saralasin and Heart-Failure

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

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

Congestive heart failure is frequently associated with elevated systemic vascular resistance. Lowering resistance can improve cardiac performance and alleviate symptoms. The angiotensin-converting enzyme inhibitors offer a new way to lower resistance and have certain advantages, including the inhibition of compensatory mechanisms. However, skillful use of these compounds demands a thorough understanding of their pharmacologic properties and of the pathophysiology of congestive heart failure.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Captopril; Heart Failure; Hemodynamics; Humans; Myocardial Contraction; Renin-Angiotensin System; Saralasin; Teprotide

Topics: Animals; Antihypertensive Agents; Captopril; Dogs; Guinea Pigs; Heart Failure; Humans; Renin; Renin-Angiotensin System; Saralasin; Teprotide

In anaesthetized dogs that were sodium-depleted or subjected to thoracic caval constriction, Sar1-Ala8-angiotensin II produced a striking decrease in aldosterone secretion; also, arterial pressure fell while plasma renin activity (PRA) increased. Recent preliminary observations in conscious dogs during angiotensin II blockade with measurements of the plasma aldosterone level, arterial pressure and PRA have confirmed these observations; a striking fall in plasma aldosterone and arterial pressure occurred while PRA increased. In the rat, sodium depletion produced a marked increase in PRA and aldosterone secretion; studies with angiotensin II blockade during administration of the nonapeptide converting enzyme inhibitor or Sar1-Ala8-angiotensin II demonstrated an important role for angiotensin II in mediating the increase in aldosterone secretion during sodium depletion in the rat. In experimental high output failure secondary to a large aortic-caval fistula, angiotensin II blockade revealed that angiotensin II decreases renal blood flow and helps to maintain the level of arterial pressure; thus, the kidney participates in the compensatory action of angiotensin II to increase total peripheral resistance. Angiotensin II blockade in both one and two-kidney renal hypertensive dogs revealed that angiotensin II was important in the pathogenesis of the acute phase, but in chronic renal hypertension the mechanisms appeared to be angiotensin II-dependent.

Topics: Aldosterone; Angiotensin II; Animals; Blood Pressure; Dogs; Heart Failure; Hypertension, Renal; Kidney; Rats; Regional Blood Flow; Renin; Saralasin; Species Specificity; Time Factors

The renin-angiotensin system is activated in the majority of patients with chronic congestive heart failure. This may be part of the pathophysiology of the disease, a secondary phenomenon, or the result of intense diuretic therapy. Irrespective of the mechanism of renin-angiotensin activation, converting enzyme inhibitors are an effective form of therapy as well as a means to evaluate pathophysiologic mechanisms of congestive heart failure. Because of the activation of the renin-angiotensin system, angiotensin-mediated vasoconstriction and aldosterone-mediated sodium retention can be suppressed and, in some individuals, completely blocked by converting enzyme inhibitors. Improved forward cardiac flow and reduction of pulmonary congestion occur with reversal of vasoconstriction, so that relief of edema, due to enhanced sodium and water excretion, will occur. While it is easy to identify a close correlation between markers of renin-angiotensin activity and the initial response to converting enzyme inhibitors, it is more difficult to identify this response long-term. This may be due to changes in dietary sodium intake, intensity of diuretic therapy, or alteration in renal blood flow and function. Clinically, however, the response to converting enzyme inhibitors is favorable in the majority of people.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Enalapril; Enalaprilat; Enzyme Activation; Heart Failure; Heart Rate; Hemodynamics; Humans; Renin-Angiotensin System; Saralasin; Sodium; Vasoconstriction

The chronic heart insufficiency is essentially characterized by a disturbed regulative function of the peripheral circulation. These processes taking place within efforts for compensation close the chain of the vicious circle. The vasodilators with their different principles of effect affect in various places of the vegetative nervous system up to the smooth musculature of the vessels and modulate the peripheral part of the cardiovascular system. Via a changed behaviour of the impedance also with the arterial vasodilation the ejection behaviour of the insufficed hearts changes. With the increase of the ejection fraction the filling pressure can decrease, also when only the arterial branch of the periphery of the vessels is influenced. In case of an additional vasodilation of the capacity vessels greater influences of the preload are present. As a rule after the full use of the conventional therapy with digitalis and saluretics is resorted to the adjuvant therapy with vasodilators. Good experiences in the therapy of chronic heart insufficiency are present above all for hydralazine and prazosin as well as increasingly also for captopril, when vasodilating and at the same time positively inotropic medicaments are disregarded. In future, depending upon haemodynamic and neurohumoral (PNA, PRAA) findings in problematic cases and aimed additional adjuvant therapy will be aspired to.

