Cardiovascular effects of torcetrapib in conscious and pentobarbital-anesthetized dogs.
Torcetrapib is a cholesteryl ester transfer protein inhibitor with an undesired response of increasing arterial pressure in humans. Pressor responses to torcetrapib have been demonstrated in multiple preclinical species. However, these studies have not related plasma concentrations to observed effects. Our purpose was to 1) characterize the cardiovascular responses of torcetrapib in conscious and anesthetized dogs with measured plasma concentrations; and 2) characterize the hemodynamic effects contributing to hypertension using comprehensively instrumented anesthetized dogs. Torcetrapib was dosed orally (3, 30 mg/kg) and intravenously (0.01, 0.33, 0.1 mg/kg) in conscious and anesthetized dogs, respectively. Mean arterial pressure and heart rate were monitored in both models; additional parameters were measured in anesthetized dogs. Plasma drug concentrations were assessed in both models. In conscious and anesthetized dogs, torcetrapib increased mean arterial pressure 25 and 18 mm Hg and heart rate 35 and 21 beats/min, at 2.94 and 3.99 microg/mL, respectively. In anesthetized dogs, torcetrapib increased pulmonary arterial pressure, both systemic and pulmonary hypertension driven by increases in vascular resistance. The compound increased rate pressure product and myocardial contractility while decreasing time to systolic pressure recovery and ejection time. Thus, torcetrapib-induced pressor responses are mediated by systemic and pulmonary vasoconstriction and are associated with increased myocardial oxygen consumption and positive inotropy.
Polakowski
James S
JS
Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6119, USA. jim.polakowski@abbott.com
King
Andrew J
AJ
Campbell
Thomas J
TJ
Nelson
Richard A
RA
Preusser
Lee C
LC
Kempf-Grote
Anita J
AJ
Marsh
Kennan C
KC
Gintant
Gary A
GA
Cox
Bryan F
BF
Mittelstadt
Scott W
SW
D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D002319:Cardiovascular System / Q000187:drug effects*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors; D004285:Dogs; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D010424:Pentobarbital / Q000008:administration & dosage*; D011804:Quinolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013686:Telemetry; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D053480:Cholesterol Ester Transfer Proteins; D011804:Quinolines; C483909:torcetrapib; D010424:Pentobarbital