Myocardial beta-adrenoceptor down-regulation by norepinephrine is linked to reduced norepinephrine uptake activity.
Chronic administration of norepinephrine for 8 weeks has been shown to reduce neuronal norepinephrine uptake activity and increase interstitial norepinephrine concentration in the heart. To determine whether the changes could lead to myocardial beta-adrenoceptor down-regulation or beta-adrenergic subsensitivity, we measured left ventricular contractile responses to dobutamine, myocardial beta-adrenoceptor density, beta subtype distribution, competitive inhibition agonist binding, and adenylyl cyclase activity activation by isoproterenol, 5'-guanylylimidodiphosphate, and forskolin in dogs after a norepinephrine or saline infusion for 8 weeks. We found that norepinephrine infusion reduced myocardial beta-adrenoceptor density, beta(1)-adrenoceptor subtype density, and high-affinity site for isoproterenol. Left ventricular contractile responses to dobutamine were reduced in the norepinephrine-infused animals. In addition, norepinephrine infusion decreased the basal adenylyl cyclase activity and the adenylyl cyclase responses to isoproterenol, 5'-guanylylimidodiphosphate, and forskolin. The findings indicate that a decrease in cardiac norepinephrine uptake predisposes the heart to norepinephrine-induced myocardial beta-adrenoceptor down-regulation, and that norepinephrine, when present in a sufficient amount over a long period as it is in chronic heart failure, can reduce myocardial beta-adrenergic responsiveness by both homologous and heterologous desensitization.
Dong
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Cardiology Unit, Box 679, Cardiology Research Laboratories, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester NY, USA.
Yatani
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Mohan
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Liang
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D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D004285:Dogs; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol / Q000378:metabolism / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D016276:Ventricular Function
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D007457:Iodine Radioisotopes; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D004280:Dobutamine; D020120:Iodocyanopindolol; C049763:CGP 20712A; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D009638:Norepinephrine