Topics: Adrenergic beta-Agonists; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Captopril; Clonidine; Heart Failure; Hemodynamics; Humans; Myocardial Contraction; Prazosin; Saralasin; Vascular Resistance; Vasodilator Agents

Congestive heart failure is an unusual complication of the hyperreninemia of Wilms' tumors. Cases with bilateral tumors present a difficult management problem. This is a report of the successful medical management of a child with congestive heart failure secondary to hyperreninemia from bilateral Wilms' tumor. Hypertension and hyperreninemia were extensively documented. Their etiologic relation to the congestive heart failure was supported by the patient's improved cardiac function following specific renin-angiotensin blockade. With unilateral tumors, surgical excision corrects the hypertension; however, with large bilateral tumors, excision is out of the question. A unique feature of this case is the ability to control the blood pressure with saralasin. With subsequent antitumor therapy, renin concentrations decreased proportional to tumor size, and renin angiotensin blocking therapy could be discontinued.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Pressure; Dactinomycin; Echocardiography; Heart Failure; Humans; Hypertension, Renal; Infant; Kidney Neoplasms; Male; Neoplasms, Multiple Primary; Renin; Renin-Angiotensin System; Saralasin; Ultrasonography; Vincristine; Wilms Tumor

The renin-angiotensin system has been shown to participate in the pathophysiology of chronic heart failure in many patients. However, the immediate assessment of this contribution in individual patients may sometimes be difficult. As a pharmacologic estimate of angiotensin II receptor activity, we infused the angiotensin II analogue, saralasin, in 20 patients with severe chronic congestive heart failure (CHF). The infusion resulted in blood pressure responses ranging from an agonist pressor response (increased systemic resistance) in patients with low intrinsic renin-angiotensin system activity, to an antagonist depressor response (decreased systemic resistance) in patients with marked activation of the renin-angiotensin system. The ability of the saralasin response to pharmacologically estimate angiotensin II receptor activity in CHF was further revealed by two physiologic maneuvers that decrease endogenous circulating angiotensin II and angiotensin II receptor occupancy. Both converting enzyme inhibition with captopril and sodium repletion, factors known to decrease endogenous angiotensin II activity, provoked agonist responses to saralasin infusion. Furthermore, saralasin was able to reverse the orthostatic hypotension precipitated by converting enzyme inhibition of angiotensin-dependent vascular tone. In summary, saralasin provided a means to estimate angiotensin receptor activity and may therefore serve as a probe of angiotensin-mediated vasoconstriction in the pathophysiology of chronic CHF.

Topics: Adult; Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Captopril; Chronic Disease; Female; Heart Failure; Hemodynamics; Humans; Hypotension, Orthostatic; Male; Middle Aged; Receptors, Angiotensin; Receptors, Cell Surface; Renin; Saralasin; Sodium

Converting enzyme inhibition of the renin-angiotensin system has proved a valuable therapeutic approach in patients with severe chronic congestive heart failure. In the present study, a new long-acting converting enzyme inhibitor (enalapril) was evaluated with acute single dose testing (10, 20 or 40 mg) in nine patients with severe chronic congestive heart failure. Four hours after administration, there was a significant reduction of systemic vascular resistance (-19%) and pulmonary wedge pressure (-19%); in addition, there were related increases of cardiac index (+16%) and stroke index (+19%) (probability [p] less than or equal to 0.05 for all changes). This was associated with an increase of plasma renin activity (9 +/- 3 to 35 +/- 11 ng/ml per hour) and a decrease of plasma aldosterone (19 +/- 4 to 9 +/- 2 ng/100 ml) (p less than 0.02 for both). With long-term therapy (1 month), there was improvement of exercise tolerance time and lessening of symptoms based on the New York Heart Association classification. Hemodynamic improvement was maintained in most, but not all, patients. There was no orthostatic hypotension during head-up tilt and hemodynamic values in the upright position were associated with normalization of intracardiac pressures. Long-term converting enzyme inhibition was indicated by a persistent increase of plasma renin activity (16 +/- 2 ng/ml per hour) and a decrease of plasma aldosterone (8 +/- 3 ng/100 ml). In addition, relative angiotensin II receptor occupancy was decreased as judged by the pharmacodynamic response to infusion of the angiotensin II analog saralasin. In conclusion, the long-acting converting enzyme inhibitor, enalapril, was effective in patients with chronic congestive heart failure; however, additional studies will be necessary to further delineate the optimal dose range and identify those patients who are most likely to respond to the drug.

