Hypotensive Effect and Cerebral Blood Flow Increasing Action of OPC-13340, a New Long Acting Ca antagonist, in Aged SHR

Abstract

Recently, the number of aged people is increasing year by year, and it is getting a very important subject to treat properly the aged hypertensive patients. It is well known that cerebral blood flow is auto-regulated and maintained at constant level independent of the perfusion pressure (blood pressure). However, the lower break point of pressure-blood flow curve shifts to the right (high blood pressure side) in hypertensive patients, and sometimes drastic hypotension causes decrease of cerebral blood flow and results in cerebral ischemia. So that anti-hypertensive agents which have mild hypotensive action and do not decrease cerebral blood flow are preferable in these aplication.OPC -13340 (methy 3-phenyl-2(E)-propyl 1 , 4-dihydro-2, 6-dimethyl 4-(3-nitrophenyl)-3, 5-pyridine dicarboxylate) is a new long acting Ca antagonist (J ARDIOVASC PHARMACOL 15: 836, 1990) now undergoing clinical trials as an anti-hypertensive as well as an anti-anginal agent with once daily treatment. In this study, the hypotensive action and effects on the cerebral blood flow (CBF) of OPC-140were examined in normotensive Wistar rats (NTR) and aged spontaneously hypertensive rats (SHR) comparing with those of nicardipine and nimodipine.M aterials and Methods (1) Measurement of blood pressure: Male Wistar rats (15 weeks old) or SHR (52 weeks old) were anesthetized with sodium pentobarbital and cannulated into the abdominal aorta, and the blood pressure was measured in conscious state after 2 days of the surgery. m easurement of CBF: Male Wistar rats (10 weeks old) or SHR (50 weeks old) were anesthetized and hydrogen electrodes were implanted stereotactically into deep cerebrum and cortex. After more than 2 weeks, the CBF was measured in conscious state using hydrogen clearance method.(3) Drugs: Drugs were dissolved in 90% polyethylene glycol 400, and orally administered in the volume of 1ml/kg. The control experiments using solvent were carried out for both measurement. (4) Statistics: Multiple group comparisons were done by analysis of variance (ANOVA), followed by urkey's test using SAS program. Results and Discussion: In NTR, OPC-13340 (10mg/kg) significantly decreased systolic blood pressure (sBP) about 25mmHg, and increased CBF 50-60% in both cortex and deep cerebrum from 1hr to 8hr after administration (P<0.01). Nicardipine or nimodipine (30mg/kg) caused same extent of hypotension as OPC-13340, but increased CBF only 20-30%. On the other hand, in the case of aged SHR, OPC-13340 (1mg/kg) decreased sBP about 36mmH and tended to increase CBF 10-15%. OPC-13340 (3mg/kg) decreased sBP about 50mmHg, and in this case CBF did not increase. In contrast to this, nicardipine (3 and 10mg/kg) dropped the sBP about 35 and 50mmHg, respectively, and significantly decreased the CBF by 10-20% compared to prevalue. These data suggest following findins, (1) OC-13340 has more potent CBF increasing action comared with nicardipine or nimodipine at the dose of same hypotensive action in NTR.(2) In aged SHR, moderate hypotensive treatment does not dro CBF, b...

OPC‐13340, a New Potent and Long‐Acting Dihydropyridine Calcium Antagonist

“…The effect of OPC-13340 on cerebral blood flow was examined in conscious, nonrestrained rats using the hydrogen clearance method (16). In normotensive rats, OPC-I3340 (3 and 10 mg/kg p.0.)…”