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Chronic angiotensin I-converting enzyme inhibition can be associated with aldosterone escape. We investigated the effects of enalapril, spironolactone, and their combination on hemodynamics and cardiac remodeling in cardiomyopathic hamsters to determine whether these drugs could exert additive effects. Cardiomyopathic hamsters, Bio TO-2 dilated strain, were orally treated with enalapril (20 mg. kg. day ) and/or spironolactone (20 mg. kg. day ) according to a 2 x 2 factorial design from 120 days of age. Animals were investigated at 180 (10 animals per group) and 240 (16 animals per group) days of age. Compared with corresponding untreated groups, enalapril significantly decreased mean blood pressure (-18%); enalapril and spironolactone significantly increased cardiac output (+28%, +11%) and femoral blood flow (+10%, +12%) and significantly decreased systemic (-38%, -17%) and femoral (-26%, -13%) vascular resistances. Enalapril and spironolactone significantly decreased left ventricle cavity area (-21%, -26%) and left (-34%, -47%) and right (-37%, -48%) ventricle collagen density. Spironolactone significantly increased left ventricle wall thickness (+4%). There were significant enalapril x spironolactone interactions for most variables (compared with control group, +52%, +36%, +45% for cardiac output; +26%, +28%, +26% for femoral blood flow; -50%, -30%, -45% for systemic vascular resistance; -33%, -20%, -35% for femoral vascular resistance; -27%, -31%, -40% for left ventricle cavity area; and -46%, -58%, -60% for left and -39%, -50%, -66% for right ventricle collagen density in enalapril, spironolactone, and enalapril + spironolactone groups, respectively). In cardiomyopathic hamsters, enalapril and spironolactone in combination did not improve hemodynamics more than enalapril alone but induced stronger effects than each drug alone on cardiac remodeling.

The use of beta-blockers reduces angiotensin II levels, but could not adequately suppress aldosterone production. Thus, the combination of a beta-blocker with an aldosterone receptor antagonist could exert additive effects. The effects of metoprolol and spironolactone and their combination on hemodynamics and cardiac remodeling in cardiomyopathic hamsters (CMH) were investigated. The Bio TO-2 dilated strain of CMH was treated orally with metoprolol (10 mg/kg/day), spironolactone (20 mg/kg/day), or both according to a 2 x 2 factorial design (24 animals per group) from 120 days of age and during 120 days. As compared to corresponding untreated groups, metoprolol significantly decreased mean blood pressure (-7%), and metoprolol and spironolactone significantly increased cardiac output (18% and 19%, respectively), mesenteric blood flow (11% and 14%), and femoral blood flow (13% and 17%), and significantly decreased systemic (-24% and -15%), mesenteric (-14% and -13%) and femoral (-19% and -10%) vascular resistances. Metoprolol significantly increased renal blood flow (22%) and significantly decreased renal vascular resistance (-23%). Metoprolol and spironolactone significantly decreased the cavity area of the left ventricle (-21% and -32%, respectively) and the collagen density of the left (-36% and -39%) and right (-38% and -43%) ventricles. Although the combination did not induce stronger effects than each drug alone on the systemic and most regional hemodynamic variables, it did have a stronger effect on the cardiac remodeling (compared to control group: -24%, -34%, and -46% for the left ventricle cavity area, -33%, -35%, and -62% for collagen density in the left ventricle, and -52%, -57%, and -59% for collagen density in the right ventricle, respectively, in the metoprolol, spironolactone, and metoprolol + spironolactone groups). In CMH, metoprolol and spironolactone combined did not improve hemodynamics more than each drug alone, but did exert additive effects on cardiac remodeling.

