Taurine is the most abundant free amino acid in heart and skeletal muscle. In the present study, the effects of hereditary taurine deficiency on muscle function were examined in taurine transporter knockout (taut-/-) mice. These mice show an almost complete depletion of heart and skeletal muscle taurine levels. Treadmill experiments demonstrated that total exercise capacity of taut-/- mice was reduced by >80% compared with wild-type controls. The decreased performance of taut-/- mice correlated with increased lactate levels in serum during exercise. Surprisingly, cardiac function of taut-/- mice as assessed by magnetic resonance imaging, echocardiography, and isolated heart studies showed a largely normal phenotype under both control and stimulated conditions. However, analysis of taut-/- skeletal muscle revealed electromyographic abnormalities. (1)H nuclear magnetic resonance spectroscopy of tissue extracts showed that in the heart of taut-/- mice the lack of taurine was compensated by the up-regulation of various organic solutes. In contrast, a deficit of >10 mM in total organic osmolyte concentration was found in skeletal muscle. The present study identifies taurine transport as a crucial factor for the maintenance of skeletal muscle function and total exercise capacity, while cardiac muscle apparently can compensate for the loss of taurine.
It has been suggested that serotonin (5-hydroxytryptamine) type-4 (5-HT4) receptors modulate the sensitivity of intrinsic afferents of the intestinal mucosa. We studied the involvement of 5-HT4receptors in the modulation of extrinsic afferent sensitivity of the intestinal wall. During distension ramps, mechanoreceptive rectal afferents in sacral dorsal roots were examined in decerebrate anaesthesia-free cats using the selective 5-HT4receptor partial agonist, tegaserod (HTF 919), and the 5-HT4receptor antagonist, SB 203186. The static discharge rate of the afferents evoked by rectal distension decreased after intravenous (i.v.) administration of tegaserod at intraluminal pressures above 30 mmHg, with the most effective reduction occurring at 50 mmHg. The effect was dose-dependent, with maximal reduction occurring at 1.2 mg kg-1 bodyweight, and could be partly reversed by i.v. administration of SB 203186. Tegaserod did not alter the pressure-volume relationship (compliance) of the rectum. It is tentatively concluded that 5-HT4receptor activation has an inhibitory effect on intramural mechanoreceptors in the cat's rectum. Our results are in line with the observation that tegaserod relieves the sensory symptoms of patients suffering from irritable bowel syndrome.
The afferent input from the rectum to the central nervous system (CNS) has yet to be thoroughly characterized. The characteristics of mechanoreceptive rectal afferents have been studied in unanaesthetized decerebrate cats. Following lumbo-sacral laminectomy, single-unit activity (occasionally multi-unit activity) was recorded from centrally cut filaments of the sacral dorsal roots (predominantly S2), while a balloon was inflated in the rectum. Starting from their background activities (mean 15.1 imp sec-1, SD 7.6 imp sec-1), afferent discharge rate increased with increasing balloon pressure (mean threshold 6.3 mmHg, SD 3.6 mmHg). The dependence of firing rate on intrarectal pressure began to flatten out at 25 mmHg (mean; SD 10 mmHg). For 22 out of 29 units (76%) complete saturation occurred at 35 mmHg (mean; SD 15 mmHg) with a maximum discharge rate of 31 imp sec-1 (mean; SD 12.6 imp sec-1). In a number of recording sessions, cyclical rectal contractions were observed. In these cases, changes in firing of the units were closely related to changes in intrarectal pressure. Pressure-related afferent activity could be enhanced by parasympathomimetic drugs which augmented rectal contractions. We conclude that sacral dorsal roots contain afferents from low-threshold mechanoreceptors located in the rectal wall, and that these afferents monitor the filling state and contraction level of the rectum.
The interaction between dopaminergic and cholinergic systems in the mammalian central nervous system, which is thought to have important implications in the pathophysiology of major extrapyramidal disorders, has never been adequately demonstrated in vivo. Renshaw cell burst responses to single electrical shocks to lumbar ventral roots in spinalized and decerebrated rats were studied. In this monosynaptic cholinergic pathway, apomorphine, a dopaminergic receptor agonist, inhibited whereas the D2-antagonist sulpiride facilitated the burst responses. The mutual antagonism of the two drugs and the depression coupled with the faster decay of post-tetanic potentiation of Renshaw cells by apomorphine demonstrate the involvement of presynaptic D2-receptors through which dopamine can modulate acetylcholine-mediated central synaptic transmission in vivo. The study also provides further evidence for the involvement of the spinal cord in extrapyramidal disorders.
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