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α 1 ‐Adrenoceptor activation of PKC ‐ε causes heterologous desensitization of thromboxane receptors in the aorta of spontaneously hypertensive rats
Author(s) -
Zhao Yingzi,
Vanhoutte Paul M,
Leung Susan W S
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13157
Subject(s) - phenylephrine , protein kinase c , medicine , endocrinology , receptor , activator (genetics) , aorta , desensitization (medicine) , thromboxane a2 , calponin , chemistry , signal transduction , blood pressure , biochemistry , smooth muscle
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 PGE 2 . 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 W estern blotting respectively. Key Results In aorta of 18 weeks SHR , but not age‐matched WKY , pre‐exposure to phenylephrine inhibited subsequent contractions to PGE 2 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 PKC activator, phorbol 12,13‐dibutyrate, also inhibited subsequent contractions to PGE 2 in SHR aortae. The selective inhibitor of PKC ‐ε, ε‐ V 1‐2, abolished the desensitization caused by pre‐exposure to phenylephrine. Two molecular PKC bands were detected and their relative intensities differed in 36‐week‐old WKY and SHR vascular smooth muscle. The m RNA expressions of PKC ‐α, PKC ‐ε, PK ‐ N 2 and PKC ‐ζ and of G protein‐coupled kinase ( GRK )‐2, GRK 4 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, α 1 ‐adrenoceptor activation desensitizes TP receptors through activation of PKC ‐ε. This heterologous desensitization is a consequence of the chronic exposure to high arterial pressure.