PHARMACOLOGY OF VASCULAR AL-ADRENERGIC RECEPTORS

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The overall long-term objective of this research is to understand the dynamic interplay between regulation, expression, and function of human vascular adrenergic receptors (ARs) in health and disease. Within this context, this proposal focuses on human alpha1-ARs by examining mechanisms underlying vessel specific alpha1-AR subtype expression in normoxia and hypoxia, as well as examination of genomic alpha1a-AR mutations associated with hypertension. One unique aspect of alpha1-AR pharmacology is that expression and function of vascular alpha1-ARs depends on species studied and vascular bed examined. In contrast to rat and mouse, where A1b and alpha1d-ARs predominate and mediate contraction in many vessels, recent data from the investigators' laboratory demonstrates that alpha1a-ARs predominate in virtually all human arterial (e.g. coronary, hepatic, mammary, mesenteric, pulmonary, renal) and many venous beds. In addition to expression at RNA and protein levels, they have confirmed that alpha1a-ARs mediate human vessel contraction. They now propose examining mechanisms underlying vessel specific expression of human alpha1-AR subtypes by testing the hypothesis that differential human vascular alpha1-AR expression (alpha1>alpha1d) results from a combination of vessel specific 5'-regulatory sequences and tissue specific transcription factors; the alpha1d is chosen for this comparison since it is absent in many human vessels where alpha1aARs are expressed. The investigators recently cloned and characterized 6.2kb 5'UTR of the human alpha1-AR gene (Razik, et al. J Biol Chem, 1997; 272: 28237-28246); therefore they are in a unique position to test this hypothesis in both normoxia and hypoxia. Since alpha1a-ARs predominate in human splanchnic and resistance arterial beds, their second specific aim examines whether specific genetic polymorphisms result in enhanced alpha1-AR vascular expression and/or constitutively activity that correlates with hypertension. In this regard, they have identified a linkage between the region of human chromosome 8 where the alpha1-AR resides and systolic blood pressure. In addition, they recently identified 3 polymorphisms in 1.3kb alpha1-AR coding region in pilot studies from 5 individuals. Additional polymorphisms will be sequenced from 192 individuals to identify clinically relevant polymorphisms). They propose testing these polymorphisms for functional significance in tissue culture and correlating each polymorphism with vascular.