Cardiovascular effects of the novel Ca²⁺‐sensitiser EMD 57033 in pigs at rest and during treadmill exercise

Abstract

1 To date no study has described the cardiovascular e ects of increased myo®lament Ca 2+ responsiveness in awake animals both under resting conditions and during treadmill exercise. In the present study we therefore investigated the systemic, pulmonary and coronary haemodynamic actions of the Ca 2+ sensitizer EMD 57033 in 16 chronically instrumented awake pigs at rest and during treadmill exercise, and compared these to the haemodynamic actions of the Ca 2+ sensitizer/phosphodiesterase inhibitor pimobendan. 2 Under resting conditions EMD 57033 (0.2, 0.4 and 0.8 mg kg 71 min 71 , i.v.) produced dosedependent increases in LVdP/dt max (up to 65+17% (mean +s.e.mean), P40.05) and stroke volume (up to 20+3%, P40.05), with an increase in heart rate only after the highest dose (22+5%, P40.05), while mean aortic blood pressure and LVdP/dt min were not altered. EMD 57033 had also no e ect on pulmonary vascular resistance, but produced dose-dependent decreases in systemic vascular resistance (32+4%, P40.05), and coronary vascular resistance (44+2%, P40.05). These e ects were essentially unchanged when animals were pretreated with non-selective b-adrenoceptor blockade, indicating that phosphodiesterase inhibition did not contribute to the positive inotropic actions of EMD 57033. 3 During exercise at 2, 3, and 4 km h 71 , the positive inotropic actions of EMD 57033 gradually waned at higher levels of exercise. This may have been caused by the exercise-induced increase in b-adrenergic activity, because after pretreatment with propranolol the positive inotropic actions of EMD 57033 were preserved at all levels of exercise. In contrast, the positive inotropic and chronotropic e ects of pimobendan were ampli®ed during exercise, but were abolished (at rest) or markedly attenuated (during exercise) after pretreatment with propranolol. 4 The responses to EMD 57033 during exercise after combined a-and b-adrenergic receptor blockade were not di erent from those after b-adrenergic receptor blockade alone, indicating that the positive inotropic actions of EMD 57033 were not mediated via or did not depend on intact a-adrenergic receptor activity. 5 In conclusion, EMD 57033 increases left ventricular myocardial contractility in awake pigs. During exercise this e ect is partially o set by the increased b-adrenergic activity, with no e ect of a-adrenergic activity, suggesting that EMD 57033 may be most e ective in patients with severe loss of b-adrenergic responsiveness.

Autonomic control of cardiovascular performance and whole body O2 delivery and utilization in swine during treadmill exercise

“…However, when humans exercise in swine, b-adrenoceptor blockade resulted in lower HR and the supine position, which is more comparable to the body LVdP/ dt and higher SVR under resting conditions, position of quadrupeds, SV increases are much less max confirming previous observations from our laboratory that (|25%) [41]. This is the result of an increase in SV to significant b-adrenergic activity is present in swine in the approximately 80% of the maximum SV when changing resting state [9]. This contrasts with studies in awake from the upright to the supine position, so that only a resting dogs [44,45] and resting (supine) humans [46,47], slightly further increase is possible during subsequent in which b-adrenergic activity can be minimal.…”

“…Haemodynamic measurements were repeated and the rectal temperature was measured Full details of all experimental procedures have been while the animals were standing on the treadmill. Subpublished previously [6][7][8][9]. Briefly, swine were sedated sequently, a five-stage exercise protocol was begun (1, 2, with ketamine (30 mg / kg, i.m.…”

Small and large animal models in cardiac contraction research: Advantages and disadvantages

“… References: a (Stubenitsky, van der Weerd, Haitsma, Verdouw, & Duncker, 1997), b (Kasner, et al, 2007) …”

Role of adenosine in the regulation of coronary blood flow in swine at rest and during treadmill exercise

“…Adaptation of animals to the laboratory conditions started 1 wk before the day of surgery and continued until 10 days postoperative. Full details of the experimental procedures have been published previously (7,9,37,38).…”