Additional Hypotensive Effect of Endothelin-1 Receptor Antagonism in Hypertensive Dogs Under Angiotensin-Converting Enzyme Inhibition

Donckier, Julian; Massart, Pierre-Emmanuel; Hodeige, D; Mechelen, Henri Van; Clozel, Jean‐Paul; Laloux, Olivier; Ketelslegers, Jean‐Marie; Charlier, Aa.; Heyndrickx, Guy R.

doi:10.1161/01.cir.96.4.1250

Cited by 33 publications

(20 citation statements)

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“…7 In contrast, both nonselective ET A/B or selective ET A receptor blockade 2,5 and ACE inhibition alone 5,13 had only minor hypotensive effects in normal dogs. From the results of a recent study, we proposed a close interaction of ET and the renin-angiotensin system, such that during blockade of ET A receptors an increased effect of angiotensin II may compensate for the lack of vasoconstrictor activity of ET.…”

Section: Discussionmentioning

confidence: 97%

“…Similarly, nonselective ET A/B receptor blockade by bosentan exerted an additional hypotensive effect in hypertensive dogs during ACE inhibition. 7 Combined administration of bosentan and an ACE inhibitor also resulted in pronounced hypotensive effects in rats with chronic heart failure. 8 The mechanisms underlying this interaction between ET receptor blockade and the renin-angiotensin system are still unclear.…”

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confidence: 99%

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Stimulation of the Renin-Angiotensin System by Endothelin Subtype A Receptor Blockade in Conscious Dogs

et al. 1999

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Abstract-Previous studies in dogs have shown additive or even synergistic effects of combined angiotensin-converting enzyme inhibition and either nonselective endothelin subtype A/B (ET A/B ) or selective endothelin subtype A (ET A ) receptor blockade on renal vascular resistance and mean arterial blood pressure. A possible mechanism underlying this interaction may be a stimulation of the renin-angiotensin system during endothelin (ET) receptor blockade. We therefore investigated whether plasma renin activity and renin release are regulated by the ET A receptor. Experiments were made in conscious, chronically instrumented dogs receiving either saline or the selective ET A receptor antagonist LU 135252 (10 mg/kg IV). Eighty to 100 minutes after the administration of LU 135252 (nϭ5), heart rate (99Ϯ7 versus 81Ϯ6 bpm; PϽ0.05) and renal blood flow (327Ϯ40 versus 278Ϯ36 mL/min; PϽ0.05) were increased significantly, whereas mean arterial blood pressure tended to be lower (93Ϯ5 versus 105Ϯ7 mm Hg). These changes were associated with a 2-fold increase in plasma renin activity (0.74Ϯ0.12 versus 0.37Ϯ0.10 ng angiotensin I per milliliter per hour; PϽ0.05).Measurements of renin release at various renal perfusion pressures (nϭ5) with the use of a vascular occluder implanted around the left renal artery revealed that ET A receptor blockade did not alter renin release at resting renal perfusion pressure (78Ϯ25 versus 71Ϯ39 U/min) but strongly enhanced the sensitivity of pressure-dependent renin release Ͻ80 mm Hg Ϸ2.2-fold. In conclusion, selective ET A receptor blockade is associated with a stimulation of the circulating renin-angiotensin system, which results from both a sensitization of pressure-dependent renin release and a larger proportion of blood pressure values falling into the low pressure range, where renin release is stimulated. These findings strengthen the view that ET and the renin-angiotensin system closely interact to regulate vascular resistance and provide a physiological basis for synergistic hypotensive effects of a combined blockade of both pressor systems. (Hypertension. 1999;33:1420-1424.)Key Words: endothelin Ⅲ receptors, endothelin Ⅲ renal blood flow Ⅲ renin-angiotensin system Ⅲ renin E xogenous endothelin (ET), predominantly by activating endothelin subtype A (ET A ) receptors, is a strong constrictor of renal and systemic vessels, but the relevance of endogenous ET for the maintenance of basal vascular tone and blood pressure is still controversial. In healthy subjects, short-term blockade of ET A receptors 1 had no effects on blood pressure and renal blood flow (RBF). In addition, nonselective blockade of ET A and endothelin subtype B (ET B ) receptors did not affect blood pressure in anesthetized dogs. 2 In contrast, intra-arterial infusion of an ET A receptor blocker in normotensive humans caused strong increases in forearm blood flow, indicating a pronounced reduction in vascular resistance. 3,4 An interaction of ET and the renin-angiotensin system could account for the lack of large blood pressu...

