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.

KEYWORDS:

• Amlodipine
• chronopharmacology
• circadian clock genes
• left ventricular hypertrophy
• plasminogen activator inhibitor-1
• spontaneously hypertensive rats (SHR)
• valsartan

Acknowledgments

The authors gratefully acknowledge the excellent technical assistance of Ms. Simona Kolembusova.

Declaration of interest

PP is an employee of Novartis Slovakia S.R.O. Other authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Funding

The work was supported by the following Grants: APVV-15-0685 Theranostic potential of components of alternative RAS in modulation of right ventricular function and dysfunction from the Slovak Research and Development Agency (JK) and Grant 1/0294/15 from the Science Grant Agency (VEGA), Slovak Republic (PK).

Additional information

Funding

The work was supported by the following Grants: APVV-15-0685 Theranostic potential of components of alternative RAS in modulation of right ventricular function and dysfunction from the Slovak Research and Development Agency (JK) and Grant 1/0294/15 from the Science Grant Agency (VEGA), Slovak Republic (PK).