Impotence is a common disorder that affects an estimated 10 million American men. There is a widespread demand for treatment of impotence, as evidenced by an estimated 400,000 outpatient visits and more than 30,000 hospital admissions, in 1985. The desire for treatment, especially through pharmacological means, requires the continuous development of research in this field in order to understand the basic physiological and biochemical mechanisms involved in erection. Pharmacological manipulation of penile smooth muscle tone with the injection of vasoactive drugs, such as alpha-adrenergic blockers, is now a commonly used treatment for impotence. The possibility of treating impotence with oral medications is one of the desired objectives in the future. To this end, detailed knowledge of the biochemical and physiological properties of the neurotransmitter receptor systems that modulate penile smooth muscle is essential. In this grant proposal our efforts will be directed towards identification, analysis, quantitation and regulation of expression of neurotransmitter receptor subtypes in the various cellular elements of human corpus cavernosum (HCC) and rabbit corpus cavernosum (RCC) and the possible interactions among these receptors. In order to understand the role of neurotransmitters in the modulation of erectile tissue function, it is necessary to elucidate the biochemical and physiological mechanisms mediated by the neurotransmitter receptors. The overall objective of this proposal is to increase our knowledge and understanding of the biochemical and physiological mechanisms modulating smooth muscle tone of erectile tissue via neurotransmitter receptors. We propose to investigate the regulation of expression, cellular location, density and distribution of muscarinic acetylcholine receptor and alpha1-adrenergic receptor subtypes in HCC and RCC. Also, we propose to investigate the modulation of acetylcholine (ACh) binding by vasoactive intestinal peptide (VIP) and identify and characterize the VIP receptors and its possible modulation by prostaglandins. Our approach involves: a) generation of site-specific antibodies and immunocytochemical analysis; b) in vitro binding studies and autoradiography; c) in situ hybridization, Northern blots and RNase protection assays; and d) physiological experimentation in organ chambers. It is anticipated that these studies will lead to better understanding of the mechanisms of neurotransmitter receptors in erectile function and to the development of specific therapeutic strategies for better treatment of impotence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK040025-05
Application #
3240102
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1988-04-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Moreland, R B; Kim, N; Nehra, A et al. (2003) Functional prostaglandin E (EP) receptors in human penile corpus cavernosum. Int J Impot Res 15:362-8
Moreland, R B; Nehra, A; Kim, N N et al. (2002) Expression of functional prostaglandin D (DP) receptors in human corpus cavernosum smooth muscle. Int J Impot Res 14:446-52
Moreland, R B; Albadawi, H; Bratton, C et al. (2001) O2-dependent prostanoid synthesis activates functional PGE receptors on corpus cavernosum smooth muscle. Am J Physiol Heart Circ Physiol 281:H552-8
Udelson, D; L'Esperance, J; Morales, A M et al. (2000) The mechanics of corporal veno-occlusion in penile erection: a theory on the effect of stretch-associated luminal constrictability on outflow resistance. Int J Impot Res 12:315-27
Kim, N N; Goldstein, I; Moreland, R B et al. (2000) Alpha-adrenergic receptor blockade by phentolamine increases the efficacy of vasodilators in penile corpus cavernosum. Int J Impot Res 12 Suppl 1:S26-36
Traish, A; Kim, N N; Moreland, R B et al. (2000) Role of alpha adrenergic receptors in erectile function. Int J Impot Res 12 Suppl 1:S48-63
Moreland, R B; Kim, N N; Nehra, A et al. (2000) Misoprostol induces relaxation of human corpus cavernosum smooth muscle: comparison to prostaglandin E1. Int J Impot Res 12:107-10
Traish, A; Kim, N N; Huang, Y H et al. (2000) Cyclic AMP regulates mRNA expression of alpha-1d and alpha-2a adrenergic receptors in cultured human corpus cavernosum smooth muscle cells. Int J Impot Res 12 Suppl 1:S41-47
Traish, A; Moreland, R B; Huang, Y H et al. (1999) Development of human and rabbit vaginal smooth muscle cell cultures: effects of vasoactive agents on intracellular levels of cyclic nucleotides. Mol Cell Biol Res Commun 2:131-7
Traish, A M; Kim, N N; Goldstein, I et al. (1999) Alpha-adrenergic receptors in the penis: identification, characterization, and physiological function. J Androl 20:671-82

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