Cardiovascular actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vivo studies

Br J Pharmacol. 2002 Jan;135(2):344-55. doi: 10.1038/sj.bjp.0704483.

Abstract

BAY 41-8543 is a novel non-NO-based stimulator of sGC. This study investigates the acute effects of BAY 41-8543 on haemodynamics in anaesthetized rats and dogs, its long-term effects in conscious hypertension rat models and its antiplatelet effects. In anaesthetized dogs, intravenous injections of BAY 41-8543 (3 - 100 microg kg(-1)) caused a dose-dependent decrease in blood pressure and cardiac oxygen consumption as well as an increase in coronary blood flow and heart rate. In anaesthetized normotensive rats, BAY 41-8543 produced a dose-dependent and long-lasting blood pressure lowering effect after intravenous (3 - 300 microg kg(-1)) and oral (0.1 - 1 mg kg(-1)) administration. A dose-dependent and long-lasting decrease in blood pressure was also observed in conscious spontaneously hypertensive rats with a threshold dose of 0.1 mg kg(-1) p.o. After 3 mg kg(-1) the antihypertensive effect lasted for nearly 24 h. After multiple dosages, BAY 41-8543 did not develop tachyphylaxis in SHR. BAY 41-8543 prolonged the rat tail bleeding time and reduced thrombosis in the FeCl(3) thrombosis model after oral administration. In a low NO, high renin rat model of hypertension, BAY 41-8543 prevented the increase in blood pressure evoked by L-NAME and reveals a kidney protective effect. In this model, the overall beneficial effects of BAY 41-8543 manifested as both antiplatelet effect and vasodilatation were reflected in a significant reduction in mortality. The pharmacological profile of BAY 41-8543 suggests therefore that this compound has the potential to be an important research tool for in vivo investigations in the sGC/cGMP field and it also has the potential of being a unique clinical utility for treatment of cardiovascular diseases.

MeSH terms

  • Animals
  • Animals, Genetically Modified / genetics
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Cardiovascular System / drug effects
  • Dogs
  • Dose-Response Relationship, Drug
  • Enzyme Activators / pharmacology*
  • Female
  • Guanylate Cyclase / metabolism*
  • Hemodynamics / drug effects*
  • Hemodynamics / physiology
  • Male
  • Morpholines / pharmacology*
  • Nitric Oxide* / metabolism
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Inbred SHR
  • Rats, Wistar / genetics

Substances

  • BAY 41-8543
  • Enzyme Activators
  • Morpholines
  • Pyrimidines
  • Nitric Oxide
  • Guanylate Cyclase