Abstract
Plasma adenosine levels are elevated in cardiovascular disease including hypertension and heart failure, and the nucleoside has been proposed to serve as an endogenous antimyocardial remodeling factor. We studied the modulation of phenylephrine-induced hypertrophy by adenosine receptor activation in isolated neonatal cultured ventricular myocytes. Phenylephrine (10 μM) increased cell size by 35% and significantly increased expression of atrial natriuretic peptide. These effects were reduced by the stable adenosine analog 2-chloroadenosine and were completely blocked by the adenosine A1 receptor agonist N6-cyclopentyladenosine (1 μM), the A2A receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5′-N-ethylcarboxamidoadenosine (100 nM), and the A3 receptor agonist N6-(3-iodobenzyl)adenosine-5′–methyluronamide (100 nM). The antihypertrophic effects of all three agonists were completely reversed by their respective antagonists. Phenylephrine significantly up-regulated expression of the immediate early gene c-fos especially within the first 30 min of phenylephrine treatment. These effects were almost completely inhibited by all adenosine receptor agonists. Although phenylephrine also induced early stimulation of both p38 mitogen-activated protein kinase and extracellular signal-regulated kinase, these responses were unaffected by adenosine agonists. The expression of the G-protein regulatory factors RGS2 and RGS4 were increased by nearly 3-fold by phenylephrine treatment although this was completely prevented by adenosine receptor agonists. These agents also blocked the ability of phenylephrine to up-regulate Na/H exchange isoform 1 (NHE1) expression in hypertrophied myocytes. Thus, our results demonstrate an antihypertrophic effect of adenosine acting via multiple receptor subtypes through a mechanism involving down-regulation of NHE1 expression. The ability to prevent regulators of G-protein signaling (RGS) up-regulation further suggests that adenosine receptor activation minimizes signaling which leads to hypertrophic responses.
Footnotes
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Supported by the Canadian Institutes of Health Research.
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doi:10.1124/jpet.104.073122.
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ABBREVIATIONS: CPA, N6-cyclopentyladenosine; CGS 21680, 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine; IB-MECA, N6-(3-iodobenzyl)adenosine-5′–methyluronamide; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; CSC, 8-(3-chlorostyryl) caffeine; MRS 1523, 3-propyl-6-ethyl-5[ethyl(thio)carbonyl]-2-phenyl-4-propyl-3-pyridinecarboxylate; NHE1, sodium hydrogen exchanger isoform 1; ANP, atrial natriuretic peptide; bp, base pair(s); PCR, polymerase chain reaction; RGS, regulator of G-protein signaling; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated protein kinase.
- Received June 28, 2004.
- Accepted September 27, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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