Topics: Adult; Angiotensin II; Blood Pressure; Body Weight; Female; Humans; Hypertension; Male; Renal Dialysis; Renin; Saralasin; Time Factors

Specific antagonists of angiotensin II (AII) such as saralasin might theoretically be of great value in the recognition of angiotensinogenic hypertension. Evidence is presented to show the importance of overcoming any existing sodium overload and of administering saralasin first in small and then in larger amounts by infusion (or injection). When this was done in 600 hypertensive patients, 62 showed a fall in blood pressure of more than 10/8 mm Hg. Further tests in 50 of these subjects indicated that the fall in blood pressure was associated with high peripheral levels of plasma renin activity (PRA) and/or abnormal renal vein PRA ratios in 94%. The procedure rarely failed to detect even mild forms of angiotensinogenic hypertension. In 62 patients found to have angiotensinogenic hypertension, the responsible lesions included unilateral renal arterial stenosis with good contralateral renal function (29%), bilateral renal disease (21%), Cushing's syndrome (6%), small vessel disease or specific excess of renin production - without other detectable renal disease - (31%) and incompletely evaluated disorders (13%). Saralasin has been of great value in simply and reliably demonstrating the presence or absence of an angiotensinogenic component in a large group of hypertensive patients.

Topics: Adult; Angiotensin II; Animals; Blood Pressure; Cushing Syndrome; Drug Administration Schedule; Humans; Hypertension; Kidney; Male; Rats; Renal Artery Obstruction; Renal Veins; Renin; Saralasin; Sodium

The effect of saralasin in lowering blood pressure and plasma aldosterone concentration in normal subjects, both sodium-replete and sodium-deplete, and in patients with various forms of hypertension, is closely related to the basal plasma angiotensin II concentration. These findings confirm and extend earlier studies of angiotensin II/arterial pressure and angiotensin II/aldosterone dose-response curves. They also emphasize the importance of the renin-angiotensin system in the control of aldosterone in sodium depletion and in renal hypertension.

Topics: Aldosterone; Angiotensin II; Blood Pressure; Diet; Humans; Hyperaldosteronism; Hypertension; Kidney Failure, Chronic; Male; Renal Artery Obstruction; Renin; Saralasin; Sodium; Time Factors

An understanding of the possible role of excessive angiotensin II activity in the pathogenesis of hypertension in every patient is therapeutically desirable, but it is frustrated by the lack of complete reliability of peripheral plasma measurements of renin activity. Observation of a clear-cut, supranormal decrease in blood pressure during the intravenous infusion of the angiotensin II antagonist, saralasin, has provided a far more reliable indication of the presence of an angiotensinogenic component in the hypertension. There is convincing evidence, however, that the presence of sodium-overload may prevent a decrease in blood pressure during saralasin infusion in persons known to have angiotensinogenic hypertension and that saralasin may cause a slight decrease in the blood pressure of normal subjects after natriuresis. For these reasons, it is important to study hypotensive responses to saralasin under standardized conditions after the administration of a potent diuretic and to compare the observations with those made on normal subjects under identical circumstances. This angiotensin antagonist may be used in the therapy of malignant or advanced hypertension and as an aid to therapeutic decisions in hypertensive patients who have known renal diseases, are taking oral contraceptives or have had severe trauma to the area of the kidneys. Side effects of saralasin are limited to excessive falls in blood pressure levels, mainly when vasodilators or ganglioplegic drugs are being taken at the time of the saralasin infusion, and excessive rises in blood pressure levels, especially in hypertensive subjects with "low renin" activity during high rates of saralasin infusion or after intravenous injections of large boluses. This safe and reliable drug is a valuable tool in the investigation and therapy of hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Female; Furosemide; Humans; Hypertension; Hypertension, Malignant; Rabbits; Renin; Saralasin; Sodium

