Comparison Of Pharmacological Effects Of (Rac)-m-Nisoldipine, (S)-m-Nisoldipine And (R)-m-Nisoldipine

M-Nisoldipine (m-Nis) is the isomer of Nisoldipine (Nis). Our pevious studies showed that (Rac)-m-Nis could inhibit vascular smooth muscle contraction, dilate coronary artery, decrease after load and oxygen consumption of heart. It is expected to become an ideal medicine in treating hypertension, ischemic heart disease, coronary artery disease, and atherosclerosis. (Rac)-m-Nis was splited into (R)-m-Nis and (S)-m-Nis by Hebei Medical University. The objective of the present study was to investigate the difference of the antihypertensive effect among of (Rac)-m-Nis, (S)-m-Nis and (R)-m-Nis on conscious SHR and give evidence for the medicine development and clinical medication.Part One The acute antihypertensive effect of (Rac)-m-Nis oldipine, (S)-m-Nisoldipine and (R)-m-Nisoldipine in conscious SHRObjective: To compare the acute antihypertensive effect of (Rac)-m-Nisoldipine, (S)-m-Nisoldipine and (R)-m -Nisoldi- -pne in conscious spontaneously hypertensive rats (SHR) and provide experimental evidence for its clinical application. Methods: Qualified SHRs aged 13 weeks were divided randomly into 4 groups (n=10): (Rac)-m-Nis group; (S)-m-Nis group; (S)-m-Nis group; solvent control group. A single dose (1.5mg/kg, 0.75mg/kg, 0.4mg/kg, 0.2mg/kg or 0.1mg/kg) of drug was intragastricly administered. Before drug administration, BP and HR were measured as control value at 0h. Then BP and HR of SHR in all groups were measured at 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h after medication.Results: At 1.5mg/kg dose level, significant reduction of BP in SHR occurred at 1h after drug administration (P<0.01) in drug-treated gruops compared with that at 0h. The maximal hypotensive effect reached at 2h, and lower BP was kept for 24 hours (P<0.05). The maximal hypotensive effect hadn't statistical difference among drug-treated gruops (P>0.05). At 0.75mg/kg dose level, significant reduction of BP in SHR occurred at 1h after drug administration (P<0.01) in drug-treated groups compared with that at 0h. The maximal hypotensive effect reached at 2h, and lower BP was kept for 12 hours (P<0.05). The maximal hypotensive effect hadn't statistical difference among drug-treated gruops (P>0.05). At 0.4mg/kg dose level, significant reduction of BP in SHR occurred at 1h after drug administration (P<0.01) in drug-treated gruops compared with that at 0h. The maximal hypotensive effect reached at 2h, and lower BP was kept for 8 hours (P<0.05). The maximal hypotensive effect hadn't statistical difference among drug-treated gruops (P>0.05). At 0.2mg/kg dose level, significant reduction of BP in SHR occurred at 1h after drug administration (P<0.01) in drug-treated gruops compared with that at 0h. The maximal hypotensive effect reached at 2h, and lower BP was kept for 6 hours (P<0.05). The maximal hypotensive effect hadn't statistical difference among drug-treated gruops (P>0.05). At 0.1mg/kg dose level, significant reduction of BP in SHR occurred at 1h after drug administration (P<0.01) in drug-treated gruops compared with that at 0h. The maximal hypotensive effect reached at 2h, and lower BP was kept for 4 hours (P<0.05). The maximal hypotensive effect hadn't statistical difference among drug-treated gruops (P>0.05). At all dose levels, HR had no significant change in drug-treated gruops (P>0.05). The solvent had no significant effect on BP and HR.Conclusion: (Rac)-m-Nisoldipine, (S)-m-Nisoldipine and (R)-m-Nisoldipine had obviously hypotensive effect after single oral administration with similar potency.Part Two Chronic antihypertensive effect of (Rac)-m-Nis oldipine, (S)-m-Nisoldipine and (R)-m-Nisoldipine in conscious SHR Objective: To compare the chronic antihypertensive effect of (Rac)-m-Nisoldipine, (S)-m-Nisoldipine and (R)-m-Nisoldipine in conscious spontaneously hypertensive rats (SHR) and provide experimental evidence for its clinical application.Methods: Qualified SHRs aged 18 weeks were divided randomly into 4 groups (n=10): (Rac)-m-Nis