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Treprostinil potentiates the positive inotropic effect of catecholamines in adult rat ventricular cardiomyocytes.

ABSTRACT: BACKGROUND AND PURPOSE: Prostanoids have been shown to improve exercise tolerance, hemodynamics and quality of life in patients with pulmonary arterial hypertension (PAH). We investigated whether treprostinil exerts direct contractile effects on cardiomyocytes that may explain partly the beneficial effects of these drugs. EXPERIMENTAL APPROACH: Ventricular cardiomyocytes from adult rats were paced at a constant frequency of 0.5 to 2.0 Hz and cell shortening was monitored via a cell edge detection system. Twitch amplitudes, expressed as percent cell shortening of the diastolic cell length, and maximal contraction velocity, relaxation velocity, time to peak of contraction and time to reach 50% of relaxation were analyzed. KEY RESULTS: Treprostinil (0.15 - 15 ng ml(-1)) slightly increased contractile dynamics of cardiomyocytes at clinically relevant concentrations. However, the drug significantly improved cell shortening of cardiomyocytes in the presence of isoprenaline, a beta-adrenoceptor agonist. Treprostinil exerted this effect at all beating frequencies under investigation. Treprostinil mimicked this potentiating effect in a Langendorff preparation as well. The potentiating effect of treprostinil on isoprenaline-dependent cell shortening was no longer seen after phosphodiesterase inhibition. Long-term cultivation of cardiomyocytes with treprostinil did not modify load free cell shortening of these cells, but reduces the duration of contraction. CONCLUSIONS AND IMPLICATIONS: We conclude that the clinically used prostanoid treprostinil potentiates the positive inotropic effects of catecholamines in adult ventricular cardiomyocytes. This newly described effect may contribute to the beneficial clinical effects of prostanoids in patients with PAH.

SUBMITTER: Fontana M

PROVIDER: S-EPMC2014129 | biostudies-other | 2007 Jul

REPOSITORIES: biostudies-other

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Project description:ATP is released as a cotransmitter together with catecholamines from sympathetic nerves. In the heart ATP has been shown to cause a pronounced positive inotropic effect and may also act in synergy with beta-adrenergic agonists to augment cardiomyocyte contractility. The aim of the present study was to investigate the inotropic effects mediated by purinergic P2 receptors using isolated mouse cardiomyocytes. Stable adenine nucleotide analogs were used and the agonist rank order for adenine nucleotide stimulation of the mouse cardiomyocytes was AR-C67085>ATPgammaS>2-MeSATP>>>2-MeSADP=0, that fits the agonist profile of the P2Y11 receptor. ATPgammaS induced a positive inotropic response in single mouse cardiomyocytes. The response was similar to that for the beta1 receptor agonist isoproterenol. The most potent response was obtained using AR-C67085, a P2Y11 receptor agonist. This agonist also potentiated contractions in isolated trabecular preparations. The adenylyl cyclase blocker (SQ22563) and phospholipase C (PLC) blocker (U73122) demonstrated that both pathways were required for the inotropic response of AR-C67085. A cAMP enzyme immunoassay confirmed that AR-C67085 increased cAMP in the cardiomyocytes. These findings are in agreement with the P2Y11 receptor, coupled both to activation of IP3 and cAMP, being a major receptor for ATP induced inotropy. Analyzing cardiomyocytes from desmin deficient mice, Des-/-, with a congenital cardiomyopathy, we found a lower sensitivity to AR-C67085, suggesting a down-regulation of P2Y11 receptor function in heart failure. The prominent action of the P2Y11 receptor in controling cardiomyocyte contractility and possible alterations in its function during cardiomyopathy may suggest this receptor as a potential therapeutic target. It is possible that agonists for the P2Y11 receptor could be used to improve cardiac output in patients with circulatory shock and that P2Y11 receptor antagonist could be beneficial in patients with congestive heart failure (CHF).

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Treprostinil potentiates the positive inotropic effect of catecholamines in adult rat ventricular cardiomyocytes.

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