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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/H1917    most recent 00258.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Siedlecka, U. Articles by Terracciano, C. M. N. PubMed PubMed Citation Articles by Siedlecka, U. Articles by Terracciano, C. M. N.

Effects of clenbuterol on contractility and Ca²⁺ homeostasis of isolated rat ventricular myocytes

¹Heart Science Centre and ²Cardiac Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom

Submitted 11 March 2008 ; accepted in final form 2 September 2008

Clenbuterol, a compound classified as a β₂-adrenoceptor (AR) agonist, has been employed in combination with left ventricular assist devices (LVADs) to treat patients with severe heart failure. Previous studies have shown that chronic administration of clenbuterol affects cardiac excitation-contraction coupling. However, the acute effects of clenbuterol and the signaling pathway involved remain undefined. We investigated the acute effects of clenbuterol on isolated ventricular myocyte sarcomere shortening, Ca²⁺ transients, and L-type Ca²⁺ current and compared these effects to two other clinically used β₂-AR agonists: fenoterol and salbutamol. Clenbuterol (30 µM) produced a negative inotropic response, whereas fenoterol showed a positive inotropic response. Salbutamol had no significant effects. Clenbuterol reduced Ca²⁺ transient amplitude and L-type Ca²⁺ current. Selective β₁-AR blockade did not affect the action of clenbuterol on sarcomere shortening but significantly reduced contractility in the presence of fenoterol and salbutamol (P < 0.05). Incubation with 2 µg/ml pertussis toxin significantly reduced the negative inotropic effects of 30 µM clenbuterol. In addition, overexpression of inhibitory G protein (G_i) by adenoviral transfection induced a stronger clenbuterol-mediated negative inotropic effect, suggesting the involvement of the G_i protein. We conclude that clenbuterol does not increase and, at high concentrations, significantly depresses contractility of isolated ventricular myocytes, an effect not seen with fenoterol or salbutamol. In its negative inotropism, clenbuterol predominantly acts through G_i, and the consequent downstream signaling pathways activation may explain the beneficial effects observed during chronic administration of clenbuterol in patients treated with LVADs.

β-adrenoceptor; G proteins; heart failure; cardiac myocytes