Saralasin was infused into 52 untreated hypertensive patients. Immediate, transient pressor responses occurred in 94 per cent followed by a more gradual sustained change in blood pressure reaching an apogee in about 20 minutes. Most (86 per cent) patients with high renin values had sustained depressor responses irrespective of sodium balance. In contrast, during a normal sodium intake, the drug produced a neutral (45 per cent) or mildly pressor (50 per cent) response in patients with normal renin and pressor responses in patients with low renin values. Sodium depletion abolished pressor responses and resulted in depressor responses in 64 per cent of the patients with normal renin values. The pretreatment angiotensin level appeared to determine direction and amplitude of the response to saralasin, since increases and decreases in diastolic pressure exhibited a highly significant relationship to the control renin lever (r = 0.80, p less than 0.001). Above a neutral range of control renin values, from 2 to 7 ng Al/ml/hour, depressor responses were the rule, and below it pressor responses were consistent. Sodium balance also appeared to determine the amplitude of the response. In a subset of patients with similar renin values (range 1.4 to 2.2 ngAl/ml/hour), the induced pressor responses correlated directly with the 24-hour sodium excretion (p less than 0.05). For all patients, the induced pressure change also was related to the rate of sodium excretion (r = 0.53, p less than 0.001). The data suggest that saralasin behaves as a partial competitive agonist of angiotensin II. For this reason, saralasin testing provided only a rough physiologic validation for renin profiling. Thus, depressor responses expose most patients with high renin values. Neutral responses occur in many patients with normal renin and intermediate renin values. But pressor responses occur in subjects with either low or normal renin levels and they may reflect sodium and volume excess associated with a partial or relative absence of renin. Accordingly, due to its partial agonism, saralasin testing under-estimates the renin factor. Hence, the drug cannot be used to identify or exclude renin involvement in the blood pressure in the large majority of hypertensive patients who do not exhibit depressor responses. For them an agent devoid of agonism is required. Moreover, prior sodium depletion as a device to increase the frequency of depressor responses to saralasin does not measure intrinsic re

Topics: Angiotensin II; Blood Pressure; Humans; Hypertension; Renin; Saralasin; Sodium

Topics: Angiotensin II; Blood Pressure; Humans; Hypertension; Hypertension, Renal; Saralasin

Topics: Angiotensin II; Humans; Hypertension; Renin; Saralasin

Topics: Adult; Angiotensin II; Blood Pressure; Glomerular Filtration Rate; Humans; Hypertension; Middle Aged; Renin; Saralasin

Blood pressure reduction with saralasin infusion was seen only in hypertensive patients with abnormally elevated basal plasma renin and angiotensin II levels, and after sodium depletion the reduction in blood pressure was more marked. In normal subjects, and in hypertensives with plasma renin and angiotensin II levels within the normal range, there was no marked fall in blood pressure across saralasin infusion regardless of the sodium status of the individual. Plasma aldosterone concentration fell during saralasin infusion in those subjects with high baseline renin and angiotensin II levels. This fall occurred in the sodium replete and deplete states. In the normal subjects, and those hypertensives with normal plasma renin levels, there was no fall in aldosterone in the sodium replete state. However, after sodium depletion the expected rise in aldosterone was abolished during saralasin infusion, the plasma aldosterone falling to within the normal sodium replete range, rising again after the saralasin infusion was stopped. This study supports the concept of a direct role for renin and angiotensin II in the maintenance of hypertension in those subjects with elevated basal plasma renin. Plasma aldosterone would appear to be controlled, at least in part, by the prevailing plasma angiotensin II level in those subjects with elevated basal levels of angiotensin II; that is in high renin hypertensives, and in normal subjects and normal renin hypertensives who are sodium deplete.

Topics: Adult; Aldosterone; Angiotensin II; Blood Pressure; Depression, Chemical; Diet; Female; Humans; Hypertension; Male; Middle Aged; Renin; Saralasin; Sodium

Patients with essential hypertension were sodium deprived by five days on a 10 mM sodium diet and were then infused with an incremental infusion of saralasin, a competitive inhibitor of angiotensin II. Patients with normal renin hypertension showed no change in lying or standing blood pressure during the infusion of saralasin. Angiotensin II is not, therefore, directly maintaining blood pressure in these patients when sodium deprived by diet, and is therefore unlikely to be playing any direct role in maintaining their blood pressure on their normal sodium intake. Patients with low renin hypertension showed a significant rise in blood pressure during saralasin infusion. Saralasin may be a further method of distinguishing low renin hypertensives from other hypertensives if they are infused when sodium deprived by diet.

Topics: Angiotensin II; Blood Pressure; Diet; Humans; Hypertension; Renin; Saralasin; Sodium

Topics: Angiotensin II; Blood Pressure; Humans; Hypertension; Renin; Saralasin

1. Infusion of angiotensin II antagonist failed to restore the blood pressure of short-term Goldblatt 2-kidney hypertensive rats to normal levels before and after sodium restriction. 2. The blood pressure of both normal and sodium-restricted Goldblatt 2 hypertensive rats remained elevated 6 h after bilateral nephrectomy. 3. The residual hypertension found during antagonist infusion and after bilateral nephrectomy is not maintained by the renin-angiotensin system or sodium retention.

