Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide

Am J Physiol Heart Circ Physiol. 2010 Oct;299(4):H1153-9. doi: 10.1152/ajpheart.01101.2009. Epub 2010 Jul 16.

Abstract

BAY 41-8543 is a nitric oxide (NO)-independent stimulator of soluble guanylyl cyclase (sGC). Responses to intravenous injections of BAY 41-8543 were investigated under baseline and elevated tone conditions and when NO synthase (NOS) was inhibited with N(ω)-nitro-L-arginine methyl ester (L-NAME). Under baseline conditions, intravenous injections of BAY 41-8543 caused small decreases in pulmonary arterial pressure, larger decreases in systemic arterial pressure, and increases in cardiac output. When pulmonary arterial pressure was increased to ∼30 mmHg with an intravenous infusion of U-46619, intravenous injections of BAY 41-8543 produced larger dose-dependent decreases in pulmonary arterial pressure, and the relative decreases in pulmonary and systemic arterial pressure in response to the sGC stimulator were similar. Treatment with L-NAME markedly decreased responses to BAY 41-8543 when pulmonary arterial pressure was increased to similar values (∼30 mmHg) in U-46619-infused and in U-46619-infused plus L-NAME-treated animals. The intravenous injection of a small dose of sodium nitroprusside (SNP) when combined with BAY 41-8543 enhanced pulmonary and systemic vasodilator responses to the sGC stimulator in L-NAME-treated animals. The present results indicate that BAY 41-8543 has similar vasodilator activity in the systemic and pulmonary vascular beds when pulmonary vasoconstrictor tone is increased with U-46619. These results demonstrate that pulmonary and systemic vasodilator responses to BAY 41-8543 are significantly attenuated when NOS is inhibited by L-NAME and show that vasodilator responses to BAY 41-8543 are enhanced when combined with a small dose of SNP in L-NAME-treated animals. The present results are consistent with the concept that pulmonary and systemic vasodilator responses to the sGC stimulator are NO-independent; however, the vasodilator activity of the compound is greatly diminished when endogenous NO production is inhibited with L-NAME. These data show that BAY 41-8543 has similar vasodilator activity in the pulmonary and systemic vascular beds in the rat.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Circulation / drug effects*
  • Blood Circulation / physiology
  • Blood Pressure / drug effects
  • Cardiac Output / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Guanylate Cyclase / metabolism*
  • Male
  • Models, Animal
  • Morpholines / pharmacology*
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitroprusside / pharmacology
  • Pulmonary Circulation / drug effects*
  • Pulmonary Circulation / physiology
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Vasodilation / drug effects*
  • Vasodilation / physiology
  • Vasodilator Agents / pharmacology

Substances

  • BAY 41-8543
  • Enzyme Inhibitors
  • Morpholines
  • Pyrimidines
  • Vasodilator Agents
  • Nitroprusside
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Guanylate Cyclase
  • NG-Nitroarginine Methyl Ester