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

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 μg 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 μg 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.British Journal of Pharmacology (2002) 135 , 344–355; doi: 10.1038/sj.bjp.0704483