Topics: Administration, Oral; Aged; Chronic Disease; Dipeptides; Enalapril; Female; Heart Failure; Hemodynamics; Humans; Hypotension, Orthostatic; Long-Term Care; Male; Middle Aged; Oligopeptides; Saralasin; Teprotide; Time Factors

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

In an earlier study of guinea pigs with constriction of the pulmonary artery (PA) for 30 days, hindquarters' vascular resistance was maintained primarily by humoral mechanisms. In the present study, we investigated the contribution of circulating catecholamines, angiotensin II, and other constrictor stimuli to hindquarters' vascular resistance by observing vasodilator responses to specific competitive antagonists. Pressure-flow curves indicated vascular resistances in isolated, perfused, sympathectomized hindquarters of anesthetized guinea pigs. Phentolamine produced significantly greater (P less than 0.05) vasodilatation in animals with constriction of pulmonary artery than in sham animals [Sar1-Ala8]angiotensin II produced no vasodilation in either group. After alpha-adrenergic blockade, papaverine produced similar vasodilatation and similar final perfusion pressures in both groups. It appears that circulating catecholamines and augmented vasoconstrictor responsiveness to norepinephrine are totally responsible for the increased humoral regulation of vascular resistance in this experimental model of right ventricular hypertrophy.

Topics: Angiotensin II; Animals; Cardiomegaly; Catecholamines; Dopamine; Epinephrine; Guinea Pigs; Heart Failure; Norepinephrine; Papaverine; Phentolamine; Phenylephrine; Saralasin; Sympathetic Nervous System; Tyrosine 3-Monooxygenase; Vascular Resistance

Five of 11 normotensive patients with congestive heart failure responded to an infusion of the specific angiotensin II antagonist, saralasin, by reducing systemic vascular resistance from 2274 +/- 418 to 1690 +/- 351 dynes/sec/cm-5 (mean +/- standard error). This decrease was accompanied by a reduction in left ventricular filling pressure from 19.4 +/- 5.9 to 11.6 +/- 4.0 mm Hg, an increase in cardiac index from 2.2 +/- 0.4 to 2.7 +/- 0.4 l/min/m2 and a decrease in mean arterial pressure from 95 +/- 9.8 to 86 /+- 8.6 mm Hg. In the other 6 patients with congestive heart failure and in 4 controls, saralasin produced either no change or slight increases in systemic vascular resistance. Plasma renin activity did not differentiate responders from non-respnders. Specific inhibition of angiotensin may provide a means for reducing inappropriately high peripheral resistance in some patients with congestive heart failure.

Topics: Adult; Aged; Angiotensin II; Cardiac Catheterization; Cardiac Output; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Saralasin; Vascular Resistance

The role of the renin angiotensin system was evaluated in 18 normotensive patients with chronic congestive heart failure and in 5 controls. No correlation was observed between plasma renin activity and cardiac index. There was a significant inverse correlation between renin and pulmonary capillary wedge pressure (r = -0.61, P less than 0.01). Renin values of the patients appeared to be increased when compared with controls with similar left ventricular filling pressure. Specific angiotensin II inhibition by saralasin decreased arterial pressure in 8 out of 14 patients: their renin was significantly higher than that of the remaining 6 patients (P less than 0.01). The 2 patients with the lowest renin levels responded to saralasin with a blood pressure increase. Left ventricular filling pressure decreased in all but these latter 2 patients with either little change or an increase in stroke volume. Thus, renin levels appear to be increased in normotensive patients with congestive heart failure when related to left ventricular filling pressure. Renin via angiotensin II plays a role in the blood pressure control of many patients with congestive heart failure. In some patients angiotensin II blockade appears to improve cardiac function by unloading the left ventricle.

