Cardiovascular profile of the calcium sensitizer EMD 57033 in open‐chest anaesthetized pigs with regionally stunned myocardium

Abstract

1 Ca 2+ sensitizers enhance systolic function, but may impair relaxation in vitro; these e ects may di er in stunned and normal myocardium. We therefore studied the e ect of EMD 57033 on systolic and diastolic function of normal and stunned porcine myocardium in vivo. 2 Myocardial stunning by 15 min coronary occlusion and 30 min reperfusion abolished systolic shortening (SS) (baseline 13+1%) and decreased end-systolic elastance (E es ) from 67+7 to 47+5 mmHg mm 71 (both P50.05). Maximum rate of fall of myocardial elastance (dE/dt min ) decreased from 7850+100 to 7320+30 mmHg mm 71 s 71 , while the time constant t e of the decay of elastance increased from 58+3 to 68+6 ms (both P50.05). End-diastolic elastance (E ed ) was unchanged although the zero pressure intercept (L 0,ed ) had increased. 3 In the stunned region, EMD 57033 (0.2 mg kg 71 min 71 for 60 min, i.v., n=7) increased SS to 19+2%, E es to 287+40 mmHg mm 71 , dE/dt min to 73630+640 mmHg mm 71 s 71 and decreased t e to 50+3 ms, while E ed remained unchanged. In the normal region, EMD 57033 increased SS from 14+2 to 18+3%, E es from 59+4 to 263+23 mmHg mm 71 , dE/dt min from 7480+70 to 72280+700 mmHg mm 71 s 71 and decreased t e from 91+12 to 61+3 ms (all P50.05), while E ed remained unchanged. These responses were minimally a ected by adrenoceptor blockade (n=7). Vehicle (n=7) had no e ect on either region. 4 EMD 57033 increased cardiac output (up to 27+8%) and LVdP/dt max (86+19%). Mean aortic pressure decreased (19+7%) due to systemic vasodilation that was not amenable to blockade of adrenoceptors or NO synthesis. 5 In conclusion, EMD 57033 restored systolic and diastolic function of stunned myocardium, and produced similar improvements in systolic and diastolic function in normal myocardium. British Journal of Pharmacology (2000)

Augmented systolic response to the calcium sensitizer EMD-57033 in a transgenic model with troponin I truncation

“…This augmentation occurred to a substantially greater extent in transgenic hearts than in controls, suggesting a specific capacity of this agent to affect the underlying defect. Despite basal diastolic dysfunction in TnI- hearts, diastolic function was enhanced by EMD-57033, consistent with prior in vivo studies (5,37). These data support a particular utility of EMD-57033 (and potentially similar calcium sensitizers) to treat myocardial dysfunction associated with TnI-proteolytic fragmentation.…”

“…In these models, and unlike the present data, EMD-57033 was similarly effective in augmenting systolic function in the pathological model, as it was in parallel studies of control muscles, regional ventricular segments, or whole hearts. Some studies of regional myocardial stunning in the pig have also found similar responses in control and depressed myocardium (5). However, the pathophysiology of stunning in the pig appears to principally relate to altered calcium transients, rather than myofilament defects (20).…”

“…EMD-57033 has been demonstrated to be effective in treating cardiac dysfunction in a number of animal models, including regional and global models of cardiac stunning, tachycardia-induced cardiac failure, volume overload-induced failure, and myocardial infarction-induced cardiac dysfunction (5,6,16,36,42,45). In these models, and unlike the present data, EMD-57033 was similarly effective in augmenting systolic function in the pathological model, as it was in parallel studies of control muscles, regional ventricular segments, or whole hearts.…”

“…We employed the thiadiazinone compound EMD-57033, which influences troponin C (TnC), to alter myofilament protein interaction and augment force generation (40). EMD-57033 has been shown to improve systolic function in in vivo and in vitro models of heart failure (6,22,36) and enhances diastolic function in vivo (5,37). We provide novel evidence that the TnI- mutation is preferentially sensitive to this agent.…”

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

“…It has been found to increase the Ca 2+ -sensitivity of both myofibrillar ATPase and force development by skinned muscle fibers [71,72]. In vivo studies have also demonstrated that EMD 57033 enhances cardiac contractile function without affecting Ca 2+ -homeostasis [73][74][75][76][77]. The myofibrillar Ca 2+ -sensitizing effect of EMD 57033 is stereo-specific.…”