Effects of a Specific Endothelin-Converting Enzyme Inhibitor on Cardiac, Renal, and Neurohumoral Functions in Congestive Heart Failure

Abstract

BACKGROUND--Endothelin (ET)-1 is generated from big ET-1 by endothelin-converting enzyme (ECE). Plasma big ET-1 and ET-1 levels are strongly related to survival in patents with congestive heart failure (CHF). Because selective enzymatic processing of ET-1 formation appears to be an important therapeutic target for CHF, we investigated the acute effects of a specific ECE inhibitor on cardiorenal and endocrine functions in CHF compared with those of a selective ETA receptor antagonist. METHODS AND RESULTS--CHF was induced in beagle dogs by rapid right ventricular pacing (270 bpm, 14 days). Two incremental doses of a specific ECE inhibitor, FR901533, or a selective ETA receptor antagonist, FR139317 (1 and 3 mg/kg, n=8, respectively), were injected into dogs with CHF. FR901533 and FR139317 decreased mean arterial pressure and pulmonary capillary wedge pressure associated with reduction in systemic and pulmonary vascular resistance. These agents increased cardiac output but did not affect left ventricular fractional shortening. FR139317 exerted a greater depressor effect on mean arterial pressure than FR901533 (P<0.05). These agents decreased plasma atrial natriuretic peptide levels, but only FR901533 decreased plasma renin activity, angiotensin II, and aldosterone levels. Neither agent changed the plasma norepinephrine level despite the fall in blood pressure. These drugs increased the urinary water and sodium excretion rate associated with increases in the glomerular filtration rate and renal plasma flow, and the incremental magnitude induced by FR139317 was larger than that by FR901533 (P<0.05). CONCLUSIONS--An ETA receptor antagonist appeared to induce greater vasodilative effects on systemic and renal vasculature in CHF than an ECE inhibitor. However, the ECE inhibitor reduced the secretion of neurohumoral factors that are activated in proportion to the severity of CHF. Our acute complementary data may support the importance of the role of ECE in CHF and provide a rationale foundation for investigating the usefulness of long-term treatment with ECE inhibitors in CHF.

Contribution of Vascular NAD(P)H Oxidase to Endothelial Dysfunction in Heart Failure and the Therapeutic Effects of HMG-CoA Reductase Inhibitor

“…CHF was induced by rapid right ventricular pacing in young adult beagle dogs, 10-12 months of age, as previously described. [13][14][15] After the dogs had recovered from the surgery for at least 14 days, the pacemaker was programmed for 240 beats/min and pacing was continued for 29 days.…”

“…On the 29th day after the initiation of pacing, the pacemaker was deactivated and arterial blood pressure and echocardiographic measurements were subsequently performed with the dogs in the conscious state as described previously. [13][14][15] Blood was collected for plasma total cholesterol and neurohumoral assays of plasma angiotensin II concentrations and plasma renin activity (PRA) as previously described. [13][14][15] After the echocardiogram, to evaluate endotheliumdependent and -independent vasodilation, all dogs were given thiopental sodium to provide conscious sedation and allowed to breathe spontaneously during the procedure.…”

“…[13][14][15] Blood was collected for plasma total cholesterol and neurohumoral assays of plasma angiotensin II concentrations and plasma renin activity (PRA) as previously described. [13][14][15] After the echocardiogram, to evaluate endotheliumdependent and -independent vasodilation, all dogs were given thiopental sodium to provide conscious sedation and allowed to breathe spontaneously during the procedure. A Doppler flow probe was placed on the femoral artery to measure femoral blood flow (FBF) with the VF-1 Pulsed Doppler Flow System (Crystal Biotech Inc, USA) as previously described.…”

Bradykinin Improves Left Ventricular Diastolic Function Under Long-Term Angiotensin-Converting Enzyme Inhibition in Heart Failure

“…CHF was induced by rapid right ventricular pacing in beagles, as previously described. 9,10 After the dogs recovered from instrumental surgery for Ն14 days, the pacemaker was programmed at a rate of 270 bpm, and pacing was continued for 22 days.…”

Dual ECE/NEP Inhibition on Cardiac and Neurohumoral Function During the Transition From Hypertrophy to Heart Failure in Rats

“…This is in agreement with the findings reported by Pelletier et al 31 However, we feel that selective inhibition of ECE may not be sufficient to reduce the circulating levels of ET-1 because substantial levels of mature ET-1 are still found in ECE-1 Ϫ/Ϫ or double ECE-1 Ϫ/Ϫ /ECE-2 Ϫ/Ϫ knockout mice 32,33 as well as in rats with heart failure treated with selective ECE inhibitor. 34 These results not only underscore the superiority of this new compound to selective NEP inhibitor in the treatment of experimental heart failure but also indicate the potential of using circulating ET-1 levels as a biomarker of improvement of CHF. …”