The inotropic and beta blocking effects of a chimeric molecule that putatively inhibits both type III phosphodiesterase and beta adrenoceptors in anesthetized dogs.
The hemodynamic and beta adrenergic blocking effects of GI104313, a chimeric molecule containing a phosphodiesterase-inhibiting pyradazinone and a beta blocking phenoxpropanolamine, were examined in barbiturate-anesthetized, vagotomized dogs. The results of these studies were compared to those of indolidan, a known phosphodiesterase inhibitor, and xamoterol, a partial beta adrenoceptor agonist. The compounds were infused at six increasing dose rates in 10-min intervals. Isoproterenol (0.5 microgram/kg) was administered before each dose increment to determine beta adrenoceptor responsiveness. In a separate set of experiments, the hemodynamic effects of GI104313, indolidan and xamoterol were examined in the presence of complete beta blockade with atenolol. GI104313 elicited dose-dependent increases in heart rate, contractility (+dP/dt) and cardiac output and decreases in arterial blood pressure, left ventricular end diastolic pressure and systemic vascular resistance in unpretreated and atenolol-pretreated dogs. However, GI104313 was less potent hemodynamically in atenolol-pretreated animals. This was evidenced by a 4-fold dextral shift in the dose-response relation for several hemodynamic variables. In unpretreated dogs, GI104313 elicited potent dose-dependent blockade of the heart rate, diastolic blood pressure and +dP/dt responses to isoproterenol. Greater than 95% inhibition of isoproterenol response was attained at 1 mumol/kg GI104313 for all observed variables. Indolidan increased contractility and heart rate and decreased diastolic blood pressure in a dose-related fashion. Indolidan did not modify the stimulatory effects of isoproterenol. Atenolol had modest effects on indolidan's hemodynamic effect, only shifting its inotropic effect 2-fold. Xamoterol produced hemodynamic and beta blocking effects similar to GI104313.(ABSTRACT TRUNCATED AT 250 WORDS)
Shaffer
J E
JE
Department of Pharmacology, Glaxo Research Institute, Glaxo Inc., Research Triangle Park, North Carolina.
Grizzle
M K
MK
Anderson
D K
DK
Wheeler
T N
TN
D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006333:Heart Failure / Q000188:drug therapy; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects*; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; C081664:Gl 104313