My long term career goal is to clarify how the microvascular smooth muscle cell integrates the large array of neural, humoral and local physio-chemical signals that it receives into an appropriate contractile response. My immediate research goal is to expand my current focus on the role of cell membrane receptors to include 2nd messenger systems and intracellular ion activity in the regulation of smooth muscle at the cellular, isolated microvessel and in situ microvascular levels. This requires, in addition to my current applications of receptor pharmacology, in situ microcirculatory and systemic hemodynamic analyses, the new techniques of receptor autoradiography and immuno-cytochemistry and in situ ion probe microfluorimetry. The objective of this proposal is to focus on alpha-adrenoceptor subtypes on microvascular smooth muscle type may be differentially governed by a heterogeneous distribution of alpha 1 and alpha 2 adrenoceptors (arterioles- alpha1/alpha2, precapillary spincters- alpha2, muscular venules-alpha2/alpha1), and that metabolic, myogenic, physiochemical (eg, temperature, pH), hormonal (eg, ANF) and neural (synaptic vs. extrasynaptic) signals interact selectively with alpha1 or alpha2 responses. Thus 3 novel hypotheses will be distinct microvascular segments. (2) alpha subtypes contraction is modulated differently by intrinsic and extrinsic controllers. (3) Heterogeneity of receptor distribution and sensitivity to smooth muscle controllers confers distinct regulatory features on microvascular segments: ie, alpha receptor subtypes serve unique physiological functions. Intravital microscopy of skeletal muscle and intestinal microvasculature will be used to characterize alpha adrenoceptors (K/M, pA2, receptor reserve) Aim I); examine interaction among intrinsic and extrinsic controllers on alpha subtype contraction (Aim II); determine the functional and anatomic (autoradiography) distribution of pre- and postjunctional alpha receptors across the microvasculature (Aim III); and examine whether alpha subtypes serve distinct physiological roles. The result will clarify basic mechanisms of microvascular regulation and may lead to new insights in the pathophysiology and treatment of peripheral vascular disorders.
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