title: Decreased sensitivity to vasoconstrictors in aortic rings after acute exposure to nitric oxide.
abstract: 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.
authors: Department of Physiology, University of Michigan, Ann Arbor 48109-0622, USA.
authors: N L
authors: NL
authors: Kanagy
authors: J R
authors: JR
authors: Charpie
authors: J
authors: J
authors: Dananberg
authors: R C
authors: RC
authors: Webb
mesh_terms: D036002:ADP Ribose Transferases; D017607:Aluminum Compounds / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D005459:Fluorides / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D026423:S-Nitroso-N-Acetylpenicillamine; D013997:Time Factors; D014661:Vasoconstriction / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D017607:Aluminum Compounds; D000634:Aminoquinolines; D009285:Naphthoquinones; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D011189:Potassium Chloride; D026423:S-Nitroso-N-Acetylpenicillamine; C041715:6-anilino-5,8-quinolinedione; D036002:ADP Ribose Transferases; D006162:Guanylate Cyclase; D010396:Penicillamine; D006152:Cyclic GMP; D005459:Fluorides; C035342:1,4-naphthoquinone; C032311:aluminum fluoride