Nitric oxide blunts the endothelin-mediated pulmonary vasoconstriction in exercising swine.
We have previously shown that vasodilators and vasoconstrictors that are produced by the vascular endothelium, including nitric oxide (NO), prostanoids and endothelin (ET), contribute to the regulation of systemic and pulmonary vascular tone in swine, in particular during treadmill exercise. Since NO and prostanoids can modulate the release of ET, and vice versa, we investigated the integrated endothelial control of pulmonary vascular resistance in exercising swine. Specifically, we tested the hypothesis that increased NO and prostanoid production during exercise limits the vasoconstrictor influence of ET, so that loss of these vasodilators results in exaggerated ET-mediated vasoconstriction during exercise. Fifteen instrumented swine were exercised on a treadmill at 0-5 km h(-1) before and during ET(A)/ET(B) receptor blockade (tezosentan, 3 mg kg(-1) I.V.) in the presence and absence of inhibition of NO synthase (N(omega)-nitro-L-arginine, 20 mg kg(-1) I.V.) and/or cyclo-oxygenase (indometacin, 10 mg kg(-1) I.V.). In the systemic circulation, ET receptor blockade decreased vascular resistance at rest, which waned with increasing exercise intensity. Prior inhibition of either NO or prostanoid production augmented the vasodilator effect of ET receptor blockade, and these effects were additive. In contrast, in the pulmonary bed, ET receptor blockade had no effect under resting conditions, but decreased pulmonary vascular resistance during exercise. Prior inhibition of NO synthase enhanced the pulmonary vasodilator effect of ET receptor blockade, particularly during exercise, whereas inhibition of prostanoids had no effect, even after prior NO synthase inhibition. In conclusion, endogenous endothelin limits pulmonary vasodilatation in response to treadmill exercise. This vasoconstrictor influence is blunted by NO but not by prostanoids.
Houweling
Birgit
B
Experimental Cardiology, Thoraxcentre, Erasmus MC, University Medical Centre Rotterdam, the Netherlands.
Merkus
Daphne
D
Dekker
Marjolein M D
MM
Duncker
Dirk J
DJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D005082:Physical Exertion / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D013552:Swine; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; D019335:Nitroarginine; D009569:Nitric Oxide; C120582:tezosentan; D019001:Nitric Oxide Synthase; D007213:Indomethacin