Receptor systems affecting force of contraction in the human heart and their alterations in chronic heart failure.
Catecholamines acting through beta 1- and beta 2-adrenergic receptors cause positive inotropic and chronotropic effects in the human heart. However, recent evidence suggests that in the human heart other receptor systems can also affect heart rate and contractility. Positive inotropic effects can be mediated by receptor systems acting through accumulation of intracellular cyclic adenosine monophosphate (cAMP; Gs-protein-coupled receptors such as 5-hydroxytryptamine(5-HT)4-like, histamine H2, and vasoactive intestinal peptide) or by receptor systems acting independently of cAMP, possibly through the phospholipase C/diacylglycerol/inositol-1,4,5-trisphophate pathway (such as alpha 1-adrenergic, angiotensin II, and endothelin). In the nonfailing human heart, activation of all these receptor systems induces only submaximal positive inotropic effects compared with those caused by beta-adrenergic receptor stimulation, indicating that in humans the cardiac beta-adrenergic receptor/Gs-protein/adenylate cyclase pathway is the most powerful mechanism to increase heart rate and contractility. However, the human heart contains only a few spare receptors for beta-adrenergic receptor-mediated positive inotropic effects and nearly all beta-adrenergic receptors are needed to cause maximal inotropic effects. Thus any decrease in the number of beta-adrenergic receptors will automatically lead to a reduction in functional responsiveness of beta-adrenergic receptors. In chronic heart failure the number and responsiveness of cardiac beta-adrenergic receptors are reduced, presumably because of the enhanced sympathetic drive to the heart and hence endogenous down-regulation by an elevated release of (cardiac-derived) norepinephrine, and this loss in cardiac beta-adrenergic receptor function is strongly related to the severity of the disease. However, beta 1- and beta 2-adrenergic receptors are differentially changed in different forms of heart failure. In dilated cardiomyopathy and possibly in aortic valve disease the number of cardiac beta 1-adrenergic receptors is selectively reduced without alteration in the number of beta 2-adrenergic receptors (although beta 2-adrenergic receptors become somewhat uncoupled). In ischemic cardiomyopathy, mitral valve disease, and possibly tetralogy of Fallot, the number of both beta 1- and beta 2-adrenergic receptors is concomitantly decreased. Because of the lack of a substantial receptor reserve, such a decrease in the number of beta-adrenergic receptors is accompanied by reduced inotropic and chronotropic responses to beta-adrenergic receptor stimulation in vitro and in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
Brodde
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OE
Biochemical Research Laboratories, Medizinische Klinik und Poliklinik, University of Essen, Germany.
Hillemann
S
S
Kunde
K
K
Vogelsang
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M
Zerkowski
H R
HR
D000262:Adenylyl Cyclases / Q000502:physiology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000737:chemistry*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D011953:Receptors, Cyclic AMP / Q000502:physiology
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D011956:Receptors, Cell Surface; D011953:Receptors, Cyclic AMP; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases