Antihypertensive and cardioprotective effects of different monotherapies and combination therapies in young spontaneously hypertensive rats – A pilot study

Abstract

Spontaneously hypertensive rats (SHR) are an established animal model for antihypertensive treatment. The aim of this pilot study was a systematic search for two lines of antihypertensive treatment – a monotherapy and a combination of two drugs – to be applied in a future study on old SHR. Originally, representatives of three drug classes recommended for antihypertensive therapy in humans should be applied, namely captopril (CAP) as an antagonist of the renin-angiotensin-aldosterone system, nifedipine (NIF) as calcium channel blocker and propranolol (PROP) as β-adrenergic blocker. As we observed that PROP had been poorly ingested, all groups with PROP therapy were excluded from the study. CAP (60 mg kg −1 d -1 ), NIF (10 mg kg −1 d -1 ) or both were administered orally to seven-week-old SHR over 3 weeks. A further group of SHR received no treatment (SHR/CTRL). Age-matched normotensive Wistar-Kyoto rats served as normotensive controls. We examined the effect of the antihypertensive therapies on systolic blood pressure, heart weight and on histological and biochemical markers of cardiac hypertrophy and fibrosis. CAP proved to be the most effective treatment reducing blood pressure and relative heart weight significantly compared to SHR/CTRL without reaching normotensive values. Beginning cardiac fibrosis observed in SHR/CTRL was completely abrogated with CAP treatment. Similar effects were achieved with a combination of CAP and NIF. CAP as monotherapy and CAP + NIF as combination therapy were chosen for the forthcoming study on old SHR.

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

“…In SHR, hypertension develops in a very early period of life. Seven-week-old SHR showed 50% higher SBP values than normotensive Wistar-Kyoto rats (WKY) of the same age, and during the following three weeks, their SBP increased significantly to almost 170% of WKY [ 14 ]. During this early stage, SHR developed functional and morphological vascular changes [ 22 , 23 ] which are associated with vascular hypertrophy and increasing vascular resistance, thus leading to cardiac pressure overload [ 24 ].…”

“…A ribonuclease protection assay was performed as previously described [ 14 ] to determine mRNA expression of atrial natriuretic peptide (ANP), transforming growth factor-β 1 (TGF-β 1 ), TGF-β 2 and TGF-β 3 , matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinases 2 (TIMP-2) and collagen types I (Coll I) and III (Coll III) in the LV.…”

“…For the evaluation of cardiac fibrosis, sections were examined with an Axioscope microscope (Carl Zeiss, Oberkochen, Germany), digitized with AxioCam MRc 5 (Carl Zeiss, Oberkochen, Germany) and evaluated using the Photoshop CS6 image processing program. A score ranging from 0 to 3 was applied to assess the histological degree of fibrosis: 0 = no signs of fibrosis; 0.5 = marginal perivascular fibrosis and/or marginal interstitial fibrosis; 1 = perivascular fibrosis + mild interstitial fibrosis; 2 = perivascular fibrosis + moderate interstitial fibrosis; 3 = fibrosis of the entire heart [ 14 ].…”

“…However, even if antihypertensive therapy is well-adjusted and controlled, a late-onset treatment may be less effective than a treatment started in the very early stages of hypertension. Studies in SHR showed that antihypertensive treatment starting in a very early phase of life (between four and 10 weeks of age) reduced blood pressure (BP) even to normotension [ 3 , 12 ] and prevented left ventricular hypertrophy and fibrosis [ 7 , 13 , 14 ]. In contrast, the same treatment starting at a later stage of life (24 to 30 weeks of age) had a much lower antihypertensive effect [ 3 , 15 ].…”

“…Specifically, captopril (CAP) as an antagonist of the RAAS and nifedipine (NIF) as a calcium channel blocker were applied. CAP as monotherapy and a combination of CAP and NIF proved to be the most effective treatments with respect to BP lowering and to preventing cardiac hypertrophy and fibrosis [ 14 ]. These two therapeutic regimens were chosen for the present study to treat 60-week-old SHR over a period of 22 weeks.…”