saralasin and Hypotension

Hormonal systems such as vasopressin (AVP) and the renin-angiotensin-aldosterone system (RAS) have been reported to become activated during anesthesia and surgery. The purpose of this study was to examine the relative importance of AVP and angiotensin II (AII) in blood pressure control during isoflurane anesthesia in rats.. Rats were given an AVP V1-receptor antagonist (AVP-a, 10 microg kg(-1)), the AII receptor antagonist saralasin (SAR, 20 microg kg(-1) min(-1)) and hexamethonium (HEX, 10 mg kg(-1)) intravenously in random order, awake or anesthetized with isoflurane.. AVP-a had no effect on mean arterial pressure (MAP) in awake or anesthetized animals, but reduced MAP by 20.0+/-2.2% in the anesthetized rats which previously had been treated with SAR and/or HEX. SAR infusion had no effect on MAP when administered to conscious rats, but decreased MAP by 12.0+/-4.4% during anesthesia. Ganglionic blockade with HEX consistently lowered MAP in the conscious and anesthetized animals.. It is concluded that AVP contributes to the maintenance of blood pressure when the autonomic nervous system (ANS) and/or RAS are blocked during isoflurane anesthesia. SAR infusion leads to hypotension during anesthesia, but not in conscious rats. These findings indicate that AII is of importance for blood pressure maintenance during isoflurane anesthesia in rats, and that apparent pressor effects of AVP come into play when RAS and/or ANS are blocked.

Topics: Anesthesia, Inhalation; Anesthetics, Inhalation; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine Vasopressin; Autonomic Nervous System; Blood Pressure; Consciousness; Ganglionic Blockers; Hexamethonium; Hormone Antagonists; Hypotension; Infusions, Intravenous; Isoflurane; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Saralasin; Vasoconstrictor Agents; Vasopressins

We reported that intravenous infusion of angiotensin II (ANG II) stimulated ventilation (VE) in conscious dogs. Other studies in our laboratory have demonstrated that increases in respiration occurred in association with activation of the renin-angiotensin system during acute hypotension and during hypercapnia. Therefore, in conscious dogs (n = 5), we examined the effects of ANG II receptor blockade with intravenous saralasin (0.5 micrograms.kg-1.min-1) on respiratory responses during progressive nitroprusside-induced hypotension and during the ventilatory response to increased inspired fraction of CO2 (VRC). During hypotension (mean arterial pressure decreased approximately 20%) combined with ANG II receptor blockade, VE, heart rate, and arginine vasopressin increases were attenuated compared within unblocked studies. With ANG II receptor blockade during hypotension, alveolar ventilation and arterial PCO2 (PaCO2) were unchanged, which contrasted with a doubling of alveolar ventilation and a decrease of 4.8 +/- 1 Torr in PaCO2 in unblocked studies. During hypercapnia, the slope of the VRC was not affected by ANG II receptor blockade, but with 6.5% inspired CO2 fraction, VE and PaCO2 were lower than in unblocked studies. These results indicated that ANG II contributed to the respiratory response to a modest hypotension but did not affect respiratory sensitivity to CO2.

Topics: Acute Disease; Angiotensin II; Animals; Arginine Vasopressin; Blood Glucose; Blood Pressure; Dogs; Hypercapnia; Hypotension; Male; Nitroprusside; Osmolar Concentration; Oxygen Consumption; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Respiration; Saralasin

Angiotensin II (ANG II) and vasopressin participate in baroreflex regulation of adrenocorticotropic hormone (ACTH), glucocorticoid, and renin secretion. The purpose of this study was to determine whether this participation is enhanced in water-deprived dogs, with chronically elevated plasma ANG II and vasopressin levels, compared with water-replete dogs. The baroreflex was assessed by infusing increasing doses of nitroprusside (0.3, 0.6, 1.5, and 3.0 micrograms.kg-1.min-1) in both groups of animals. To quantitate the participation of ANG II and vasopressin, the dogs were untreated or pretreated with the competitive ANG II antagonist saralasin, a V1-vasopressin antagonist, or combined V1/V2-vasopressin antagonist, either alone or in combination. The findings were as follows. 1) Larger reflex increases in ANG II, vasopressin, and glucocorticoids, but not ACTH, were produced in water-deprived dogs compared with water-replete dogs. 2) ANG II blockade blunted the glucocorticoid and ACTH responses to hypotension in water-deprived dogs, but not water-replete dogs. In contrast, vasopressin blockade reduced the ACTH response only in water-replete dogs. 3) Vasopressin or combined vasopressin and ANG II blockade reduced the plasma level of glucocorticoids related either to the fall in arterial pressure or to the increase in plasma ACTH concentration in water-replete dogs, and this effect was enhanced in water-deprived dogs. 4) In both water-deprived and water-replete animals, saralasin and/or a V1-antagonist increased the renin response to hypotension, but a combined V1/V2-antagonist did not. These results reemphasize the importance of endogenous ANG II and vasopressin in the regulation of ACTH, glucocorticoid, and renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenocorticotropic Hormone; Angiotensin II; Animals; Dogs; Female; Glucocorticoids; Hypotension; Male; Nitroprusside; Reflex; Renin; Saralasin; Vasopressins; Water Deprivation

In anesthetised rats, infusion of angiotensin II increased mean arterial pressure and inhibited the depressor responses to acetylcholine administration. Low doses of angiotensin did not exert this effect. This and other data obtained suggest that angiotensin II inhibits cardiovascular effects of the cholinergic system tonically.

