Hemodynamic response and effects on myocardial energetics of 3-cyano-2-morpholino-5-(pyrid-4-yl)pyridine (AWD 122-14) in anesthetized minipigs.
AWD 122-14, a new positive inotropic and vasodilating agent, was investigated in comparison to amrinone, milrinone and dopamine in anesthetized minipigs. AWD 122-14 (1.17.10(-7)-37.5.10(-7) mol/kg) increased dose-dependent left ventricular contractility (LV dp/dtmax) (122x5 +/- 11x3%; ED50 = 8.1x10(-7) to mol/kg). Dopamine (2.64x10(-8)-21x12 x 10(-8) mol/kg) in comparison increased contractility up to 153.1 +/- 44.9% of control value and is about 20 times more potent than AWD 122-14 at the ED50 value and about 10 times more potent at the ED30 value. Amrinone (1.60x10(-6)-16.90x10(-6) mol/kg) and milrinone (1.48x10(-7)-23.70x10(-7) mol/kg) only slightly increased contractility in anesthetized minipigs, but they appear to posses a similar pharmacological profile like AWD 122-14. The hemodynamic effects were associated with an increase in myocardial oxygen consumption (E1: 18.8 +/- 10.0%) due to the marked increases in LV dp/dtmax and heart rate. LVMW was unchanged and LVSW decreased (-29.0 +/- 10.2%) after application of AWD 122-14. The reduction in left ventricular work (LVMW, LVSW) and the increase in myocardial oxygen consumption led to a decrease of left ventricular external mechanical efficiency of the non-failing minipig heart (Etam: -21.1 +/- 9.4%). Additional hemodynamic effects of AWD 122-14 were studied under calcium channel blockade (verapamil, nifedipine). After pretreatment with verapamil the agent (1.17.10(-7)-18.75.10(-7) mol/kg i.v.) increased left ventricular contractility between 42.9 +/- 41.6% and 58.5 +/- 33.3%. After pretreatment with nifedipine the agent induced a dose-dependent increase in LV dp/dtmax between 11.1 +/- 7.7% and 47.8 +/- 23.7%.(ABSTRACT TRUNCATED AT 250 WORDS)
Rohde
E
E
Research Institute of Molecular Pharmacology, Berlin.
Wiesner
B
B
Muschick
P
P
D000676:Amrinone / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D020105:Milrinone; D009025:Morpholines / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature
D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D009025:Morpholines; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011728:Pyridones; C077469:3-cyano-2-morpholino-5-(pyrid-4-yl)pyridine; D020105:Milrinone; D000676:Amrinone; D004298:Dopamine