Angiotensin converting enzyme inhibition modulates endogenous endothelin in chronic canine thoracic inferior vena caval constriction.

Clavell, Alfredo L.; Mattingly, M. T.; Stevens, Tracy L.; Nir, Amiram; Wright, R. Scott; Aarhus, Lawrence L.; Heublein, Dennise M.; Burnett, John C.

doi:10.1172/jci118544

Cited by 65 publications

(28 citation statements)

References 36 publications

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“…6,21 In heart failure, the level of ET-1 has been shown to be elevated in the plasma; however, its local significance in the hypertrophic and failing myocardium remains unresolved. 22 In contrast to its potential as a cardiac growth factor and to its presumed concordant activation with the cardiac angiotensin system, 23,24 we observed that the cardiac ET-1 system was not activated in the established LVH stage. This observation was consistently supported by long-term bosentan treatment, which, in contrast to temocapril, did not diminish the progression of LVH.…”

Section: Iwanaga Et Almentioning

confidence: 58%

Differential Effects of Angiotensin II Versus Endothelin-1 Inhibitions in Hypertrophic Left Ventricular Myocardium During Transition to Heart Failure

et al. 2001

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Background-In view of their mutual crosstalk, the roles of angiotensin II (Ang II) and endothelin-1 (ET-1) in the myocardium are assumed to be synergistic and supplemental. Methods and Results-In the phase of compensated left ventricular (LV) hypertrophy of Dahl salt-sensitive rats, Ang II peptide and the ACE mRNA in the LV were increased by 1.6-and 3.8-fold, respectively. In contrast, ET-1 peptide and the preproET-1 mRNA remained unchanged. In subsequent congestive heart failure (CHF), Ang II and ACE mRNA did not show further increases. But ET-1 and the mRNA were increased de novo by 5.3-and 4.1-fold, respectively. In ascending aorta-banded rats, the local activations of Ang II and ET-1 also showed a differential time course between LV hypertrophy and CHF. Long-term treatments of Dahl salt-sensitive rats with temocapril (an ACE inhibitor) and with bosentan (a mixed ET receptor blocker) equally improved long-term survival. Temocapril reduced the LV/body weight ratio and ameliorated LV fractional shortening. Conversely, although bosentan equally improved fractional shortening, it did not reduce the increase in LV mass. Combined treatment with these 2 drugs further ameliorated the animal's survival without additional decreases in systolic pressure. Conclusions-The pathophysiological roles in the myocardium during the transition to CHF differ qualitatively betweenAng II and ET-1. Thus, long-term therapy with a combination of ACE inhibition and ET antagonism may provide a new approach for heart failure in humans.

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Section: Iwanaga Et Almentioning

confidence: 58%

Differential Effects of Angiotensin II Versus Endothelin-1 Inhibitions in Hypertrophic Left Ventricular Myocardium During Transition to Heart Failure

et al. 2001

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“…14,31 Finally, the effect of ET blockade might be less pronounced when administered in the presence of an ACE inhibitor, because of the fact that chronic ACE inhibition inhibits the activation of the ET system. 32 Finally, it cannot be excluded that, in our experimental conditions, Tr already induces a maximal improvement of survival, excluding additional improvement after the combination therapy. In any case, whether a synergistic effect on long-term survival of concomitant ET A and ACE antagonism exists in humans is still unknown.…”

Section: Discussionmentioning

confidence: 80%

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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“…37 The salutary effects of ACE inhibitors are attributed to their actions on different pathways, including the modulation of endogenous ET concentrations and activity. 38,39 Drugs were given over a prolonged period in these studies, suggesting an antiatherogenic effect. 37 Hence, long-term inhibition of ET, blunting its atherogenic actions, 40,41 may also be beneficial.…”

Section: Discussionmentioning

confidence: 97%

Acute Endothelin-Receptor Inhibition Does Not Attenuate Acetylcholine-Induced Coronary Vasoconstriction in Experimental Hypercholesterolemia