Topics: Acetylcholine; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Dose-Response Relationship, Drug; Drug Interactions; Female; Hypotension; Male; Neostigmine; Oligopeptides; Rats; Receptors, Cholinergic; Renin-Angiotensin System; Saralasin; Teprotide; Time Factors

It was previously shown that the vasoconstrictory response to hypotension was similar in the mucosa of the small bowel and the colon but was significantly higher in the muscularis of the latter than that of the former. To understand the mechanism of this differential response of the muscularis of the small bowel and the colon, the present study investigated the effect of an angiotensin II inhibitor (saralasin) on the hypotension-induced vasoconstriction of the mucosa and the muscularis of these two locations of the gastrointestinal tract. Dogs were used. Hypotension was induced by hemorrhage to reduce blood pressure by 40 mm Hg. Blood flow was measured by 15-microns radiolabeled microspheres. Saralasin was infused intravenously for 20 minutes at a rate of 0.05 mg.kg-1 bolus followed by 1 microgram.kg-1.min-1. Saralasin had no effect on the basal blood flow of the mucosa or the muscularis of the small bowel or on the hypotension-induced vasoconstriction of these two layers of the small bowel. In contrast, saralasin decreased blood flow to the mucosa (-28%; P less than 0.001) and increased blood flow to the muscularis (+140%; P less than 0.001) of the colon under basal conditions and also reduced the hypotension-induced vasoconstriction of the colonic muscularis (P less than 0.01). These and supplementary data indicate that there is a difference between the small bowel and the colon in local activity of vascular angiotensin system and that this system is most active in the colonic muscularis where it plays a significant role in the vasoconstrictory response to hypotension.

Topics: Angiotensin II; Animals; Blood Vessels; Dogs; Gastrointestinal Hemorrhage; Hemodynamics; Hypotension; Intestines; Regional Blood Flow; Saralasin; Vascular Resistance

Naloxone reverses hemorrhagic hypotension in the conscious guinea-pig. Captopril and saralasin impede this naloxone effect, suggesting that angiotensin II is involved in naloxone action. This is compatible with previous work which has shown that B-endorphin inhibits the centrally mediated pressor action of angiotensin II, and that naloxone blocks this effect. Naloxone may be interacting with the postulated brain renin-angiotension II system or may be blocking the action of shock-induced circulating angiotensin II on a centrally located area such as the hypothalamus.

Topics: Animals; Blood Pressure; Captopril; Guinea Pigs; Hemorrhage; Hypotension; Hypothalamus; Naloxone; Neural Inhibition; Receptors, Opioid; Renin-Angiotensin System; Saralasin

This study was performed to assess the possible contribution of endogenous angiotensin II (AII) to the regulation of urinary kallikrein excretion. The AII antagonist saralasin or the saline vehicle was infused into the aorta above the renal arteries of pigs under halothane-O2/N2O anaesthesia. Systemic and renal functional parameters were followed for 140 min and during stimulation of the reninangiotensin system by haemorrhage. Urinary kallikrein excretion, determined as kininogenase activity, was increased immediately upon both initiation and termination of the 2 h saralasin infusion into pigs not subjected to haemorrhage. Renal cortical blood flow (RCBF) was maintained, in both saline and saralasin-treated animals at blood pressures as low as 70 mm Hg, while glomerular filtration rate was dissociated during saralasin infusion. As long as RCBF was maintained, urinary kallikrein excretion rate was elevated during the progressive hypotension in both saline and saralasin-treated animals. These findings confirm a close relationship between the maintenance of RCBF and increased activity of the kallikrein-kinin system whether or not AII is antagonized, and indicate that during haemorrhage the kallikrein-kinin system is stimulated by a mechanism not involving AII.

Topics: Angiotensin II; Animals; Glomerular Filtration Rate; Hemorrhage; Hypotension; Kallikreins; Renal Circulation; Saralasin; Swine; Time Factors

The active fragment derived from factor XII (factor XIIf) was purified from human plasma and administered intravenously to normotensive conscious rats. Factor XIIf-mediated hypotension was dose-dependent and augmented by pretreatment with captopril, an inhibitor of the angiotensin I- and bradykinin-processing enzyme. In contrast, factor XIIf-induced hypotension was not enhanced by blockade of the renin-angiotensin system by saralasin, a competitive antagonist of angiotensin II at the vascular receptor level. These results suggest that factor XIIf-mediated hypotension is due to the formation of bradykinin.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Captopril; Factor XII; Factor XIIa; Hypotension; Male; Peptide Fragments; Rats; Rats, Inbred Strains; Saralasin

