No abstract

Peptide YY (PYY), an anorectic peptide, is secreted postprandially from the distal gastrointestinal tract. PYY(3-36), the major form of circulating PYY, binds to the hypothalamic neuropeptide Y Y2 receptor (Y2-R) with a high-affinity, reducing food intake in rodents and humans. Additional gastrointestinal hormones involved in feeding, including cholecystokinin, glucagon-like peptide 1, and ghrelin, transmit satiety or hunger signals to the brain via the vagal afferent nerve and/or the blood stream. Here we determined the role of the afferent vagus nerve in PYY function. Abdominal vagotomy abolished the anorectic effect of PYY(3-36) in rats. Peripheral administration of PYY(3-36) induced Fos expression in the arcuate nucleus of sham-operated rats but not vagotomized rats. We showed that Y2-R is synthesized in the rat nodose ganglion and transported to the vagal afferent terminals. PYY(3-36) stimulated firing of the gastric vagal afferent nerve when administered iv. Considering that Y2-R is present in the vagal afferent fibers, PYY(3-36) could directly alter the firing rate of the vagal afferent nerve via Y2-R. We also investigated the effect of ascending fibers from the nucleus of the solitary tract on the transmission of PYY(3-36)-mediated satiety signals. In rats, bilateral midbrain transections rostral to the nucleus of the solitary tract also abolished PYY(3-36)-induced reductions in feeding. This study indicates that peripheral PYY(3-36) may transmit satiety signals to the brain in part via the vagal afferent pathway.

Angiotensin (Ang) II has two major receptor isoforms, AT1 and AT2. Currently, AT1 antagonists are undergoing clinical trials in patients with cardiovascular diseases. Treatment with AT1 antagonists causes elevation of plasma Ang II which selectively binds to AT2 and exerts as yet undefined effects. Cardiac AT2 level is low in adult hearts, whereas its distribution ratio is increased during cardiac remodeling and its action is enhanced by application of AT1 antagonists. Although in AT2 knock-out mice sensitivity to the pressor action of Ang II was increased, underlying mechanisms remain undefined. Here, we report the unexpected finding that cardiac-specific overexpression of the AT2 gene using alpha-myosin heavy chain promoter resulted in decreased sensitivity to AT1-mediated pressor and chronotropic actions. AT2 protein undetectable in the hearts of wild-type mice was overexpressed in atria and ventricles of the AT2 transgenic (TG) mice and the proportions of AT2 relative to AT1 were 41% in atria and 45% in ventricles. No obvious morphological change was observed in the myocardium and there was no significant difference in cardiac development or heart to body weight ratio between wild-type and TG mice. Infusion of Ang II to AT2 TG mice caused a significantly attenuated increase in blood pressure response and the change was completely blocked by pretreatment with AT2 antagonist. This decreased sensitivity to Ang II-induced pressor action was mainly due to the AT2-mediated strong negative chronotropic effect and exerted by circulating Ang II in a physiological range that did not stimulate catecholamine release. Isolated hearts of AT2 transgenic mice perfused using a Langendorff apparatus also showed decreased chronotropic responses to Ang II with no effects on left ventricular dp/dt max values, and Ang II-induced activity of mitogen-activated protein kinase was inhibited in left ventricles in the transgenic mice. Although transient outward K+ current recorded in cardiomyocytes from AT2 TG mice was not influenced by AT2 activation, this study suggested that overexpression of AT2 decreases the sensitivity of pacemaker cells to Ang II. Our results demonstrate that stimulation of cardia AT2 exerts a novel antipressor action by inhibiting AT1-mediated chronotropic effects, and that application of AT1 antagonists to patients with cardiovascular diseases has beneficial pharmacotherapeutic effects of stimulating cardiac AT2.

SUMMARY1. y-Aminobutyric-acid-(GABA) and pentobarbitone-induced C1-currents (IC1) were studied in isolated frog sensory neurones after suppression of Na+, K+ and Ca2+ currents using a suction-pipette technique combining internal perfusion with voltage clamp.2. All GABA-sensitive neurones responded to pentobarbitone. Both GABA-and pentobarbitone-induced IC, reversed at the Cl-equilibrium potential (EC1).3. The dose-response curve for maxima of GABA-induced IC, was sigmoidal with a mean concentration producing a half-maximum response, Ka of 2 x 1O-5 M at a Hill coefficient of 1-8. In the presence of pentobarbitone, the GABA dose-response curve shifted to the left without affecting the saturating maximum current. 4. At high concentrations, both GABA and pentobarbitone could also potentiate the pentobarbitone-and GABA-induced IC, respectively, while pre-treatment with one of the two markedly attenuated currents induced by the other, indicating a 'cross-desensitization '. 5. In the presence of pentobarbitone, the augmented response was voltage dependent and this augmentation was much greater in the inward-current direction than outward.6. In producing IC,, pentobarbitone and its stereoisomers were potent in the order of (-) isomer > (± ) racemic mixture > (+ ) isomer. A stereospecific facilitatory action of pentobarbitone on GABA responses was also found in the same order.7. Responses to GABA, homotaurine, taurine, ,-alanine, 5-aminovaleric acid, (+ )-and (-)-y-amino-/3-hydroxybutyric acid and muscimol were equally enhanced by pentobarbitone, though its action on glycine-induced IC, was less effective.8. Picrotoxin inhibited the GABA-and pentobarbitone-induced IC, from either side of membrane, while internal application of GABA and pentobarbitone did not exert any effect. 9. It was concluded that pentobarbitone binds to the 'barbiturate receptors' located close to the GABA receptor-Cl-channel complex, and directly affects the GABA-GABA receptor interactions rather than the ionic channels.

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is hydrolyzed by angiotensin-converting enzyme, is a natural regulator of hematopoiesis. Here it is shown that Ac-SDKP inhibits TGF-␤ action in mesangial cells. Because TGF-␤ is thought to play a pivotal role in the development and progression of glomerulonephritis, the therapeutic effects of Ac-SDKP on an established model of renal dysfunction and histologic alteration in Wistar-Kyoto rats with anti-glomerular basement membrane nephritis was examined. Fourteen days after the induction of anti-glomerular basement membrane nephritis, the rats were treated subcutaneously with Ac-SDKP at a dose of 1 mg/kg per d for 4 wk. Treatment with Ac-SDKP significantly improved proteinuria and renal dysfunction, including increased plasma blood urea nitrogen and creatinine levels and decreased creatinine clearance. Histologic examination showed severe glomerulosclerosis and interstitial fibrosis in the vehicle-treated rats, whereas these histologic injuries were significantly ameliorated in rats that were treated with Ac-SDKP. The histologic improvements were accompanied by the suppression of gene and protein expression of fibronectin, interstitial collagen, and TGF-␤1 in the nephritic kidney. Furthermore, treatment with Ac-SDKP resulted in the inhibition of Smad2 phosphorylation, an increase in Smad7 expression in the kidney, and reduction of macrophage accumulation into the glomeruli and tubulointerstitium in nephritic rats. In conclusion, Ac-SDKP significantly ameliorated the progression of renal dysfunction and fibrosis even after the establishment of nephritis. The inhibitory effect of Ac-SDKP was mediated in part by the inhibition of TGF-␤/Smad signal transduction and the inflammatory response. These findings suggest that Ac-SDKP treatment may be a novel and useful therapeutic strategy for the treatment of progressive renal diseases.