Article
Impaired Vasodilator Function in Hypertension: The Role of Alterations in Receptor–G Protein Coupling

https://doi.org/10.1016/S1050-1738(98)00022-XGet rights and content

Abstract

Defects in vascular relaxation mechanisms may have an important role in the pathogenesis and maintenance of the elevation in peripheral vascular resistance characteristic of the hypertensive state. Receptor systems that mediate vasorelaxation via elevation of vascular smooth muscle intracellular cAMP concentrations appear to be globally impaired. Recent studies have indicated that this defect may be due to alterations in the transmembrane signaling processes that link receptor activation with the stimulation of adenylyl cyclase. Reduced G-protein function has been reported. However, increased activity of a member of a family of enzymes, the G protein–receptor kinases (GRK), which reduces the efficiency of coupling between the receptor and G protein, may be the key factor accounting for impaired receptor-mediated adenylyl cyclase activation and impaired vasodilator function in the hypertensive state.

References (125)

  • M.D. Lograno et al.

    Changes of vascular smooth muscle reactivity in hypertensive rats

    Pharmacol Res

    (1989)
  • J. Marcil et al.

    Enhanced expression of GI-protein procedes the development of blood pressure in spontaneously hypertensive rats

    J Mol Cell Cardiol

    (1997)
  • T. Murakami et al.

    Reduction in the activity of the stimulatory guanine nucleotide-binding protein in the myocardium of spontaneously hypertensive rats

    Mol Cell Cardiol

    (1987)
  • Y. Nishimura et al.

    Relaxant response of isolated basilar arteries to calcitonin gene-related peptide in stroke-prone spontaneously hypertensive rats

    Jpn J Pharmacol

    (1992)
  • S. Pippig et al.

    Overexpression of β-arrestin and β-adrenergic receptor kinase augment desensitization of β2-adrenergic receptors

    J Biol Chem

    (1993)
  • P. Robberecht et al.

    Comparison of β-adrenergic receptors and adenylylate cyclase system with muscarinic receptors and guanylate cyclase activities in the heart of spontaneously hypertensive rats

    Biochem Pharmacol

    (1981)
  • M.K. Sim et al.

    Altered responsiveness of the aorta of hypertensive rats to histamine and acetylcholine

    Jpn J Pharmacol

    (1985)
  • M.S. Amer et al.

    Aberrations of cyclic nucleotide metabolism in the hearts and vessels of hypertensive rats

    Proc Natl Acad Sci USA

    (1974)
  • T.C. Amerini et al.

    Effect of aging and hypertension on vasorelaxant activity of calcitonin gene-related peptidea comparison with other vasodilator agents

    J Cardiovasc Pharmacol

    (1994)
  • M.B. Anand-Srivastava

    Enhanced expression of inhibitory guanine nucleotide regulatory protein in spontaneously hypertensive rats

    Biochem J

    (1992)
  • M.B. Anand-Srivastava

    G-proteins and adenylyl cyclase signalling in hypertension

    Mol Cell Biochem

    (1996)
  • J.A. Angus

    Role of the endothelium in the genesis of cardiovascular disease

    Clin Exp Pharmacol Physiol

    (1996)
  • S. Arribas et al.

    Norepinephrine-induced relaxations in rat aorta mediated by endothelial β adrenoceptors. Impairment by ageing and hypertension

    J Pharmacol Exp Ther

    (1994)
  • P. Arvola et al.

    Quinapril treatment and arterial smooth muscle responses in spontaneously hypertensive rats

    Br J Pharmacol

    (1993)
  • M. Asano et al.

    Reduced β adrenoceptor interactions of norepinephrine enhance contraction in the femoral artery from spontaneously hypertensive rats

    J Pharmacol Exp Ther

    (1982)
  • M. Asano et al.

    Evidence for reduced β-adrenoceptor coupling to adenylate cyclase in femoral arteries from spontaneously hypertensive rats

    Br J Pharmacol

    (1988)
  • D.R. Bell

    Vascular smooth muscle responses to endothelial autacoids in rats with chronic coarctation hypertension

    J Hypertens

    (1993)
  • D.R. Bell et al.

