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 presser activity of the stable thromboxane A₂ analogue, U-46619 (9,11-dideoxy-9α-(methanoepoxy) prostaglandin F(2α)), in anesthetized open-chest Sprague-Dawley rats (n = 6-9 per group). NO synthase inhibition, as obtained by N(ω)-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 (Δ heart rate = -42 ± 8 beats/min; P < 0.05 vs. vehicle) and delayed- (> 30 min) onset pulmonary hypertension (Δ mean 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 (Δ mean 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 ([1 S-[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; Δ mean 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 presser responses, strongly suggesting that in addition to mediating pulmonary vasoconstriction, TP receptor activation also concomitantly releases NO within the pulmonary vasculature.