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-9 alpha-(methanoepoxy) prostaglandin F2 alpha), in anesthetized open-chest Sprague-Dawley rats (n = 6-9 per group). NO synthase inhibition, as obtained by N omega-nitro-L-arginine methyl ester (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 slight bradycardia (delta heart rate = -42 +/- 8 beats/min; P < 0.05 vs. vehicle) and delayed- (> 30 min) onset pulmonary hypertension (delta 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 approximately 50% the L-NAME-associated systemic hypertension did not alter the late rise in mean pulmonary arterial pressure (delta 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 (delta = 8.8 +/- 2.0 and 21.2 +/- 1.9 mmHg at 1.25 and 20 micrograms/kg i.v. respectively; both P < 0.01 vs. vehicle). U-46619 (1.25 micrograms/kg)-induced increases in mean pulmonary arterial pressure were fully antagonized by the thromboxane A2/prostanoid (TP) receptor 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). Injection of U-46619 (1.25 micrograms/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; 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 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.
Valentin
J P
JP
Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, Castres, France.
Bessac
A M
AM
Maffre
M
M
John
G W
GW
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000768:Anesthesia, General; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000502:physiology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester