title: 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 effects of increased myofilament Ca2+ 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 Ca2+ sensitizer EMD 57033 in 16 chronically instrumented awake pigs at rest and during treadmill exercise, and compared these to the haemodynamic actions of the Ca2+ sensitizer/phosphodiesterase inhibitor pimobendan. 2. Under resting conditions EMD 57033 (0.2, 0.4 and 0.8 mg kg(-1) min(-1), i.v.) produced dose-dependent increases in LVdP/dt(max) (up to 65+/-17% (mean+/-s.e.mean), P < or = 0.05) and stroke volume (up to 20+/-3%, P < or = 0.05), with an increase in heart rate only after the highest dose (22+/-5%, P < or = 0.05), while mean aortic blood pressure and LVdP/dt(min) were not altered. EMD 57033 had also no effect on pulmonary vascular resistance, but produced dose-dependent decreases in systemic vascular resistance (32+/-4%, P < or = 0.05), and coronary vascular resistance (44+/-2%, P < or = 0.05). These effects were essentially unchanged when animals were pretreated with non-selective beta-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(-1), 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 beta-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 effects of pimobendan were amplified 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 alpha- and beta-adrenergic receptor blockade were not different from those after beta-adrenergic receptor blockade alone, indicating that the positive inotropic actions of EMD 57033 were not mediated via or did not depend on intact alpha-adrenergic receptor activity. 5. In conclusion, EMD 57033 increases left ventricular myocardial contractility in awake pigs. During exercise this effect is partially offset by the increased beta-adrenergic activity, with no effect of alpha-adrenergic activity, suggesting that EMD 57033 may be most effective in patients with severe loss of beta-adrenergic responsiveness.
authors.affiliation: Experimental Cardiology, Thoraxcenter, Cardiovascular Research Institute COEUR, Erasmus University Rotterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Stubenitsky
authors.forename: R W
authors.initials: RW
authors.lastname: van der Weerd
authors.forename: D B
authors.initials: DB
authors.lastname: Haitsma
authors.forename: P D
authors.initials: PD
authors.lastname: Verdouw
authors.forename: D J
authors.initials: DJ
authors.lastname: Duncker
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010805:Physical Conditioning, Animal / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012146:Rest / Q000502:physiology; D013552:Swine; D013829:Thiadiazines / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011804:Quinolines; D013829:Thiadiazines; C070609:EMD 53998; C041648:pimobendan