Assessment of ability of levcromakalim and sodium nitroprusside to reverse the cardiovascular effects of nitric oxide synthase inhibition in the anaesthetised pig.

Abstract

The aim was to test the ability of levcromakalim, a potassium channel opener, and sodium nitroprusside, a nitric oxide donor, to reverse the systemic and pulmonary vasoconstrictor actions of NG-nitro-L-arginine methyl ester (L-NAME), and thus to restore cardiac output in anaesthetised pigs. In separate groups of pigs administration of a bolus of L-NAME (10 mg.kg-1) was followed either by no further agent (control group; n = 8) or by increasing bolus doses of levcromakalim (10, 20, and 40 micrograms.kg-1; n = 8) or by increasing infused doses of sodium nitroprusside (1, 2, and 4 micrograms.kg-1.min-1 for 15 min at each dose). The same doses of levcromakalim and sodium nitroprusside were also given to pigs (n = 6 in each group) which had been pretreated with saline rather than L-NAME. The changes in systemic and pulmonary haemodynamic indices and cardiac output as a result of each intervention were measured at each stage and compared between and within drug groups. In each group, the bolus of L-NAME caused increases in systemic vascular resistance, mean arterial pressure, pulmonary vascular resistance, and mean pulmonary artery pressure, and a reduction in cardiac output. These effects were significantly different from pretreatment values at 15 min, and were maintained for at least 60 min when no further agent was given. The subsequent administration of levcromakalim caused significant reductions in systemic vascular resistance and mean arterial pressure, the effects being greater than in animals that had been pretreated with saline rather than L-NAME. Pulmonary vascular resistance and mean pulmonary artery pressure were also reduced, but to a lesser degree. Cardiac output was partially but significantly restored. The subsequent administration of sodium nitroprusside caused significant reductions in systemic vascular resistance, mean arterial pressure, pulmonary vascular resistance, and mean pulmonary artery pressure. These effects were significantly greater than those in animals that had been pretreated with saline rather than L-NAME. Cardiac output was weakly, though significantly restored. Increased systemic vascular resistance following a bolus of L-NAME (10 mg.kg-1) is reversed by subsequent administration of levcromakalim (10-40 micrograms.kg-1) or sodium nitroprusside (1-4 micrograms.kg-1.min-1) associated with partial restoration of cardiac output. The degree to which cardiac output is restored by these two agents is limited by a concomitant reduction in preload.