The defecation reflex is composed of rectal distension-evoked rectal (R-R) reflex contractions and synchronous internal anal sphincter (R-IAS) reflex relaxations in guinea pigs. These R-R and R-IAS reflexes are controlled via extrinsic sacral excitatory nerve pathway (pelvic nerves), lumbar inhibitory nerve pathways (colonic nerves) and by intrinsic cholinergic excitatory and nitrergic inhibitory nerve pathways. The effect of mosapride (a prokinetic benzamide) on the intrinsic reflexes, mediated via enteric 5-HT4 receptors, was evaluated by measuring the mechanical activity of the rectum and IAS in anesthetized guinea pigs using an intrinsic R-R and R-IAS reflex model resulting from chronic (two to nine days) lumbosacral denervation (PITH). In this model, the myenteric plexus remains undamaged and the distribution of myenteric and intramuscular interstitial cells of Cajal is unchanged. Although R-R and R-IAS reflex patterns markedly changed, the reflex indices (reflex pressure or force curve-time integral) of both the R-R contractions and the synchronous R-IAS relaxations were unchanged. The frequency of the spontaneous R and IAS motility was also unchanged. Mosapride (0.1-1.0 mg/kg) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indices (maximum: 2.76) from that of the control (1.0) 6-9 days following chronic PITH. The dose-response curve was similar to that in the intact guinea pig, and had shifted to the left from that in the guinea pig after acute PITH. A specific 5-HT4 receptor antagonist, GR 113808 (1.0 mg/kg), decreased both reflex indices by approximately 50% and antagonized the effect of mosapride 1.0 mg/kg. This was quite different from the result in the intact guinea pig where GR 113808 (1.0 mg/kg) did not affect either of the reflex indices. The present results indicate that mosapride enhanced the intrinsic R-R and R-IAS reflexes and functionally compensated for the deprivation of extrinsic innervation. The actions of mosapride were mediated through endogenously active, intrinsic 5-HT4 receptors which may be post-synaptically located in the myenteric plexus of the anorectum.
We assessed gastric myoelectric functioning in patients with various gastrointestinal symptoms and to determine the utility of electrogastrography in differentiating specific disease entities. Electrogastrography with a water load was performed in 101 patients with reflux disease, 55 patients with active gastric ulcer, 59 patients with functional dyspepsia, and 30 controls. Upper gastrointestinal symptoms were assessed in each patient. Electrogastrography was abnormal in 41 (40.6%) patients with reflux disease, 31 (56.4%) patients with active gastric ulcer, and 26 (44.1%) patients with functional dyspepsia (P=NS). Water load tolerance was greater in controls than any patient group (all P<0.05). Symptoms predicted abnormal electrogastrography in reflux patents with satiety (OR=2.9; P<0.05) and in dyspeptic patients with nausea (OR=3.1; P<0.05). Although electrogastrography is helpful in differentiating subgroups of patients with nausea or satiety, it cannot directly differentiate disease states such as reflux disease, gastric ulcer, and functional dyspepsia.
Using the perfused kidneys of age-matched controls and streptozotocin (STZ)-induced diabetic rats, we previously demonstrated that endothelial dysfunction is present in STZ-induced diabetic rats and that acetylcholine (ACh) increases the level of 6-keto-prostaglandin F1α (a metabolite of prostacyclin) in the effluent from such perfused kidneys. Here, we investigated whether the ACh-induced relaxation in the perfused kidney is modulated by prostacyclin and/or thromboxane A2 (TXA2) in the STZ-induced diabetic state. ACh-induced renal vasodilatation was significantly weaker in STZ-induced diabetic rats than in age-matched controls, and it was not affected by treatment with 10 μM furegrelate (TXA2-synthase inhibitor) or 1 μM SQ29548 (TXA2- receptor antagonist) in either group. However, it was attenuated by 10 μM tranylcypromine (prostacyclin-synthesis inhibitor), but only in the diabetic group. These results suggest that the endothelium-dependent relaxation induced by ACh in the renal vascular bed of STZ-induced diabetic rats is regulated by prostacyclin, not by TXA2. Increased prostacyclin-signaling may occur to help compensate for the impaired endothelial function seen in the kidney in long-term diabetic states.
Using perfused kidneys isolated from age-matched controls and streptozotocin (STZ)-induced diabetic rats, we investigated the effects of arachidonic acid (AA) on perfusion pressure in the presence of methoxamine. AA elicited a transient contraction followed by a sustained relaxation in each group. The amplitude of contraction was smaller in the diabetic group than in the control group, whereas the amplitude of the sustained relaxation was greater in the former than in the latter group. In the diabetic group, the AA-induced sustained relaxation was completely inhibited by indomethacin [cyclooxygenase (COX) inhibitor], SKF525A [cytochrome P450 (CYP450) inhibitor], or clotrimazole (epoxygenase inhibitor), but not by furegrelate [thromboxane A2 (TXA2)-synthase inhibitor], SQ29548 (TXA2-receptor antagonist), or baicalein [lipoxygenase (LOX) inhibitor]. In the diabetic kidney, more-or-less additive inhibitions of the AA-induced relaxation were seen when indomethacin was given with either SKF525A or clotrimazole. These results suggest that in the STZ-induced diabetic perfused kidney, vasorelaxant metabolites derived from AA (probably COX and/or CYP450 metabolites) are increased, and may serve to regulate vascular tone.