Abstract
BACKGROUND
Cardiac hypertrophy and failure are major complications of hypertension.
OBJECTIVES
The beneficial effect of treatment with antihypertensive drugs on serum levels of brain natriuretic peptide (BNP) was examined in patients with essential hypertension.
METHODS
Antihypertensive drugs were administered to 88 hypertensive patients (44 diabetic and 44 nondiabetic) whose systolic blood pressure was greater than 140 mmHg and/or diastolic blood pressure was greater than 90 mmHg. Other antihypertensive drugs were added every two months until the blood pressure fell below 130/85 mmHg. Candesartan, benidipine, bisoprolol or celiprolol, and bunazosin were administered in this order.
RESULTS
The mean systolic blood pressure was reduced from 163.7±11.6 mmHg to 121.8±7.5 mmHg after 12 months in patients with diabetes and from 167.6±12.3 mmHg to 122.8±7.5 mmHg in patients without diabetes. The mean diastolic blood pressure was also significantly reduced in patients with and without diabetes. Serum BNP levels were reduced from 52.2±38.8 pg/mL to 38.8±30.9 pg/mL in patients with diabetes and from 47.1±34.2 pg/mL to 35.8±22.5 pg/mL in patients without diabetes. In patients older than 70 years of age, serum BNP levels were reduced from 56.3±39.3 pg/mL to 40.2±23.0 pg/mL in those with diabetes and from 54.6±32.9 pg/mL to 38.0±16.0 pg/mL in those without diabetes.
CONCLUSIONS
These results indicate that combination therapy with antihypertensive drugs is usually necessary to reduce blood pressure to below 130/85 mmHg and to improve serum BNP levels.
Keywords: Angiotensin II receptor blocker, Brain natriuretic peptide, Calcium antagonist, Combination therapy, Hypertension
The aim of treatment for hypertension is to reduce its complications, such as cerebrovascular and cardiovascular disorders. The cardiovascular disorders are of two major types: cardiac hypertrophy and failure, and ischemic heart disease. Cardiac hypertrophy is thought to be an adaptation to maintain the heart’s pumping function under the pressure overload induced by high blood pressure (1,2). If the severity and/or duration of pressure overload are excessive, cardiac function becomes compromised and heart failure occurs.
Brain natriuretic peptide (BNP) was first found in porcine brain tissue and then later in the myocardium (3,4). The serum BNP level increases when ventricular wall stress is enhanced. Measurement of serum BNP levels is very useful for early diagnosis of heart failure because BNP is secreted from the ventricles and is a specific index reflecting the early stage of myocardial dysfunction and the severity of heart failure (5–7).
Based on guidelines from recent major clinical trials of therapies for hypertension, we treated hypertensive patients with combinations of antihypertensive drugs to obtain blood pressure below 130/85 mmHg, which is the upper limit of normal stipulated in these guidelines (8), and examined the effect of treatment on serum BNP levels. Because hypertensive patients with diabetes mellitus are reportedly more prone to cardiovascular disease than hypertensive patients without diabetes (9), we examined the effects of antihypertensive treatment on the serum BNP levels in both types of patients.
METHODS
Antihypertensive drugs were administered to hypertensive out-patients attending Aoto Hospital, Japan, whose systolic blood pressure was greater than 140 mmHg and/or diastolic blood pressure was greater than 90 mmHg even after diet therapy for at least two months. Candesartan (8 mg, once a day), an angiotensin II receptor blocker, was administered first, and if the blood pressure did not fall below 130/85 mmHg after two months of candesartan treatment, benidipine (4 mg, once a day), a calcium antagonist, was added next. If the blood pressure did not fall below 130/85 mmHg within a further two months after addition of benidipine, the dose of benidipine was increased to 8 mg (once a day). Then, if the blood pressure did not fall below 130/85 mmHg after two further months, celiprolol (200 mg, once a day), a beta1-blocker with intrinsic sympathomimetic action (ISA), was added. In patients whose heart rate was over 80 beats/min or whose electrocardiograph showed ischemic changes, bisoprolol (5 mg, once a day), a beta1-blocker without ISA, was administered instead of celiprolol. If the blood pressure still did not fall below 130/85 mmHg after addition of the beta1-blocker, bunazosin (3 mg, once a day), an alpha1-blocker, was administered.