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Section: Discussionmentioning

confidence: 97%

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confidence: 99%

Stimulation of the Renin-Angiotensin System by Endothelin Subtype A Receptor Blockade in Conscious Dogs

et al. 1999

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“…Additionally, losartan, an antagonist of angiotensin type 1 receptors, was recently shown to abolish angiotensin II-induced rises of ET-1 levels in aortas of Wistar-Kyoto rats [37]. However, these findings [35, 36, 37]do not allow the exclusion of either the relevance of potentiated ET-1 release during hemodialysis to blood pressure or the interactions between ET-1 and the renin-angiotensin system under ACE blockade, because the hypotensive effect of bosentan, an ET-1 receptor antagonist, was demonstrated in dogs with perinephritis-associated hypertension despite preceding maximal ACE inhibition [38]. …”

Section: Discussionmentioning

confidence: 99%

Effect of a Hemodialysis Session on Plasma Levels of Endothelin-1 in Hypertensive and Normotensive Subjects with End-Stage Renal Failure

Surdacki

Sułowicz

Wieczorek-Surdacka

et al. 1999

Nephron

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Background: Elevated plasma endothelin-1 (ET-1) was found in end-stage renal failure (ESRF). However, there are discordant reports on the influence of hypertension on plasma ET-1 in ESRF and on the effect of hemodialysis on ET-1 concentrations. Aim: To compare the time course of plasma ET-1 during hemodialysis in hypertensive (HT) and normotensive (NT) ESRF patients. Methods: Plasma ET-1 and mean blood pressure (MP) were measured in 12 HT patients and 11 matched NT patients on maintenance hemodialysis at baseline (B), after a 2.5–3.5 h hemodialysis with ultrafiltration (P1) and after a subsequent 1 h isovolumic dialysis (P2). Results: In HT patients, plasma ET-1 increased at P1 with no further change after P2 (B vs. P1 and P2, p < 0.05). In NT patients, ET-1 levels were similar at B, P1 and P2. In HT, but not in NT subjects, volume loss correlated with change of ET-1 at P1. In HT patients, MP fell during P1 and tended to return towards baseline at P2. In NT patients, MP dropped after P1 and remained lower also at P2. Conclusion: Hypertensive ESRF subjects exhibit potentiated ET-1 release on hemodialysis, possibly stimulated by volume depletion with sympathetic activation, which may attenuate hypotensive hemodialysis effects thus contributing to hypertension in ESRF.

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“…As has been previously demonstrated, combined endothelin receptor antagonism in our study significantly increased ET-1 levels at 12 weeks compared with the control group and the selective ET-A antagonist group. 45 Additionally, selective ET-A antagonism did not increase plasma ET-1 levels. Thus, this supports the idea that the ET-B receptor was inhibited only in the combined endothelin receptor antagonist group.…”

Section: Best Et Al April 6 1999mentioning

confidence: 94%

Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia

et al. 1999

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Background-Endothelin-1 (ET-1) is an endothelium-derived peptide that constricts coronary vessels through stimulation of the ET-A and ET-B receptors. Experimental porcine hypercholesterolemia is associated with impaired coronary endothelial function and elevated ET-1 concentrations. This study was designed to test the hypothesis that chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. Methods and Results-Acetylcholine (10 Ϫ6 to 10 Ϫ4 mol/L) was serially infused into the left anterior descending coronary artery in pigs at baseline and after 12 weeks of a high-cholesterol diet. In the interim, the animals were randomized to 3 groups: Group 1 received no therapy, group 2 received 3 mg/kg per day RO 48-5695, a combined ET-A/ET-B receptor antagonist, and group 3 received 4 mg/kg per day ABT-627, a selective ET-A receptor antagonist. Percent change in coronary artery diameter, coronary blood flow, and coronary vascular resistance were calculated on the basis of quantitative coronary angiography and intracoronary Doppler. At 12 weeks, total cholesterol was significantly and similarly increased in all groups. Chronic endothelin receptor antagonism significantly increased coronary blood flow in response to acetylcholine at 12 weeks (group 1: Ϫ41.6%Ϯ10.7%, group 2: Ϫ4.7%Ϯ11.9%, group 3: 11.4%Ϯ7.4%). Conclusions-Chronic

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Additional Hypotensive Effect of Endothelin-1 Receptor Antagonism in Hypertensive Dogs Under Angiotensin-Converting Enzyme Inhibition

Abstract: Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.

Cited by 33 publications

References 24 publications

Stimulation of the Renin-Angiotensin System by Endothelin Subtype A Receptor Blockade in Conscious Dogs

Stimulation of the Renin-Angiotensin System by Endothelin Subtype A Receptor Blockade in Conscious Dogs

Effect of a Hemodialysis Session on Plasma Levels of Endothelin-1 in Hypertensive and Normotensive Subjects with End-Stage Renal Failure

Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia

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