MYOCARDIAL ADRENERGIC DENERVATION SUPERSENSITIVITY DEPENDS ON A POSTRECEPTOR MECHANISM NOT LINKED WITH INCREASED CAMP PRODUCTION

被引:30
作者
HAMMOND, HK [1 ]
ROTH, DA [1 ]
FORD, CE [1 ]
STAMNAS, GW [1 ]
ZIEGLER, MG [1 ]
ENNIS, C [1 ]
机构
[1] UNIV CALIF SAN DIEGO,DEPT MED,DIV CARDIOL,SAN DIEGO,CA 92103
关键词
G-PROTEINS; GS; GI; SIGNAL TRANSDUCTION; DENERVATION SUPERSENSITIVITY; CATECHOLAMINES;
D O I
10.1161/01.CIR.85.2.666
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background. Two major hypotheses have been proposed to explain catecholamine supersensitivity after myocardial denervation, but neither sufficiently explains certain features of the phenomenon. In addition, a nonsurgical method for long-term myocardial adrenergic denervation is desirable but has not been accomplished or described with respect to catecholamine supersensitivity. Methods and Results. We have accomplished chronic myocardial adrenergic denervation by using 6-hydroxydopamine (6-OHDA). Sixteen weeks after 6-OHDA administration to newborn pigs, we found substantial myocardial adrenergic denervation associated with beta-adrenergic receptor (beta-AR) downregulation. Despite decreased beta-AR number, the dose of isoproterenol yielding 50% maximal heart rate change (ED50) was decreased, and heart rates during exercise showed increased responsiveness despite decreased circulating catecholamines. Thus, stimulation of fewer receptors yielded an increased response, implying improved signal transduction efficiency. Competitive binding studies with isoproterenol showed an increased proportion of beta-AR with high-affinity binding in myocardial membranes from 6-OHDA pigs, suggesting that interaction between beta-AR and cardiac G(s) may contribute to improved signal transduction efficiency. However, measures of adenylyl cyclase activity indicated marked reduction in beta-AR-dependent and G(s)-dependent cAMP production in myocardial membranes from denervated animals despite a normal amount of cardiac G(s) and decreased G(i). Conclusions. We have demonstrated that substantial, long-term myocardial adrenergic denervation is possible using 6-OHDA. Denervation supersensitivity in this model does not depend on enhanced cAMP stimulation but rather depends on postreceptor elements in the beta-AR-responsive pathway that may be independent of G(s)-activated adenylyl cyclase activity. In this model of adrenergic denervation supersensitivity, beta-receptors, through G(s), may be linked to an alternative effector that drives heart rate responsiveness.
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页码:666 / 679
页数:14
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