Decreased sensitivity to vasoconstrictors in aortic rings after acute exposure to nitric oxide. Kanagy, Nancy L., John R. Charpie, Jamie Dananberg, R. Clinton Webb. Department of Physiology, University of Michigan, Ann Arbor, MI 48109-0622
APStracts 3:0011H, 1996.
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 hours 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. EC50 [mu]mol/L: control = 0.016, NO = 0.14), aluminum fluoride (i.e. EC50 mmol/L: control = 1.66, NO = 2.29) and KCl (i.e. EC50 mmol/L: control = 5.9, NO = 23.9). Similar shifts were seen for 2 other NO donors. The SNAP -induced shift was not attenuated by a guanylyl cyclase inhibitor, LY83583 (10 [mu]mol/L), and was not mimicked by 8-Br-cGMP (100 [mu]mol/L). It was attenuated by 1,4-naphthoquinone (50 [mu]mol/L), 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) but prevented by LY83583 (1.6+/-0.36). ADP-ribosylation of 3 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. 

Received 16 June 1995; accepted in final form 13 December 1995.
APS Manuscript Number H548-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 22 January 96