Nitric oxide in systemic and pulmonary hypertension

Abstract

Endothelium-derived nitric oxide (NO) is an important gas molecule in the regulation of vascular tone and arterial pressure. It has been considered that endothelial dysfunction with impairment of NO production contributes to a hypertensive state. Alternatively, long-term hypertension may affect the endothelial function, depress NO production, and thereby reduce the dilator action on vasculatures. There were many studies 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 experiments in our laboratory revealed that an NO synthase inhibitor, N(G)-nitro-L-arginine monomethyl ester (L-NAME) caused elevation of arterial pressure (AP) in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). The magnitude of AP increase following NO blockade with L-NAME was much higher in SHR than WKY. In other experiments 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. Furthermore, these changes were not different between SHR and WKY. The increase in AP and total peripheral resistance (TPR) following NO blockade in SHR were significantly greater than those in WKY, despite higher resting values of AP and TPR in SHR. In connection with the results of other studies, we propose that heterogeneity with respect to the involvement of NO (impairment, no change or enhancement) in the development of hypertension may exist among animal species, hypertensive models and different organ vessels. Our study in SHR provide evidence to indicate that the effects of basal release of NO on the arterial pressure and peripheral resistance are not impaired, but enhanced in the hypertensive state. The increase in NO production may provide a compensatory mechanism 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 vasoconstriction during hypoxia. With the measurement of NO release in the pulmonary vein, we found that ventilatory hypoxia produced pulmonary hypertension 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 hypoxia, the increased NO formation in the pulmonary circulation similarly exerts a compensatory mechanism to offset the degree of pulmonary vasoconstriction.

Nitric Oxide In Mesenteric Vascular Reactivity: A Comparison Between Rats With Normotension And Hypertension

“…According to our earlier studies, 12,21–23 the mean arterial pressure of SHR reached a constant hypertensive state of 150–160 mmHg after 12 weeks of age while that of WKY rats remained at approximately 120 mmHg. In order to exclude all possible influence after the in situ mesenteric perfusion was performed, the basal MPP of SHR was adjusted to 160 mmHg and that of WKY rats was adjusted to 120 mmHg by adjusting the flow rate (6 and 4 mL/min, respectively).…”

“…Therefore, Li and Bukoski 11 claimed that there was no change in ‘endothelium‐dependent vasorelaxation’ in the hypertensive state. Our recent studies on arterial haemodynamics 12,21,22 have revealed different findings. Acute NO synthase (NOS) blockade with the NOS inhibitor N G ‐nitro‐ L ‐arginine methyl ester ( L ‐NAME) caused an increase in arterial pressure and total peripheral resistance.…”

Insulin attenuates endotoxin-induced acute lung injury in conscious rats

“…Several reports have indicated that NO is involved in the pathogenesis of ALI or acute respiratory distress syndrome in animals or humans with endotoxemia (6 -8). Although endogenous NO production is important for the maintenance of homeostatic condition in many tissues and organs (28 -32), overproduction of NO may be harmful in certain pathologic conditions such as sepsis and infections (33)(34)(35).…”

Inhibition of Inducible Nitric Oxide Synthase Attenuates Acute Endotoxin‐induced Lung Injury in Rats

“…In anaesthetized rats, endotoxin produces systemic hypotension accompanied by the release of pro‐inflammatory cytokines, nitric oxide (NO), the expression of inducible nitric oxide synthase (iNOS) and, finally, acute pulmonary oedema (APO) 5,8,11,13 . In experiments performed using isolated and perfused lungs, exogenous and endogenous NO plays a pivotal role in the APO induced by air embolism, 14,15 fat embolism, 16 ischaemia/reperfusion, 17,18 amphetamine intoxication, 19 phorbol myristate acetate, 20 virus infections 16,21 and endotoxaemia 5,11,13,22 …”