Inge Oudman

The effect of the creatine analogue beta-guanidinopropionic acid on energy metabolism: a systematic review.

Background Creatine kinase plays a key role in cellular energy transport. The enzyme transfers high-energy phosphoryl groups from mitochondria to subcellular sites of ATP hydrolysis, where it buffers ADP concentration by catalyzing the reversible transfer of the high-energy phosphate moiety (P) between creatine and ADP. Cellular creatine uptake is competitively inhibited by beta-guanidinopropionic acid. This substance is marked as safe for human use, but the effects are unclear. Therefore, we systematically reviewed the effect of beta-guanidinopropionic acid on energy metabolism and function of tissues with high energy demands. Methods We performed a systematic review and searched the electronic databases Pubmed, EMBASE, the Cochrane Library, and LILACS from their inception through March 2011. Furthermore, we searched the internet and explored references from textbooks and reviews. Results After applying the inclusion criteria, we retrieved 131 publications, mainly considering the effect of chronic oral administration of beta-guanidinopropionic acid (0.5 to 3.5%) on skeletal muscle, the cardiovascular system, and brain tissue in animals. Beta-guanidinopropionic acid decreased intracellular creatine and phosphocreatine in all tissues studied. In skeletal muscle, this effect induced a shift from glycolytic to oxidative metabolism, increased cellular glucose uptake and increased fatigue tolerance. In heart tissue this shift to mitochondrial metabolism was less pronounced. Myocardial contractility was modestly reduced, including a decreased ventricular developed pressure, albeit with unchanged cardiac output. In brain tissue adaptations in energy metabolism resulted in enhanced ATP stability and survival during hypoxia. Conclusion Chronic beta-guanidinopropionic acid increases fatigue tolerance of skeletal muscle and survival during ischaemia in animal studies, with modestly reduced myocardial contractility. Because it is marked as safe for human use, there is a need for human data.

Creatine kinase is associated with failure of hypertension treatment

Background: Failure of hypertension treatment is a major clinical issue because of the high prevalence and the associated mortality risk. We have reported evidence that creatine kinase increases blood pressure through greater sodium retention and cardiovascular contractility, by rapidly providing ATP for these functions. Therefore, we hypothesized that high creatine kinase is associated with failure of antihypertensive treatment. Method: We analyzed a cross-sectional, random multiethnic sample of the general population (N = 1444), aged 34–60 years. The primary outcome was the independent association between resting serum creatine kinase and treated uncontrolled hypertension in the population, using multinomial logistic regression analysis. Results: Hypertension prevalence was, respectively, 26.8; 30.8; and 41.2% for the lowest (<88 IU/l) through the highest population creatine kinase tertile (>145 IU/l; P < 0.001). Treatment failed in 72.9% of participants within the highest creatine kinase tertile vs. 46.7% within the lowest tertile (P = 0.004). In logistic regression analysis, creatine kinase was the main predictor of treatment failure (adjusted odds ratio 3.7; 95% confidence interval 1.2–10.9), independent of age, sex, BMI, fasting glucose, ethnicity, or education level. Conclusion: Creatine kinase is associated with failure of antihypertensive therapy. Further investigations concerning this association might help improve treatment strategies for difficult-to-treat hypertension.

Resistance Artery Creatine Kinase mRNA and Blood Pressure in Humans

Hypertension remains the main risk factor for cardiovascular death. Environmental and biological factors are known to contribute to the condition, and circulating creatine kinase was reported to be the main predictor of blood pressure in the general population. This was proposed to be because of high resistance artery creatine kinase-BB rapidly regenerating ATP for vascular contractility. Therefore, we assessed whether creatine kinase isoenzyme mRNA levels in human resistance arteries are associated with blood pressure. We isolated resistance-sized arteries from omental fat donated by consecutive women undergoing uterine fibroid surgery. Blood pressure was measured in the sitting position. Vessels of 13 women were included, 6 normotensive and 7 hypertensive, mean age 42.9 years (SE, 1.6) and mean systolic/diastolic blood pressure, 144.8 (8.0)/86.5 (4.3) mm Hg. Arteriolar creatine kinase isoenzyme mRNA was assessed using quantitative real-time polymerase chain reaction. Normalized creatine kinase B mRNA copy numbers, ranging from 5.2 to 24.4 (mean, 15.0; SE, 1.9), showed a near-perfect correlation with diastolic blood pressure (correlation coefficient, 0.9; 95% confidence interval, 0.6–1.0) and were well correlated with systolic blood pressure, with a 90% relative increase in resistance artery creatine kinase B mRNA in hypertensives compared with normotensives, normalized copy numbers were, respectively, 19.3 (SE, 2.0) versus 10.1 (SE, 2.1), P=0.0045. To our knowledge, this is the first direct evidence suggesting that resistance artery creatine kinase mRNA expression levels concur with blood pressure levels, almost doubling with hypertension. These findings add to the evidence that creatine kinase might be involved in the vasculature’s pressor responses.