Topics: Adult; Aged; Angiotensin II; Blood Pressure; Cardiac Output; Female; Heart; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Renin; Saralasin

A patient with intractable congestive cardiac failure secondary to renovascular hypertension and severe coronary artery disease was infused with the competitive antagonist of angiotensin II, saralasin acetate. The infusion produced an impressive increase in cardiac output and left ventricular stroke work index in parallel with a striking decrease in the systemic and pulmonary vascular resistance, the coronary resistance, and the myocardial oxygen consumption. It is suggested that angiotensin inhibition may present advantages over other forms of treatment of congestive cardiac failure in selected cases.

Topics: Angiotensin II; Cardiac Output; Cardiac Volume; Coronary Circulation; Heart Failure; Humans; Hypertension, Renal; Male; Middle Aged; Oxygen Consumption; Pulmonary Circulation; Renin; Saralasin; Vascular Resistance

1. In the dog constriction of the thoracic region of the inferior vena cava increases water intake and extracellular and plasma fluid volumes. 2. Restriction of water intake to the pre-operative level for 2 weeks reduces the measured extracellular fluid volume to the pre-operative level. 3. Administration of the competitive angiotensin inhibitor, saralasin acetate, to two dogs in congestive cardiac failure following thoracic caval constriction markedly reduced their water intake. 4. These results suggest that increased fluid intake is probably important in the aetiology of the oedema associated with congestive cardiac failure, probably through the renin-angiotensin system.

Topics: Angiotensin II; Animals; Blood Proteins; Dogs; Edema; Extracellular Space; Female; Heart Failure; Hematocrit; Ligation; Male; Osmolar Concentration; Plasma Volume; Potassium; Saralasin; Sodium; Thirst; Vena Cava, Inferior; Water Deprivation

Dogs with experimental high-output heart failure (HOF) exhibit marked retention of salt and water secondary to hypersecretion of both renin and aldosterone. The present study was undertaken to evaluate the systemic and intrarenal arteriolar action of angiotensin II (AII) in dogs with HOF and to provide additional information about the role of AII in low-output states. The intravenous infusion of a specific AII antagonist, [Sar1, Ala8]AII (6 mug/kg min-1), into conscious dogs with HOF decreased the mean arterial pressure (AP) from 101 +/- 7 to 83 +/- 7 mmHg (P less than 0.01) after 45 min of infusion. Intrarenal arterial infusion of the AII antagonist (0.2 and 2.0 mug/kg min-1) into anesthetized dogs with HOF also decreased AP and produced a marked increase in renal blood flow (RBF) with no changes in either creatinine clearance or sodium excretion. Similar results were obtained during the intrarenal infusion of the antagonist into sodium-depleted dogs and dogs with thoracic vena caval constriction, but not in normal dogs. The data demonstrate an important role for AII in the regulation of AP and RBF in high- and low-output states.

Topics: Angiotensin II; Animals; Blood Pressure; Creatinine; Dogs; Female; Glomerular Filtration Rate; Heart Failure; Kidney; Regional Blood Flow; Renin; Saralasin; Sodium

Acute thoracic inferior vena cava constriction results in alterations in renal hemodynamics which may explain the characteristic antinatriuretic response. Since adrenalvein-aldosterone secretion is increased within 30 minutes of acute caval constriction and elevated plasma-renin activity is found in the chronic caval dog, we sought to determine whether the renal hemodynamic alterations observed in acute caval constriction are due to the intrarenal action of angiotensin II. The renal response to acute caval constriction in dogs receiving unilateral renal arterial infusion of a specific competitive antagonist of angiotensin II, 1-sarcosine-8-alanine-agiotensin II, was studied. Effective blockade did not alter the renal hemodynamic or antinatriuretic response to acute caval constriction. As a model of chronic sodium retention, dogs with chronic congestive heart failure produced by tricuspid insufficiency and pulmonary stenosis were similarly studied. Effective renal blockade to antiotensin II did not affect renal hemodynamics or urinary sodium excretion. The renal hemodynamic and antinatriuretic responses to acute caval constriction and chronic congestive heart failure are not dependent on the intrarenal action of angiotensin II.

Topics: Angiotensin II; Animals; Constriction; Dogs; Female; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Kidney; Kidney Cortex; Metabolic Clearance Rate; Regional Blood Flow; Renin; Saralasin; Sodium; Time Factors; Vena Cava, Inferior