Increase in myofibrillar Ca2+ sensitivity induced by UD-CG 212 Cl, an active metabolite of pimobendan, in canine ventricular myocardium.
ABSTRACT We performed experiments in canine ventricular trabeculae loaded with aequorin to elucidate the mechanism of positive inotropic effect of UD-CG 212 Cl (4,5-dihydro-6-[2-(4-hydroxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3(2H)-pyridazinone), an active metabolite of pimobendan. The maximum response to UD-CG 212 Cl achieved at 10(-5) M was 18% of ISOmax and it was associated with an increase in Ca2+ transients of 7% of ISOmax. For a given increase in force, the increase in Ca2+ transients induced by UD-CG 212 Cl was less than that induced by elevation of [Ca2+]o. The positive inotropic effect of UD-CG 212 Cl was not associated with an impairment of relaxation and it was abolished by carbachol. In conclusion, UD-CG 212 Cl has a positive inotropic effect partly due to an increase in myofibrillar Ca2+ sensitivity that is exerted via cross talk with a signal transduction pathway that involves cAMP.
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ABSTRACT: Ca2+ sensitizers act on the central mechanism (Ca2+ binding affinity of troponin C) and/or downstream mechanisms (thin filament regulation of actin and direct action on crossbridge cycling) of cardiac E-C coupling. Ca2+ sensitizers have mechanistic and energetic advantages over the agents that act through the upstream mechanism (intracellular Ca2+ mobilization). Ca2+ sensitizers and the agents that act through cyclic AMP-mediated signaling process have been postulated to belong to different classes, however, recent experimental findings revealed that certain Ca2+ sensitizers, such as levosimendan, OR 1896 and UD-CG 212 Cl, require cyclic AMP-mediated signaling for induction of the Ca2+ sensitizing effect. No clinically available agents act primarily via Ca2+ sensitization, but the positive inotropic effect of pimobendan and levosimendan is partly due to an increase in myofilament Ca2+ sensitivity. These agents are the hybrid of Ca2+ sensitizer and PDE III inhibitor. The extent of contribution of Ca2+ sensitizing effect of these agents to the clinical effectiveness to improve the hemodynamics in patients with heart failure is uncertain. Nevertheless pieces of evidence have been accumulating that these agents with Ca2+ sensitizing effect are clinically more effective than the agents that act purely via the upstream mechanism.Cardiovascular Drugs and Therapy 10/2001; 15(5):397-403. · 2.67 Impact Factor
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ABSTRACT: AIM: We evaluated the effect of pimobendan, a positive inotropic agent, in elderly patients with frequent readmission as a result of heart failure despite conventional therapy. METHODS: Pimobendan was given to five male patients with severe chronic heart failure (New York Heart Association class III-IV) (age range 69-89 years; mean 78 ± 8 years; ischemic cardiomyopathy in three cases, dilated cardiomyopathy in two cases) who required repeated admission for heart failure despite conventional therapy with angiotensin inhibitors, beta-blockers, diuretics and anti-arrhythmic agents. After the addition of pimobendan at a dose of 1.25-3.75 mg/day, we evaluated serum levels of brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), septal e' and left ventricular end-diastolic diameter (LVDD) by echocardiography, as well as readmission rates for more than 2 years. RESULTS: The serum level of BNP significantly decreased after treatment with pimobendan, although its level returned to pretreatment levels after 2 years. LVEF significantly improved after the treatment, with the improvement continuing beyond the 2 years, although LVDD did not change after treatment. Septal e' significantly improved after the treatment, although its level returned to pretreatment levels at 2 years after the treatment. Readmission rates significantly decreased for 2 years after the treatment, although one patient required cardiac resynchronization therapy for severe heart failure, and another patient required cardiac pacemaker implantation for sick sinus syndrome 2 years after adding pimobendan. CONCLUSIONS: Pimobendan in conjunction with conventional therapy for heart failure decreases the readmission rate in elderly patients with severe heart failure for at least 2 years. Geriatr Gerontol Int 2013; ●●: ●●-●●.Geriatrics & Gerontology International 04/2013;