Correlation of function and energy metabolism in rat ischemic skeletal muscle by ³¹P-NMR spectroscopy: Effects of torbafylline

The aim of this study was to correlate function of rat ischemic skeletal muscle directly with energy metabolism, to investigate the effects of torbafylline, a novel xanthine derivative potentially useful for the treatment of peripheral vascular occlusive disease and other ailments of skeletal muscle, and to get insight into its mechanism of action. Phosphocreatine (PCr), inorganic phosphate (Pi) and pH were estimated at rest, during induced contractions and during the recovery phase after cessation of electrical stimulation in rat hind limb muscles with two weeks unilateral chronic ligation of the femoral artery. Concomitantly, contraction force was measured in terms of tension developed during the stimulation interval. The effects of torbafylline [7-ethoxymethyl-1-(5-hydroxy-5- methylhexyl)3-methylxanthine] on the above parameters were studied after chronic oral gavage (25 mg/kg body weight per day); treatment started the day after surgery and the last drug application was performed the day of the final experiments. Control animals received physiological saline under the same conditions. During rest no major differences could be detected either in PCr and Pi levels or in pH between the different muscles, ischemic or not and treated or not. During compelled contractions, PCr and pH decreased and Pi increased in all muscles. Differences between muscles and treatments emerged as the PCr drop was more pronounced in ischemic saline treated muscles and the Pi increase in drug treated muscles (normal and ischemic) were clearly less marked than in saline treated ones. Contraction force decreased rapidly during the 12 min electrical direct stimulation and fatigability increased from 67% in normal muscle to 88% in ischemic muscle. Drug treatment induced strikingly less fatigability as it was 44.5% in normal and only 62% in ischemic muscle. However, most marked differences in metabolite levels and pH were measured during the recovery period. As an indication of disturbed energy balance, the recovery of PCr, Pi and pH was seriously hampered in ischemic saline treated muscles; especially pH being still significantly decreased during the entire chosen recovery period of 15 min. Torbafylline not only restored function but also helped the muscle recover faster and better from exhaustion, as all the parameters returned gradually to normal levels.