Topics: Angiotensin II; Animals; Blood Pressure; Female; Hypertension; Nephrectomy; Rats; Saralasin; Sodium

1. Plasma renin activity (PRA) and renin dependency of the blood pressure was analysed in ten patients with various forms of hypertension before and during treatment with volume depletion and/or propranolol. Renin dependency was tested by infusion of the specific competitive angiotensin II antagonist Sar1-Ala8-angiotensin II (P113). 2. The P113-induced fall of the blood pressure did correlate with the log PRA (r=0-888, P less than 0-001). This correlation was found irrespective of different types of hypertension and treatment schedules. 3. During volume depletion, PRA was stimulated and renin dependency of the blood pressure increased. Propranolol therapy suppressed PRA during normovolaemia as well as during volume depletion, and this was accompanied by a decrease of the renin dependency. 4. No incication was found that a given PRA is of special importance for blood pressure elevation in different patients. 5. Suppression of PRA by propranolol is one of the anti-hypertensive mechanisms of this drug.

Topics: Adolescent; Adult; Blood Pressure; Blood Volume; Diuretics; Female; Humans; Hypertension; Male; Middle Aged; Propranolol; Renin; Saralasin

1. Saralasin (Sar1-Ala8-angiotensin II), a competitive inhibitor of angiotensin II (AII), has been infused into normal subjects and patients with essential hypertension when deprived of sodium by 5 days of a 10 mmol/day sodium diet. 2. When saralasin was given by an incremental rate of infusion starting at 0-25 microng min-1 kg-1, sodium-deprived normal subjects showed a fall in standing blood pressure with no change in lying blood pressure, sodium-deprived normal-renin hypertensive patients showed no change in lying or standing blood pressure and sodium-deprived low-renin patients showed a significant sustained rise in lying and standing blood pressure. 3. These findings suggest that: (a) standing blood pressure in sodium-deprived normal subjects is angiotensin II dependent; (b)normal-renin hypertensive patients when sodium deprived by diet alone do not appear to be angiotensin II dependent (angiotensin II is unlikely therefore to be directly maintaining their blood pressure on their normal sodium intake);(c) the rise in blood pressure seen in low-renin hypertensive patients with saralasin may be a further way of distinguishing this group of patients.

Topics: Angiotensin II; Blood Pressure; Humans; Hypertension; Male; Renin; Saralasin; Sodium

1. In all three renin sub-groups of essential hypertension, the state of sodium balance determines the degree of participation of the renin-angiotensin system in sustaining high blood pressure. 2. Even the low-renin type can become renin-dependent when sufficient sodium depletion has bee achieved. 3. The main difference between patients of these sub-groups appears to be their variable capacity to become depleted of sodium under standard dietary regimens.

Topics: Aldosterone; Angiotensin II; Blood Pressure; Humans; Hypertension; Male; Renin; Saralasin; Sodium

1. Injections of antagonists of angiotensin II into the cerebral ventricles of normotensive and spontaneously hypertensive rats were performed in order to assess the role of the isorenin-angiotensin system in the brain. 2. No hypotensive effect was obtained in either normotensive or hypertensive rats, suggesting that intracranial isoangiotensin has little role in the pathogenesis of spontaneous hypertension in the rat.

Topics: Angiotensin II; Animals; Blood Pressure; Cerebral Ventricles; Hypertension; Male; Rats; Saralasin

Hypertension was produced in 25 rabbits by constricting the right renal artery and leaving the opposite kidney intact (two-kidney hypertension). After 30 days mean arterial pressure and plasma renin activity (PRA) were significantly elevated (P less than 0.01), and arterial pressure was correlated with PRA (r = 0.551, P less than 0.01); however, not all hypertensive rabbits had elevated PRA, and in animals in which sodium balance was monitored, only rabbits in negative sodium balance had increased levels of PRA. To investigate the role of angiotensin II (A-II) in the hypertension, [1-sarcosine,8-alanine]angiotensin II was infused at 6 mug/kg per min for 30 min in anesthetized hypertensive animals (n = 25). For the group, arterial pressure fell significantly (P less than 0.01), but several animals with minimal hypertension failed to give a depressor response. The declines in arterial pressure were highly correlated with PRA (r = 0.853, P less than 0.01). Aldosterone secretion in hypertensive animals was correlated with PRA (r = 0.851, P less than 0.01). Thus, two-kidney hypertension in the rabbit persists with normal PRA, but during periods of spontaneous sodium depletion, A-II plays a role in the maintenance of the hypertension.