We have assessed the influence of acute bilateral nephrectomy, of captopril and saralasin, on the hypotensive activity of neurotensin (NT) and of various hypotensive drugs in pentobarbital-anesthetized rats. The results show that the hypotensive activity of NT and of compound 48/80 (C48/80), in contrast to that of histamine, of 5-hydroxytryptamine and of hexamethonium, is markedly reduced, especially for NT, in nephrectomized as compared to sham operated rats. The pretreatment of rats with captopril (10 mg kg-1, i.v.) or with saralasin (20 micrograms kg-1 min-1, i.v.) was found to inhibit significantly the hypotensive activity of NT and of C48/80. Adrenalectomy restored partially the hypotensive activity of NT in nephrectomized rats. The potent vasopressin antagonist [d(CH2)5 Tyr(Me)AVP] did not alter the refractoriness of nephrectomized rats to the hypotensive activity of NT. Neither nephrectomy nor saralasin were found to interfere with the ability of NT or of C48/80 to evoke an increase of plasma histamine level or of the hematocrit. The results were interpreted as an indication that NT produces part of its hypotensive effect in anesthetized rats by reducing the activity of the renin angiotensin system. The results also suggest that part of the refractoriness of nephrectomized rats to the hypotensive activity of NT could be due to the release of catecholamines from adrenal glands by NT. Endogenous vasopressin does not appear to contribute to the refractoriness of nephrectomized rats to the hypotensive action of NT.

Topics: Angiotensin II; Animals; Blood Pressure; Captopril; Hematocrit; Histamine; Histamine Release; Hypotension; Male; Nephrectomy; Neurotensin; p-Methoxy-N-methylphenethylamine; Proline; Rats; Rats, Inbred Strains; Saralasin

The participation of angiotensin II (ANG II) in the maintenance of arterial blood pressure during hypotensive hemorrhage was examined in unanesthetized, baroreceptor-denervated dogs. When mean aortic blood pressure was reduced to 69.0 +/- 2.2 mmHg, plasma renin activity increased from 0.6 +/- 0.3 ng ANG I X ml-1 X h-1 during the prehemorrhage control period to 4.5 +/- 1.6. Twenty minutes after the hemorrhage, mean aortic blood pressure rose to 78.9 +/- 3.1 mmHg. Subsequent infusion of the angiotensin II antagonist saralasin (5.2-14.0 micrograms X kg-1 X min-1) decreased mean aortic pressure to 59.6 +/- 3.3 mmHg. When 5% dextrose was infused in place of saralasin, mean aortic pressure was 79.3 +/- 4.3 mmHg. The lower aortic blood pressure caused by saralasin infusion was the result of a significant decrease in total peripheral resistance. Resistance was 10.3 +/- 3.2 mmHg X l-1 X min lower during saralasin infusion than during dextrose infusion. We conclude that baroreceptor reflexes are not essential for the elevation of plasma renin activity during hemorrhage. In baroreceptor-denervated dogs subjected to hypotensive hemorrhage, the increased formation of ANG II has a vasoconstrictor action that contributes to the maintenance of arterial blood pressure.

Topics: Angiotensin II; Animals; Aorta; Blood Pressure; Cardiac Output; Carotid Sinus; Denervation; Dogs; Heart Rate; Hemorrhage; Hypotension; Pressoreceptors; Renin-Angiotensin System; Saralasin; Vascular Resistance; Vasoconstriction

The mechanism of the hypotensive response to captopril was investigated in pithed and urethane anesthetized rats. Cumulative intravenous doses of captopril produced dose-dependent hypotensive responses which were correlated with blockade of the pressor response to angiotensin I. Angiotensin II responses were unaffected. Infusions of saralasin, an angiotensin receptor antagonist, inhibited the hypotensive action of captopril, the degree of antagonism being correlated with inhibition of angiotensin II pressor responses. Bilateral nephrectomy lowered blood pressure to approximately the same level as captopril and completely abolished the hypotensive effect of captopril. No evidence was obtained for the involvement of endogenous bradykinin or prostaglandins in the hypotensive action of captopril. It is concluded that in pithed and urethane anesthetized rats, captopril mediates its hypotensive response by removing the renal renin-angiotensin system, most probably via inhibition of angiotensin I - converting enzyme. The results contrast with similar studies conducted in anesthetized dogs. In this species, the mechanism of action of captopril remains for further resolution.

Topics: Angiotensin I; Angiotensins; Animals; Blood Pressure; Bradykinin; Captopril; Dose-Response Relationship, Drug; Hypotension; Indomethacin; Male; Nephrectomy; Proline; Rats; Saralasin

Topics: Adult; Angiotensin II; Female; Furosemide; Humans; Hypertension, Renovascular; Hypotension; Infusions, Parenteral; Saralasin

Topics: Adult; Angiotensin II; Female; Hemodynamics; Humans; Hypotension; Injections, Intravenous; Male; Middle Aged; Saralasin

Topics: Angiotensin II; Hemodynamics; Humans; Hypertension, Renal; Hypotension; Infusions, Parenteral; Male; Middle Aged; Saralasin

Topics: Adult; Angiotensin II; Female; Humans; Hypertension, Renal; Hypotension; Renin; Saralasin; 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

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

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

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