The antihypertrophic action of ACE inhibitors in the heart results partly from local potentiation of bradykinin. We have demonstrated that the antihypertrophic action of bradykinin is mediated by release of nitric oxide from endothelium and elevation of cardiomyocyte cyclic GMP. Whether other paracrine factors derived from the coronary endothelium, such as prostacyclin (PGI₂), may act to prevent hypertrophy has not been explored. In the vasculature, activation by PGI₂ of IP and EP₁ prostanoid receptors elicits vasodilatation (via cyclic AMP-dependent signaling) and vasoconstriction respectively. The current objective was to determine whether IP prostanoid receptor activation has antihypertrophic actions in adult rat cardiomyocytes (ARCM). The selective IP agonist cicaprost (1µM) virtually abolished the increase in [³H]phenylalanine incorporation (a marker of hypertrophy), induced either by endothelin-1 (ET₁, 60nM, n=10, P<0.005) or by angiotensin II (1µM, n=6, P<0.005). Cicaprost also inhibited ET₁-induction of c-fos mRNA expression, an additional marker of hypertrophy in ARCM (n=5, P<0.005). In the absence of hypertrophic stimuli, cicaprost alone did not significantly influence either marker. The antihypertrophic actions of cicaprost were mimicked by the dual IP/EP₁ agonist iloprost (1µM) in the presence of the EP₁ antagonist AH6809 (3µM). Furthermore, cicaprost modestly but significantly increased cardiomyocyte cyclic AMP content by 13±6% (P<0.05, n=4), and the antihypertrophic effect of cicaprost was lost in the presence of the cyclic AMP-dependent protein kinase inhibitor H89 (1µM, n=5, P<0.05). However, ET₁ also induced increases in activity of the intracellular growth signals ERK1 (by 3-fold) and ERK2 (by 5-fold) in ARCM, and these were not inhibited by cicaprost (P<0.01, n=5). Activation of IP receptors thus represents a novel approach to prevention of hypertrophy, and this effect is linked to cyclic AMP-dependent signaling.