Role of endothelium-derived vasoactive substances in the pathogenesis of pulmonary hypertension

Pulmonary vascular endothelium synthesizes and releases two major groups of vasoactive substances, namely the endothelium-derived relating and 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 (EDHF) 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 all the characteristics of a gas, whereas its pharmacological properties are consistent with those of an endogenous nitrovasodilator. Therefore, inhalation of the gas NO is now considered as one of the most promising means to treat persistent pulmonary hypertension of the newborn. EDHF relaxes vascular smooth muscle through activation of ATP-dependent potassium channels. Both the chemical nature and the physiological role of EDHF are still unclear. The pharmacological properties of endothelin are far from being unequivocal. It is a potent vasoconstrictor when it directly acts on vascular smooth muscle. However, it can also induce the release of NO and EDHF, hence causing vasorelaxation. These effects of endothelin are mediated by various transduction pathways. Activations of ET-B receptors located on endothelium an the one hand, and ET-A receptors located on smooth muscle an the other hand, are responsible for relaxation and constriction of vascular smooth muscle, respectively. Such highly complex cellular mechanisms highlight the need for further insight Info the physiology of the cell related to the pulmonary circulation. This, in turn, will help to better define the target upon which one can try to correct the abnormal function of the cell underlying the pathophysiological processes.