Selective Endothelin-A Versus Combined Endothelin-A/Endothelin-B Receptor Blockade in Rat Chronic Heart Failure

Mulder, Paul; Boujedaini, Houssaine; Richard, Vincent; Dérumeaux, Geneviève; Henry, J. P.; Renet, Sylvanie; Wessale, Jerry L.; Opgenorth, Terry J.; Thuillez, Christian

doi:10.1161/01.cir.102.5.491

Cited by 54 publications

(31 citation statements)

References 11 publications

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“…As already reported with selective ET A , mixed ET A -ET B receptor blockers, 8,23,24 and ACE inhibitors, 22,25,26 LU 135252 and trandolapril decrease arterial blood pressure, improve cardiac hemodynamics, limit left ventricular remodeling, and increase both fractional shortening and posterior wall thickening. This, together with the decrease in cardiac preload and afterload, results in an increased stroke volume and cardiac output and prevents the deterioration of global LV function, without affecting LV dP/dt max .…”

Section: Discussionsupporting

confidence: 66%

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Long-Term Survival and Hemodynamics After Endothelin-A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition in Rats With Chronic Heart Failure

et al. 2002

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Background-In patients with congestive heart failure (CHF) receiving ACE inhibitors, acute administration of selective endothelin (ET) antagonists additionally improves systemic and cardiac hemodynamics. We investigated, in a rat model of CHF, whether such acute synergistic effects are sustained and accompanied, in the long term, by an additional limitation of left ventricular remodeling or an increase in survival. Methods and Results-Rats were subjected to coronary artery ligation and treated for 3 or 9 months with vehicle or with the ACE inhibitor trandolapril (Tr) (0.3 mg/kg Ϫ1 per day Ϫ1 ), the ET A antagonist LU 135252 (LU, 30 mg/kg Ϫ1 per day Ϫ1 ), or their combination starting 7 days after ligation. After 3 months, the combination decreased LV systolic-and end-diastolic pressures (Ϫ32% and Ϫ80%, respectively) more markedly than Tr (Ϫ21% and Ϫ61%, respectively) or LU alone (Ϫ14% and Ϫ48%, respectively). Echocardiographic studies revealed that all treatments limited LV dilatation and increased LV fractional shortening and cardiac index. All treatments equally reduced left ventricular collagen density, whereas only Tr or the combination reduced LV weight. Finally, although LU did not modify long-term survival, Tr and the combination of Tr with LU induced a similar improvement of survival. Conclusions-In this rat model, long-term combined administration of an ET A antagonist and an ACE inhibitor induces additional effects in terms of systemic and cardiac hemodynamics; however, this is not associated with an additional increase in long-term survival.

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Section: Discussionsupporting

confidence: 66%

“…9,16,22,23 In our experiments, untreated animals develop severe CHF, evidenced by an augmented LVEDP and LV cavity dilatation, as well as a progressive deterioration of LV function assessed by serial echocardiography.…”

Section: Discussionmentioning

confidence: 54%

Long-Term Survival and Hemodynamics After Endothelin-A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition in Rats With Chronic Heart Failure

et al. 2002

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“…Accumulating evidence suggests that ET-dependent signaling may significantly affect cardiac fibrosis in various forms of cardiac hypertrophy (2,9,23). It seems very likely that the primary stimuli investigated here (mechanical load, ANG II, and NE) contribute to different extents to those different aspects of cardiac remodeling.…”

Section: Discussionmentioning

confidence: 86%

Predominant activation of endothelin-dependent cardiac hypertrophy by norepinephrine in rat left ventricle

