Preventive effects of the cerebral circulation improver 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-([4-(2-methoxyphenyl)- 1-piperazinyl]methyl)isoquinoline on stroke symptoms in stroke-prone spontaneously hypertensive rats.
Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with food admixed, 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-([4-(2-methoxyphenyl)-1- piperazinyl]methyl)isoquinoline (Ro 22-4839), a novel cerebral circulation improver, for a period of 15 weeks starting from 5 weeks of age at an average daily dose of 30.6 or 66.0 mg/kg. As compared with normotensive Wistar Kyoto rats, SHRSP in the control group rapidly developed severe hypertension (244 mmHg at the end of the experiments) accompanied with deterioration of cardiovascular parameters including left ventricular hypertrophy, reduction in pumping ability and increase in peripheral vascular tone. At 20 weeks of age (i.e. at the end of experiments), 75% of SHRSP developed stroke signs and concomitant cerebral edema evidenced by the increases in water and sodium contents in the brain. These stroke symptoms were accompanied with a profound externalized shape change of erythrocytes after in vitro treatment with Ca2+ and ionophore A23187, an increased plasma level of thiobarbituric acid reacting substance (TBARS), a measure of lipid peroxides, and a decreased sensitivity of platelets to ADP. The long-term treatment with Ro 22-4839 prevented the progress of stroke and cerebral edema, although the deteriorated cardiovascular parameters were not prevented by the treatment. This compound was also found to prevent the hypersusceptibility of erythrocyte membrane to Ca2+-ionophore and Ca2+, the hypoaggregability of platelets and the elevated plasma TBARS in SHRSP. These results indicate that the beneficial effects of Ro 22-4839 in SHRSP may be attributable to its calmodulin antagonistic and anti-lipid peroxidative actions but not to its hypotensive action.
Kuwahara
T
T
Department of Pharmacology, Nippon Roche Research Center, Kamakura, Japan.
Okada
T
T
Nakamura
K
K
Himori
N
N
Yoshizaki
H
H
Matsuura
A
A
Koyama
K
K
Satoh
T
T
Nakamura
K
K
D000818:Animals; D001921:Brain / Q000378:metabolism; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D002561:Cerebrovascular Disorders / Q000517:prevention & control*; D004907:Erythrocyte Deformability / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007546:Isoquinolines / Q000627:therapeutic use*; D008054:Lipid Peroxides / Q000097:blood; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D002317:Cardiovascular Agents; D007546:Isoquinolines; D008054:Lipid Peroxides; C052931:Ro 22-4839