DESENSITIZATION OF BETA-ADRENERGIC RECEPTOR-MEDIATED VASCULAR SMOOTH-MUSCLE RELAXATION

  • 1 January 1985
    • journal article
    • research article
    • Vol. 27  (2) , 210-217
Abstract
Responsiveness to catecholamines may be blunted after prolonged exposure to an agonist; this phenomenon, termed desensitization, is often mediated by receptor down-regulation. .beta.-Adrenergic receptors mediate relaxation of vascular smooth muscle. The possibility that this response may be desensitized after prolonged exposure to increased concentrations of epinephrine was examined. Rats were treated with epinephrine infusions (300 .mu.g/kg per h from a minipump) for 7 days and had levels of plasma epinephrine 70-fold greater than those of controls. The mesenteric artery rings from the epinephrine-treated rats contracted normally when exposed to serotonin; the extext of relaxation promoted by the .beta.-adrenergic agonist isoproterenol was blunted (86 .+-. 4 vs. 43 .+-. 9%; P < 0.05). Acetylcholine and nitroglycerine, which may act through a cGMP mechanism, caused virtually identical relaxation responses in both control and epinephrine-treated groups. To determine the mechanism for the loss in responsiveness to isoproterenol, adrenergic receptors in individual mesenteric arteries were measured using [125I]cyanopindolol. Specific binding of [125I]cyanopindolol was found to have the expected characteristics of interaction with .beta. receptors. There was no difference in the number of .beta.-adrenergic receptors between control and epinephrine-treated animals (24 .+-. 5 vs. 26 .+-. 6 fmol/mg of protein), although there was significantly marked down-regulation of .beta.-adrenergic receptors in hearts (23 .+-. 2 vs. 10 .+-. 1 fmol/mg of protein; P < 0.001) and lungs (172 .+-. 29 vs. 76 .+-. 7 fmol/mg of protein; P < 0.01) in the same rats. The ability of isoproterenol to stimulate cAMP production in the mesenteric arteries from the 2 groups was not significantly different (20.3 .+-. 3.5 vs. 23.8 .+-. 4.7 pmol of cAMP/mg of protein per 2 min). Mesenteric artery relaxation was found to be decreased in response to the cAMP analog dibutyryl cAMP (45 .+-. 2.0 vs. 28 .+-. 2.0%; P < 0.001) in the epinephrine-infused rats. These data suggest that the desensitization of .beta.-adrenergic receptor-mediated smooth muscle relaxation may be caused by a mechanism distal to cAMP production.