| Losartan-induced attenuation of blood pressure in L-NAME hypertensive rats is associated with reversal of the enhanced expression of Gi alpha proteins. | |
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MedLine Citation:
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PMID: 15106810 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: We have previously reported that hearts from N-[omega]-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats exhibited an enhanced expression of Gi proteins. Since, losartan, an AT1 receptor antagonist, has been shown to attenuate the L-NAME-induced increase in blood pressure, we undertook the present studies to evaluate whether losartan-induced decreased blood pressure in this model of hypertension is associated with attenuation of enhanced expression of Gi proteins and adenylyl cyclase signalling. METHODS: L-NAME (70 mg/kg body weight) and losartan (10 mg/kg body weight), alone or in combination, were given orally to Sprague-Dawley rats for 4 weeks. The control rats received only plain tap water. The levels of inhibitory guanine nucleotide regulatory proteins (Gi alpha-2 and Gi alpha-3) and stimulatory (Gs alpha) proteins and Gi alpha mRNA in hearts were determined by immunoblotting and Northern blotting, respectively. Adenylyl cyclase activity was determined by measuring [32P]cAMP formation from [32P]ATP. RESULTS: Systolic blood pressure was enhanced in L-NAME-treated rats compared to control rats (164 +/- 5.2 versus 105 +/- 2 mmHg; n = 30), and was significantly attenuated by losartan treatment (164 +/- 5.2 mmHg versus 120 +/- 2.5 mmHg; n = 30). The expression of Gi alpha-2 and Gi alpha-3 proteins and their mRNA, which was enhanced in L-NAME-treated rats, was reversed by losartan treatment. However, losartan alone did not alter the levels of Gs alpha or Gi alpha proteins. In addition, the stimulatory effects of guanosine 5'-gamma-thiotriphosphate (GTPgammaS), isoproterenol, 5'-N-ethylcarboxamideadenosine (NECA), glucagon, forskolin (FSK) and sodium fluoride (NaF) on adenylyl cyclase, which were diminished in L-NAME-treated rats, were reversed by losartan treatment. Furthermore, the inhibition of forskolin-stimulated enzyme activity by low concentrations of GTPgammaS (receptor-independent Gi functions), which was significantly enhanced in L-NAME-treated rats, was attenuated by losartan treatment. In addition, losartan was able to reverse the attenuated receptor-mediated inhibitions of adenylyl cyclase by oxotremorine and angiotensin II towards control. CONCLUSIONS: These results suggest the implication of AT1 receptors in enhanced expression of Gi alpha proteins and increased blood pressure in L-NAME-induced hypertension. |
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Authors:
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Shehla Hashim; Madhu B Anand-Srivastava |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of hypertension Volume: 22 ISSN: 0263-6352 ISO Abbreviation: J. Hypertens. Publication Date: 2004 Jan |
Date Detail:
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Created Date: 2004-04-26 Completed Date: 2004-11-06 Revised Date: 2012-07-13 |
Medline Journal Info:
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Nlm Unique ID: 8306882 Medline TA: J Hypertens Country: England |
Other Details:
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Languages: eng Pagination: 181-90 Citation Subset: IM |
Affiliation:
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Department of Physiology and Groupe de recherche sur le système nerveux autonome, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenylate Cyclase
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drug effects,
metabolism Animals Antihypertensive Agents / pharmacology* Blood Pressure / drug effects* Disease Models, Animal Enzyme Inhibitors / pharmacology* Forskolin / pharmacology GTP-Binding Protein alpha Subunit, Gi2 GTP-Binding Protein alpha Subunits, Gi-Go / drug effects*, metabolism* Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology Hypertension / metabolism* Losartan / pharmacology* Male Models, Cardiovascular NG-Nitroarginine Methyl Ester / pharmacology* Proto-Oncogene Proteins / drug effects*, metabolism* RNA, Messenger / drug effects, metabolism Rats Rats, Inbred SHR Rats, Sprague-Dawley Sodium Fluoride / pharmacology Statistics as Topic |
| Chemical | |
Reg. No./Substance:
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0/Antihypertensive Agents; 0/Enzyme Inhibitors; 0/Proto-Oncogene Proteins; 0/RNA, Messenger; 114798-26-4/Losartan; 37589-80-3/Guanosine 5'-O-(3-Thiotriphosphate); 50903-99-6/NG-Nitroarginine Methyl Ester; 66428-89-5/Forskolin; 7681-49-4/Sodium Fluoride; EC 3.6.5.1/GTP-Binding Protein alpha Subunit, Gi2; EC 3.6.5.1/GTP-Binding Protein alpha Subunits, Gi-Go; EC 3.6.5.1/Gnai2 protein, rat; EC 4.6.1.1/Adenylate Cyclase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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