Topics: Adrenal Glands; Aldosterone; Angiotensin II; Animals; Blood Pressure; Blood Urea Nitrogen; Corticosterone; Depression, Chemical; Desoxycorticosterone; Eating; Hematocrit; Hypertension; Male; Potassium; Rabbits; Regional Blood Flow; Renin; Saralasin; Sodium

Topics: Antihypertensive Agents; Diuretics; Furosemide; Humans; Hypertension; Hypertension, Renal; Physical Exertion; Posture; Potassium; Renin; Saralasin; Water-Electrolyte Balance

Topics: Angiotensin II; Humans; Hypertension; Perfusion; Saralasin

Topics: Angiotensin II; Blood Pressure; Heart Rate; Humans; Hypertension; Hypotension; Male; Middle Aged; Saralasin

Topics: Angiotensin II; Humans; Hypertension; Hypotension, Orthostatic; Infusions, Parenteral; Male; Middle Aged; Posture; Saralasin

Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Humans; Hypertension; Oligopeptides; Rats; Renin; Saralasin; Teprotide

Topics: Angiotensin II; Blood Pressure; Humans; Hypertension; Hypotension; Infusions, Parenteral; Injections, Intravenous; Saralasin

The angiotensin-blocking agent, saralasin, was given by rapid intravenous (bolus) injection to 21 hypertensive patients. A marked depressor response (average blood-pressure decrease of 30 mm Hg systolic and 20 mm Hg diastolic at 10 minutes after injection) was noted in 13 patients, of whom 11 had renovascular hypertension and 2 had high-renin essential hypertension. No change from prebolus blood-pressure was apparent at 10 minutes in 8 control patients with essential hypertension and normal or low peripheral plasma-renin activity. In all patients, blood-pressure response to saralasin bolus (10 mg) correlated with blood-pressure response to subsequent infusion of saralasin (10 microgram/kg/min). Blood-pressure response to rapid intravenous injection of saralasin--the "saralasin bolus test"--has many characteristics of an ideal screening procedure for renin-mediated hypertension.

Topics: Adult; Angiotensin II; Blood Pressure; Humans; Hypertension; Hypertension, Renal; Injections, Intravenous; Renin; Saralasin; Time Factors

Topics: Aldosterone; Aminoglutethimide; Angiotensin II; Animals; Dehydroepiandrosterone; Humans; Hypertension; Hypertension, Renal; Mineralocorticoids; Natriuresis; Norepinephrine; Patient Compliance; Phenoxybenzamine; Renal Artery Obstruction; Renin; Saralasin; Spironolactone

Inhibition of the angiotensin I converting enzyme with SQ 20.881 results in a 2 to 35 fold increase in plasma renin concentration in normal rats and in spontaneously hypertensive rats. The effect is transient, lasting for 1 to 3 hours even in the presence of prolonged blockade. The relative increase is independent of the pretreatment plasma renin concentration. The blood pressure is unchanged in conscious rats in which the effect of SQ 20.881 on plasma renin is believed to be due to a blockade of the negative feedback of angiotensin II on renin release. In anaesthetized rats, SQ 20.88) has an additional hypotensive effect which augments the increase in plasma renin. Saralasin is without effect on blood pressure and plasma renin in conscious normal rats and in spontaneously hypertensive rats, while it causes a transient 3 to 27 fold increase in plasma renin concentration in anaesthetized rats. It is suggested that this increase is hardly due to an interception of the feedback, but to the concomitant fall in blood pressure, as a similar hypotension and increase in plasma renin is produced by dihydralazine. It is furthermore found that Saralasin blocks renin release induced by SQ 20.881. This demonstrates that Saralasin is bound to the receptors in the juxtaglomerular cells and has slight, agonistic properties there. Both in conscious rats and in anaesthetized adrenalectomized rats substituted with DOCA and salt, SQ 20.881 as well Saralasin causes transient increases in plasma renin concentration. If such rats are only substituted with salt and not with DOCA, the effects of both blockers are in the form of severe hypotension and a permanent elevation of plasma renin.

Topics: Adrenalectomy; Anesthesia; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Depression, Chemical; Desoxycorticosterone; Female; Hydralazine; Hypertension; Juxtaglomerular Apparatus; Oligopeptides; Rats; Renin; Saralasin; Sodium Chloride; Stimulation, Chemical; Teprotide; Time Factors