Moser

Faulhaber

Wiesner

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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It is still unclear, however, which primary stimulus specifically activates ET-dependent signaling pathways. We therefore examined in adult rats (n ϭ 51) the effects of a selective ET A receptor antagonist in experimental models of cardiac hypertrophy, in which myocardial growth is predominantly initiated by a single primary stimulus. Rats were exposed to mechanical overload (ascending aortic stenosis), increased levels of circulating ANG II (ANG II infusion combined with hydralazine), or adrenergic stimulation (infusion of norepinephrine in a subpressor dose) for 7 days. All experimental treatments significantly increased left ventricular weight/body weight ratios compared with untreated rats, whereas systolic left ventricular peak pressure was increased only after ascending aortic stenosis. ET A receptor blockade exclusively reduced norepinephrine-induced cardiac hypertrophy and atrial natriuretic peptide gene expression. Blood pressure levels and heart rates remained unaffected during ET A receptor blockade in all experimental groups. These data indicate that in rat left ventricle, the ET-dependent signaling pathway leading to early development of cardiac hypertrophy and fetal gene expression is primarily activated by norepinephrine. angiotensin II; endothelin-A receptor; gene expression; norepinephrine; remodeling ENDOTHELIN (ET) is a potent vasoconstrictor that was first described by Yanagisawa and co-workers in 1988 (35). During the past years, it has become clear that in addition to its hemodynamic effects, ET-1 can also act as a growth-promoting hormone in the myocardium. Initial observations made on isolated cardiomyocytes revealed an increase of protein biosynthesis and cellular volume after the addition of ET-1 to the culture medium (11). Consecutive studies in intact animals demonstrated a stimulation of the cardiac ET system in several forms of extrinsic cardiac hypertrophy (2,10,12,15,20,21), particularly during its early development (12,15,21). Correspondingly, either selective ET A subtype receptor blockade or unselective ET A/B subtype receptor blockade significantly attenuated early myocardial hypertrophy and fetal gene expression associated with renal artery stenosis (7, 9), suprarenal abdominal aortic banding (12), ANG II infusion (8), and high-dose infusion of norepinephrine (NE) (15). In all of these pathophysiologically relevant models, however, several primary stimuli, which can individually induce myocardial hypertrophy, are activated concurrently, i.e., mechanical load, the renin-angiotensin system, and/or the sympathetic nervous system. Accordingly, it remains unclear whether the cardiac ET system is specifically activated either by one or by a combined action of several primary stimuli or whether it constitutes a more general downstream signaling pathway of myocardial growth.In the present study, we therefore sought to design experimental paradigms of extrinsically induced cardiac hypertrophy, in which myocardial growth is predominantly initiated by a single primary stimulus. To incr...

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“…4 ABT-627 was given with the drinking fluid, adjusted weekly to maintain proper dosage of 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 . 18 The following experimental groups were investigated: Male HanSD ϩ HS (nϭ24) Male TGR ϩ HS (nϭ21) Male TGR ϩ HS ϩ bosentan (nϭ16) Male TGR ϩ HS ϩ ABT-627 (nϭ16)…”

Section: Animalsmentioning

confidence: 99%

Early Endothelin-A Receptor Blockade Decreases Blood Pressure and Ameliorates End-Organ Damage in Homozygous Ren-2 Rats

et al. 2005

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Abstract-We have recently found that nonselective endothelin ET A /ET B receptor blockade markedly improves survival rate and ameliorates end-organ damage in male homozygous rats transgenic (TGR) for the mouse Ren-2 renin gene without lowering blood pressure. Key Words: hypertension Ⅲ kidney Ⅲ antihypertensive drugs Ⅲ end-organ damage Ⅲ systolic Ⅲ experimental models E ndothelin-1 (ET-1) has been described as one of the most powerful vasoconstrictors 1,2 that also plays a role in the regulation of renal hemodynamics and salt and water excretion. 3 Moreover, numerous studies have shown that the ET system plays an important role in the pathogenesis of saltsensitive models of hypertension and in associated end-organ damage. 4 The nephroprotective effect of ET receptor blockade in these models is comparable with blockade of the renin-angiotensin system. 5 The beneficial effects of ET receptor blockers in modulating target-organ damage arises from their antiproliferative actions. 6 There is, however, a large discrepancy in the effect of ET between various models of hypertension. Animal models with exogenously administered angiotensin II (ANG II) exhibit an ET-dependent component, whereas hypertensive models with endogenously enhanced production of ANG II do not. 7 In our previous study, we showed that bosentan treatment substantially improved the survival rate in homozygous rats transgenic (TGR) for the mouse Ren-2 renin gene fed either normal-salt or high-salt diet without blood pressure (BP)-lowering effect. 8 Whereas the protective action of nonselective ET blockade has attracted much attention in homozygous TGR, 8,9 there is no information available concerning the effect of selective ET A blockade on the course of hypertension and end-organ damage in homozygous TGR and little information is available in heterozygous animals. 10,11 It is well-known that young animals are more susceptible to various hypertensive stimuli 12 and also that interventions made in these early periods are more effective than when adopted lately in the life. 13 However, in Dahl-sensitive rats it has been shown that ET A receptor blockade was efficient in adult but not in young animals. 14 The transgenic hypertensive TGR(mRen2)27 rat model 15 is a valuable monogenetic model of renin-dependent (and thus ANG II-dependent) hypertension, which exhibits functional and structural changes of the kidney usually found in hyper-

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Selective Endothelin-A Versus Combined Endothelin-A/Endothelin-B Receptor Blockade in Rat Chronic Heart Failure

Cited by 54 publications

References 11 publications

Long-Term Survival and Hemodynamics After Endothelin-A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition in Rats With Chronic Heart Failure

Long-Term Survival and Hemodynamics After Endothelin-A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition in Rats With Chronic Heart Failure

Predominant activation of endothelin-dependent cardiac hypertrophy by norepinephrine in rat left ventricle

Early Endothelin-A Receptor Blockade Decreases Blood Pressure and Ameliorates End-Organ Damage in Homozygous Ren-2 Rats

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