• F J Heijenbrok, M J Mathy, M Pfaffendorf, and P A van Zwieten.
• Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, The Netherlands. f.j.heijenbrok@int.azg.nl
• Naunyn Schmiedebergs Arch. Pharmacol. 2000 Dec 1;362(6):504-11.

AbstractBalloon denudation of the rat carotid artery leads to an immediate decrease in beta-adrenoceptor-medi-ated vasodilator response. However, this arterial function becomes significantly enhanced during subsequent formation of neointima with the endothelial cell lining still being absent. It was therefore hypothesized that chronic suppression of endothelium-dependent nitric oxide (NO) synthesis may eventually upregulate the beta-adrenoceptor system on vascular smooth muscle. To investigate this hypothesis, male Wistar rats were treated chronically with the L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME) to inhibit the synthesis of NO (i.e. 15 mg/kg per day or 0.06 mmol/kg per day for 6 weeks p.o.). Prior to the experiments the mean arterial blood pressure (MAP) was significantly elevated in the L-NAME-treated rats (i.e. 128.4+/-3.4 mmHg vs. 100.0+/-2.9 mmHg, L-NAME vs. control, n=4, P<0.05). The functional properties of the isolated vessel preparations were established by isometric force measurement in a myograph setup, in the absence of L-NAME. The maximal contractile responses to high potassium chloride solution (100 mM), to the alpha1-adrenoceptor agonist phenylephrine, and to the thromboxane A2-agonist U46619, were not influenced by chronic L-NAME-treatment in the carotid and mesenteric artery preparations. The vasodilator responses to the cholinergic agonist methacholine were significantly impaired in the carotid arteries of L-NAME-treated animals: 30.9+/-7.9% vs. 64.6+/-2.0%, P<0.05, L-NAME vs. control, n=10. However, these responses appeared not to be modulated in the mesenteric artery preparations after chronic L-NAME treatment. Separate experiments showed that these responses could be blocked both in the rat carotid and mesenteric artery with L-NAME (10 mM) in vitro. Addition of the NO synthase substrate L-arginine could partially but significantly reverse this blockade. Chronic inhibition of NO synthesis caused significant deterioration of beta-adrenoceptor-mediated vasodilator responses. For carotid arteries: Emax=36.1+/-9.4% vs. 65.9+/-6.0%, P<0.05, L-NAME vs. control, n=5; and pD2=6.7+/-0.2 and 7.4+/-0.1, respectively, P<0.05, n=5. For mesenteric arteries: pD2=7.7+/-0.0 and 8.0+/-0.0, respectively, P<0.05, n=5. From these data, it may be concluded that chronic L-NAME treatment results in a stable impairment of the endothelium-dependent NO system in the rat carotid but not mesenteric arteries. The stated hypothesis fails as the beta-adrenoceptor-induced vasorelaxation of carotid and mesenteric arteries became significantly impaired, rather than enhanced. Taken together, the beta-adrenoceptor function in the rat carotid artery is apparently more dependent on endothelial NO synthesis than that in the rat mesenteric artery.

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