This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. It is estimated that approximately 9.5 million men over 65 will suffer from benighn prostate hyperplasia (BPH) in 2010, and of these men 87% will suffer hypertension(HTN) and 40% will have a previous admission for heart failure. Although HTN responds positively to alpha1-adrenergic receptor (alpha1-AR) antagonist treatment, the treatment of HTN with alpha1-AR antagonists is at best a third-line option due to an increased incidence of heart failure as highlighted in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). In the heart, alpha1-ARs regulate postnatal growth and myocardial adaptation to stress, and an alpha1A-ERK signaling pathway protects cardiac myocytes from stress. Blockade of alpha1-AR signaling could explain the deleterious effects of alpha1-AR antagonist administration in patients with HTN. In contrast to HTN, BPH is treated effectively with administration of alpha1-AR antagonists and currently several alpha1-AR antagonists are FDA approved for treatment of BPH. This presents a unique circumstance in men where individuals who suffer from both diseases are in a perilous situation where treatment of BPH with an alpha1-AR antagonist can have potentially serious cardiac side effects. Given the common coexistence of HTN and BPH, understanding the interplay of alpha1-ARs in their treatment could have tremendous value in patient treatment options. Recently we demonstrated that alpha1-ARs are expressed on cardiac myocyte nuclear membranes which challenged the long-held dogma that all G-protein coupled receptors (GPCR) localized to the plasma membrane, which is the case for a proportion of alpha1-ARs in prostate smooth muscle cells (SMC). In SMC, a membrane impermeable alpha1-AR antagonist, CGP-12177 (CGP) can inhibit smooth muscle tension whereas this compound, in our preliminary experiments, does not block beneficial alpha1-AR signaling in cardiac myocytes. The overall objective of this research is to determine the localization of alpha1-AR subtypes in prostate and vascular SMCs, how localization impacts signaling, and the efficacy of the membrane impermeable alpha1-AR antagonist CGP in reducing HTN without increasing the indices of heart failure.
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