Abstract
In human and animal hypertension models, increased activity of G-protein-coupled receptor kinase (GRK) 2 determines a generalized decrease of β-adrenergic vasodilatation. We analyzed the possibility of differential changes in the expression and functionality of α1A, α1B, α1D, β1, β2, and β3-ARs also being involved in the process. We combined the quantification of mRNA levels with immunoblotting and functional studies in aortas of young and adult spontaneously hypertensive rats (SHRs) and their controls (Wistar Kyoto). We found the expression and function of β1-adrenoceptors in young prehypertensive SHRs to be higher, whereas a generalized increase in the expression of the six adrenoceptors and GRK2 was observed in aortas of adult hypertensive SHRs. α1D- and β3-Adrenoceptors, the subtypes that are more resistant to GRK2-mediated internalization and mostly expressed in rat aorta, exhibited an increased functional role in hypertensive animals, showing two hemodynamic consequences: 1) an increased sensitivity to the vasoconstrictor stimulus accompanied by a decreased sensitivity to the vasodilator stimulus (α1D-ARs are the most sensitive to agonists, and β3-ARs are the least sensitive to agonists); and 2) a slower recovery of the basal tone after adrenergic stimulus removal because of the kinetic characteristic of the α1D subtype. These functional changes might be involved in the greater sympathetic vasoconstrictor tone observed in hypertension.
Footnotes
-
This work was supported by the Spanish Comisión Interministerial de Ciencia y Tecnología [Grant SAF2004-01541]; Generalitat Valenciana [Grants GV2004-B-085, GRUPOS05-038]; and Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias [Grant FIS PI070509]; and by the Spanish Ministry of Education and Science [Fellowships AP-2004-3536 and AP-2005-5076].
-
doi:10.1124/jpet.108.146043.
-
ABBREVIATIONS: AR, adrenoceptor or adrenergic receptor; GRK, G-protein-coupled receptor kinase; SHR, spontaneously hypertensive rat; WKY, Wistar Kyoto; SBP, systolic blood pressure; RT, reverse transcription; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Ct, threshold cycle; SR58611A, ethyl {(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphthalen-2-yloxy}acetate hydrochloride; BMY 7378, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride; 5-methylurapidil, 5-methyl-6[[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]amino]-1,3-dimethyluracil); phenylephrine, (R)-(-)-1-(3-hydroxyphenyl)-2-methylaminoethanol hydrochloride; prazosin, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine hydrochloride.
- Received September 12, 2008.
- Accepted December 4, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|