Synergsim Of Two Different Antihypertensive Agents On Lowering, Stabilizing Blood Pressure And Preventing From End Organ Damage In Hypertensive Rats

INTRODUCTIONCardiovascular disease (CVD), including stroke, is the most common cause of death and disability in developed countries, and hypertension is one of the most important modifiable risk factors for these outcomes. The relationship between blood pressure (BP) and CVD mortality is positive, strong, continuous, graded, and predictive, for those with or without coronary heart disease, and it increases with age. Abundant clinical trial data indicate that lowering BP with antihypertensive drugs effectively reduces risk of a variety of CVD outcomes, including cardiovascular death, as well as total mortality. Outcome benefits have been seen with BP-lowering regimens based on thiazide-type diuretics or β-adrenergic receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, or angiotensin receptor blockers (ARBs).Notably, randomized controlled trials have shown that singledrug treatment usually is not adequate to achieve goal BPs in most hypertensive patients, particularly those with systolic hypertension. For persons with BP >20/10 mmHg above goal, initial treatment with 2 drugs, usually including a thiazide-type diuretic, is recommended by JNC 7 because of the high risk of this patient group.High BP level is not the unique factor determining hypertensive end-organ damage. It has been proposed that blood pressure variability (BPV) may be an important factor determining end organ damage in hypertension. In addition, arterial baroreflex dysfunction is another feature of hypertension. It has been well recognized that BRS is impaired in hypertensive humans and animals. Combination antihypertensive drugs simplify dosing regimens, improve compliance, improve hypertension control, decrease dose-dependent side-effects, and reduce cost as the first-line treatment of hypertension. We have find combination therapy may represent an optimal way to control BPV, including hydrochlorothiazide, reserpine;atenolol and amlodipine, markedly reduced BPV in SHRs.This work was designed to investigate ? the possible synergism of hydrochlorothiazide and nitrendipine on lowering blood pressure and blood pressure variability (BPV) in spontaneously hypertensive rats (SHR). (2) the possible synergism of hydrochlorothiazide and enalapril on lowering blood pressure, blood pressure variability (BPV) and the organ protection of long-term treatment with combination of hydrochlorothiazide and enalapril in spontaneously hypertensive rats (SHR). (3) the possible synergism of atenolol and amlodipine on lowering blood pressure blood pressure variability (BPV) and the organ protection of long-term treatment with combination of hydrochlorothiazide and enalapril in spontaneously hypertensive rats (SHR), deoxycorticosterone acetate (DOCA) rats, two kidney one clipper (2K1C) rats and Lyon hypertensive strain (LH) rats.METHODSAt first, seventy SHR were randomly divided into 7 groups. They were respectively given 0.8% carboxymethylcellulose sodium (control), hydrochlorothiazide (10, 20 mg/kg), nitrendipine (5, 10 mg/kg) and the combinations of hydrochlorothiazide and nitrendipine (10 + 5, 20 + 10 mg/kg). The drugs were given via a catheter of gastric fistula. Blood pressure was recorded from one hour before drug administration for 5 hours in conscious freely moving rats.Secondly, seventy SHR were randomly divided into 7 groups. They were respectively given 0.8% carboxymethylcellulose sodium (control), hydrochlorothiazide (10 mg/kg), enalapril (2, 4, 8 mg/kg) and the combinations of hydrochlorothiazide and enalapril (10 + 2, 10 + 4, 10 + 8 mg/kg). The drugs were given via a catheter of gastric fistula. Blood pressure was recorded from one hour before drug administration for 5 hours in conscious freely moving rats. From probability sum analysis, it was found that the combination of hydrochlorothiazide and enalapril with a proportion of 5:2 was the best combination. To study the effect of the organ protection of long-term treatment with combination of hydrochlorothiazide and enalapril in SHR. Sixty SHR were randomly divided into 6 groups. Normal dietwithout drugs (control), hydrochlorothiazide (7.5 mg/kg), enalapril (3mg/kg) and the combinations of hydrochlorothiazide and enalapril (3.75+ 1.5, 7.5 + 3, and 15 + 6 mg/kg/d) were given in rat chow for 16 weeks in SHR. Blood pressure (BP) was then recorded during 4 hours in conscious state. After the determination of baroreflex sensitivity, rats were killed for organ-damage evaluation.Thirdly, fifty SHR, DOCA, 2K1C, LH respectively were randomly divided into 5 groups. Normal diet without drugs (control), atenolol (lOmg/kg), amlodipine (lmg/kg) and the combinations of atenolol and amlodipine (5 + 0.5,10 + 1 mg/kg/d) were given in rat chow for 16 weeks Blood pressure (BP) was then recorded during 6 hours in conscious state. After the determination of baroreflex sensitivity, rats were killed for organ-damage evaluation.RESULTSWhen either hydrochlorothiazide or nitrendipine was used alone with low dose (lOmg/kg, 5mg/kg) could not decrease SBP obviously whereas combination of these two drugs significantly decreased SBP and DBP values in SHR. A synergistic effect on SBP and DBP reduction was found in combination therapy (q=l.S6 for SBP). The present work found that combination of these two drugs could prolong the effective time in evidence when they were used alone and might be more effective in control of BPV than monotherapy. A synergistic effect on SBPV reduction was found in combination therapy, (q =1.94 on high dose, 1.79 on low dose)It was found that combination of hydrochlorothiazide and enalapril significantly decreased blood pressure and systolic blood pressure variability. From probability sum analysis, it was found that the combination of hydrochlorothiazide and enalapril with a proportion of 5:2 was the best combination. We found that long-term treatment with the combinations of hydrochlorothiazide and enalapril manifested obvious BP, BPV reduction and organ protection in SHR.In this work, chronic treatment with combination of low-dose amlodipine and atenolol, an obvious synergism decreased on BP, BPV reduction and the organ protection was found in combination therapy in rats (SHR), deoxycorticosteroneacetate (DOCA) rats, two kidney one clipper (2K1C) rats and Lyon hypertensive strain (LH) rats.CONCLUSSIONIn conclusion, short-treatment with a combination of hydrochlorothiazide and nitrendipine possessed an obvious synergism on BP and BPV reduction in SHR. It is promising the combination would also enhancement of BRS and protective end organ in long-term treatment.Short-treatment with a combination of hydrochlorothiazide and enalapril possessed an obvious synergism on BP and BPV reduction in SHR. The synergism is greatest when the dose proportion of the 2 drugs is 5: 2. The combination would also enhance BRS and protective end organ in long-term treatment.We found that long-term treatment with the combinations of atenolol and amlodipine possessed obvious BP and BPV reduction, enhancement of BRS and organ protection in four different types of hypertensive animals.