Cardiovascular effects of KRN2391 in anesthetized dogs: a comparison with cromakalim and nitroglycerin.
The cardiovascular effects of KRN2391, N-cyano-N'-(2-nitroxyethyl)-3-pyridine carboximidamide monomethanesulfonate, were compared with those of cromakalim and nitroglycerin in anesthetized dogs. KRN2391 (3-30 micrograms/kg, i.v.), cromakalim (3-30 micrograms/kg, i.v.) and nitroglycerin (1-10 micrograms/kg, i.v.) produced a dose-related decrease of the mean blood pressure with concomitant increase in heart rate. The increase in heart rate caused by cromakalim was lower than that caused by KRN2391 and nitroglycerin. Left ventricular end-diastolic pressure was decreased by all doses of KRN2391 and nitroglycerin. Cromakalim at 3 and 10 micrograms/kg decreased this end-diastolic pressure but increased it at 30 micrograms/kg. Left ventricular dP/dt was increased by KRN2391 and nitroglycerin but was decreased by cromakalim. KRN2391 and cromakalim produced a dose-dependent increase in aortic and coronary blood flow. Nitroglycerin showed biphasic changes in aortic and coronary blood flow, i.e., an initial increase followed by a decrease. At equipotent hypotensive doses, the increase in coronary blood flow induced by KRN2391 was greater than that by cromakalim and nitroglycerin, and total peripheral and coronary vascular resistances were decreased by KRN2391 and cromakalim. Nitroglycerin showed biphasic changes in total peripheral and coronary vascular resistances, i.e., these resistance showed an initial decrease followed by an increase. The relative decrease of coronary vascular resistance compared to the total peripheral vascular resistance was greater for KRN2391 than for cromakalim and nitroglycerin. The changes in hemodynamic parameters caused by KRN2391 were inhibited by pretreatment with glibenclamide (5 mg/kg, i.v.). These results suggest that the hemodynamic profile of KRN2391 is closer to that of cromakalim than to that of nitroglycerin, but that the selectivity for the coronary vascular bed is higher for KRN2391 than for cromakalim. In addition, it is considered that, compared with KRN2391 and nitroglycerin, cromakalim has a low selectivity for the vasculature vs the myocardium.
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
S
S
Kaneta
T
T
Yokoyama
H
H
Izumi
T
T
Izawa
N
N
Ogawa
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; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D017725:Ventricular Pressure / Q000187:drug effects
D001578:Benzopyrans; D015221:Potassium Channels; D011725:Pyridines; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; C070492:N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate; D005996:Nitroglycerin