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 A(2) analogue, U- 46619 (9,11-dideoxy-9 alpha-(methanoepoxy) prostaglandin F-2 alpha), i n anesthetized open-chest Sprague-Dawley rats (n = 6-9 per group). NO synthase inhibition, as obtained by N-omega-nitro-L-arginine methyl es ter (L-NAME; 0.63 mg/kg i.v. + 20 mg/kg/h), induced sustained systemic hypertension (mean maximal increase, Delta, in mean systemic arterial pressure = 38 +/- 6 mmHg; P < 0.05 vs. vehicle) associated with sligh t bradycardia (Delta heart rate = - 42 +/- 8 beats/min; P < 0.05 vs. v ehicle) and delayed-(> 30 min) onset pulmonary hypertension (Delta mea n pulmonary arterial pressure = 10 +/- 3.4 mmHg; P < 0.05 vs. vehicle) . In separate experiments, when mean systemic arterial pressure was ma ximally increased by L-NAME, the difference between mean pulmonary art erial pressure and mean left atrial pressure was greater in L-NAME-tre ated rats (41 +/- 16% compared to 10 +/- 1% in the vehicle group; P < 0.05), strongly suggesting that spontaneously released NO modulated pu lmonary vascular resistance. L-Arginine at a dose which reduced by sim ilar to 50% the L-NAME-associated systemic hypertension did not alter the late rise in mean pulmonary arterial pressure (Delta mean pulmonar y arterial pressure = 12 +/- 4 mmHg; P = NS vs. L-NAME alone). U-46619 , elicited rapid, dose-dependent, and transient increases in mean pulm onary arterial pressure (Delta = 8.8 +/- 2.0 and 21.2 +/- 1.9 mmHg at 1.25 and 20 mu g/kg i.v. respectively; both P < 0.01 vs. vehicle). U-4 6619 (1.25 mu g/kg)-induced increases in mean pulmonary arterial press ure were fully antagonized by the thromboxane A(2)/prostanoid (TP) rec eptor antagonist, SQ 29,548 ([1S-[1 alpha,2 alpha(5Z),3 alpha,4 alpha] ]-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). I njection of U-46619 (1.25 mu g/kg), 15 min after L-NAME administration , evoked a 24.7 +/- 0.9 mmHg increase in mean pulmonary arterial press ure (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 a ntagonized by SQ 29,548, (iii) significantly attenuated during coadmin istration of L-NAME and L-arginine (10 mg/kg i.v. + 160 mg/kg/h; Delta 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 vas omotor tone is regulated by spontaneously released NO. Moreover, pulmo nary vascular NO attenuates TP receptor-mediated presser responses, st rongly suggesting that in addition to mediating pulmonary vasoconstric tion, TP receptor activation also concomitantly releases NO within the pulmonary vasculature.