Nitric oxide regulation of TP receptor-mediated pulmonary vasoconstriction in the anesthetized, open-chest rat

We investigated the influence of endothelial nitric oxide (NO) on the pulmonary pressor activity of the stable thromboxane A2 analogue, U-46619 (9,11-dideoxy-9α-(methanoepoxy) prostaglandin F2α), in anesthetized open-chest Sprague-Dawley rats (n=6–9 per group). NO synthase inhibition, as obtained by Nω-nitro-l-arginine methyl ester (l-NAME; 0.63 mg/kg i.v.+20 mg/kg/h), induced sustained systemic hypertension (mean maximal increase, Δ, in mean systemic arterial pressure=38±6 mmHg; P<0.05 vs. vehicle) associated with slight bradycardia (Δheart rate=−42±8 beats/min; P<0.05 vs. vehicle) and delayed- (>30 min) onset pulmonary hypertension (Δmean pulmonary arterial pressure=10±3.4 mmHg; P<0.05 vs. vehicle). In separate experiments, when mean systemic arterial pressure was maximally increased by l-NAME, the difference between mean pulmonary arterial pressure and mean left atrial pressure was greater in l-NAME-treated rats (41±16% compared to 10±1% in the vehicle group; P<0.05), strongly suggesting that spontaneously released NO modulated pulmonary vascular resistance. l-Arginine at a dose which reduced by ∼50% the l-NAME-associated systemic hypertension did not alter the late rise in mean pulmonary arterial pressure (Δmean pulmonary arterial pressure=12±4 mmHg; P=NS vs. l-NAME alone). U-46619, elicited rapid, dose-dependent, and transient increases in mean pulmonary arterial pressure (Δ=8.8±2.0 and 21.2±1.9 mmHg at 1.25 and 20 μg/kg i.v. respectively; both P<0.01 vs. vehicle). U-46619 (1.25 μg/kg)-induced increases in mean pulmonary arterial pressure were fully antagonized by the thromboxane A2/prostanoid (TP) receptor antagonist, SQ 29,548 ([1S-[1α,2α(5Z),3α,4α]]-7-[3-[[2-[(phenyl-amino)-carbonyl] hydrazino] methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid) (0.63 mg/kg i.v.+0.63 mg/kg/h). Injection of U-46619 (1.25 μg/kg), 15 min after l-NAME administration, evoked a 24.7±0.9 mmHg increase in mean pulmonary arterial pressure (P<0.01 vs. U-46619 in control rats), which was (i) greater than that produced by a 16-fold higher dose of U-46619 alone, (ii) fully antagonized by SQ 29,548, (iii) significantly attenuated during coadministration of l-NAME and l-arginine (10 mg/kg i.v.+160 mg/kg/h; Δmean pulmonary arterial pressure=14.6±4.3 mmHg; P<0.05 vs. U-46619 following l-NAME alone and P=NS vs. U-46619 in control rats). These results indicate that, under normal circumstances, pulmonary vasomotor tone is regulated by spontaneously released NO. Moreover, pulmonary vascular NO attenuates TP receptor-mediated pressor responses, strongly suggesting that in addition to mediating pulmonary vasoconstriction, TP receptor activation also concomitantly releases NO within the pulmonary vasculature.