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Ramipril improves nitric oxide availability in hypertensive rats with failing hearts after myocardial infarction

Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, D-65926 Frankfurt/Main, Germany, Wolfgang.Linz{at}aventis.com

Gabi Itter

Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, D-65926 Frankfurt/Main, Germany

Lawrence W Dobrucki

Ohio University, Department of Chemistry and Biochemistry, Athens, OH 45701-2979, USA

Tadeusz Malinski

Ohio University, Department of Chemistry and Biochemistry, Athens, OH 45701-2979, USA

Gabriele Wiemer

Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, D-65926 Frankfurt/Main, Germany

A markedly decreased aortic nitric oxide (NO) availability, probably due to impaired endothelial nitric oxide synthase activity with enhanced O₂- and peroxynitrite production, seems to be attributable to endothelial dysfunction in spontaneously hypertensive rats (SHR) with severe congestive heart failure (CHF). In this study, we investigated the chronic effect of the angiotensin-converting enzyme inhibitor, ramipril (RA) and the loop diuretic, frusemide (FU), as well as the combination of both on endothelial NO, O₂- and peroxynitrite production in aortae from SHR with failing hearts after myocardial infarction (MI).

Heart failure was induced by permanent occlusion of the left coronary artery. SHR were randomised to receive either placebo, RA, (1 mg/kg/day), FU (4 mg/kg/day) or RA+FU (1 and 4 mg/kg/day, respectively). Treatments were started two weeks following MI and continued for six weeks. Reduced aortic and coronary flow indices in the working heart, which can be considered as markers for endothelial function, were significantly normalised and improved, respectively, by RA, FU or RA+FU-treatment. Similarly, all three treatment regimens significantly enhanced the reduced calcium ionophore (CaI)-induced NO-release (assessed by a NO-sensitive microsensor) from aortic endothelial cells of placebo- treated animals with CHF. Concomitantly, the increased CaI-stimulated O ₂production (assessed by an electrochemical sensor) in aortic endothelial cells of placebo-treated animals with CHF was significantly reduced by RA and RA+FUtreatment. Treatment with RA and RA+FU also attenuated the dramatic increase in endothelial peroxynitrite concentration (chemiluminescence method), which was observed in placebo-treated rats with CHF. FU did not counteract improved haemo- and cardiodynamic parameters by RA.

Thus, RA and FU act synergistically to enhance bioavailability of endothelium-derived NO, and this may contribute to the clinical usefulness of the combination of these drugs in treatment of heart failure.

Key Words: congestive heart failure • ramipril • frusemide • nitric oxide • superoxide • spontaneously hypertensive rats

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