Search

Angiotensin II receptor blockade (ARB) increases vasorelaxation in heart failure by enhancing endothelial nitric oxide (NO). To determine the effects of valsartan on NO-mediated peripheral vascular function after myocardial infarction (MI), we treated adult male Sprague-Dawley rats immediately after MI with valsartan for 3 weeks (sham, n = 10; MI, n = 11) and 6 weeks (sham, n = 6; MI, n = 8). At both time points, valsartan lowered (P < 0.05) left ventricular (LV) systolic pressure (103 +/- 4 and 107 +/- 4 vs. 93 +/- 3 and 85 +/- 4 mm Hg, respectively) and LV end-diastolic pressure (25 +/- 1 and 25 +/- 2 to 13 +/- 2 and 18 +/- 3 mm Hg, respectively). Valsartan lowered (P < 0.05) LV dP/dt only at 6 weeks (4676 +/- 168 and 4503 +/- 232 vs. 4539 +/- 281 and 3372 +/- 417 mm Hg/sec); valsartan shortened (P < 0.05) the time constant of LV relaxation or tau only at 3 weeks (24.2 +/- 1.8 and 26.5 +/- 2.3 vs. 20.1 +/- 0.7 and 23.8 +/- 1.4 msec). At 6 weeks, the vasorelaxation response to acetycholine in aortic rings was decreased (P < 0.05) with MI and improved at acetycholine doses (10, 10, and 10; P < 0.06) with valsartan. Endothelial nitric oxide synthase (eNOS) protein was undetectable in aortic tissue from valsartan treated rats or from aortic tissue incubated with valsartan (2.5, 25, and 50 mg/mL). These data suggest that valsartan improves cardiac function after MI by modulating LV remodeling, decreasing LV end-diastolic pressure, and enhancing both LV diastolic and endothelial function. These effects are mediated, in part, by NO but upregulation of eNOS may not be required for improved systemic endothelial function in heart failure.

This study was designed to determine if the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA), now in clinical trials for heart failure, alters endothelial function after myocardial infarction (MI). Three weeks after MI, adult Sprague-Dawley rats were randomly assigned to DITPA (375 microg/100 g subcutaneous) or no treatment of 3 weeks. In MI rats, left ventricular (LV) end-diastolic pressure and LV dP/dt decreased (P < 0.05). DITPA did not change MAP (87 +/- 10 versus 90 +/- 7 mm Hg) or LV end-diastolic pressure (23 +/- 3 versus 19 +/- 9 mm Hg) but did lower (P < 0.05) LV dP/dt (4,633 +/- 797 versus 3,650 +/- 1,236 mm Hg/s). In aortic segments from MI rats, DITPA enhanced the acetylcholine dependent vasorelaxation (59 +/- 11% at 10(-4) M, P < 0.05) and isoproterenol induced vasorelaxation (57 +/- 13% at 10(-4) M, P < 0.05). The increases in vasorelaxation were blocked with l-NAME and restored with L-arginine. Treatment with DITPA increased (P < 0.05) eNOS protein content in aortic tissue from sham rats (3.8 +/- 2.8 to 44.5 +/- 7.1 integrated intensity units (II)/microg) and in MI rats (5.3 +/- 3.4 to 28.3 +/- 8.9 II/microg). In endothelial cells, 24 hours' treatment with DITPA (10 microM) increased (P < 0.01) eNOS protein expression from 22.1 +/- 4.8 to 52.7 +/- 16.8 II/microg protein and DITPA (20 microM) increased eNOS to 49.1+/- 15.2 II/microg protein. The thyroid analog DITPA enhances endothelial nitric oxide and beta-adrenergic-mediated vasorelaxation by increasing nitric oxide in the vasculature.

We wished to determine whether enhanced bioavailability of bradykinin (BK) and vasodilatory prostaglandins contribute to renovascular and sodium-handling effects of angiotensin-converting enzyme (ACE) inhibition after myocardial infarction (MI). We studied rats after coronary artery ligation treated for 3 weeks with captopril or losartan (2 g/L drinking water for each agent). Hemodynamic and renal function studies were performed in conscious rats before and after sequential infusion BK inhibitor (BKI, 0.02 ng/kg/min) and indomethacin (1 mg/kg). Myocardial infarction increased filtration fraction (FF) 20% (p < .004) but did not change glomerular filtration rate (GFR), urine flow (UF), renal blood flow (RBF), renal vascular resistance (RVR), urine sodium (UNa), or fractional excretion of sodium (FENa). Captopril decreased (p < 0.001) mean arterial pressure (MAP) 25%, UF 61%, RVR 65%, and FENa 75% and increased (p < 0.05) GFR 22%, and RBF 34%. Losartan decreased (p < 0.05) MAP 27%, UF 52%, RVR 21%, and FENa 44%. In captopril-treated MI rats, BKI decreased (p < 0.05) GFR 22% and RBF 25% and increased (p < 0.05) RVR 32%, UNa 43%, and FENa 28%, whereas indomethacin decreased (p < 0.05) GFR 24% and increased (p < 0.05) UNa 86% and FENa 112%. In losartan-treated MI rats, BKI increased (p < 0.05) UNa 42% and FENa 60%, whereas indomethacin increased (p < 0.05) UNa 79% and FENa 85%. Activation of the BK and prostaglandin systems may play an important role in regulating renal function during chronic ACE inhibition, primarily by enhancing the renal vasodilatory effects of angiotensin II (AII) blockade.