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Creatine kinase inhibition lowers systemic arterial blood pressure in spontaneously hypertensive rats: a randomized
Fares A Karamat1, Inge Oudman, Yentl C Haan
1aDepartment of Vascular Medicine bLaboratory for Genetic and Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam cDepartment of Vascular Medicine and Pharmacology, Erasmus Medical Center, Rotterdam dDepartment of Obstetrics and Gynaecology and Reproductive Biology Laboratory eDepartment of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands fThe Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, Ohio, USA.
Insights
Creatine kinase inhibition safely lowered blood pressure (BP) in hypertensive rats. This suggests targeting the creatine kinase system may offer a new therapeutic approach for managing hypertension.
Area of Science:
- Biochemistry
- Physiology
- Pharmacology
Background:
- Creatine kinase (CK) is a key predictor of blood pressure (BP).
- CK activity is strongly correlated with resistance artery contractility and renal sodium retention.
- CK rapidly regenerates ATP, crucial for cellular energy balance in pressor responses.
Purpose of the Study:
- To investigate the potential of CK inhibition as a strategy for reducing blood pressure.
- To assess the effects of a specific CK inhibitor on BP in a relevant animal model.
Main Methods:
- A 4-week randomized controlled trial was conducted using spontaneously hypertensive rats.
- Rats received either standard chow or chow supplemented with beta-guanidinopropionic acid (a CK inhibitor).
- Blood pressure was measured using the tail-cuff method; vasodilation and renal renin expression were also assessed.
Main Results:
- Creatine kinase inhibition significantly reduced systolic and diastolic blood pressure compared to controls (P < 0.001).
- The BP reduction was observed to be safe and reversible.
- Evidence of enhanced vasodilation and a diuretic effect were noted in the treatment group.
Conclusions:
- This study provides the first evidence for the blood pressure-lowering effects of creatine kinase inhibition.
- Modulating the creatine kinase system presents a potential novel therapeutic target for hypertension.
- Further research into CK system modulation for hypertension treatment is warranted.
Objective:
Creatine kinase is reported to be a main predictor of blood pressure (BP) in the general population, with a strong correlation between resistance artery creatine kinase expression and clinical BP in humans. The enzyme rapidly regenerates ATP near cytoplasmic ATPases involved in pressor responses, including resistance artery contractility and renal sodium retention. Therefore, we assessed whether creatine kinase inhibition reduces BP.
Methods:
We implemented the 'Animal Research: Reporting of In Vivo Experiments' guideline. In a 4-week randomized controlled trial, male 16-week-old spontaneously hypertensive rats (N = 16) were randomly assigned to the specific competitive creatine kinase inhibitor beta-guanidinopropionic acid (3%)-supplemented chow vs. standard chow. BP measured by the tail-cuff method was the main outcome. Other outcomes included vasodilation in isolated arteries and renal renin expression.
Results:
Creatine kinase inhibition reduced BP safely and reversibly. Mean baseline BP of, respectively, 191.5 (standard error 4.3) mmHg SBP and 143.1 (4.1) mmHg DBP was reduced by, respectively, 42.7 (5.5) mmHg SBP and 35.6 (5.0) mmHg DBP (P < 0.001) compared with controls, with evidence of enhanced vasodilation and a diuretic effect.
Conclusion:
To our knowledge, this is the first report on the BP-lowering effect of creatine kinase inhibition. Our data indicate that modulation of the creatine kinase system is a potential novel treatment target for hypertension.
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