Individual variability of cardiovascular sensitivity to anesthetics (i.e. degree of circulatory instability) is both a clinical and basic science problem rooted in the fundamental mechanisms of anesthetic action. Preliminary studies have shown that the Dahl Salt-Sensitive rat (SS) exhibits a significantly greater cardiovascular sensitivity to numerous anesthetic agents, compared to the SS.BN. 13 and Brown Norway (BN) rat. In the SS.BN. 13 rat, a single complete homozygous substitution of chromosome number 13 from the BN has been introgressed into an otherwise unchanged SS genetic background. Although similar to the BN in cardiovascular response to anesthetics, the SS.BN. 13 has less than 2% background genetic divergence from the SS compared to 77% in the BN. Thus it is superior (to the BN) as a """"""""control"""""""" strain to compare with the SS to study these responses. The overall objective of this proposal is to compare and clarify mechanisms underlying differences in the effects of sodium pentobarbital. and propofol (as representative anesthetics) on the regulation of peripheral vascular smooth muscle (VSM) tone in the SS and SS.BN. 13 strains. Additional confirmation of isogenic backgrounds will be accomplished by measuring cardiovascular sensitivity to sodium pentobarbital and propofol in other consomic strains. Then, effects of these anesthetics on VSM tone in small mesenteric artery resistance vessels will be indirectly assessed and compared in SS and SS.BN. 13 by: (1) Measurement of in situ VSM transmembrane potential responses to specific pharmacological blockers of the activity of K+ channels, intracellular second messengers, and endothelium-derived vasodilators; (2) Patch clamp measurements of individual K+ channel properties in mesenteric arterial myocytes. This proposal provides a means to identify differences in the specific mechanisms of anesthetic-induced attenuation of VSM tone in small resistance vessels that, in turn, contribute to cardiovascular sensitivity differences. Such detailed characterization of mechanisms will form the basis for planned (future) genotyping studies. Of particular value in using this model is the availability of 2 animal strains that exhibit significant differences in cardiovascular sensitivity but are genetically identical, except for a single controlled chromosomal substitution virtually eliminating any background genetic variability and differences in VSM that are unrelated to the observed anesthetic sensitivity. Additionally, this model also greatly facilitates development of congenic sub strains (partial chromosomal substitutions) for use in subsequent genetic mapping studies.
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| Stadnicka, Anna; Contney, Stephen J; Moreno, Carol et al. (2009) Mechanism of differential cardiovascular response to propofol in Dahl salt-sensitive, Brown Norway, and chromosome 13-substituted consomic rat strains: role of large conductance Ca2+ and voltage-activated potassium channels. J Pharmacol Exp Ther 330:727-35 |
| Stekiel, Thomas A; Contney, Stephen J; Bosnjak, Zeljko J et al. (2006) Chromosomal substitution-dependent differences in cardiovascular responses to sodium pentobarbital. Anesth Analg 102:799-805 |
