Inhibition of Endogenous Nitric Oxide Synthesis Potentiates the Effects of Sodium Nitroprusside but Not of Adenosine in Experimental Pulmonary Hypertension

Abstract

This study examined the systemic and pulmonary vasodilator effects of sodium nitroprusside (SNP) and adenosine during experimental pulmonary hypertension with and without inhibition of endogenous NO synthesis. Male New Zealand White rabbits were anesthetized and mechanically ventilated. The NO synthesis inhibitor N^G-nitro-L-arginine methyl ester (L-NAME) was administered to 15 of the 28 rabbits. Pulmonary hypertension was then produced in all rabbits by U46619, a thromboxane A₂ mimetic. SNP was infused in 14 rabbits (7 L-NAME, 7 control) at doses of 0.5–20 µg/kg/min; adenosine was infused in the other 14 rabbits (8 L- NAME, 6 control) at doses of 12.5–300 µg/kg/min. The U46619 dose required to produce pulmonary hypertension was significantly lower in the L-NAME group. SNP dose-dependently decreased pulmonary (Ppa) and systemic (Psa) artery pressures and systemic vascular resistance (SVR). Both Ppa and Psa were decreased more with SNP in the L-NAME than in the no L-NAME group. The SNP ED₅₀ for the decrease in PVR was almost threefold lower in the L-NAME group. Adenosine dose-dependently decreased Ppa, Psa, PVR and SVR. The adenosine ED₅₀ for the decreases in PVR and SVR were similar in the L-NAME group and the control group. We conclude that inhibition of endogenous NO synthesis shifts the dose-response curves for both the pulmonary and systemic vasodilator effects to the left for the nitrovasodilator SNP but not for the non-nitrovasodilator adenosine.

Increased expired NO and roles of CO2 and endogenous NO after venous gas embolism in rabbits

“…It is not due to a general toxic eVect on, for example, circulation or respiration as rabbits tolerate several hours of the employed L-NAME dose with periods of marked hypoxic challenge (Persson et al 1990). It has been shown in rabbits that NOS inhibition slightly increases basal pulmonary vascular resistance (Persson et al 1990) and severely augments the pulmonary hypertension induced by hypoxia (Persson et al 1990) and a thromboxane A 2 -mimetic (Wall et al 1999). A contributing factor to the reduced survival rate in the present study and in that of WisloV et al (2003) could thus be that NOS inhibition resulted in a pulmonary hypertension that worsened the impact of VGE in the lung circulation.…”

Increase in exhaled nitric oxide and protective role of the nitric oxide system in experimental pulmonary embolism

“…Previously, it has been shown that endogenous NO synthesis inhibition does not affect basal pulmonary arterial pressure in dogs ( Sander et al ., 2003 ) and moderately increases basal pulmonary vascular resistance in rabbits ( Persson et al ., 1990 ), and severely augments hypoxic vasoconstriction in rabbits ( Persson et al ., 1990 ) and dogs ( Sander et al ., 2003 ). Another example of a condition where inhibited NO synthesis enhances pulmonary hypertension is during thromboxane A 2 mimetic‐induced pulmonary hypertension in rabbits ( Wall et al ., 1999 ). It is also known that endogenous NO is a regulator of heart performance ( Paulus and Bronzwaer, 2004 ) and that acute NO synthase inhibition reduces myocardial oxygen consumption and myocardial contractility ( Sherman et al ., 1997 ).…”