RESUMEN
1. The method of action of cardiac glycosides is commonly explained by the 'pump-inhibition hypothesis': inhibition of the Na+/K+-ATPase allows [Na+]i to rise, eventually reversing Na+/Ca2+ exchange. The resulting influx of Ca2+o increases [Ca2+]i, thereby activating intracellular Ca2+-dependent ATPases and, hence, energy demand. This sequence has been presumed to occur during diastole as well as systole. However, it has been reported that dihydro-ouabain-induced potentiation of heat production by quiescent ventricular trabeculae persists in the absence of Ca2+o. This implies that the pump-inhibition hypothesis is inapplicable during diastole. 2. We tested this implication by: (i). measuring the rate of oxygen consumption (Vo2) of arrested guinea-pig whole-hearts; (ii). measuring[Ca2+]i in quiescent ventricular trabeculae; and (iii). mathematical modelling using software (Oxsoft Heart, Oxford Software, Oxford, UK) based on DiFrancesco-Noble formalism. 3. Upon induction of arrest, whole heart Vo2 fell to one-quarter of its 'beating' value. Subsequent perfusion with ouabain (20 micromol/L), in the presence of Ca2+o, increased Vo2 fourfold. This increase was prevented by withholding Ca2+o. Comparable results were obtained in quiescent trabeculae: ouabain increased [Ca2+]i only if Ca2+o was present. Mathematical modelling readily simulated these experimental results. 4. We conclude that influx of Ca2+o is mandatory for potentiation of cardiac basal metabolism by cardiac glycosides.
Asunto(s)
Metabolismo Basal/efectos de los fármacos , Calcio/farmacología , Cardiotónicos/farmacología , Corazón/efectos de los fármacos , Miocardio/metabolismo , Ouabaína/farmacología , Animales , Calcio/metabolismo , Femenino , Cobayas , Corazón/fisiología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Técnicas In Vitro , Masculino , Modelos Biológicos , Consumo de Oxígeno/efectos de los fármacos , Perfusión , Cloruro de Potasio/farmacologíaRESUMEN
Blood pressure displays an oscillation at 0.1 Hz in humans that is well established to be due to oscillations in sympathetic nerve activity (SNA). However, the mechanisms that control the strength or frequency of this oscillation are poorly understood. The aim of the present study was to define the dynamic relationship between SNA and the vasculature. The sympathetic nerves to the kidney were electrically stimulated in six pentobarbital-sodium anesthetized rabbits, and the renal blood flow response was recorded. A pseudo-random binary sequence (PRBS) was applied to the renal nerves, which contains equal spectral power at frequencies in the range of interest (<1 Hz). Transfer function analysis revealed a complex system composed of low-pass filter characteristics but also with regions of constant gain. A model was developed that accounted for this relationship composed of a 2 zero/4 pole transfer function. Although the position of the poles and zeros varied among animals, the model structure was consistent. We also found the time delay between the stimulus and the RBF responses to be consistent among animals (mean 672 +/- 22 ms). We propose that the identification of the precise relationship between SNA and renal blood flow (RBF) is a fundamental and necessary step toward understanding the interaction between SNA and other physiological mediators of RBF.