Studies Of Antihypertensive Drugs On Blood Pressure And Blood Pressure Variability In Sinoaortic-denervated Rats

Aterial baroreflex (ABR) pay an important role in the regulation of cardiovascular activities. The main physiological function maintains stability of blood pressure in a given extent. However, blood pressure is not constant, it can vary spontaneously. This variation is defined as blood pressure variability (BPV). Recent studies indicate that BPV is increased in hypertensive humans and animals. Furthermore, BPV is positively related to the severity of organ damage in hypertensive humans and animals. Therefore, reduction of BPV might represent a new strategy for the treatment of hypertension. The present work was designed to observe the effects of antihypertensive drugs on blood pressure and blood pressure variability in conscious, freely moving sinoaortic denervated rats (SAD). Furthermore, the mechanisms of reduction of BPV for antihypertensive drugs and elucidation of BPV were investigated in this dissertation.The studies demonstrate that SAD significantly increased blood pressure variability about 2 times without modification on blood pressure level compared with sham-operated rats. The doses of the four drugs were as follows: nifedipine (1.5, 3.0 mg/kg), captopril (50, 100 mg/kg), atenolol (10, 20 mg/kg) and hydrochlorothiazide (20, 40 mg/kg). They were administered via intra-gastric catheter. The decrease in blood pressure level induced by the four tested drugs was larger in SAD rats than in sham-operated rats, which arrived about 10 mmHg. Heart period was not changed by the treatment of captopril but prolonged by atenolol in both sham-operated and SAD rats. In sham-operated groups, treatment of both nifedipine and hydrochlorothiazide decreased heart period. Whereas in sinoaortic denervated ones, this tachycardia was prevented. Among the four tested drugs, it was found that only nifedipine and atenolol significantly decreased blood pressure variability in SAD rats. These results indicated that arterial baroreflex function was able to attenuate the hypotensive effects produced by antihypertensive drugs in conscious rats.Nitrendipine 5 mg/kg, amlodipine 1 mg/kg, clonidine 10ug/kg and prazosin 0.5 mg/kg were given via a catheter respectively implanted into the stomach. It was found that these four drugs significantly decreased BP and BPV in SAD rats. However, telmisartan 20 mg/kg only decreased significantly BP in SAD rats. There was no significantly change of BPV for telmisartan. Therefore, calcium antagonists and sympathetic inhibitors decreased BPV in SAD rats.The studies of the combination of nifidipine and captopril (3+100mg/kg), nifidipine and atenolo (3+10mg/kg), nifidipine and hydrochlorothiazide(3+20mg/kg), and nitrendipine and captopril(5+100mg/kg) were shown that BP and BPV were significantly lower in these four groups than these drugs alone. The results of q values showed that there was significant synergism between calcium antagonists and others drugs in lowering and stabilizing BP in SAD rats.BP and BPV were significantly decreased by constant infusion of atenolol (62.Sug/kg/min) and amlodipine (6.25ug/kg/min) in SHR rats. Furthermore, BPV was reduced when BP was maintained at control levels by simultaneous infusions of atenolol, amlodipine and phenyle, phrine. Analysis of covariance demonstrated the decrease in BPV was no correlation with the decrease in BP.Finally, clock genes (per2 and BMAL1) and AT1 receptor mRNA expression were examined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The expression of per2 and BMAL1 mRNA were lower in SAD rats than in sham-operated rats. Furthermore, per2 and BMAL1 mRNA showed attenuated circadian expression in SAD rats. However, central AT1 receptor expression was higher in SAD rats than in sham-operated rats, especially during the light phase in the SAD rats. It could be indicated that abnormal blood pressure fluctuation in SAD may involve in impaired circadian rhythms of clock genes through renin-angiotensin system.In summary, calcium antagonists and sympathetic inhibitors decreased BPV in SAD rats. This provides theoretical and experimental evidence to treat hypertension with antihypertensive drugs.