Creatine kinase inhibition lowers systemic arterial blood pressure in spontaneously hypertensive rats

Karamat, Fares A.; Oudman, Inge; Haan, Yentl C.; Kuilenburg, André B. P.; Leen, René; Danser, Jan; Leijten, Frank; Ris‐Stalpers, Carrie; Montfrans, Gert A. van; Clark, Joseph F.; Brewster, Lizzy M.

doi:10.1097/hjh.0000000000001090

Cited by 19 publications

(51 citation statements)

References 42 publications

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“…High CK might lead to greater ATP buffer capacity for renal sodium retention regardless of ancestry or ethnicity . The findings of this study add to the body of evidence indicating that CK enhances ATP buffer capacity near ATPases, resulting in higher blood pressure . We previously showed that human vascular contractility is CK‐dependent and that CK expression in resistance arteries has a near‐perfect correlation with blood pressure .…”

Section: Discussionsupporting

confidence: 55%

“…High skeletal muscle CK activity is associated with a predominance of “fast” type II fibers, lower oxidative capacity, and capillary rarefaction, which may contribute to increased peripheral resistance and blood pressure . Thus, the aggregated evidence indicates that high CK activity may enhance ATP buffer capacity in different tissues and facilitate the development of hypertension . In line with this, high resting plasma CK correlates with failure of antihypertensive therapy and treatment with an oral systemic CK inhibitor reduces blood pressure in spontaneously hypertensive rats, with evidence of attenuated vascular contractility and sodium retention …”

Section: Discussionmentioning

confidence: 86%

“…In summary, our data indicate that participants with high CK activity display reduced urinary sodium excretion after a high sodium diet. CK is known to promote high blood pressure through greater vascular contractility, and to regenerate ATP near tubular Na + /K + ‐ATPase for sodium transport . Wide interindividual variation in cellular CK activity and inherent variation in capacity to promote molecular motor activity is rather unique to humans, and this has clearly been shown to affect human cellular function .…”

Section: Discussionmentioning

confidence: 99%

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Creatine kinase and renal sodium excretion in African and European men on a high sodium diet

Brewster

Oudman

Panday

et al. 2018

J of Clinical Hypertension

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-ATPase driven sodium retention throughout the kidney. Therefore, we assessed whether resting plasma CK is associated with sodium retention after a high sodium diet. Sixty healthy men (29 European and 31 African ancestry) with a mean age of 37.2 years (SE 1.2) were assigned to low sodium intake (< 50 mmol/d) during 7 days, followed by 3 days of high sodium intake (> 200 mmol/d). Sodium excretion (mmol/24-h) after high sodium was 260.4 (28.3) in the high CK tertile versus 415.2 (26.3) mmol/24-h in the low CK tertile (P < .001), with a decrease in urinary sodium excretion of 98.4 mmol/24-h for each increase in log CK, adjusted for age and African ancestry. These preliminary results are in line with the energy buffering function of the CK system, but more direct assessments of kidney CK will be needed to further establish whether this enzyme enhances sodium sensitivity.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Creatine kinase and renal sodium excretion in African and European men on a high sodium diet

Brewster

Oudman

Panday

et al. 2018

J of Clinical Hypertension

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“…Animal and human studies found that plasma and tissue CK activity was a main determinant of blood pressure and of resistance artery contractility, while hypertension was found to be more severe in individuals with high plasma CK activity . In addition, the creatine analogue and competitive CK inhibitor GPA safely and reversibly reduced blood pressure in spontaneously hypertensive rats . Therefore, the CK enzyme system is a potential target for lowering blood pressure in humans with high plasma CK activity.…”

Section: Discussionmentioning

confidence: 99%

The acute effect of beta‐guanidinopropionic acid versus creatine or placebo in healthy men (ABC‐Trial): A randomized controlled first‐in‐human trial

