Role of endothelium-derived factors in the regulation of pulmonary vascular tone and responses
Description
The inner lining of blood vessels, the endothelium, once considered only to serve barrier and metabolic functions, also produces mediators which actively influence the underlying vascular smooth muscle. Because the endothelium normally produces vasorelaxant factors, such as endothelium-derived relaxing factor (EDRF), and vasocontracting factors, such as endothelin and thromboxane A$\sb2$ (TXA$\sb2$), the abnormal production or action of these factors may underlie vascular diseases including pulmonary and systemic hypertension, reperfusion injury, atherosclerosis, and endotoxic shock The pulmonary vascular bed exhibits an enormous capacity for adaptation to local stimuli, and the regulation of the pulmonary circulation is probably localized. Therefore, in this project it was hypothesized that local factors, particularly EDRF, could play an important role in the regulation of the pulmonary circulation. The role of these factors in the regulation of the pulmonary circulation was studied under conditions of controlled blood flow and constant left atrial pressure in isolated perfused rat lungs and in vivo in the intact-chest cat The EDRF released in response to acetylcholine and other stimuli is now widely believed to be nitric oxide (NO) or a labile nitroso compound. Like NO, EDRF activates soluble guanylate cyclase and stimulates increases in cyclic guanosine 3$\sp\prime$,5$\sp\prime$-cyclic monophosphate (cGMP) levels in vascular smooth muscle cells. In the present study, the NO synthesis inhibitor N$\sp\Omega$-nitro-L-arginine methyl ester (L-NAME) and the guanlyate cyclase inhibitor methylene blue (MB) increased pulmonary vascular resistance and selectively inhibited pulmonary vasodilator responses to exogenous acetylcholine, substance P, the cGMP-specific phosphodiesterase inhibitor Zaprinast; and to acetylcholine released endogenously. L-NAME selectively enhanced the pulmonary vasoconstrictor response to serotonin in the intact-chest cat and enhanced hypoxic pulmonary vasoconstriction in the isolated rat lung These data suggest that the basal production of endothelium-derived NO (EDNO) maintains the pulmonary vascular bed in a dilated state and is the major stimulus for the activation of soluble guanylate cyclase in the pulmonary vascular bed. Moreover, EDNO release and cGMP formation appear to play an important role in mediating vasodilator responses to endogenous and exogenous stimuli and in limiting responses to vasoconstrictor stimuli in the lung