Haemodynamic effects of acute and chronic renin inhibition in marmosets

Wood, Jeanette M.; Baum, Hans-Peter; Forgiarini, Peter; Gulati, Neelam; Jobber, R. A.; Neisius, D.; Hofbauer, Karl G.

doi:10.1097/00004872-198904002-00009

Cited by 12 publications

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“…Previous experiments ljy other investigators 11sing combinations of inhibitors of the renin-angioteiisin systeiri in similar aiiiiiial niodels liavc riot demonstrated a synergistic h).potensive eflect [Oldham et al, 1984;Wood et al, 1989Wood et al, , 1990Pals et aI. ;Wong et al, 19901.…”

Section: Introductionmentioning

confidence: 97%

Synergistic effect on reduction in blood pressure with coadministration of a renin inhibitor or an angiotensin‐converting enzyme inhibitor with an angiotensin II receptor antagonist

Fossa

DePasquale

Ringer

et al. 1994

Drug Development Research

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The effects of coadministration of a renin inhibitor, terlakiren, and an angiotensinconverting enzyme inhibitor, captopril, with the angiotensin II receptor antagonist, losartan, on blood pressure of sodium-depleted guinea pigs were studied. Dose-response relationships for terlakiren (0.1 to 3.0 mg/kg, iv), captopril (0.03 to 1.0 mgikg, iv), and losartan (0.1 to 6.0 mgikg, iv) were obtained either alone or in the presence of a submaximal dose of the other inhibitor. The hypotensive response calculated for each compound individually was subtracted from the response to each dose of the combination of inhibitors, and the results showed that statistically significant synergy with terlakiren and captopril occurred in the presence of losartan. The degree of the synergy indicated that to achieve the same response on blood pressure, the dose of each drug could be decreased approximately 2-to 7-fold when administered in combination. These results indicate that by inhibiting multiple sites in the renin-angiotensin system, synergistic effects can be produced. The relative safety of each inhibitor could be improved by large reductions in dose when used concurrently. o 1994 WiIey-Liss, Inc.

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Section: Introductionmentioning

confidence: 97%

Synergistic effect on reduction in blood pressure with coadministration of a renin inhibitor or an angiotensin‐converting enzyme inhibitor with an angiotensin II receptor antagonist

Fossa

DePasquale

Ringer

et al. 1994

Drug Development Research

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“…It is early and rate-limiting step in the synthesis of angiotensin II now generally believed that these reactions occur both in the (All), the active end-product of the RAS, is the cleavage of circulating blood and at tissue sites (Campbell, 1987; angiotensinogen by renin. This results in the formation of the J.P. van Kats etal Renin inhibition and cardiac contractility animals (Tree et al, 1989;Wood et al, 1989;1990;Schaffer et al, 1990; Fischli et al, 1991;1994; Kleinert et al, 1992;Clozel & Fischli, 1993;Wessale et al, 1993a,b; However, due to the low oral bioavailability of the renin inhibitors studied so far, these agents are not widely used.…”

Section: Introductionmentioning

confidence: 99%

“…More recent studies using non-peptidic renin inhibitors have focussed mainly on their ability to lower blood pressure and do not address cardiac effects. The blood pressure lowering effects of these inhibitors appear to be caused by inhibition of the RAS (Tree et al, 1989;Wood et al, 1989;1990; Fischli et al, 1991;Clozel & Fischli, 1993;Fisher et al, 1994). It is still a matter of debate whether this involves RAS inhibition in the circulation or at tissue sites (van den Meiracker Fischli et al, 1991;1994).…”

Section: Introductionmentioning

confidence: 99%

Assessment of the role of the renin‐angiotensin system in cardiac contractility utilizing the renin inhibitor remikiren

