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Dissertation
Mechanisms of desensitization of alpha-adrenergic responses in rat-tail artery after prolonged stimulation of the alpha-1 adrenergic receptor: role of nitric oxide
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Aug 2001
DOI:
https://doi.org/10.17918/00007391
Abstract
Prolonged stimulation of the alpha-1 adrenergic receptor results in decreased norepinephrine stimulated contractility and inositol phosphate accumulation in rat-tail artery. The decreased responses are accompanied with changes in membrane bound G[alpha]q and G[alpha]i levels. Inhibiting the nitric oxide producing enzyme, nitric oxide synthase, using L-NAME, prevents the decrease in contractility and inositol phosphate accumulation. The nitric oxide donor GSNO decreases receptor-stimulated inositol phosphate accumulation. Receptor-stimulated inositol phosphate accumulation and contractility were decreased by exposure to 8-Bromo-cyclic-GMP. Inhibiting cyclic GMP dependent protein kinase with Rp-8-Bromo-cyclic GMP prevents decrease in [alpha]-1 adrenergic receptor-stimulated contractility and inositol phosphate accumulation. The decreases in contraction and inositol phosphate accumulation seen in response to 8-Bromo-cyclic GMP stimulation are not accompanied by changes in the levels of G[alpha] proteins or [alpha]-1 adrenoceptor levels. Phenylephrine-stimulated [alpha]-1 adrenergic receptor coupling to G[alpha]a proteins is decreased in membranes from tail arteries exposed to 8-Bromo-cGMP. Inhibiting the calcium-dependent neutral protease, calpain can prevent the decrease in G[alpha] protein levels in response to prolonged [alpha]-1 adrenergic receptor stimulation. Inhibition of calpain, however, did not prevent the development of decreased responses of contractility or inositol phosphate accumulation. The data suggest that prolonged stimulation of [alpha]-1 adrenergic receptors in tail arteries with phenylephrine increases the levels of endothelial nitric oxide synthase levels. The activation of protein kinase G that would be expected from increased NO production as a result of NOS upregulation uncouples the alpha-1 adrenergic receptor from G proteins thereby resulting in desensitization.
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Details
- Title
- Mechanisms of desensitization of alpha-adrenergic responses in rat-tail artery after prolonged stimulation of the alpha-1 adrenergic receptor
- Creators
- Vijay S. Iyer
- Contributors
- Eitan Friedman (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- viii, 9-105 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888717304721