The proposed studies will investigate the direct relaxant actions of halogenated anesthetics (HAs) on vascular tissue, which result in vasodilation. The investigator's long-term objective is to understand the effects of anesthetics on the vascular tree during normal, pathologic, and drug-induced states at a cellular and biochemical level. Preliminary studies using both in vivo and in vitro methods in two species indicate that halothane selectively interferes with post-junctional alpha2-adrenergic mediated vasoconstriction, when compared with the alpha1 responses. The hypotheses are advanced that: (a) preferential inhibition of alpha2-adrenergic vasoconstriction is an important mechanism of halogenated anesthetic vasodilation (HAV); (b) HAs also interfere with non-adrenergic vasoconstrictor processes mediated by physiologic agonists; (c) when stimulated by HAs, endothelial cells release an """"""""endothelial-derived relaxing factor"""""""" which directly relaxes vascular smooth muscle; and (d) HAs also produce vasodilation by reducing ionized calcium availability within vascular smooth muscle cells. These hypotheses will be tested using standard in vivo (pithed anesthetized rat) and in vitro (isolated vascular ring) pharmacologic techniques. Dose-response curves to a variety of specific agonists and antagonists will be constructed in the presence and absence of HAs (halothane, enflurane, and isoflurane) at different concentrations. Experimental conditions will also be modified (e.g. removal of extracellular Ca+2) to help define sites of action. The ability of HAs to alter the potency, maximum and slope of the dose-response curves will be investigated. Such modern pharmacologic methods have never been applied to the study of HAV. If hypotheses (a) and (b) are confirmed, then it may be possible to counteract HAV by the selective activation of mechanisms not depressed by the anesthetic. The research protocol has been designed to facilitate identifying such vasoactive processes. The data will be analyzed to answer three questions: (1) what are the mechanisms of action of HAV? (2) can these mechanisms explain interactions between HAs and vasodilator drugs, including calcium blockers? and (3) what drugs can be used to attenuate or reverse deleterious HAV? This proposed research will greatly expand our basic knowledge of the sites of action of HAs and may improve the ability to effectively manage episodes of serious hypotension during anesthesia, especially in patients with cardiovascular disease.
| Larach, D R; Schuler, H G (1991) Direct vasodilation by sevoflurane, isoflurane, and halothane alters coronary flow reserve in the isolated rat heart. Anesthesiology 75:268-78 |
| Larach, D R (1991) Direct actions of volatile anesthetics on the coronary vasculature. Adv Exp Med Biol 301:289-94 |
| Greiner, A S; Skeehan, T M; Larach, D R et al. (1990) Vascular responses to dopamine and dobutamine in the awake calf during constant aortic flow or constant aortic pressure. J Cardiovasc Pharmacol 15:392-7 |
| Gibbs, N M; Larach, D R; Skeehan, T M et al. (1989) Halothane induces depressor responses to noxious stimuli in the rat. Anesthesiology 70:503-10 |
| Larach, D R; Schuler, H G; Skeehan, T M et al. (1988) Mass spectrometry for monitoring respiratory and anesthetic gas waveforms in rats. J Appl Physiol 65:955-63 |
