Beta-receptor blockade decreases carnitine palmitoyl transferase I activity in dogs with heart failure.
BACKGROUND
Pharmacological inhibition of carnitine palmitoyl transferase I (CPT-I), the enzyme controlling the rate of fatty acid transport into the mitochondria, prevents the contractile dysfunction, myosin isozyme shift and deterioration in sarcoplasmic reticulum Ca2+ handling that occurs in rat models of left ventricular hypertrophy. In this study we examine whether the improved cardiac function with beta blockade therapy in heart failure is associated with an alteration in CPT-I activity.


RESULTS
We examined dogs with coronary microembolism-induced heart failure treated for 12 weeks with metoprolol (25 mg twice daily). Myocardial activities of CPT-I, medium-chain acyl co-enzyme A dehydrogenase (MCAD, a beta-oxidation enzyme), citrate synthase, and triglyceride content were measured. The progressive decrease in cardiac function was prevented by treatment with metoprolol, as reflected by an improved ejection fraction over 12 weeks in the metoprolol group (from 35% to 40%) compared to the untreated heart failure dogs (decrease from 36% to 26%). Dogs treated with metoprolol had a marked decrease in CPT-I activity (0.46 +/- 0.03 vs. 0.64 +/- 0.02 micromol min(-1) g(-1) wet weight; P < .02) along with an increase in triglyceride concentration compared to untreated heart failure dogs (3.9 +/- 0.3 v 4.9 +/- 0.2 micromol/g wet weight, respectively; P < .003). By contrast, MCAD and citrate synthase activities did not change.


CONCLUSIONS
Metoprolol induced a decrease in CPT-I activity and an increase in triglyceride content. These results suggest that the improved function observed with beta blockers in heart failure could be due, in part, to a decrease in CPT-I activity and less fatty acid oxidation by the heart.
Panchal
A R
AR
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-4970, USA.
Stanley
W C
WC
Kerner
J
J
Sabbah
H N
HN
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000097:blood*; D004195:Disease Models, Animal; D004285:Dogs; D005227:Fatty Acids / Q000378:metabolism; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008790:Metoprolol / Q000627:therapeutic use*; D051381:Rats; D013318:Stroke Volume / Q000187:drug effects; D014280:Triglycerides / Q000032:analysis
D000319:Adrenergic beta-Antagonists; D005227:Fatty Acids; D014280:Triglycerides; D002334:Carnitine O-Palmitoyltransferase; D008790:Metoprolol