A continued study on the bisoprolol and isosorbide dinitrate transdermal patches:cardiovascular protection in spontaneously hypertensive rats

The objective of the present study is to examine cardiovascular protective action of a newly developed transdermal patch by incorporating bisoprolol and isosorbide dinitrate in spontaneously hypertensive rats. As the combination therapy with these two synergistic drugs at low doses through a suitable form of administration could provide optimal therapeutic benefit, we further evaluated the effects of a 42 d period of anti-hypertensive treatment in spontaneously hypertensive rats. Rats were divided into the following five groups： control （blank patch）, bisoprolol fumarate tablets （BP-FT, 20.0 mg/kg, i.g.）, bisoprolol transdermal patch （BP-TP, 20.0 mg/kg）, isosorbide dinitrate transdermal patch （ISDN-TP, 20.0 mg/kg）, and the combination of BP and ISDN in a transdermal patch at low doses （8 and 12 mg/kg, respectively）. The effects of treatment were evaluated via biochemical indicators related to cardiovascular protection, structure and function. The combination therapy had synergistic anti-hypertensive effects and significantly reduced blood pressure with the benefit of controlling blood pressure variability compared to BP-FT and BP-TP. The combined treatment also reduced heart rate as well as BP-FT and BP-TP, while ISDN-TP had no evident effects on blood pressure, heart rate, and cardiovascular protection. Combination therapy was superior to BP-TP and BP-FT at increasing blood atrial natriuretic peptide and nitric oxide, while also reducing cardiac hydroxyproline and endothelin-1 with no difference in blood endothelin-1 and cardiac malondialdehyde levels. Cardiovascular remodeling differed among the groups, with the combination therapy reducing cardiac hypertrophy and the aortic media/lumen ratio. The consequential improvements in relaxation in response to cumulative concentrations of acetylcholine may explain the associated improvement in endothelial function. Combi- nation treatment with a transdermal patch exhibited a synergistic therapeutic effect. Such favorable cardiovascular effects with nitric oxide donors and β-blockade combination through a transdermal patch may provide long-term cardiovascular protection during anti-hypertensive treatment.

Quantitative Evaluation of the Antiischemic Effect of Isosorbide Dinitrate

Objectives To evaluate the anti- ischemic effect of ISDN on the patients with coronary heart disease . The change in the size of the defect area as percentage of the entire myocardium as determined by the unfolded surface mapping between the baseline and after ISDN infusion reflects the anti-ischemic effect of ISDN. Methods and Results 99m Tc-MIBI myocardial perfusion SPECT images were acquired, and reconstruction of the bull's eye map and unfolded surface mapping were performed according to the dates of tomography images. In the group (99mTc-MIBI was injected at 30 minutes after the start of ISDN iv drip) : at the 65% threshold value, the percentage of the defect area size in the whole ventricle was 33.01 ± 5.35% at baseline, (28.9 ±5.23)% after ISDN was infused (P < 0.05); at the 55% threshold value, the percentage of the defect area size in the whole ventricle was (22.06±5.58)% at baseline, (19.60±4.07)% after ISDN was infused (P < 0.05); the sum of defect blood ST segments is 60 at baseline, 51 after ISDN was infused. In the group (99mTc-MIBI was injected at 60 minutes after the start of ISDN iv drip): at the 65% threshold value, the percentage of the defect area size in the whole ventricle was (29.20±5.08)% at baseline, (20.81±4.16)% after ISDN was infused (P < 0.001); at the 55% threshold value, the percentage of the defect area size in the whole ventricle was (21.2 ± 5.49)% at baseline, (17.52±5.59)% after ISDN was infused (P < 0.001); the sum of defect blood ST segments is 58 at baseline, 47 after ISDN was infused. In the group (99mTc-MIBI was injected at 150 minutes after the start of ISDN iv drip) : at the 65% threshold value, the percentage of the defect area size in the whole ventricle was (32.87 ±6.46)% at baseline, (20.81±4.16)% after ISDN was infused (P < 0.001); at the 55% threshold value, the percentage of the defect area size in the whole ventricle was (18.42± 5.17)% at baseline, (14.18±3.61)% after ISDN was infused (P< 0.001); the sum of defect blood ST segments was 64 at baseline, 41 after ISDN was infused. Conclusions The unfolded surface mapping of 99mTc- MIBI myocardial perfusion image can be used as a method of quantitatively evaluating the anti-ischemic effect of drugs and ISDN iv drip can improve the blood flow in myocardium (myocardium perfusion).

