Recent in vitro studies of large vessels and in vivo studies of whole beds indicate that vascular smooth muscle (VSM) can possess 2 types of alpha adrenergic receptors (R) that mediate contraction, designated alpha1 and alpha2. Both their relative distribution and modes of post-R signal transduction have received much attention. However it is not known if they are subject to different physiological regulation, and hence their involvement in pathology and therapeutic interventions remains poorly understood. Prior to our work, no studies had examined alpha R subtypes across the microcirculation. We have found, using intravital microscopy of skeletal muscle, that large arterioles important in control of peripheral resistance functionally have both Rs with alpha2 dominant; small terminal arterioles that regulate capillary flow and blood-tissue exchange appear to have only alpha2 Rs. The overall goal of this proposal is to determine whether this distinct R distribution is important in adrenergic control of peripheral circulation, and if alpha1 and alpha2 contraction of micro-VSM is differentially modulated by other extrinsic and intrinsic controls. This distinct R distribution itself suggest different physiological roles for the 2 Rs. We have preliminary evidence that metabolic (eg, pH, PO2, adenosine), physiochemical (eg, temperature, myogenic stretch), hormonal (eg, ANF) and neural signals interact selectively with alpha1 or alpha2 responses. The hypotheses to be examined are that (1) the heterogeneity of R distribution and sensitivity to smooth muscle controllers confers distinct regulatory features on microvascular segments, and (2) differences in post-R 2nd messenger signalling pathways (""""""""coupling"""""""") of alpha1 and alpha2 Rs are involved in conferring selective modulation of R responses by intrinsic and extrinsic determinants of micro-VSM tone. The following Specific Aims to address these hypotheses will be examined with intravital microscopy of skeletal and intestinal microvasculatures, microfluorimetry (intracellular Ca++) of isolated microvessels, and anatomical localization of alpha adrenoceptor type and density.
Aim I To determine if myogenic mechanisms interact selectively with alpha2 and alpha2 adrenoceptor contraction, and the cellular basis for this interaction.
Aim II. To determine the physiological relevance of selective inhibition of alpha2 adrenoceptor contraction of micro-VSM by local metabolic feedback signals (tissue O2, pH, adenosine), and the cellular mechanism for this inhibition.
Aim III. To determine if either alpha1 or alpha2 adrenoceptors are preferentially activated by neuronally released NE in the microcirculation, and whether alpha2 receptors are responsible for """"""""escape"""""""" from sympathetic nerve stimulation.
Aim I V. To determine the transmembrane signaling pathways and Ca coupling of alpha1 and alpha2 adrenoceptors n microvascular smooth muscle.
Aim V. To determine how alpha1 and alpha2 receptors are anatomically distributed in the microcirculation of normotensive and hypertensive animals. The results will clarify basic mechanisms of microvascular regulation and may lead to new insights into the pathophysiology and treatment of peripheral vascular disorders.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Experimental Cardiovascular Sciences Study Section (ECS)
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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