How Effective Is a Late-Onset Antihypertensive Treatment? Studies with Captopril as Monotherapy and in Combination with Nifedipine in Old Spontaneously Hypertensive Rats

Abstract

Background: A major problem in the treatment of human hypertension is the late diagnosis of hypertension and, hence, the delayed start of treatment. Very often, hypertension has existed for a long time and cardiac damage has already developed. Therefore, we tested whether late-onset antihypertensive treatment is effective in lowering blood pressure (BP) and in reducing or even preventing left ventricular hypertrophy and fibrosis. Methods: Twenty-one male 60-week-old spontaneously hypertensive rats (SHR) were included. Fourteen rats received oral treatment with captopril (CAP) either as monotherapy or combined with nifedipine (CAP + NIF) over 22 weeks. Seven untreated SHR served as controls. We examined the therapeutic effects on BP, heart weight and histological and biochemical markers of left ventricular remodeling and fibrosis. Results: At 82 weeks of age, BP was reduced in the CAP and CAP + NIF groups by 44 and 51 mmHg, respectively (p < 0.001), but not in untreated controls. Despite the late therapy start, cardiac hypertrophy and fibrosis were attenuated compared to controls. Both treatments reduced heart weight by 1.2 mg/g (25%, p = 0.001) and collagens I and III by 66% and 60%, respectively (p < 0.001), thus proving nearly equivalent cardioprotective efficacy. Conclusion: These data clearly emphasize the benefit of antihypertensive treatment in reducing BP and mitigating the development of cardiac damage even when treatment is started late in life.

Keywords: ECM markers; LV hypertrophy; antihypertensive therapy; blood pressure monitoring; cardiac fibrosis; old SHR.

Figure 1

Systolic blood pressure of old SHR expressed as mean ± SEM at baseline (60 weeks of age; hatched columns) and at the final measurement after 22 weeks of experiment (82 weeks of age; filled columns). Significance marks: # significant vs. baseline measurement (p < 0.001); * significant vs. CTRL (p < 0.001).

Figure 2

(a): Heart weight-to-body weight ratio (HW/BW; in mg/g) expressed as mean ± SEM; (b): mRNA expression of atrial natriuretic peptide (ANP, in % of GAP-DH) expressed as median (line in the box) with 25th/75th percentiles (boxes) and 10th/90th percentiles (whiskers). All values were obtained from 82-week-old SHR. Significance marks: * significant vs. CTRL (p ≤ 0.001).

Figure 3

(a–c): mRNA expression of TGF-β isoforms (in % of GAP-DH) in the LV. (d,e): Protein concentrations of TGF-β₁ and TGF-β₂ (in % of CTRL) in the LV. Data are given as median (line in the box) with 25th/75th percentiles (boxes) and 10th/90th percentiles (whiskers). All values were obtained from 82-week-old SHR. Significance marks: * significant vs. CTRL; Ø significant vs. CAP.

Figure 4

(a,b): MMP-2- and TIMP2 mRNA expression (in % of GAP-DH) in the LV. (c): MMP-2 activity (in % of CTRL) in the LV. Data are given as median (line in the box) with 25th/75th percentiles (boxes) and 10th/90th percentiles (whiskers). All values were obtained from 82-week-old SHR. Significance marks: * significant vs. CTRL.

Figure 5

Coll I (a) and Coll III (b) mRNA expression (in % of GAP-DH) in the LV. Data are given as median (line in the box) with 25th/75th percentiles (boxes) and 10th/90th percentiles (whiskers). All values were obtained from 82-week-old SHR. Significance marks: * significant vs. CTRL (p < 0.001).

Figure 6

Hearts of 82-week-old CTRL and treated SHR in trichrome staining (10-fold magnification; the scale bar in part C represents 0.1 mm). (A): CTRL, perivascular and marked interstitial fibrosis, fibrosis degree of the group 2.3 ± 0.11; (B): CAP, perivascular and slight interstitial fibrosis, fibrosis degree of the group 1.8 ± 0.05; (C): CAP + NIF, perivascular and interstitial fibrosis, fibrosis degree of the group 2.1 ± 0.07 (data are given as means ± SEM).