Karamat

Horjus

Haan

et al. 2017

Brit J Clinical Pharma

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AimsIncreasing evidence indicates that the ATP‐generating enzyme creatine kinase (CK) is involved in hypertension. CK rapidly regenerates ATP from creatine phosphate and ADP. Recently, it has been shown that beta‐guanidinopropionic acid (GPA), a kidney‐synthesized creatine analogue and competitive CK inhibitor, reduced blood pressure in spontaneously hypertensive rats. To further develop the substance as a potential blood pressure‐lowering agent, we assessed the tolerability of a sub‐therapeutic GPA dose in healthy men.MethodsIn this active and placebo‐controlled, triple‐blind, single‐centre trial, we recruited 24 healthy men (18–50 years old, BMI 18.5–29.9 kg m−2) in the Netherlands. Participants were randomized (1:1:1) to one week daily oral administration of GPA 100 mg, creatine 5 g, or matching placebo. The primary outcome was the tolerability of GPA, in an intent‐to‐treat analysis.ResultsTwenty‐four randomized participants received the allocated intervention and 23 completed the study. One participant in the placebo arm dropped out for personal reasons. GPA was well tolerated, without serious or severe adverse events. No abnormalities were reported with GPA use in clinical safety parameters, including physical examination, laboratory studies, or 12‐Lead ECG. At day 8, mean plasma GPA was 213.88 (SE 0.07) in the GPA arm vs. 32.75 (0.00) nmol l−1 in the placebo arm, a mean difference of 181.13 (95% CI 26.53–335.72).ConclusionIn this first‐in‐human trial, low‐dose GPA was safe and well‐tolerated when used during 1 week in healthy men. Subsequent studies should focus on human pharmacokinetic and pharmacodynamic assessments with different doses.

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“…The blood pressure was measured using an indirect blood pressure meter (Softron Biotechnology, Beijing, China). During the measurement of the blood pressure, we tried to minimalize stress for the animals (Karamat et al, 2016).…”

Section: Grouping and Experimental Protocolmentioning

confidence: 99%

Magnolol Reduces Renal Ischemia and Reperfusion Injury via Inhibition of Apoptosis

et al. 2017

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Magnolol, a constituent of the bark of Magnolia officinalis, has been reported to decrease myocardial stunning and infarct size. In this study, we investigated whether magnolol can reduce renal ischemia and reperfusion (I/R) injury. Renal I/R, induced by a 60-min occlusion of bilateral renal arteries and a 24-h reperfusion, significantly increased blood urea nitrogen (BUN) and creatinine levels, and caused histological damage to the kidneys of rats. Apoptosis, as evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and caspase-3 activation, was significantly increased in the kidneys. Furthermore, serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were significantly elevated, while the interleukin-10 (IL-10) level was suppressed. However, intravenous pretreatment with magnolol at doses of 0.003 mg/kg and 0.006 mg/kg 10 min before renal I/R significantly limited the increases of BUN, creatinine, the histological damage, and apoptosis in the kidneys. The increases in TNF-α, IL-1β, and IL-6, and the decrease in IL-10 were also significantly inhibited. Additionally, magnolol increased Bcl-2 and decreased Bax in the kidneys. Phosphorylation of the prosurvival kinases, including Akt and extracellular signal-regulated kinases 1 and 2 (ERK1/ 2), was elevated, while phosphorylation of the pro-apoptotic mitogen-activated protein kinases, including p38 and c-Jun N-terminal kinase (JNK), was suppressed. In conclusion, magnolol reduces renal I/R injury. The underlying mechanisms for this effect might be related to the prevention of apoptosis, possibly via the inhibition of both extrinsic and intrinsic apoptotic pathways, including the reduction of TNF-α production and the modulation of pro-and anti-apoptotic signaling elements.

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Creatine kinase inhibition lowers systemic arterial blood pressure in spontaneously hypertensive rats

Abstract: 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.

Cited by 19 publications

References 42 publications

Creatine kinase and renal sodium excretion in African and European men on a high sodium diet

Creatine kinase and renal sodium excretion in African and European men on a high sodium diet

The acute effect of beta‐guanidinopropionic acid versus creatine or placebo in healthy men (ABC‐Trial): A randomized controlled first‐in‐human trial

Magnolol Reduces Renal Ischemia and Reperfusion Injury via Inhibition of Apoptosis

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