group; (S)-m-Nis group; (R)-m-Nis group; solvent control group. Drugs were given by oral administration once daily for 14 days. BP and HR were measured at d0, d1, d3, d5, d7, d8, d9, d10, d12 and d14. AT 2d and 4d after withdrawal of durgs, BP and HR were measured again.Results: At the dose of 0.1mg/kg, significant reduction of BP (P<0.05) occurred on 8th day after administration and reached peak effect on 12th day. After withdrawal of drugs, their hypotensive effects lasted nearly 4 days. The maximal hypotensive effect hadn't statistical difference among drug-treated groups (P>0.05). HR had no significant change in drug-treated gruops (P>0.05). The solvent had no significant effect on BP and HR. At the dose of 0.05mg/kg, the drugs had no obvious effects on HR and BP (P>0.05).Conclusion: At the dose of 0.1mg/kg, (Rac)-m-Nis oldipine, (S)-m-Nisoldipine and (R)-m-Nisoldipin- -e had obviously hypotensive effect after multiple oral administration with similar potency. At the dose of 0.05mg/kg, the drugs had no obvious influence on BP and HR. Part Three Effects of (Rac)-m-Nisoldipine, (S)-m-Ni soldip ine and (R)-m-Nisoldipine on heamodynamics and heart remodering in SHRObjective: To examine effects of (Rac)-m-Nisoldipine (S)-m-Nisoldipine and (R)-m-Nisoldipine on hemodynamics and myocardium pathomorphology in SHRMethods: 24 Qualified SHRs aged 22 weeks were divided randomly into 4 groups (n=6): (Rac)-m-Nis group; (S)-m-Nis group; (R)-m-Nis group; solvent control group. The drugs were given by intragastric administration once daily at 8 am. After treatment for 8 weeks, the SHR was placed on operation table after abdominal anesthesia by sodium pentobarbital (40mg/kg), a median incision was made on cervical part, and the right common carotid artery was separated. A cardiac catheter was inserted into the left ventricular cavity via the right carotid artery and connected to MS4000U system for examining hemodynamics parameters including HR, LVSP, LVEDP, tdp/dt and±dp/dtmax. Then heart was quickly removed, left ventricle was isolated and left ventricular mass index (LVMI) was calculated. Pathomorphological changes of the left ventricle were observed through hematoxylin-eosin staining and transverse diameter of myocardium (TDM) was measured by eyepiece micrometer under microscope (×400). Results: 1 In hemodynamics experiment, compared to solvent control group, no obviously change in HR was found, but LVSP and LVEDP in all treatment groups were significantly decreased. LVSP was 232.8±15.5mmHg, 213.6±10.9 mmHg, 212.2±13.3 mmHg, 214.9±10.4 mmHg in solvent control group, (Rac)-m-Nis group(P<0.05), (S)-m-Nis group(P<0.05) and (R)-m-Nis group(P<0.05) respe ctively. There was no statistic discrepancy among of treatment groups (P>0.05). LVEDP was 13.5±4.6 mmHg, 7.4±3.9 mmHg, 7.1±4.1 mmHg, 6.2±3.0 mmHg in solvent control group, (Rac)-m-Nis group(P<0.05), (S)-m-Nis group(P<0.05) and (R)-m-Nis group(P<0.05) respectively, there was no statistic discrepancy among drug-treated groups (P>0.05). There were little changes in tdp/dt and±dp/dtmax in all m-Nis groups (P>0.05).2 The pathological damages of left ventricle in solvent control group were characterized by severe proliferation of left ventricular myocardium, myocyte hypertrophy, number of nucleus increased, cardiac muscle fiber twisted, and significant interstitial fibrosis, which were greatly improved by drug administration.3 Left ventricle mass index (LVMI) was 3.25±0.18mg/kg in solvent control group, which was higher (P<0.05) than that in (Rac)-m-Nis group (3.02±0.14mg/kg), (S)-m-Nis group (3.02±0.17mg/kg) and (R)-m-Nis group (2.90±0.12mg/kg). Transverse diameter of myocardium (TDM) in (Rac)-m-Nis group, (S)-m-Nis group and (R)-m-Nis group was significantly decreased compared with that in solvent control group (P<0.05).Conclusion: The (Rac)-m-Nisoldipine, (S)-m-Nisoldipine and (R)-m-Nisoldipine all could relieve left ventricular hypertrophy, decrease interstitial fibrosis and improve cardiac systolic and diastolic function. The pharmacological effect and potency were similar.