Pharmacologic evaluation of isometric contraction-relaxation coupling indexes in rabbit ventricular muscle

Investigations of the coupling between contraction and relaxation (contract ion-relaxation [CRC] process) in isometric conditions are essential in dete rmining whether pharmacologic interventions or cardiac diseases specificall y modify isometric relaxation (intrinsic lusitropic effect) or change it in proportion with the accompanying changes in contractility (or inotropy). F or this purpose, the CRC process is quantified by various indexes, derived from differentiation and/or curve fitting the whole or rt laxation phase of the isometric twitch, one of the most used being tau, the time constant of the final iso(volu)metric phase of relaxation. Nevertheless, the possible redundancy and validity of such indexes have not been thoroughly investigat ed. Accordingly, we performed a pharmacologic evaluation of such indexes in isolated rabbit ventricular muscles isometrically contracting in vitro. us ing modifiers of either intracellular Ca2+ handling (nifedipine. ryanodine, 2,5-di-tert-butyl-benzohydroquinone, all negative inotropic compounds, and BAY K 8644, a positive inotropic drug), or myofibrillar Ca2+ sensitivity ( CGP 48506, a Ca2+ sensitizer, and butanedione monoxime, a Ca2+ desensitizer , respectively positive and negative inotropic compounds). The isometric tw itch in control conditions and in the presence of increasing concentration of each compound was analyzed to determine the classically used CRC and/or lusitropic indexes, derived either from single parameters such as the maxim al rate or contraction and rt laxation (+ dT(max) and -dT(max), respectivel y), or from curve fitting of the whole, or part, of the twitch. As the rate of isometric relaxation is dependent on myofilament properties, we expecte d that compounds modifying myofibrillar Ca2+ sensitivity in an opposite dir ection (CGP 48506 vs butanedione monoxime) would be the: only drugs exertin g: an intrinsic lusitropic and opposite effect on a validated CRC index. Re sults showed that (1) none of the tested compounds affected the slope of th e linear relationship between peak twitch tension and dT(max), a previously assumed CRC index, sensitive only to myofibrillar Ca2+ sensitivity modifie rs; (2) the lusitropic parameter B, derived from mathematical curve fitting of the whole isometric twitch, and the ratio +dT(max)/dT(max), exhibited s imilar drug-and dose-dependency, but no opposite sensitivity to CGP 48506 a nd BDM for either index: and (3) negative inotropic compounds dose-dependen tly slowed relaxation (and conversely for positive inotropes). whether the latter was quantified by the rate constant beta, derived from double expone ntial curve fitting of the whole relaxation phase, or by the time constants tau(L) and tau(E). derived from the curve fitting (logistic and monoexpone ntial, respectively) of the final phase of relaxation. Nevertheless, the ph armacologicly induced changes in beta were statistically significant at low er concentrations and exhibited less individual variability, compared with the time constants. We demonstrate that intrinsic lusitropic changes can be quantified by the value of the slope of the relationship relating beta to peak isometric tension: the slope value was unchanged by Ca2+ handling modi fiers, decreased by CGP 48506, and reversed by BDM (indicating number, nega tive, and positive intrinsic lusitropic effects respectively). Based on the se data, we propose that the linear relationship between beta and peak isom etric tension could bz used a new method to assess whether pharmacologic in terventions or cardiac diseases exert intrinsic effects on isometric relaxa tion. (C) 2000 Elsevier Science Inc. All rights reserved.