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


METHODS
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.


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
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.
Fontana
M
M
Physiologisches Institut, Justus-Liebig-Universität, Giessen, Germany.
Olschewski
H
H
Olschewski
A
A
Schlüter
K-D
KD
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002395:Catecholamines / Q000502:physiology; D048429:Cell Size / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000318:Adrenergic beta-Agonists; D000959:Antihypertensive Agents; D002395:Catecholamines; D011464:Epoprostenol; D007545:Isoproterenol; C427248:treprostinil