Abstract
Various Gq protein-coupled receptor agonists such as the α1 adrenoceptor agonist phenylephrine, angiotensin II, and endothe-lin-1 are potent hypertrophic factors. There is evidence of potential cross talk between these agents, particularly in terms of endothelin-1 as playing a central role in mediating the actions of other hypertrophic factors. Using cultured rat neonatal ventricular myocytes, we assessed the potential cross talk between these factors and sought to examine the potential underlying mechanisms. Twenty-four-hour exposure to either agent produced significant hypertrophy as determined by cell size and molecular markers. Although the hypertrophic effects of phenylephrine and angiotensin II were expectedly prevented by α1 and AT1 receptor antagonists, respectively, these effects were also blocked by the ETA receptor antagonist BQ123 [cyclo(d-Asp-Pro-d-Val-Leu-d-Trp)] but not by the ETB antagonist BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl-l-γ-methylleucyl-d-1-methoxycarbonyltryptophanyl-d-norleucine). Both phenylephrine and angiotensin II significantly increased protein expression of both endothelin receptor subtypes. Both phenylephrine and angiotensin II produced significant activation of p38 as well as extracellular signal-regulated protein kinase and c-Jun NH2-terminal kinase, although this was unaffected by endothelin receptor blockade. Further studies revealed that the effects of phenylephrine and angiotensin II were mediated by stimulated endothelin-1 production occurring via two separate mechanisms: angiotensin II by increasing the levels of the endothelin-1 precursor prepro endothelin-1 and phenylephrine by upregulating endothelin-converting enzyme 1. Our results indicate that the endothelin-1 system plays an obligatory role in the hypertrophic response to both phenylephrine and angiotensin II in cultured myocytes through a mechanism independent of mitogenactivated protein kinase activation.
Footnotes
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DOI: 10.1124/jpet.104.065185.
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ABBREVIATIONS: PE, phenylephrine; AngII, angiotensin II; ET-1, endothelin 1; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated protein kinase; JNK, c-Jun NH2-terminal kinase; PD123319, 1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate; BQ123, cyclo(d-Asp-Pro-d-Val-Leu-d-Trp); BQ788, N-cis-2,6-dimethylpiperidinocarbonyl-l-γ-methylleucyl-d-1-methoxycarbonyltryptophanyl-d-norleucine; ECE-1, endothelin-converting enzyme1; PPRD, phosphoramidon; PBS, phosphate-buffered saline; RT-PCR, reverse transcription-polymerase chain reaction; PCR, polymerase chain reaction; ANP, atrial natriuretic peptide; MLC, myosin light chain.
- Received January 6, 2004.
- Accepted March 8, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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