mRNA levels of circadian clock components Bmal1 and Per2 alter independently from dosing time-dependent efficacy of combination treatment with valsartan and amlodipine in spontaneously hypertensive rats

Abstract

Chronopharmacological effects of antihypertensives play a role in the outcome of hypertension therapy. However, studies produce contradictory findings when combination of valsartan plus amlodipine (VA) is applied. Here, we hypothesized different efficacy of morning versus evening dosing of VA in spontaneously hypertensive rats (SHR) and the involvement of circadian clock genes Bmal1 and Per2. We tested the therapy outcome in short-term and also long-term settings. SHRs aged between 8 and 10 weeks were treated with 10 mg/kg of valsartan and 4 mg/kg of amlodipine, either in the morning or in the evening with treatment duration 1 or 6 weeks and compared with parallel placebo groups. After short-term treatment, only morning dosing resulted in significant blood pressure (BP) control (measured by tail-cuff method) when compared to placebo, while after long-term treatment, both dosing groups gained similar superior results in BP control against placebo. However, mRNA levels of Bmal1 and Per2 (measured by RT-PCR) exhibited an independent pattern, with similar alterations in left and right ventricle, kidney as well as in aorta predominantly in groups with evening dosing in both, short-term and also long-term settings. This was accompanied by increased cardiac mRNA expression of plasminogen activator inhibitor-1. In summary, morning dosing proved to be advantageous due to earlier onset of antihypertensive action; however, long-term treatment was demonstrated to be effective regardless of administration time. Our findings also suggest that combination of VA may serve as an independent modulator of circadian clock and might influence disease progression beyond the primary BP lowering effect.

Chronopharmacology of high blood pressure—a critical review of clinical evidence

“…With the study length being the only difference between these two studies, this fact might indicate that the duration of treatment can also influence the chrono-effect. Similar results were also confirmed in preclinical settings (Potucek et al, 2017).…”

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“…Potucek, et al evaluated the efficacy of morning versus evening dosing of 10 mg/kg of valsartan and 4 mg/kg of amlodipine in spontaneously hypertensive rats, and observed that only morning dosing resulted in significant BP control after short-term (1 week) treatment while both dosing groups gained similar superior results in BP control after long-term (6 weeks) treatment. This study indicated that morning administration proved to be advantageous due to earlier onset of antihypertensive action whereas the efficacy of longterm treatment was regardless of administration time [52].…”

Recent advances in understanding the circadian clock in renal physiology

“…In this study, single nucleotide polymorphism (SNP) databases were analyzed to discover that SNPs in the Bmal1 gene are associated with hypertension in humans [28]. In a recent study, SHR treated with a combination of a calcium channel blocker and an angiotensin receptor blocker to reduce blood pressure also exhibited a reduction in Bmal1 mRNA levels in the kidneys [29]. Inducible, kidney-specific knockout mice have been studied to determine the role of Bmal1 specifically in renal nephrons using Bmal1 lox/lox/Pax8-rtTA/LC1 mice [30].…”

“…The Hygia Project is an ongoing assessment of a much larger population where clinical reports are analyzed from multiple health facilities [59,60]. Additionally, a recent study in rats used hypertensive therapy in the morning and evening and found that treatment before the inactive period was more beneficial for the rats than before the active [29]. However, this was only seen with short-term treatment of 1 week and no difference was seen with long-term treatment [29].…”

“…Additionally, a recent study in rats used hypertensive therapy in the morning and evening and found that treatment before the inactive period was more beneficial for the rats than before the active [29]. However, this was only seen with short-term treatment of 1 week and no difference was seen with long-term treatment [29]. The American Diabetes Association has acknowledged these results and has even suggested administration of antihypertensive drugs in the evening [61].…”