Exogenous nitric oxide centrally enhances pulmonary reactivity in the normal and hypertensive rat

Abstract

1. Chronic hypoxia causes sustained pulmonary hypertension and, although impairment of the pulmonary endothelial nitric oxide (NO) pathway has been implicated, no study has described the central role of NO in modulating pulmonary vascular tone and reactivity. Centrally, NO inhibits sympathetic outflow, so we hypothesised that central NO would modulate pulmonary vascular tone and its reactivity to acute hypoxia, especially in the hypertensive state. 2. Male adult Sprague-Dawley rats were exposed to normoxia (N) or chronic hypoxia (CH; 12% O2) for 14 days. Mean pulmonary arterial pressure (MPAP), systemic mean arterial blood pressure (MABP), cardiac output and heart rate were then measured in pentobarbitone-anaesthetized, artificially ventilated rats. The N and CH rats were exposed to acute hypoxia (10% O2 for 4 min) after the intracerebroventricular (i.c.v.) administration of artificial cerebrospinal fluid (control) and then again after either i.c.v. NG-nitro-L-arginine methyl ester (L-NAME; 150 microg in 10 microL) or 3-morpholino-sydnonimine hydrochloride (SIN-1; 100 microg in 10 microL). 3. Chronic hypoxia caused pulmonary hypertension (MPAP 20+/-1 vs 30+/-1 mmHg in N and CH rats, respectively) and attenuated acute hypoxic pulmonary vasoconstriction (HPV). Central inhibition of NO synthesis (by l-NAME) did not alter baseline MPAP or the acute HPV in either N or CH rats, but it did elevate MABP. The NO donor SIN-1 did not alter baseline MPAP, but it did enhance (N rats) or restore (CH rats) the HPV and decreased MABP. 4. The results of the present study indicate that central NO has a limited role in the tonic modulation of MPAP during normoxia and after chronic hypoxia. However, the acute HPV seems to be enhanced by exogenous NO.

Pulmonary Vascular Reactivity of Spontaneously Hypertensive Rats Is Exacerbated in Response to the Central Administration of Exogenous Nitric Oxide

“…The SIN-1-induced reduction in PAP was brought about by a decrease in CO, in which the decrease in HR had a significant role, without altering PVR. These results concur with those of a previous report, 24 indicating that the central nitroxidergic system may only have a somewhat limited role in modulating 'tonic' pulmonary vascular tone, particularly in the hypertensive state.…”

“…24 In the present study, similar observations were recorded for WKY rats, but the unique result of the present study is the fact that accentuation of the HPV by central NO was considerably larger for SHR. Although the underlying mechanism(s) by which NO enhances HPV remains to be confirmed, we postulate that a central NO-induced decrease in sympathetic activity is likely to be a primary factor.…”

“…These results are somewhat surprising because we have demonstrated previously that central l-NAME does not alter pulmonary vascular tone in SpragueDawley rats. 24 The reasons for the discrepancy are uncertain. Although the present results may implicate the importance of central NO in modulating tonic pulmonary vascular tone (i.e.…”

“…We have reported previously that acute central NOS inhibition does not modify the cardiovascular responses to acute hypoxia. 24 After fully recovering from the bolus dose of l-NAME (> 10 min), rats were given a bolus i.c.v. injection of vehicle and then exposed to hypoxia (10% O 2 balanced by N 2 ) for 4 min.…”

The Chemistry of Bioactive Mesoionic Heterocycles

“…Using SIN-1 (32), central NO administration has been shown to enhance acute hypoxic pulmonary vasoconstriction (HPV) [45], and accentuation of the HPV by NO is exacerbated in spontaneously hypertensive rats (SHR) compared with Wister-Kyoto (WKY) rats [46].…”