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1 Experimental Cardiology, Thoraxcentre, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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 ETA/ETB receptor blockade (tezosentan, 3 mg kg–1
I.V.) in the presence and absence of inhibition of NO synthase (N
-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.
(Received 6 July 2005;
accepted after revision 28 July 2005;
first published online 4 August 2005)
Corresponding author D. J. Duncker: Experimental Cardiology, Thoraxcentre, Erasmus MC, University Medical Centre Rotterdam, PO Box 1738, 3000 DR Rotterdam, the Netherlands. Email: d.duncker{at}erasmusmc.nl
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