    Selective effect of high arterial pressure in hypertension upon inhibition of cGMP versus cAMP mediated vascular relaxation

    Clin Exp Hypertens

    (1996)
  • R.C. Bhalla et al.

    Characteristics of hormone-stimulated adenylate cyclase in vascular smooth musclealtered activity in spontaneously hypertensive rat

    Blood Vessels

    (1982)
  • P.C. Bhalla et al.

    Ontogenetic development of isoproterenol subsensitivity of myocardial adenylate cy-clase and β-adrenergic receptors in spontaneously hypertensive rats

    Biochem Biophys Acta

    (1980)
  • W.M. Blankesteijn et al.

    β-Adrenergic relaxation in mesenteric resistance arteries of spontaneously hypertensive and Wistar-Kyoto ratsthe role of precontraction and intracellular Ca2+

    J Cardiovasc Pharmacol

    (1996)
  • S.J. Blumenthal et al.

    Myocardial adrenergic receptors and adenylate cyclase in the developing spontaneously hypertensive rat

    Clin Exp Hypertens A

    (1982)
  • M. Böhm et al.

    Desensitization of adenylate cyclase and increase of Giα in cardiac hypertrophy due to acquired hypertension

    Hypertension

    (1992)
  • M. Böhm et al.

    Cardiac adenylyl cyclase, β-adrenergic receptors and G proteins in salt-sensitive hypertension

    Hypertension

    (1993)
  • M. Böhm et al.

    Treatment in hypertension cardiac hypertrophy, I

    Neuropeptide Y and β-adrenoceptors. Hypertension

    (1995)
  • H.C.M. Boonen et al.

    Mesenteric small artery changes after vasoconstrictor infusion in young rats

    J Cardiol Pharmacol

    (1993)
  • K.R. Borkowski et al.

    An altered β-adrenoreceptor-mediated modulation of noradrenaline-induced vasoconstriction in spontaneously hypertensive rate mesenteric arteries

    J Auton Pharmacol

    (1984)
  • M.R. Bristow et al.

    β1- and β2-adrenergic receptor–mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium

    Mol Pharmacol

    (1989)
  • C. Cauvin et al.

    Decreased relaxation of isolated mesenteric resistance vessels from 2-kidney, 1 clip Goldblatt hypertensive rats

    Clin Exp Hypertens A

    (1983)
  • M.H.C. Carvalho et al.

    Reactivity of aorta and mesenteric microvessels to drugs in spontaneously hypertensive ratsrole of the endothelium

    J Hypertens

    (1987)
  • P. Chatelain et al.

    Secretin and VIP-stimulated adenylate cyclase from rat heart

    Eur J Physiol

    (1980)
  • J.B. Cheng et al.

    Vascular relaxation in the spontaneously hypertensive rat

    J Cardiovasc Pharmacol

    (1981)
  • T.H. Chiu

    Age-dependent changes in the myocardial adenylate cyclase of normotensive and spontaneously hypertensive rat

    Pharmacology

    (1981)
  • C.J. Clark et al.

    Guanine nucleotide regulatory protein alterations in the Milan hypertensive rat strain

    J Hypertens

    (1993)
  • C.J. Clark et al.

    Guanine nucleotide regulatory proteins in the spontaneously hypertensive rat

    Hypertension

    (1993)
  • M.L. Cohen et al.

    Decreased vascular relaxation in hypertension

    J Pharmacol Exp Ther

    (1976)
  • J.P. Cooke et al.

    Nitric oxide synthaserole in the genesis of vascular disease

    Ann Rev Med

    (1997)
  • N.K. Dadkar et al.

    Peripheral vascular smooth muscle relaxation in normotensive and hypertensive rats

    J Pharm Pharmacol

    (1980)
  • S.A. Doggrell et al.

    Loss of maximum attenuation and receptor reserve for isoprenaline at the beta2-adrenoceptors of the portal veins of hypertensive rats

    J Hypertens

    (1995)
  • R.A. Felder et al.

    A renal dopamine-1 receptor defect in two genetic models of hypertension

    Am J Hypertens

    (1990)
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