Selective effects of lomerizine, a novel diphenylmethylpiperazine Ca2+ channel blocker, on cerebral blood flow in rats and dogs.
1. In the present study we examined the effects of a new Ca2+ channel blocker (lomerizine), an antimigraine drug, on cerebral cortical blood flow (CBF) in anaesthetized rats (laser Doppler flowmetry) and on vertebral blood flow in anaesthetized beagle dogs (electromagnetic flowmeter). 2. Lomerizine (1.25-10 mg/kg, p.o.) dose-dependently increased CBF in rats without affecting blood pressure (BP) or heart rate (HR). 3. The plasma concentration of lomerizine (free base) in anaesthetized rats at 30 and 60 min after the initial administration of 5 mg/kg, p.o., time at which there was a significant increase in CBF, was similar to that reported in healthy subjects receiving lomerizine at 10 mg (2 x 5 mg)/day, p.o., a dose that significantly reduces the frequency and mean duration of headache attacks. 4. Flunarizine (10 mg/kg, p.o.) did not increase CBF significantly. Flunarizine (20 mg/kg, p.o.) did not increase CBF, but did decrease BP 30-120 min after its administration. 5. Lomerizine (2.5 and 5 mg/kg, intraduodenally) dose-dependently increased vertebral blood flow in dogs without significantly changing BP or HR. With 10 mg/kg intraduodenal lomerazine, vertebral blood flow remained elevated from 20 to 240 min after administration and BP was decreased from 20 to 120 min. 6. Thus, lomerizine had a greater effect on CBF than on BP and HR and, therefore, it may be clinically effective in conditions associated with circulatory disturbances in the brain, such as migraine, without producing systemic effects (e.g. hypotension) generally seen with other Ca2+ channel blockers.
Hara
H
H
Department of Pharmacology, Kanebo Ltd, Osaka, Japan.
Shimazawa
M
M
Sasaoka
M
M
Yamada
C
C
Iwakura
Y
Y
Sakai
T
T
Maeda
Y
Y
Yamaguchi
T
T
Sukamoto
T
T
Hashimoto
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000097:blood / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005444:Flunarizine / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D017078:Laser-Doppler Flowmetry; D008297:Male; D010879:Piperazines / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013131:Spine / Q000098:blood supply / Q000187:drug effects
D002121:Calcium Channel Blockers; D010879:Piperazines; C052424:lomerizine; D005444:Flunarizine