Saralasin, an angiotensin antagonist, was used to study the role of renin-angiotensin in the vasodilator-beta-blocker drug interaction in hypertensive subjects. Plasma renin activity was elevated by withdrawal of propranolol in seven patients using minoxidil and propranolol. After propranolol withdrawal, saralasin caused hypotension (100/60 mm Hg or less) in five. Propranolol lowered blood pressure and plasma renin activity and diminished the hypotensive response to saralasin. Saralasin induced renin release in all patients, an effect blocked by propranolol. We conclude that angiotensin can be the major determinant of blood pressure in vasodilator-drug treated patients, that propranolol lowering of blood pressure in this vasodilator-beta-blocker drug interaction is related to suppression of renin release, and that the angiotensin feed-back-suppression mechanism for inhibiting renin release in functionally located proximal to beta-adrenergic receptors mediating renin release.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Blood Pressure; Depression, Chemical; Drug Interactions; Humans; Hypertension; Minoxidil; Posture; Propranolol; Receptors, Adrenergic; Renin; Saralasin; Stimulation, Chemical; Vasodilator Agents

1. Angiotensin is produced by the intrinsic isorenin--angiotensin system. 2. Angiotensin is secreted into the cerebrospinal fluid of nephrectomized rats. 3. Angiotensin in cerebrospinal fluid elevates systemic blood pressure. 4. Rats with hereditary diabetes insipidus are virtually non-responsive to intraventricular angiotensin. 5. Angiotensin II is elevated in the cerebrospinal fluid of spontaneously hypertensive rats. 6. An intraventricular perfusion of the angiotensin II receptor-blocking agent P 113 decreases blood pressure in spontaneously hypertensive rats.

Topics: Angiotensin II; Angiotensins; Animals; Blood Pressure; Brain; Diabetes Insipidus; Hypertension; Injections, Intraventricular; Rats; Saralasin

Peripheral plasma renin activity (PRA) is not invariably elevated in patients whose ischemic renal lesion is causing hypertension. Infusions of an angiotensin II antagonist, 1-sar-8-ala-angiotensin II (P-113), have been used to determine whether the blood pressure responses might indicate angiotensin dependence in 221 consecutive hypertensive patients. In 32 patients P-113 infusion reversibly reduced blood pressure, and almost all of these "P-113 responders" had elevated renal vein and/or peripheral PRA levels, together with evidence of renal ischemia. Among the 189 "P-113 nonresponders," peripheral PRA was elevated in seven (3.8%), and renal vein PRA ratio was abnormal in two patients, who might represent exceptions to the otherwise successful record of the P-113 response in identifying "angiotensinoginic" hypertensives.

Topics: Adult; Aged; Angiography; Angiotensin II; Blood Pressure; Humans; Hypertension; Ischemia; Kidney; Middle Aged; Nephrectomy; Radioisotope Renography; Regional Blood Flow; Renal Veins; Renin; Saralasin; Urography

Topics: Angiotensin II; Blood Pressure; Blood Volume; Humans; Hyperaldosteronism; Hypertension; Renin; Saralasin; Sodium; Teprotide

Clonidine was nonhypotensive in conscious unrestrained rats maintained on a normal sodium intake. In contradistinction, clonidine caused a dose-related hypotension in conscious unrestrained rats subjected to sodium depletion via furosemide. The plasma renin activity of normal and sodium-depleted rats was reduced after the administration of clonidine (100 mug/kg, iv) by 22.8% and 34.4%, respectively. Intravenous infusion of an angiotensin II antagonist, 1-Sar-8-Ala-angiotensin II, caused a significant reduction of arterial blood pressure in sodium-depleted rats but not in normal rats. Similarly, bilateral nephrectomy reduced arterial blood pressure and completely abolished the hypotensive effect of clonidine in sodium-depleted rats. Subcutaneous administration of chlorisondamine caused a significantly greater reduction of arterial blood pressure in sodium-depleted rats than it did in normal rats. Treatment of normal and sodium-depleted rats with 6-hydroxydopamine reduced the arterial blood pressure of both groups to approximately 85 mm Hg and completely abolished the hypotensive effect of clonidine in the sodium-depleted rats. The data presented in this paper are consistent with the conclusion that clonidine acts at some site in the sympathetic nervous system of sodium-depleted rats to inhibit renal nerve activity with a resultant suppression of renin secretion and a reduction of the angiotensin II-maintained arterial blood pressure. A similar sequence of events occurring in normal rats would not result in hypotension because their arterial blood pressure is not maintained by angiotensin II.

Topics: Animals; Blood Pressure; Clonidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Furosemide; Heart Rate; Hydroxydopamines; Hypertension; Hyponatremia; Hypotension; Male; Nephrectomy; Rats; Renin; Saralasin

Topics: Angiotensin II; Animals; Blood Pressure; Cats; Cerebral Ventricles; Drug Synergism; Hypertension; Injections, Intraventricular; Oligopeptides; Phentolamine; Saralasin; Stimulation, Chemical; Teprotide