α1 -Adrenoceptor activation of PKC-ε causes heterologous desensitization of thromboxane receptors in the aorta of spontaneously hypertensive rats.

BACKGROUND AND PURPOSE:In the aorta of adult spontaneously hypertensive (SHR), but not in that of normotensive Wistar-Kyoto (WKY), rats, previous exposure to phenylephrine inhibits subsequent contractions to PGE2 . The present experiments were designed to examine the mechanism(s) underlying this inhibition. EXPERIMENTAL APPROACH:Isometric tension was measured in isolated rings of SHR and WKY aortae. Gene expression and protein presence were measured by quantitative real-time PCR and Western blotting respectively. KEY RESULTS:In aorta of 18 weeks SHR, but not age-matched WKY, pre-exposure to phenylephrine inhibited subsequent contractions to PGE2 that were mediated by thromboxane prostanoid (TP) receptors. This inhibition was not observed in preparations of pre-hypertensive 5-week-old SHR, and was significantly larger in those of 36- than 18-week-old SHR. Pre-exposure to the activator, phorbol 12,13-dibutyrate, also inhibited subsequent contractions to PGE2 in SHR aortae. The selective inhibitor of ε-V1-2, abolished the desensitization caused by pre-exposure to phenylephrine. Two molecular duanyu1531 bands were detected and their relative intensities differed in 36-week-old WKY and SHR vascular smooth muscle. The mRNA expressions of duanyu1531-ε, PK-N2 and and of G protein-coupled kinase (GRK)-2, GRK4 and β-arrestin2 were higher in SHR than WKY aortae. CONCLUSIONS AND IMPLICATIONS:These experiments suggest that in the SHR but not the WKY aorta, α1 -adrenoceptor activation desensitizes TP receptors through activation of This heterologous desensitization is a consequence of the chronic exposure to high arterial pressure.

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