Influence of Isoproterenol on Contractile Protein Function, Excitation-Contraction Coupling, and Energy Turnover of Isolated Nonfailing Human Myocardium

Abstract

Previous animal experiments indicated that the effects of catecholamines on myocardial function and subcellular systems vary considerably depending on the species and type of myocardium investigated. In the present study, we used isometric force and heat measurements to investigate the influence of isoproterenol on energetics of excitation-contraction coupling and contractile proteins in isolated nonfailing human myocardium. Isoproterenol, in an average concentration of 0.8±0.3 μM, resulted in a significant increase in peak twitch tension, maximum rate of tension rise and maximum rate of tension fall by 46% (P<0.025), 126% (P<0.001) and 137% (P<0.005), respectively (37°C, 60 beat/min). The amount and rate of excitation-contraction coupling-related heat evolution (tension-independent heat) increased by 116% (P<0.03) and 176% (P<0.02), respectively. Furthermore, the relationship of tension-independent heat to isometric tension or tension-time integral increased by 47% (P<0.05) and 91% (P<0.01), respectively. That is, the energy used in calcium cycling increased by a greater proportion than did mechanical output. Isoproterenol increased the rate of the acto-myosin crossbridge high-energy phosphate hydrolysis (tension-dependent heat rate) by 61% (P<0.006) and decreased the force-time integral (consistent with decrease in the attachment time) of the individual crossbridge cycle by 21% (P<0.025). Decreased crossbridge force-time integral with isoproterenol indicates decreased economy of isometric force production at the level of the contractile proteins. Increased energy turnover of excitation-contraction coupling processes and reduced force-time integral generation by the individual crossbridge cycle resulted in increased myocardial energy turnover as indicated by a 41% increase in the ratio of total activity related heat per tension-time integral (P<0.02). The efficiency of the metabolic recovery process as assessed by the ratio of initial heat to total activity related heat, was similar with and without isoproterenol (0.52±0.05 v 0.49±0.03; P>0.05). Thus, isoproterenol significantly influences excitation-contraction coupling processes and crossbridge cycling, thereby increasing myocardial energy turnover per unit of isometric force production in the human myocardium.