The serum BNP levels were measured before the start of anti-hypertensive therapy, and at six months and 12 months after the start of therapy, respectively.
Statistical analysis was performed using the paired Student’s t test.
RESULTS
In total, 88 patients were examined: 44 patients with diabetes (average age 64.9 years) and 44 patients without diabetes (average age 64.7 years). All the diabetic patients had type II diabetes and had been treated with oral hypoglycemic agents. Among the patients with diabetes, benidipine was used in 43, beta1-blockers were used in 31 and bunazosin was used in four. Among the patients without diabetes, benidipine was used in 43, beta1-blockers were used in 29 and bunazosin was used in four (Table 1). The average number of antihypertensive agents used was 2.77 in the diabetics and 2.73 in the nondiabetics. In the patients with diabetes after 12 months of treatment, the systolic blood pressure was reduced from 163.7±11.6 mmHg (mean ± SD) to 121.8±7.5 mmHg and the diastolic blood pressure from 93.7±8.2 mmHg to 68.9±5.9 mmHg (Figure 1). In the patients without diabetes, the systolic blood pressure was reduced from 167.6±12.3 mmHg to 122.8±7.5 mmHg and the diastolic blood pressure from 97.2±9.8 mmHg to 73.4±6.8 mmHg (Figure 2). In patients with pretreatment serum BNP levels exceeding 20 pg/mL, which is the normal upper limit, the serum BNP levels were reduced from 52.2±38.8 pg/mL to 38.8±30.9 pg/mL in patients with diabetes and from 47.1±34.2 pg/mL to 35.8±22.5 pg/mL in patients without diabetes (Figure 3). In elderly patients (older than 70 years), the serum BNP levels were also significantly reduced by lowering the blood pressure to below 130/85 mmHg in both those with and without diabetes (Figure 4). The HbA1c levels in blood were not changed by treatment with antihypertensive drugs in patients with diabetes. Hyperlipidemic patients were treated with statins. There were also no significant changes in the levels of serum lipids in patients with or without diabetes.
TABLE 1.
Combination of antihypertensive drugs
| n | |
|---|---|
| Patients with diabetes | |
| Candesartan (8 mg) | 1 |
| Candesartan (8 mg) + benidipine (4 mg) | 2 |
| Candesartan (8 mg) + benidipine (4 mg) + benidipine (4 mg) | 10 |
| Candesartan (8 mg) + benidipine (4 mg) + benidipine (4 mg) + celiprolol (200 mg) | 16 |
| Candesartan (8 mg) + benidipine (4 mg) + benidipine (4 mg) + celiprolol (200 mg) + bunazosin (3 mg) | 4 |
| Candesartan (8 mg) + bisoprolol (5 mg) + benidipine (4 mg) | 2 |
| Candesartan (8 mg) + bisoprolol (5 mg) + benidipine (4 mg) + benidipine (4 mg) | 9 |
| Patients without diabetes | |
| Candesartan (8 mg) | 1 |
| Candesartan (8 mg) + benidipine (4 mg) + benidipine (4 mg) | 14 |
| Candesartan (8 mg) + benidipine (4 mg) + benidipine (4 mg) + bisoprolol (5 mg) | 13 |
| Candesartan (8 mg) + benidipine (4 mg) + benidipine (4 mg) + celiprolol (200 mg) | 8 |
| Candesartan (8 mg) + bisoprolol (5 mg) + benidipine (4 mg) + benidipine (4 mg) | 4 |
| Candesartan (8 mg) + benidipine (4 mg) + benidipine (4 mg) + bisoprolol (5 mg) + bunazosin (3 mg) | 3 |
| Candesartan (8 mg) + bisoprolol (5 mg) + benidipine (4 mg) + benidipine (4 mg) + bunazosin (3 mg) | 1 |
Figure 1.
