Stereoisomers of BAY K 8644 show opposite activities in the normal and ischaemic rat heart. A comparison with nifedipine.
The effects of the stereoisomers and the racemate of the calcium agonist BAY K 8644 and the calcium antagonist nifedipine were studied on the Langendorff-perfused rat heart, subjected to 30 min of global ischaemia. The results show that (-)- and (+/-)-BAY K 8644 induced a strong positive inotropic effect at 100 and 1000 nmol/l and a vasoconstricting effect which was most prominent at 1 and 10 nmol/l, respectively. At higher concentrations the flow reduction was inverted to a flow increase, closely related to the positive inotropic activity. The inotropic status induced by the agonist before the onset of ischaemia was reflected in an accelerated development of the diastolic contracture during ischaemia. During the reperfusion, a complex triphasic effect on the recovery was found, in which probably positive inotropism, vasoconstriction, metabolic and mechanical factors are involved. The (+)-enantiomer of BAY K 8644 behaved as a weak calcium antagonist showing merely vasodilatation, which accelerated the recovery from the ischaemic contracture at reperfusion. The calcium antagonistic, vasodilating effects of the (+)-enantiomer were expressed in the racemate only during the reperfusion phase, where it took an intermediate position between the effects of the (-)- and (+)-enantiomer. In contrast, nifedipine, at negative inotropic - energy saving - concentrations, diminished the height and delayed the development of the energy deprivation-induced left ventricular diastolic contracture during ischaemia. The time needed for recovery from the contracture during reperfusion was significantly shortened already at a 100 times lower, vasodilating concentration of nifedipine.
van Amsterdam
F T
FT
Department of Pharmacology and Therapeutics, University of Groningen, The Netherlands.
Punt
N C
NC
Haas
M
M
van Amsterdam-Magnoni
M S
MS
Zaagsma
J
J
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003327:Coronary Disease / Q000503:physiopathology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D014664:Vasodilation / Q000187:drug effects
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine