Effects of Na+, K+-pump inhibitors and membrane depolarizing agents on acetylcholine-induced endothelium-dependent relaxation and cyclic GMP accumulation in rat aorta

doi:10.1016/0014-2999(85)90212-2

European Journal of Pharmacology

Volume 110, Issue 2, 2 April 1985, Pages 203-209

https://doi.org/10.1016/0014-2999(85)90212-2 Get rights and content

Abstract

The purpose of this study was to investigate the effects of inhibitors of the Na⁺,K⁺-pump and membrane depolarizing agents on endothelium-dependent relaxation and elevated cyclic GMP levels induced by acetylcholine in rat thoracic aorta. Ouabain or exposure to K⁺-free or Mg²⁺-free Krebs-Ringer bicarbonate solution, agents and procedures known to inhibit the Na⁺,K⁺-pump, inhibited acetylcholine-induced relaxation and the associated increased levels of cyclic GMP. However, the inhibitory effect of ouabain on cyclic GMP levels was abolished in the absence of norepinephrine or in the presence of norepinephrine and the α-adrenergic receptor antagonist phentolamine. The membrane depolarizing agents KCl and tetraethylammonium also inhibited the acetylcholine-induced relaxation and the elevated cyclic GMP levels. Exposure to norepinephrine reduced the increased levels of cyclic GMP due to acetylcholine as compared to rested controls. This effect was inhibited by prior exposure to phentolamine, but not by the β-adrenergic receptor antagonist, propranolol. These results suggest that (1) increased activity of the Na⁺,K⁺-pump may mediate, in part, endothelium-dependent relaxation; (2) inhibition of relaxation may be due to membrane depolarization; (3) the endothelium-dependent increased levels of cyclic GMP may increase Na⁺,K⁺-pump activity; (4) a complex interaction exists between membrane polarization, the Na⁺,K⁺-pump and α-adrenergic stimulation in regulation of cyclic GMP accumulation and relaxation.

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^☆: This was supported by Research Grants AM 30787 and HL 28474 from the Natinal Institutes of Health and grants from the Veterans Administration and The Council for Tobacco Research, U.S.A., Inc.

^∗∗: Present address: Department of Pharmacology and Cell Biophysics, School of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0575, U.S.A.

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Effects of Na+, K+-pump inhibitors and membrane depolarizing agents on acetylcholine-induced endothelium-dependent relaxation and cyclic GMP accumulation in rat aorta☆

Abstract

J. Biol. Chem.

Mechanisms of action of transmitters and other substances on smooth muscle

Physiol. Rev.

Acetylcholine and bradykinin relax intrapulmonary arteries by acting on endothelial cells: role in lung vascular disease

Science

Interaction between Na+,K+ exchanges and the direct inhibitory effect of acetylcholine on canine femoral arteries

Circ. Res.

The electrogenic Na+,K+-pump in smooth muscle: physiologic and pharmacologic significance

Ann. Rev. Pharmacol. Toxicol.

The role of endothelium in the responses of vascular smooth muscle to drugs

Annu. Rev. Pharmacol. Toxicol.

The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine

Nature

Differing actions of nitroprusside and D-600 on tension and 45Ca fluxes in canine renal arteries

J. Pharmacol. Exp. Ther.

Cellular basis of nitroprusside-induced relaxation of graded responses to nirepinephrine and potassium in canine renal arteries

Arch. Int. Pharmacodyn. Ther.

Effects of sodium nitroprusside, nitroglycerin, and sodium azide on levels of cyclic nucleotides and mechanical activity of various tissues

J. Cyclic Nucleotide Res.

Regulation of adenosine cyclic 3′,5′-monophosphate and guanosine cyclic 3′,5′-monophosphate levels and contractility in bovine tracheal smooth muscle

Mol. Pharmacol.

Effects of Na⁺, K⁺-pump inhibitors and membrane depolarizing agents on acetylcholine-induced endothelium-dependent relaxation and cyclic GMP accumulation in rat aorta☆

Interaction between Na⁺,K⁺ exchanges and the direct inhibitory effect of acetylcholine on canine femoral arteries

The electrogenic Na⁺,K⁺-pump in smooth muscle: physiologic and pharmacologic significance

Differing actions of nitroprusside and D-600 on tension and ⁴⁵Ca fluxes in canine renal arteries