Hypertension Risk in Dutch Women With Symptomatic Uterine Fibroids

BACKGROUND Female-specific risk factors for cardiovascular disease are understudied. We assessed whether women with uterine fibroids have a greater hypertension risk, independent of the shared risk factors for both conditions. METHODS Blood pressure was measured in women scheduled for fibroid surgery compared to women scheduled for nonfibroid gynecological surgery and women randomly sampled from the general population. We used multivariable binary logistic regression to assess whether hypertension was more common with surgically treated fibroids, independent of age, body mass index, and African ancestry. RESULTS We included 1,342 women (542 of African ancestry), of which 272 scheduled for fibroid surgery, 385 controls scheduled for nonfibroid gynecological surgery, and 685 random population controls, with a mean age (SD) of, respectively, 43.4 (6.6), 41.3 (10.2), and 45.1 (6.6) years; and a mean body mass index (SD) of, respectively, 27.4 (5.3), 25.7 (5.7), and 28.2 (5.6) kg/m(2). Hypertension was found more frequently with surgically treated fibroids, with an occurrence of 41.9% in women with fibroids vs. 27.5% in surgical controls, and 28.3% in population controls (P < 0.001 for fibroids vs. controls). The association with hypertension was independent of age, body mass index, and African ancestry (odds ratio, 2.4; 95% confidence interval, 1.7-3.4). CONCLUSIONS Hypertension risk is higher in Dutch women with surgically treated fibroids than in surgery or population controls, independent of age, body mass index, and African ancestry. Our data add to the body of evidence indicating that women with uterine fibroids are eligible for hypertension screening.

Creatine kinase inhibition lowers systemic arterial blood pressure in spontaneously hypertensive rats: a randomized controlled trial

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.

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

Aims Increasing 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. Methods In 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. Results Twenty‐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). Conclusion In 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.

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

Creatine kinase (CK) rapidly regenerates ATP for Na+/K+‐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.

[OP.LB03.09] THE ACUTE EFFECT OF THE SPECIFIC CREATINE KINASE INHIBITOR BETA- GPA IN HEALTHY MAN (ABC-TRIAL): A RANDOMIZED PLACEBO AND ACTIVE CONTROLLED FIRST-IN-HUMAN TRIAL

Objective: There is increasing evidence that the ATP generating enzyme creatine kinase (CK) is involved in hypertension. The enzyme is central to the regeneration of ATP by using creatine phosphate and ADP, thereby forming creatine and ATP. We recently showed that beta-guanidinopropionic acid (GPA), a creatine analogue and competitive CK inhibitor, effectively and safely reduced blood pressure in the spontaneously hypertensive rat. This renders GPA to be potentially beneficial for blood pressure lowering. However, no human data are available. Therefore, according to FDA and EMEA guidelines, we assessed the tolerability of a subtherapeutic GPA dose in man. Figure. No caption available. Design and method: In this randomized, placebo and active controlled, triple blind, single center trial (randomization 1:1:1), we included healthy male volunteers, 18 to 50 years old, BMI 18.5–29.9 kg/m2, recruited in the Netherlands. The interventions consisted of one week daily oral administration of GPA in a subtherapeutic dose of 100 mg, creatine 5 gram, or placebo. The primary outcome was the tolerability of GPA as a descriptive measure, in an intent-to-treat analysis. Results: Twenty four randomized participants received the allocated intervention (8 in each treatment arm) and 23 completed the study. One participant in the placebo arm dropped out because of an external event in his family. He experienced no side effects, including not during a re-challenge with the assigned drug. GPA was well tolerated. There were no serious or severe adverse events with GPA, creatine and placebo after 1 week of active treatment, and no significant differences in safety measures including self-reported data obtained with structured and unstructured questionnaires. No abnormalities were reported from physical examination, laboratory determined toxicity including kidney and liver parameters, or cardiovascular safety including QT interval between treatment arms (Table 1). Conclusions: To our knowledge, these are the first human data of the specific CK inhibitor and potential new blood pressure lowering agent GPA. We found no evidence of toxicity with subtherapeutic doses, and will proceed to assess safety and tolerance in a dose-escalation trial in humans. Clinical trial registration number The Netherlands National Trial Register (NTR) number 4444, registered March 9, 2014.