Effects of the novel water-soluble calcium antagonist (+/-)-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate dihydrochloride on the endothelium-independent and endothelium-dependent contraction in isolated canine cerebral arteries.
The inhibitory effects of NKY-722 (+/-)-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate dihydrochloride, CAS 117241-46-0) on endothelium-independent and endothelium-dependent contractions were examined in comparison with nicardipine in isolated canine cerebral arteries. NKY-722 relaxed the cerebral arteries contracted endothelium-independently by KCl, prostaglandin F2 alpha U-46619 (a thromboxane A2 agonist) and endothelin-1 with IC50 = 2.5, 3.4, 2.8 and 3.6 x 10(-10) mol/l, respectively. On the basis of IC50 values, NKY-722 was about 2 times more effective than nicardipine. Pretreatment of NKY-722 and nicardipine inhibited the endothelium-independent contraction induced by KCl and serotonin to a similar degree. NKY-722 attenuated the endothelium-dependent contractions caused by acetylcholine (ACh), adenosine diphosphate and KO2 with IC50 = 1.7, 3.8 and 1.4 x 10(-9) mol/l, respectively. NKY-722 was about 2 times less effective than nicardipine. NKY-722 and nicardipine inhibited dose-dependently the endothelium-dependent contractions induced by hemolysate. NKY-722 was nearly equipotent to nicardipine on the phasic contraction and slightly more potent on the tonic contraction. The inhibitory effect of NKY-722 on the endothelium-independent contraction induced by KCl and the endothelium-dependent contraction induced by ACh were sustained for a longer time than that of nicardipine after repetitive wash-out. In conclusion, NKY-722 inhibited effectively the endothelium-independent and endothelium-dependent contractions in the cerebral arteries. The effect of NKY-722 was similar to, but longer-lasting than that of nicardipine.
Kanda
M
M
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd, Japan.
Shirahase
H
H
Wada
K
K
Nakamura
S
S
Matsui
H
H
Fukata
F
F
D000109:Acetylcholine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology; D004095:Dihydropyridines / Q000494:pharmacology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009529:Nicardipine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C058351:NKY 722; D012701:Serotonin; D000244:Adenosine Diphosphate; D011189:Potassium Chloride; D009529:Nicardipine; D000109:Acetylcholine