Complexes of Nitric Oxide with Nucleophiles as Agents for the Controlled Biological Release of Nitric Oxide

Abstract

Nitric oxide (NO) and drugs that generate NO are potent vasodilators. We investigated the in vivo vasodilator potential of a unique group of compounds that release NO spontaneously in solution, the NO/nucleophile complexes. The hemodynamic effects of diethylamine/NO complex (DEA/NO) (half-life < 3 min) and the spermine/NO complex (SPER/NO) (half-life > 30 min) administered intravenously were compared with those of sodium nitroprusside in anesthesized New Zealand white rabbits. Arterial pressure and systemic vascular resistance decreased, but central venous pressure, pulmonary arterial pressure, heart rate, and thermodilution cardiac output did not change in association with any of the three drugs in the doses administered. The hemodynamic effects were dose dependent. As predicted from their rates of spontaneous NO release, DEA/NO is a short-acting vasodilator with a duration similar to that of sodium nitroprusside, whereas SPER/NO is a longer-acting agent with a significant hypotensive effect 30 min after bolus injection. DEA/NO was equipotent to sodium nitroprusside, causing significant reductions in blood pressure and systemic vascular resistance at the lowest dose tested (1.5 nmol/kg). The data indicate that the NO/nucleophile complexes have predictable vasorelaxant effects in vivo as well as in vitro and suggest that their amenability to facile structure-reactivity and structure-activity modification should allow the design of NO donor drugs for a variety of applications in cardiovascular pharmacology.