Mechanisms of Supersensitivity to Sympathomimetic Amines in the Chronically Denervated Heart of the Conscious Dog

Mechanisms of denervation supersensitivity to sympathomimetic amines were studied in conscious animals. Norepinephrine, 0.1 μg/kg increased left ventricular dP/dt significantly more (4208 ± 828 mm Hg/sec) in dogs with cardiac denervation than in intact dogs (1029 ± 280 mm Hg/sec), P < 0.01, whereas responses to isoproterenol were similar in both groups. Denervation supersensitivity to isoproterenol could be demonstrated only after opposing reflex effects were blocked. After ganglionic blockade, norepinephrine still induced 2- to 3-fold greater increases in left ventricular dP/dt and 3- to 7-fold greater increases in heart rate in cardiacdenervated dogs, whereas isoproterenol and prenalterol, not taken up by presynaptic nerve endings, elicited only 40%–50% greater increases in left ventricular dP/dt and heart rate in dogs with cardiac denervation. The density of β-adrenergic receptors ([3H]dihydroalprenolol) was elevated (P < 0.01) in denervated left ventricles (105 ± 6.9 fmol/mg protein, n = 8) compared to normal left ventricles (70 ± 6.3 fmol/mg protein, n = 12). This was accompanied by enhanced isoproterenol-mediated adenylate cyclase activity. However, muscarinic cholinergic receptor density, ([3H]quinuclidinyl benzilate), decreased from control levels of 251 ± 11 fmol/mg protein (n = T) to 193 ± 14 fmol/mg protein (n = 6). Thus, chronic cardiac denervation results in up-regulation of the β-adrenergic receptor and down-regulation of the muscarinic receptor. The increased β-adrenergic receptor density and adenylate cyclase stimulation correlated well with the amount of denervation supersensitivity to isoproterenol and prenalterol, but accounted for only a minor fraction of denervation supersensitivity to norepinephrine. The major mechanism of denervation supersensitivity to norepinephrine appears to involve lack of the norepinephrine reuptake.