Effects of pimobendan, a novel inotropic agent, on intracellular calcium and tension in isolated ferret ventricular muscle

Abstract

1. In this study we have investigated the effects of a novel inotropic agent, pimobendan (UDCG 115-BS), on skinned and intact ventricular muscle from ferrets. 2. Pimobendan (20 or 100 mumol/l) increased tension at a given free [Ca2+] when applied to skinned ventricular muscle, i.e. it increased the Ca2+ sensitivity of the myofibrils. 3. Tension and intracellular free Ca2+ [( Ca2+]i) were measured simultaneously in intact papillary muscles using the aequorin technique. When 25 mumol/l pimobendan was added to the superfusing solution, a slowly developing positive ionotropic effect was produced, which was accompanied by an increase in the size of the systolic rise in [Ca2+]i (Ca2+ transients) with a similar time course. 4. In order to determine whether pimobendan increased the Ca2+ sensitivity of myofibrils in an intact papillary muscle, we compared the increase in Ca2+ transients and tension observed in response to changes in extracellular [Ca2+] with those observed in response to pimobendan. The result of this comparison was that in intact muscle pimobendan caused no apparent increase in myofibrillar Ca2+ sensitivity. 5. Pimobendan caused an abbreviation of the time course of the Ca2+ transients, but the twitch was slightly prolonged. 6. When isoprenaline was added to the superfusing solution, a positive inotropic effect was produced, which was accompanied by a marked increase in the size of the Ca2+ transients. Isoprenaline caused an abbreviation of the time course of both the Ca2+ transients and the twitch. When the Ca2+ sensitivity of the intact myofibrils was determined as described above, isoprenaline caused a desensitization. Pimobendan produced a sensitization when compared with isoprenaline. 7. These results are consistent with the hypothesis that pimobendan produces an inotropic effect in isolated cardiac muscle which is mediated both by an increase in Ca2+ sensitivity and by an increase in adenosine 3':5'-cyclic monophosphate due to its phosphodiesterase-inhibiting activity. Such a combination of activities may be particularly advantageous for an inotropic agent.

Comparative Adverse Cardiac Effects of Pimobendan and Benazepril Monotherapy in Dogs with Mild Degenerative Mitral Valve Disease: A Prospective, Controlled, Blinded, and Randomized Study

“…This positive inotropic effect of PIMO is known to result from a dual mechanism of action: an increase in calcium sensitivity of cardiac myofilaments and inhibition of cAMP breakdown by PDE III. 7,29 Surprisingly, the PIMO-induced hypercontractile state was not associated with a concomitant increase in the arterial blood pressure and the maximal aortic flow velocity and stroke volume evaluated by Doppler measurements, which is thought to represent a logical hemodynamic correlate of an increase in left ventricular contractility. Conversely, the increased systolic myocardial function was associated with a major worsening of the mitral regurgitant jet characterized by a 3-fold increase in its extension in the left atrium and an increase in both its peak velocity and duration, thus explaining a 4-fold increase in the corresponding velocity time integral.…”

“…6 Pimobendan (PIMO) is an orally active drug combining calcium-sensitizing properties with cyclic AMP phosphodiesterase (PDE) III inhibition. 7 These actions result in positive inotropic and vasodilatory effects, which may be beneficial in dogs with left ventricular systolic failure, as demonstrated in Doberman Pinschers with dilated cardiomyopathy. 8 PIMO also is registered in many countries for use in canine congestive heart failure due to MVD, and some recent studies suggest that it may be beneficial in mild to moderate stages of the disease.…”

EMD 53998 sensitizes the contractile proteins to calcium in intact ferret ventricular muscle.

“…Both groups used ferret papillary muscles and a similar general approach, but one difference was the presence of a a-blocker (bupranalol) in the experiments of one group30 but not the other. 10 In the comparison shown in Figure 6, both guanethidine and propranalol were present throughout. Note that the inotropic effects of the two drugs were similar but that EMD 53998 had virtually no effect on the amplitude of the light signal (+ 17%), whereas pimobendan increased the light signal by 270% (i.e., a 3.7-fold increase).…”

Okadaic acid, a protein phosphatase inhibitor, increases the calcium transients in isolated ferret ventricular muscle

“…Thus the overall effect might be no net change in calcium sensitivity, as observed here. Such a combination of competing intracellular actions has been proposed to account for the lack of a net calcium sensitizing effect seen in intact muscle with pimobendan (Lee, Ruegg & Allen, 1989), where a primary calcium sensitizing action of the drug is offset by its phosphodiesterase inhibiting activity (probably via increased phosphorylation of troponin I).…”