saralasin and Chronic-Disease

The performance of carotid sinus baroreceptor reflex (CSR) was characterized in chronically stressed rats by changing intracarotid sinus pressure (ISP) and constructing ISP-MAP (mean arterial pressure) relationship curve. The role of central angiotensin II (ANG II) receptors in the changes of CSR performance induced by chronic stress was determined. Rats were subjected to foot-shock stress for two weeks. The carotid sinus was isolated from the systemic circulation and the ISP changed in a stepwise manner. The results showed that in chronically stressed rats, ISP-MAP relationship curve shifted upward, the set point was significantly higher than that obtained from the unstressed group, and the reflex gain and the MAP range were significantly smaller than those in unstressed rats. After intracerebroventricular injection of saralasin (20 ng), MAP range was augmented and the set point decreased significantly. Injection of vehicle did not lead any significant differences between the parameters of the reflex measured before or after injection in either the stressed or the unstressed rats. Furthermore, administration of ANG II (10 microg) induced a significant increase in the set point and decrease in the reflex gain in the unstressed rats. The responses of CSR to ANG II were completely blocked by pretreatment of saralasin. These findings suggest that chronic stress could induce the decreased CSR function in the normotensives and central ANG II receptors involved in the resetting of CSR in the chronically stressed rats.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Baroreflex; Blood Pressure; Brain Chemistry; Carotid Sinus; Chronic Disease; Injections, Intraventricular; Male; Rats; Rats, Wistar; Receptors, Angiotensin; Saralasin; Stress, Psychological; Vasoconstrictor Agents

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

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 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

We investigated the antagonistic properties of saralasin in acute and chronic angiotension II (ANG II)-dependent hypertension. Two models of experimental hypertension were studied: (a) Rats acutely infused i.v. with ANG II to raise the blood pressure (BP) by about 35 mmHg. (b) One-clip, two-kidney renal hypertensive rats. In both experimental models increasing doses of saralasin were infused i.v., and three parameters were evaluated at each dose level: (1) fall of BP, (2) plasma concentration of saralasin, and (3) plasma concentration of ANG II. It was found that saralasin led to a more pronounced fall of BP in malignant than in benign renal hypertension. To reduce BP by about 20 mmHg, saralasin plasma concentrations had to exceed those of ANG II about 2000-fold in renal hypertension and about 7-fold in rats infused with ANG II. It is concluded that saralasin antagonises ANG II more effectively in acute than in chronic hypertension.

Topics: Acute Disease; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Chronic Disease; Hypertension, Malignant; Hypertension, Renovascular; Male; Rats; Rats, Inbred Strains; Receptors, Angiotensin; Saralasin

1. Removal of the renal artery constriction but not of the clipped kidney restored the blood pressure to normal levels in Goldblatt two-kidney rats with hypertension of more than 4 months' duration. 2. Despite the differences in blood pressure response, both surgical procedures lowered plasma renin concentration to normal or below normal values. 3. Administration of the oral converting enzyme inhibitor SQ 14 225 produced a marked fall in blood pressure in Goldblatt kidney rats with chronic hypertension. However, a prolonged infusion of the angiotensin II antagonist saralasin was quite ineffective. The difference in response to the two inhibitors may have been due to bradykinin potentiation by the converting enzyme inhibitor. 4. Although plasma renin is often elevated in Goldblatt two-kidney rats with hypertension of more than 4 months' duration, the renin-angiotensin system plays no role in the maintenance of blood pressure at this stage.

Topics: Angiotensin II; Animals; Blood Pressure; Captopril; Chronic Disease; Female; Hypertension, Renal; Hypertension, Renovascular; Nephrectomy; Proline; Rats; Renin; Saralasin