Kats

Sassen

Danser

et al. 1996

British J Pharmacology

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1. The role of the renin-angiotensin system in the regulation of myocardial contractility is still debated. In order to investigate whether renin inhibition affects myocardial contractility and whether this action depends on intracardiac rather than circulating angiotensin II, the regional myocardial effects of systemic (i.v.) and intracoronary (i.c.) infusions of the renin inhibitor remikiren, were compared and related to the effects on systemic haemodynamics and circulating angiotensin II in open-chest anaesthetized pigs (25-30 kg). The specificity of the remikiren-induced effects was tested (1) by studying its i.c. effects after administration of the AT1-receptor antagonist L-158,809 and (2) by measuring its effects on contractile force of porcine isolated cardiac trabeculae. 2. Consecutive 10 min i.v. infusions of remikiren were given at 2, 5, 10 and 20 mg min-1. Mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), systemic vascular resistance (SVR), myocardial oxygen consumption (MVO2) and left ventricular (LV) dP/dtmax were not affected by remikiren at 2 and 5 mg min-1, and were lowered at higher doses. At the highest dose, MAP decreased by 48%, CO by 13%, HR by 14%, SVR by 40%, MVO2 by 28% and LV dp/dtmax by 52% (mean values; P < 0.05 for difference from baseline, n = 5). The decrease in MVO2 was accompanied by a decrease in myocardial work (MAP x CO), but the larger decline in work (55% vs. 28%; P < 0.05) implies a reduced myocardial efficiency ((MAP x CO)/MVO2). 3. Consecutive 10 min i.c. infusions of remikiren were given at 0.2, 0.5, 1, 2, 5 and 10 mg min-1. MAP, CO, MVO2 and LV dP/dtmax were not affected by remikiren at 0.2, 0.5 and 1 mg min-1, and were reduced at higher doses. At the highest dose, MAP decreased by 31%, CO by 26%, MVO2 by 46% and LV dP/dtmax by 43% (mean values; P < 0.05 for difference from baseline, n = 6). HR and SVR did not change at any dose. 4. Thirty minutes after a 10 min i.v. infusion of the AT1 receptor antagonist, L-158,809 at 1 mg min-1, consecutive 10 min i.c. infusions (n = 5) of remikiren at 2, 5 and 10 mg min-1 no longer affected CO and MVO2, and decreased LV dP/dtmax by maximally 27% (P < 0.05) and MAP by 14% (P < 0.05), which was less than without AT1-receptor blockade (P < 0.05). HR and SVR remained unaffected. 5. Plasma renin activity and angiotensin I and II were reduced to levels at or below the detection limit at doses of remikiren that were not high enough to affect systemic haemodynamics or regional myocardial function, both after i.v. and i.c. infusion. 6. Remikiren (10(-10) to 10(-4) M) did not affect contractile force of porcine isolated cardiac trabeculae precontracted with noradrenaline. In trabeculae that were not precontracted no decrease in baseline contractility was observed with remikiren in concentrations up to 10(-5) M, whereas at 10(-4) M baseline contractility decreased by 19% (P < 0.05). 7. Results show that with remikiren i.v., at the doses we used, blood pressure was lowered primarily by vasodilation and with remikiren i.c. by car...

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“…These inhibitors are CGP-29287 (36), U-71038 (28), SR-43845 (26), Compound 12 (l), A-64662 (19). SC-46944 (8), KRI (21), CGP-38560 (35), and BW-175 (23). However, because of their low bioavailability, the doses of more than 10 mg/kg were required to cause a significant decrease in PRA by oral administration.…”

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confidence: 99%

An Orally Active Inhibitor of Human Renin, ES‐8891

Kokubu

Hiwada

Murakami

et al. 1991

Cardiovascular Drug Reviews

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Key Words: Human renin inhibitor-Marmoset-Human-Bloodpressure-Plasma renin activity-Renin mRNA.The renin-angiotensin system plays an important role in the regulation of blood pressure and in body fluid homeostasis. Inhibitors of angiotensin converting enzyme (ACE) are now widely used in patients with hypertension and congestive heart failure. The success of ACE inhibitors in the treatment of hypertension has stimulated the development of specific inhibitors of human renin. Renin inhibitors are expected to produce more selective inhibition of the renin-angiotensin system than ACE inhibitors. Since ACE converts angiotensin I (AngI) to Ang I1 and also inactivates bradykinin, enkephalins, and other biologically active peptides (30), ACE inhibitors are not specific blockers of the renin-angiotensin system. Renin acts on angiotensinogen as its only known substrate (29). Thus, renin inhibitors may have a lower incidence of adverse effects, typical for ACE inhibitors, such as flushing, dry cough, or angioedema, which may be independent of the renin-angiotensin system. Cough induced by ACE inhibitors has been suspected to be caused by the increase in bradykinin or substance P (22). Furthermore, the inhibition of the renin-angiotensin system by renin inhibitors may also contribute to our understanding of the role of the renin-angiotensin system in cardiovascular homeostasis.Hemodynamic and biochemical consequence of renin inhibition have been studied following parenteral administration. The renin inhibitors CGP-38560A (5,27) and enalkiren (6) caused no change of blood pressure in spite of renin inhibition in normotensive subjects on standard sodium diet. However, the infusion of the renin inhibitor H-142 lowered blood pressure when normal subjects were sodium depleted (33,34). In contrast, the renin inhibitors CGP-38560A (27), enalkiren (6), and A-64662 (2) significantly reduced the blood pressure in hypertensive patients on normal sodium diet without any Address correspondence and reprint requests to Prof. K.

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Haemodynamic effects of acute and chronic renin inhibition in marmosets

Cited by 12 publications

References 0 publications

Synergistic effect on reduction in blood pressure with coadministration of a renin inhibitor or an angiotensin‐converting enzyme inhibitor with an angiotensin II receptor antagonist

Synergistic effect on reduction in blood pressure with coadministration of a renin inhibitor or an angiotensin‐converting enzyme inhibitor with an angiotensin II receptor antagonist

Assessment of the role of the renin‐angiotensin system in cardiac contractility utilizing the renin inhibitor remikiren

An Orally Active Inhibitor of Human Renin, ES‐8891

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