The general hypothesis to be tested is that the general anesthetics produce a depression of the cardiovascular system by both end-organ depression of the heart and vascular smooth muscle, and a depression of the sympathetic nervous system. Furthermore, clinically important slow channel antagonists may differentially potentiate the direct negative inotropic and chronotropic effects of inhalational anesthetics. The primary goals are to provide information on the effects of inhalational anesthetics and calcium antagonists on cardiac electrophysiology and cardiac muscle contraction in order to evaluate abnormalities of impulse generation, conduction, excitation-contraction coupling and muscle contraction. In addition, since the peripheral sympathetic nervous system offers additional sites at which inhalational anesthetics can act to attenuate cardiac function through sympathetic efferent nerve activity, effects of these agents on ganglionic transmission will also be studied.
The specific aims are: a) To compare impulse generation and intracellular free calcium changed (calcium transients) in the guinea pit sine-atrial node in vitro during introduction of inhalational anesthetics and calcium antagonists. b) To compare the sensitivity and slow inward current of Purkinje fibers and contractility of ventricular muscle cells during simultaneous exposure to inhalational anesthetics and calcium antagonists. c) To determine the actions of calcium antagonists following prolonged administration on cardiovascular response of the autonomic nervous system in vivo and on cardiac electrophysiology in vitro. d) To study the effects of inhalational anesthetic agents on synaptic, presynaptic, postsynaptic and axonal neurophsiologic events. The long term goals are to describe myocardial and smooth muscle cellular mechanisms affected by general anesthetics and by acute and chronic treatment with calcium antagonists, since it is anticipated that several distinct mechanisms could be involved due to their structural diversity and pharmacologic properties.
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