The effect of an intravenous infusion of saralasin in a rising dosage on blood pressure, central haemodynamics, forearm blood flow and venous distensibility was tested in 11 subjects with chronic non-uraemic renal disease. Only 1 subject had an elevated resting plasma renin activity, and in him saralasin produced a drop in systolic and diastolic blood pressures due to a decrease of the total peripheral vascular resistance whereas the plasma renin activity markedly rose. Among the remaining 10 subjects, whose plasma renin activity was within the normotensive range, blood pressure rose transiently in 3, with the lowest dose of aralasin, due to an increase in the total peripheral vascular resistance. Both these parameters returned to the control level when continuing the infusion and increasing its dosage. Excluding this initial period from the analysis, no relevant change, even with a more than tenfold increase in the saralasin dosage and a duration of the infusion of 1 h, was found in the following: blood pressure, cardiac and stroke index, heart rate, total peripheral vascular resistance, central and peripheral venous pressures, forearm blood flow and vascular resistance, forearm blood volume and venous distensibility. The haemodynamic response to the Valsalva manoeuvre remained unaffected by saralasin. It is concluded that angiotensin plays an active role in changing the haemodynamics and in elevating the blood pressure in subjects with chronic non-uraemic renal disease only in those cases where plasma renin activity is raised.

Topics: Adult; Angiotensin II; Blood Pressure; Chronic Disease; Female; Forearm; Heart Rate; Humans; Hypertension, Renal; Kidney Diseases; Male; Middle Aged; Regional Blood Flow; Renin; Saralasin; Vascular Resistance

1 Treatment of postural hypotension due to chronic autonomic failure with fludrocortisone increased the pressor sensitivity to intravenous noradrenaline. Fludrocortisone increased the blood pressure in the standing but not the lying position. These effects of fludrocortisone may be the result of increased sensitivity of vascular receptors to noradrenaline. 2 The pressor action of angiotensin II, to which patients were supersensitive, may have involved the stimulation of alpha-adrenoceptors since it was partially antagonised by phentolamine. 3 Saralasin had a marked, paradoxical, pressor effect. This may have been mediated by vascular alpha-adrenoceptors because log dose-response curves of saralasin-induced increases in systolic pressure were shifted to the right in a parallel fashion after phentolamine. 4 Fludrocortisone treatment increased the pressor sensitivity to intravenous saralasin but not to angiotensin-II.

Topics: Aged; Angiotensin II; Autonomic Nervous System; Blood Pressure; Chronic Disease; Female; Fludrocortisone; Humans; Male; Middle Aged; Nervous System Diseases; Norepinephrine; Phentolamine; Saralasin

Topics: Acute Disease; Angiotensin II; Animals; Chronic Disease; Hypertension, Renal; Male; Rats; Renin; Saralasin

Intrarenal infusion of Sar1-Ala8 angiotensin II(P113), a competitive antagonist of angiotensin II, failed to reverse or prevent the decreased ipsilateral renal blood flow and increased renal resistance characteristic of chronic unilateral ureteral occlusion and did not significantly alter plasma renin activity in the chronic state. Thus, angiotensin II does not appear to play a significant role in the hemodynamic response to unilateral ureteral occlusion.

Topics: Acute Disease; Angiotensin II; Animals; Chronic Disease; Dogs; Female; Glomerular Filtration Rate; Kidney; Regional Blood Flow; Renin; Saralasin; Ureteral Obstruction; Vascular Resistance

1-Sar-8-ala angiotensin II (saralasin) was infused intravenously in graded doses of from 0.1 to 10 mug/kg/min to five patients with cirrhosis and ascites after three days of restricted sodium intake. In each patient blockade of AII by saralasin produced a marked fall in blood pressure, a rise in plasma renin activity (PRA) and plasma renin concentration (PRC) and, in four of the five, a fall in plasma aldosterone (PA). The rise in PRA and PRC correlated poorly with changes in blood pressure. The effects of saralasin rapidly reversed after cessation of the infusion. Plasma volume was normal or high in each case. Three patients were mildly hypotensive in the control state, and all five were resistant to the pressor effect of infused AII. After three days of salt loading, the above effects of saralasin were diminished but not abolished. In four normal subjects, after salt depletion, saralasin infusion induced qualitatively similar but much smaller changes in blood pressure, PRA and PRC. In two cirrhotic patients without ascites, after salt depletion, saralasin infusion caused a rise in blood pressure with no significant changes in PRA, PRC or PA. These results provide evidence that in patients with cirrhosis and ascites circulating AII is active in support of blood pressure, in direct suppression of renal renin release, and in stimulation of aldosterone release.

Topics: Aldosterone; Angiotensin II; Blood Pressure; Chronic Disease; Humans; Liver Cirrhosis; Renin; Saralasin