The effects of the selective angiotensin II type 1 receptor antagonist candesartan on cardiac, systemic, and regional hemodynamics and on cardiac, pulmonary, and hepatic histomorphometry were investigated in cardiomyopathic hamsters (CMHs), Bio TO-2 dilated strain, with advanced congestive heart failure (CHF). Two groups were treated orally with candesartan cilexetil at 22 or 50 mg/kg/d from 190 days of age and compared with a control group (38 animals/group). Investigations were performed at 225, 255, and 285 days of age. Left ventricle (LV) and systemic blood pressures and cardiac output and mesenteric and femoral blood flows were measured in anesthetized animals. LV cavity area, LV and right ventricle (RV) wall thickness and collagen density, and pulmonary and hepatic congestion were assessed. Compared with the control group, candesartan did not modify cardiac hemodynamics but significantly and dose-dependently decreased systemic vascular resistances (on average: -23 and -32% after 22 and 50 mg/kg, respectively) and increased stroke volume (+32 and +42%) and cardiac output (+27 and +34%). Candesartan did not modify mesenteric vascular resistances and blood flow but significantly and dose-dependently decreased femoral vascular resistances (-19 and -33%) and increased femoral blood flow (+33 and +43%). Candesartan significantly decreased LV cavity area (-14 and -8%) and LV (-15 and -31%) and RV (-16 and -24%) collagen density but did not modify LV and RV wall thickness. Candesartan decreased pulmonary congestion at 255 and 285 days of age but did not modify hepatic congestion. In CMHs with advanced CHF, candesartan cilexetil improves systemic and femoral hemodynamics, partly reverses cardiac remodeling, and decreases pulmonary congestion.

We investigated the effects of the beta1-beta2-alpha1-blocker, labetalol, in the congestive heart failure (CHF) model induced by aortic constriction in the guinea pig. One hundred days after aortic constriction, 52 animals were given either placebo, labetalol 2 mg/kg/d, or labetalol 20 mg/kg/d for 60 days. Eighteen sham-operated animals were used as controls. Investigations were performed at the end of the treatment period. Compared with sham-operated animals, banded animals receiving placebo showed signs of overt CHF with cardiac, systemic and regional (mesenteric and femoral) hemodynamic dysfunction, and pulmonary and hepatic congestion. An increase in whole heart, atria, and left and right ventricle weights associated with left ventricular cavity enlargement and left and right ventricular wall thickening indicated a remodeling process. Compared with placebo, labetalol did not significantly modify cardiac, systemic, or regional hemodynamic variables but significantly decreased pulmonary and hepatic congestion. Labetalol significantly reduced left ventricular cavity area (-10 and -20% after 2 and 20 mg/kg, respectively) and left ventricular (-4 and -16%) and right ventricular (-4 and -19%) wall thickness. In conclusion, labetalol induced partial regression of cardiac remodeling before hemodynamic improvement. This early anti-remodeling effect could play a role in the favorable effects observed with beta1-beta2-alpha1-blockers in humans.

We assessed the evolution with time of the responsiveness of three vascular beds in dilated cardiomyopathic hamsters of the Bio TO-2 strain. Eight cardiomyopathic hamsters and 8 control hamsters were investigated at 180 and 300 days of age. Thoracic aorta and mesenteric and renal artery rings were studied in isolated organ baths. Cumulative concentration-response relations to phenylephrine, acetylcholine, sodium nitroprusside, and angiotensin II were established for each ring. Maximum effect (Emax) and concentration inducing 50% of Emax (EC50) were determined from each concentration-response curve and pD2 was calculated as -log(EC50). Compared with control hamsters, in cardiomyopathic hamsters, Emax of phenylephrine was not modified in aorta, whereas it was significantly lower in mesenteric (-6% and -33% at 180 and 300 days, respectively) and renal (-17% and -24%) arteries. Emax of acetylcholine was significantly higher in aorta (+57% and +30%), mesenteric (+42% and +34%), and renal (+168% and +70%) arteries. Emax of sodium nitroprusside was significantly higher in aorta (+26% and +16%) and tended to be higher in mesenteric (+25% and +23%) and renal (+27% and +10%) arteries. Emax of angiotensin II was not modified in aorta and tended to be lower in mesenteric artery at 300 days. The pD2 of phenylephrine was significantly increased in aorta and the pD2 of sodium nitroprusside was significantly increased in aorta and renal artery. In conclusion, in dilated cardiomyopathic hamsters, endothelium-dependent and -independent vasodilations are enhanced early, demonstrating increased sensitivity of vascular smooth muscle to nitric oxide. This abnormality may be involved in the decreased responsiveness to phenylephrine and angiotensin II.