NITRIC-OXIDE IN SYSTEMIC AND PULMONARY-HYPERTENSION

Endothelium-derived nitric oxide (NO) is an important gas molecule in the regulation of vascular tone and arterial pressure. It has been con sidered that endothelial dysfunction with impairment of NO production contributes to a hypertensive state. Alternatively, long-term hyperten sion may affect the endothelial function, depress NO production, and t hereby reduce the dilator action on vasculatures. There were many stud ies to support that endothelium-dependent vasodilatation was impaired in animals and humans with long-term hypertension. However, results of some reports were not always consistent with this consensus. Recent e xperiments in our laboratory revealed that an NO synthase inhibitor, N -G-nitro-L-arginine monomethyl ester (L-NAME) caused elevation of arte rial pressure (AP) in spontaneously hypertensive rats (SHR) and normot ensive Wistar Kyoto rats (WKY). The magnitude of AP increase following NO blockade with L-NAME was much higher in SHR than WKY. In other exp eriments with the use of arterial impedance analysis, we found that L- NAME slightly or little affected the pulsatile hemodynamics including characteristic impedance, wave reflection and ventricular work. Furthe rmore, these changes were not different between SHR and WKY. The incre ase in AP and total peripheral resistance (TPR) following NO blockade in SHR were significantly greater than those in WKY, despite higher re sting values of AP and TPR in SHR. In connection with the results of o ther studies, we propose that heterogeneity with respect to the involv ement of NO (impairment, no change or enhancement) in the development of hypertension may exist among animal species, hypertensive models an d different organ vessels. Our study in SHR provide evidence to indica te that the effects of basal release of NO on the arterial pressure an d peripheral resistance are not impaired, but enhanced in the hyperten sive state. The increase in NO production may provide a compensatory m echanism to keep the blood pressure and peripheral resistance at lower levels. The phenomenon of enhanced NO release also occurs in certain type of pulmonary hypertension. We first hypothesized that a decrease in NO formation might be responsible for the pulmonary vasoconstrictio n during hypoxia. With the measurement of NO release in the pulmonary vein, we found that ventilatory hypoxia produced pulmonary hypertensio n accompanying an increase in NO production. Addition of NO inhibitor (L-NAME), blood or RBC into the perfusate attenuated or abolished the NO release, while potentiating pulmonary vasoconstriction. During hypo xia, the increased NO formation in the pulmonary circulation similarly exerts a compensatory mechanism to offset the degree of pulmonary vas oconstriction.