AJP - Heart and Circulatory Physiology, Vol 271, Issue 1 253-H260, Copyright © 1996 by American Physiological Society

ARTICLES

Decreased sensitivity to vasoconstrictors in aortic rings after acute exposure to nitric oxide

N. L. Kanagy, J. R. Charpie, J. Dananberg and R. C. Webb
Department of Physiology, University of Michigan, Ann Arbor 48109-0622, USA.

Nitric oxide (NO) has been postulated as a regulator of vascular reactivity, and the current study tested the hypothesis that NO-induced decreased sensitivity to vasoconstrictors persists following removal of NO. Endothelium-denuded segments of rat aorta were incubated 2-4 h at 37 degrees C with the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Incubation produced rightward shifts in concentration response curves for phenylephrine [i.e., half-maximum effective concentration (EC50; in microM): control = 0.016, NO = 0.14], aluminum fluoride (i.e., EC50 in mM: control = 1.66, NO = 2.29), and KCl (i.e., EC50 in mM: control = 5.9, NO = 23.9). Similar shifts were seen for two other NO donors. The SNAP-induced shift was not attenuated by a guanylyl cyclase inhibitor, LY-83583 (10 microM) and was not mimicked by 8-bromoguanosine 3',5'-cyclic monophosphate (100 microM). It was attenuated by 1,4-naphthoquinone (50 microM), an inhibitor of endogenous mono-ADP ribosyltransferases. NO incubation increased cGMP content (4.6 +/- 0.8 vs. 1.5 +/- 0.15 pmol/mg protein), an increase unaffected by 1,4-naphthoquinone (3.3 +/- 1.0 pmol/mg protein) but prevented by LY-83583 (1.6 +/- 0.36 pmol/mg protein). ADP ribosylation of three proteins was observed in membranes from HEK 293 cells: 88,66, and 38 kDa. ADP ribosylation of the 38-kDa protein was stimulated in a concentration-dependent manner by NO but was not decreased by 1,4-naphthoquinone. In conclusion, NO produces a long-lasting inhibition of vascular contractility by both a cGMP-dependent and -independent mechanism. Based on the observations of 1,4-naphthoquinone, we conclude that the cGMP-independent mechanism is not stimulation of endogenous ADP ribosylation but some other covalent modification in the pathway that mediates contraction.

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