Abstract
BackgroundThe adenosine triphosphate (ATP) regenerating enzyme creatine kinase (CK) is intimately involved in blood pressure generation. Consequently, the creatine transporter and CK inhibitor beta-guanidinopropionic acid (GPA) successfully reduced blood pressure in 16-week-old spontaneously hypertensive rats (SHR), but GPA may cause growth retardation in juvenile mammals. This report considers a serendipity observation of paradoxical growth increase after using GPA to prevent hypertension in three-week-old SHR.MethodsImplementing the “Animal Research: Reporting of In Vivo Experiments” (ARRIVE) guideline, male, three-week-old spontaneously hypertensive rats (N=22) were randomly assigned to standard soy-based (creatine-free) chow with GPA 0.1% vs control chow during four weeks (primary, t=4w) or six weeks of treatment (t=6w). Blood pressure measured by the tail-cuff method was the main outcome. Other outcomes included body mass and contractility characteristics of isolated arteries.Results Body mass at baseline was 28.4 (SE 0.71) g (n=22). With similar food intake/100 gram animal in both groups, GPA-treated rats (n=11) developed a strikingly larger body size and mass: t=4w, GPA 110.4 g (3.7) vs controls (n=11) 65.0 g (4.8) (+69.8%; p<0.001); t=6w, GPA 154.3 (4.7) vs controls 68.0 (4.7) g. There were no significant differences in cardiovascular parameters including blood pressure.DiscussionAn unexpected increase in body mass and size without concurrent blood pressure increase was observed in juvenile SHR on GPA vs control soy-based chow. It is speculated that the partial creatine agonist activity of GPA contributed to these effects. Further studies are needed to confirm these findings and better understand the impact of modulating energy metabolism in juvenile hypertension-prone mammals.
Highlights
Beta-guanidinopropionic acid (or N-(aminoiminomethyl)-beta-alanine; C4H9N3O2, GPA) is a structural isomer and competitive inhibitor of creatine (C4H9N3O2) [1,2,3]
With similar food intake/100 gram animal in both groups, GPA-treated rats (n=11) developed a strikingly larger body size and mass: t=4w, GPA 110.4 g (3.7) vs controls (n=11) 65.0 g (4.8) (+69.8%; p
adenosine triphosphate (ATP) generated by F1FoATP synthase in the mitochondrial matrix is transported by adenine nucleotide translocase to the mitochondrial intermembrane space, where mitochondrial creatine kinase (CK) catalyzes the formation of phosphocreatine from ATP
Summary
Beta-guanidinopropionic acid (or N-(aminoiminomethyl)-beta-alanine; C4H9N3O2, GPA) is a structural isomer and competitive inhibitor of creatine (C4H9N3O2) [1,2,3]. GPA is used in experimental settings to inhibit the creatine kinase enzyme system (CK, EC 2.7.3.1) [1,2,3]. The enzyme catalyzes the reaction [1]: Phosphocreatine + MgADP + H+ ↔ Creatine + MgATP. The intracellular CK system functions as a dynamic, temporal, and spatial energy buffer that may greatly enhance muscle contractility and ion transport. Other metabolic functions of this central regulatory enzyme of energy metabolism include proton buffering, and the indirect regulation of. The adenosine triphosphate (ATP) regenerating enzyme creatine kinase (CK) is intimately involved in blood pressure generation. The creatine transporter and CK inhibitor beta-guanidinopropionic acid (GPA) successfully reduced blood pressure in 16-week-old spontaneously hypertensive rats (SHR), but GPA may cause growth retardation in juvenile mammals.
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