Epinephrine, cyclic AMP, calcium, and myocardial contractility.
In the first part of this paper, a short review of the literature on the effects of catecholamines, Ca2+, and cyclic AMP on the biochemical, electrical, and mechanical properties of the heart is presented. It is concluded that the effects of epinephrine on activation of glycogenolysis and on the inotropic response of cardiac muscle are both mediated by the combined actions of Ca2+ and cyclic AMP. Since the inotropic response precedes the glycogenolytic response it is evident that increased energy metabolism is a consequence of increased heart work and not a causative factor. The available data suggest that increased tissue cyclic AMP levels resulting from catecholamine stimulation of adenyl cyclase activity alter cardiac mechanics by modulation of the basic calcium flux cycle of the heart. These effects may be mediated by cyclic AMP-stimulated phosphorylation of specific proteins located in the sarcolemma, sarcoplasmic reticulum, and myofilaments via one or more protein kinases, although experimental verfication of the possible relationship between protein phosphorylation and altered Ca2+ binding properties at specific sites in the membranes is at present largely lacking. The increased rate of tension development induced by catecholamines appears to be caused by an increased rate of Ca2+ influx across the sarcolemma during the plateau phase of the action potential, whereas the increased rate of relaxation is probably attributable to an increased rate of sequestration of intracellular Ca2+ by the sarcoplasmic reticulum. In the second part of the paper, data are presented using a working rat heart preparation to illustrate the effect of catecholamines in facilitating Ca2+ entry across the sarcolemma. Decreased left ventricular pressure development induced by addition of ruthenium red or verapamil to inhibit Ca2+ influx was relieved in a concentration-dependent manner by catecholamines. Curves of percentage change of left ventricular pressure against external Ca2+ concentration are presented which show that epinephrine increased the sensitivity of the heart to Ca2+ whereas verapamil decreased it. A half-maximal increase of left ventricular pressure was obtained with 0.6 mM Ca2+ in control hearts, 0.3 mM Ca2+ with epinephrine, and 2.9 mM Ca2+ with verapamil (10(-7)-treated hearts. Verapamil combined with epinephrine at the above concentrations gave a half-miximal increase of left ventricular pressure with 1.3 mM Ca2+. These results are discussed in relation to a model for the Ca2+ flux in the heart.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D004837:Epinephrine / Q000494:pharmacology*; D006003:Glycogen / Q000378:metabolism; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D014700:Verapamil / Q000494:pharmacology
D003994:Bucladesine; D000255:Adenosine Triphosphate; D006003:Glycogen; D014700:Verapamil; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D008274:Magnesium; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine; D004837:Epinephrine