Hasdai

Best

Cannan

et al. 1998

ATVB

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Abstract-Endothelin (ET) may mediate the enhanced coronary vasoconstriction associated with hypercholesterolemia. We hypothesized that short-term inhibition of ET receptors attenuates the coronary epicardial vasoconstrictor response to acetylcholine in experimental hypercholesterolemia. ET-1 (group I, nϭ5; 5 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and acetylcholine (group III, nϭ7; 10 Ϫ6 to 10 Ϫ4 mol/L) were given by intracoronary infusion in pigs. ET-1 and acetylcholine were also infused with the specific ETA-receptor blocker FR-139317 (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ; group II, nϭ6; group IV, nϭ6). Acetylcholine was also infused with the combined ET-receptor blocker, bosentan (0.5 mg/kg plus 1 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 , group V, nϭ5). The ETB-receptor agonist sarafotoxin 6c (5 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ; nϭ4) was also infused. The percentage change in coronary artery diameter (%⌬CAD) to the infusions was measured at baseline and after 10 weeks of high-cholesterol diet in all animals. Sarafotoxin 6c mildly reduced %⌬CAD at baseline and 10 weeks (Ϫ10Ϯ2% and Ϫ12Ϯ3%, respectively). FR-139317 did not attenuate the epicardial vasoconstrictor response to ET-1 at baseline (%⌬CAD Ϫ18Ϯ8% for group I versus Ϫ12Ϯ6% for group II; PϭNS) but did at 10 weeks (%⌬CAD Ϫ77Ϯ14% for group I versus Ϫ14Ϯ6% for group II; PϽ.05). FR-139317 did not affect the response to acetylcholine at baseline (%⌬CAD 5Ϯ2% for group III versus 7Ϯ3% for group IV, PϭNS) or at 10 weeks (%⌬CAD Ϫ23Ϯ12% for group III versus Ϫ19Ϯ7% for group IV; PϭNS). Bosentan did not affect the response to acetylcholine at baseline or 10 weeks. The ETA receptor is expressed in vascular smooth muscle, whereas the ETB receptor is localized to endothelial and smooth muscle cells. 4 Coronary vasoconstriction is mediated by both receptors. 1 We 5 recently reported that intracoronary infusion of ET-1 at pathophysiological concentrations results in coronary epicardial vasoconstriction in dogs, which was presumed to be mediated predominantly via the ETA receptor.Hypercholesterolemia is a pathophysiological state characterized by impaired coronary endothelium-dependent arterial relaxation to the endothelium-dependent vasodilator acetylcholine. 6,7 In a porcine model of diet-induced hypercholesterolemia, plasma concentrations of ET are elevated, and coronary tissue ET immunoreactivity is enhanced. 8 Moreover, intracoronary infusion of acetylcholine causes vasoconstriction and further increases plasma ET concentrations. 8 Similarly, humans with coronary endothelial dysfunction have enhanced ET immunoreactivity in the coronary circulation, with an additional rise in coronary ET levels during intracoronary infusion of acetylcholine. 9 These prior studies implicate ET as a potential mediator of endothelial dysfunction in hypercholesterolemia, possibly through stimulation of the ET receptor. The present study was designed to examine the hypothesis that selective inhibition of the ET receptor attenuates the coronary epicardial vasoconstrictor response to acetylcholine in experimental hypercholesterolemia.

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Angiotensin converting enzyme inhibition modulates endogenous endothelin in chronic canine thoracic inferior vena caval constriction.

Cited by 65 publications

References 36 publications

Differential Effects of Angiotensin II Versus Endothelin-1 Inhibitions in Hypertrophic Left Ventricular Myocardium During Transition to Heart Failure

Differential Effects of Angiotensin II Versus Endothelin-1 Inhibitions in Hypertrophic Left Ventricular Myocardium During Transition to Heart Failure

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

Acute Endothelin-Receptor Inhibition Does Not Attenuate Acetylcholine-Induced Coronary Vasoconstriction in Experimental Hypercholesterolemia

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