Effect of antihypertensive drugs on blood pressure (BP) and pulse rate (PR) in hypertensive patients with diabetes mellitus. Vertical lines are ± SD, *P<0.05, ***P<0.0001. Open circles – systolic BP; Closed circles – diastolic BP; × – PR
Figure 2.
Effect of antihypertensive drugs on blood pressure (BP) and pulse rate (PR) in hypertensive patients without diabetes mellitus. Vertical lines are ± SD, *P<0.05, ***P<0.0001. Open circles –systolic BP; Closed circles – diastolic BP; × – PR
Figure 3.
Effect of antihypertensive drugs on serum brain natriuretic peptide levels in hypertensive patients with and without diabetes whose brain natriuretic peptide levels before treatment were over 20 pg/mL. Patients with diabetes are shown in the top panel and patients without diabetes are shown at the bottom. Vertical bars indicate SD
Figure 4.
Effect of antihypertensive drugs on serum brain natriuretic peptide levels in hypertensive patients over 70 years of age with and without diabetes whose brain natriuretic peptide levels before treatment were over 20 pg/mL. Patients with diabetes are shown in the top panel and patients without diabetes are shown at the bottom. Vertical bars indicate SD
DISCUSSION
Recent clinical studies have indicated the importance of lowering blood pressure sufficiently to protect hypertensive patients from cardiovascular complications (10–12). To obtain good control of blood pressure, it has been reported that use of several antihypertensive drugs may be necessary (13,14). Moreover, the pleiotropic effects of antihypertensive drugs are beneficial for treatment of patients with hypertension. We selected candesartan as the first-choice drug for treatment of patients with hypertension because of its potent blood pressure-lowering effect and reduction of cardiac hypertrophy with few undesirable side effects (15,16). The drug has also been reported to be effective for treatment of congestive heart failure (17), and has no unfavourable influence on renal function, glucose metabolism or lipid metabolism (18–21). In our recent study (22) with spontaneously hypertensive rats, long-term administration of candesartan reduced cardiac hypertrophy and serum BNP levels, and ameliorated changes in the myocardial inter-stitium. Benidipine is also a safe drug without serious undesirable effects and has a beneficial effect of lowering blood pressure and reducing cardiac hypertrophy (23). In the present study, addition of benidipine to candesartan effectively lowered blood pressure in our patients. Beta-blockers are reported to have undesirable effects on insulin resistance and lipid metabolism (24,25). Unlike other beta-blockers, celiprolol, which has an ISA and vasodilative effects, improves insulin resistance and lipid metabolism (26). Therefore, it can be used safely for hypertensive patients with diabetes. If patients have ischemic heart disease, beta-blockers without ISA are usually used to decrease heart rate and lower myocardial oxygen consumption, although it may aggravate insulin resistance and lipid metabolism. Bisoprolol is a beta1-blocker without ISA that is reportedly effective for heart failure (27,28). According to a recent clinical study, alpha1-blockers aggravate cardiovascular performance and increase mortality in patients with congestive heart failure (29,30). However, they can be used carefully in some hypertensive patients, such as those with obesity, because they improve insulin resistance and do not affect serum lipid levels (31,32).
In the present study, there were no significant differences between patients with and without diabetes in the number of antihypertensive drugs that were necessary to obtain the target blood pressure. There were also no differences between the two groups in the number of patients who showed abnormal serum BNP levels as well as the levels of serum BNP concentration. However, a greater number of hypertensive patients with diabetes showed ischemic changes in the electrocardiograph than hypertensive patients without diabetes, suggesting that a combination of hypertension and diabetes is associated with more rapid progression of coronary sclerosis than hypertension alone.
Recent reports have indicated the prognostic benefits of blood pressure reduction treatment in elderly hypertensive patients (33–35). Serum BNP levels were significantly reduced by lowering blood pressure sufficiently even in elderly hypertensive patients (older than 70 years). This means that sufficient lowering of blood pressure is necessary even in elderly hypertensive patients for maintaining cardiac performance.
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