Hemodynamic and cardiac effects of BMS-180448, a novel K+ATP opener, in anesthetized dogs and isolated rat hearts.
Hemodynamic and cardiac effects of BMS-180448 (0.3-10 mg/kg i.v.) or cromakalim (0.01-0.3 mg/kg i.v.) were evaluated in anesthetized open-chest dogs and isolated perfused rat hearts. In the canine studies, heart rate (HR), mean arterial pressure and left ventricular pressure were measured as well as electromagnetic blood flows recorded from the aortic, renal, coronary and femoral vascular beds. BMS-180448 was 187-fold less potent than cromakalim in lowering blood pressure (ED-20 values of 7.84, and 0.042 mg/kg for BMS-180448 and cromakalim, respectively). Both compounds increased HR. Effects of BMS-180448 occurred at doses higher than those of cromakalim, but at doses slightly lower than those needed to cause hypotension (ED(HR)/ED(MABP) ratio of 0.18 for BMS-180448). BMS-180448 had no effect on myocardial contractility or relaxation over the doses studied, whereas cromakalim significantly increased +dP/dt and lowered -dP/dt. Effects on +dP/dt were associated with a decrease in blood pressure. Although BMS-180448 reduced total peripheral resistance (ED-25 = 5.75 mg/kg), it had little effect on specific vascular beds, with the exception of the coronary bed. BMS-180448, unlike cromakalim which caused more general vasodilating effects, appeared to be relatively selective in dilating the coronary vascular bed. In isolated perfused rat hearts, BMS-180448, 10-fold more potent as a cardioprotectant (EC25 = 2.7 microM) than as a cardiodepressant (ED-25 = 27.8 microM), had no effect on HR, suggesting a lack of effect of BMS-180448 on myocardial conduction. In conclusion, BMS-180448, a recently developed K+ATP opener, exerted less hypotensive and more selective vascular effects than did cromakalim. These results suggest that BMS-180448, at doses previously reported to give cardioprotection, should have a safe hemodynamic profile.
D'Alonzo
A J
AJ
Department of Cardiovascular Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Grover
G J
GJ
Darbenzio
R B
RB
Sewter
J C
JC
Hess
T A
TA
Dzwonczyk
S
S
Sleph
P G
PG
D000255:Adenosine Triphosphate / Q000502:physiology*; D000758:Anesthesia; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D019806:Cromakalim; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D000255:Adenosine Triphosphate; C084684:BMS 180448