ROLE OF ENDOTHELIUM-DERIVED VASOACTIVE SU BSTANCES IN THE PATHOGENESIS OF PULMONARY-HYPERTENSION

Pulmonary vascular endothelium synthesizes and releases two major grou ps of vasoactive substances, namely the endothelium-derived relating a nd contracting factors. Among the former the effects of nitric oxide ( NO), formely known as endothelium-derived relaxing factor (EDRF), and those of the so-called endothelium-derived hyperpolarizing factor (EDH F) have been extensively investigated. Among the latter, endothelin is probably one of the most potent endogenous vasoconstrictors. NO is a free radical which can be readily inactivated by hemoglobin. NO has al l the characteristics of a gas, whereas its pharmacological properties are consistent with those of an endogenous nitrovasodilator. Therefor e, inhalation of the gas NO is now considered as one of the most promi sing means to treat persistent pulmonary hypertension of the newborn. EDHF relaxes vascular smooth muscle through activation of ATP-dependen t potassium channels. Both the chemical nature and the physiological r ole of EDHF are still unclear. The pharmacological properties of endot helin are far from being unequivocal. It is a potent vasoconstrictor w hen it directly acts on vascular smooth muscle. However, it can also i nduce the release of NO and EDHF, hence causing vasorelaxation. These effects of endothelin are mediated by various transduction pathways. A ctivations of ET-B receptors located on endothelium an the one hand, a nd ET-A receptors located on smooth muscle an the other hand, are resp onsible for relaxation and constriction of vascular smooth muscle, res pectively. Such highly complex cellular mechanisms highlight the need for further insight Info the physiology of the cell related to the pul monary circulation. This, in turn, will help to better define the targ et upon which one can try to correct the abnormal function of the cell underlying the pathophysiological processes.