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Losartan-induced attenuation of blood pressure in L-NAME hypertensive rats is associated with reversal of the enhanced expression of Gi alpha proteins.
- Source :
-
Journal of hypertension [J Hypertens] 2004 Jan; Vol. 22 (1), pp. 181-90. - Publication Year :
- 2004
-
Abstract
- 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.<br />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.<br />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.<br />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.
- Subjects :
- Adenylyl Cyclases drug effects
Adenylyl Cyclases metabolism
Animals
Colforsin pharmacology
Disease Models, Animal
GTP-Binding Protein alpha Subunit, Gi2
Guanosine 5'-O-(3-Thiotriphosphate) pharmacology
Male
Models, Cardiovascular
RNA, Messenger drug effects
RNA, Messenger metabolism
Rats
Rats, Inbred SHR
Rats, Sprague-Dawley
Sodium Fluoride pharmacology
Statistics as Topic
Antihypertensive Agents pharmacology
Blood Pressure drug effects
Enzyme Inhibitors pharmacology
GTP-Binding Protein alpha Subunits, Gi-Go drug effects
GTP-Binding Protein alpha Subunits, Gi-Go metabolism
Hypertension metabolism
Losartan pharmacology
NG-Nitroarginine Methyl Ester pharmacology
Proto-Oncogene Proteins drug effects
Proto-Oncogene Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0263-6352
- Volume :
- 22
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of hypertension
- Publication Type :
- Academic Journal
- Accession number :
- 15106810
- Full Text :
- https://doi.org/10.1097/00004872-200401000-00028