Inhalation anesthetics may simultaneously cause vasoconstriction and vasodilation in different vascular beds. Little information is available as to the mechanisms of action of the anesthetics on resistance vessels. The general hypothesis in this application is that inhalational anesthetics have similar mechanisms of action in systemic arteries of different sizes, but that differential contractile responses of these vessels are due to opposing effects of the anesthetics on calcium mobilization. The overall goal of this proposal is to elucidate mechanisms of action of anesthetics in contraction of vascular smooth muscle from various conduit and resistance vascular beds in the rabbit.
In Aim 1, by measuring isometric tension the applicant will establish whether there are differential responses to inhalational anesthetics in a variety of systemic vascular beds utilizing isolated arterial rings. The effects of the anesthetics on the intracellular sites (the sarcoplasmic reticulum [SR] and the contractile proteins) of contractile processes will be examined in skinned arterial rings.
In Aim 2, measuring fura-2 fluorescence and phosphorylated states of myosin light chain, the applicant will assess whether changes in tension caused by the anesthetics in skinned rings are due to direct release of Ca2+ from the SR or are due to Ca2+-independent activation of contractile proteins.
In Aim 3, using skinned arterial rings, the applicant will assess whether ryanodine- and IP3-receptors share SR Ca2+ stores in different sized arteries.
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