Lack of nitrate tolerance in isosorbid dinitrate- and sodium nitroprusside-induced relaxation of rabbit internal anal sphincter

AIM: To investigate the tolerance development against the relaxant effect of nitric oxide donating drug isosorbide dinitrate (ISDN) and sodium nitropruside (SNP) in internal anal sphincter (IAS) smooth muscle. METHODS: Relaxation responses of ISDN, and electrical fi eld stimulation (EFS) were obtained before and after tolerance induction by ISDN incubation. RESULTS: ISDN (10-7-10-4 mol/L) and SNP (10-8-10-4 mol/L) caused a concentration-dependent relaxation on the basal tonus of the isolated rabbit IAS strips. After a period of 2 h incubation of the 6 x 10-4 mol/L ISDN the relaxation effects of ISDN and SNP did not change compared to control strips. EFS evoked frequency-dependent relaxation in internal anal sphincter smooth muscle and Emax obtained from control strips were not changed in ISDN tolerance-inducing condition. In this study nitrate tolerance was not observed in rabbit IAS smooth muscle. CONCLUSION: This result shows that nitric oxide donating drugs relaxes the internal anal sphincter of the rabbits without the development of tolerance.

Nitroester drug's effects and their antagonistic effects against morphine on human sphincter of Oddi motility

AIM: To evaluate the effects of nitroester drugs on human sphincter of Oddi (SO) motility and their antagonistic effects against morphine which shows excitatory effect on Oddi's sphincter motility.METHODS: The effects of these drugs on SO were evaluated by means of choledochofiberoscopy manometry.A total of 67 patients having T-tubes after cholecystectomy and choledochotomy were involved in the study, they were randomly divided into glyceryl trinitrate (GTN) group,isosorbide dinitrate (ISDN) group, pentaerythritol tetranitrate (PTN) group, morphine associated with GTN group, morphine associated with ISDN group and morphine associated with PTN group. Basal pressure of Oddi's sphincter (BPOS), amplitude of phasic contractions (SOCA), frequency of phasic contractions (SOF), duration of phasic contractions (SOD), duodenal pressure (DP) and common bile duct pressure (CBDP) were scored and analyzed. Morphine was given intramuscularly while nitroester drugs were applied sublingually.RESULTS: BPOS and SOCA decreased significantly after administration of ISDN and GTN, BPOS reduced from 10.95±7.49 mmHg to 5.92±4.04 mmHg (P＜0.05) evidently after application of PTN. BPOS increased from 7.37±5.58mmHg to 16.60±13.87 mmHg, SOCA increased from 54.09±38.37 mmHg to 100.70±43.51 mmHg, SOF increased from 7.15±3.20 mmHg to 10.38±2.93 mmHg and CBDP increased 3.75±1.95 mmHg to 10.49±8.21 mmHg (P＜0.01)evidently after injection of morphine. After associated application of ISDN and GTN, the four indications above decreased obviously. As for application associated with PTN,SOCA and SOF decreased separately from 100.64±44.99mmHg to 66.17±35.88 mmHg and from 10.70±2.76 mmHg to 9.04±1.71 mmHg (P＜0.05) markedly.CONCLUSION: The regular dose of GTN, ISDN and PTN showed inhibitory effect on SO motility, morphine showed excitatory effect on SO while GTN, ISDN and PTN could antagonize the effect of morphine. Among the three nitroester drugs, the effect of ISDN on SO was most significant.

A Clinical Investigation on Tong Xin Luo Capsule in Treatment of Coronary Heart Disease with Silent Myocardial Ischemia

36 cases of coronary heart disease with silent myocardial ischemia (SMI) were treated sequentially with Tong Xin Luo (TXL) capsule and isosorbide dinitrate in random order. The results showed that both drugs were effective in decreasing episodes of SMI and shortening the duration of asymptomatic myocardial ischemia. TXL, however, was found with a better action and was superior to isosorbide dinitrate. It was also found that TXL could improve diastolic function of the left ventricle as well.