Central Effects of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) on Gastric Motility and Emptying in Rats

Pituitary adenylate cyclase activatingpolypeptide (PACAP) is a new member of thesecretinglucagon-vasoactive intestinal peptide (VIP)peptide family. PACAP is widely distributed not only inthe mammalian brain but also in the gastrointestinal tract.Here, we investigated the effects of central andperipheral administrations of PACAP on gastric motilityand gastric emptying in rats. We found that theintracerebroventricular or intracisternal injection of PACAP increasedgastric motility in a dose-dependent manner. Theintracisternal injection of PACAP delayed gastricemptying. These central effects of PACAP on gastricmotility and emptying were blocked by bilateralvagotomy. In contrast, intravenous administration ofPACAP decreased gastric motility and delayed gastricemptying. The peripheral inhibitory effect wasunaffected by bilateral vagotomy, adrenalectomy,phentolamine, and propranolol. We investigated theeffect of PACAP38 on blood glucose levels (BGL) at thesame doses as those used in the gastric motility andemptying studies in urethane-anesthetized rats. Theintravenous but not intracerebroventricular injection ofPACAP38 (1-8 nmol/rat) produced a significant increasein the BGL. We conclude that PACAP has opposite central and peripheral effects on gastricmotility, ie, central PACAP activates the vagal pathwayin the central nervous system to increase gastricmotility, whereas peripheral PACAP inhibits gastricmotility via an unknown pathway. The delay in gastricemptying after the central administration of PACAP mightbe due to the lack of coordinated gastropyloroduodenalcontraction, whereas that after the peripheral administration might be due to the inhibitionof gastric contraction, and this effect may be relatedto the hyperglycemic action of PACAP.     

Increased Gastric Bicarbonate Secretion in Portal Hypertensive Anesthetized Rats (Role of Prostaglandins and Nitric Oxide)

Gastric bicarbonate secretion might be modifiedin portal hypertension as a consequence of theintramucosal increase in prostaglandins and nitric oxidecontent. Therefore, we studied gastric bicarbonate secretion in control and portal hypertensiverats and investigated the role of prostaglandins andnitric oxide. Basal gastric bicarbonate secretion wasstudied in rats, using a gastric pH back-titration technique, two weeks after partial portal veinligation or a sham operation. The effects of thefollowing drugs were investigated: the prostaglandinsynthase inhibitor indomethacin (5 mg/kg intravenously), prostaglandin (PGE₂) (1 mg/kgintravenously), the nitric oxide synthase inhibitorsN^G-nitro-L-arginine methyl ester (LG NAME, 5mg/kg intravenously) andN^G-monomethyl-L-arginine (L-NMMA, 50 mg/kgintravenously), and the nitric oxide donor nitroprusside (5mmol/liter in the gastric perfusate). Plasma leakage inthe gastric wall was also measured after Evans blue dyeinjection in portal hypertensive and sham-operated rats pretreated by indomethacin (5 mg/kg,intravenously) and L-NAME (5 mg/kg, intravenously).Basal bicarbonate secretion was significantly increasedin portal hypertensive rats as compared to controls. After indomethacin, the bicarbonate secretionwas significantly reduced to a similar level in bothgroups. PGE₂ increased bicarbonate secretionsignificantly more in portal hypertensive rats than insham-operated rats. The NO synthase inhibitor L-NMMAsignificantly increased bicarbonate secretion in portalhypertensive rats only, while the other inhibitor,L-NAME, increased it significantly more in portalhypertensive than in the sham-operated rats. Plasma leakagein portal hypertensive rats, which was increased in thebasal condition as compared to control, was furtherenhanced by indomethacin but not by L-NAME pretreatment. The nitric oxide donor significantly reducedbicarbonate secretion in portal hypertensive rats toreach a similar level as in sham-operated rats. Basalgastric bicarbonate secretion is increased in portal hypertensive rats. This could be due to anenhanced prostaglandin mucosal level. Nitric oxide,which reduces bicarbonate secretion, may contribute tolimiting prostaglandin-induced bicarbonateoverproduction.     

ACE Inhibition by Enalaprilate Stimulates Duodenal Mucosal Alkaline Secretion via a Bradykinin Pathway in the Rat

The effects of enalaprilate on duodenal mucosalalkaline secretion (in situ titration) and mean arterialblood pressure were investigated inchloralose-anesthetized male rats. A bolus injection ofenalaprilate (0.7 mg/kg intravenously) increased alkalinesecretion by about 60%, and this response was resistantto guanethidine (5 mg/kg intravenously),splanchnicotomy, and vagotomy. Furthermore, angiotensinII infusion (0.25-2.5 g/kg/hr intravenously)following the administration of enalaprilate failed toinfluence this response. Bradykinin (10^-6-10^-4 M) applied topically to theserosal surface of the duodenal segment under study increased dose-dependentlythe duodenal mucosal alkaline secretion, an effect thatcould be blocked by the selective bradykinin receptorsubtype-2 antagonist HOE140 (100 nmol/kg intravenously). HOE140 also antagonized the response toenalaprilate. These data suggest that enalaprilateincreases duodenal mucosal alkaline secretion via alocal bradykinin pathway involving receptors of thebradykinin receptor subtype-2 antagonist, rather than byblockade of endogenous angiotensin II or by centralautonomic neural regulation.     

Glucagon-like Peptide-1 Retards Gastric Emptying and Small Bowel Transit in the Rat (Effect Mediated Through Central or Enteric Nervous Mechanisms)

This study investigated effects of glucagon-likepeptide-1(7-36)amide (GLP-1) on gastric emptying, smallintestinal transit, and contractility of smooth musclestrips in rats. GLP-1 at doses of 10 and 20 pmol/kg/min administered intravenouslydose-dependently retarded transit of the small intestine(P < 0.001), while only the higher dose of 20pmol/kg/min retarded gastric emptying (P < 0.01).GLP-1 at concentrations up to 10^-4 M didnot affect the basal tone or contractility of thegastrointestinal muscle strips that were stimulated withelectric field stimulation or acetylcholine. Our resultsdemonstrate that small intestinal transit seems moresensitive than gastric emptying to inhibition by GLP-1at physiologic levels in plasma. Furthermore, thisinhibition appears to be mediated through centralmechanisms rather than through peripheral actions. Thus,GLP-1 is suggested to inhibit gastric emptying and smallintestinal transit through an indirect effect viacentral or enteric nervous mechanisms.     

Acid and Hyperosmolal Solutions in the Upper Intestine of Chronic Gastric Fistula Rats Inhibit Gastric Acid Secretion by Different Mechanisms

In chronic gastric fistula rats 0.20 M HC1 and 1200 mOsm × kg^-1 solution of polyethylene glycol (PEG) infused into a duodenal loop anastomosed to the jejunum (Roux-en-Y) produced maximal inhibition of pentagastrin-stimulated acid secretion, which amounted to 60% and 50%, respectively. In the present study in Roux-en-Y rats with gastric fistula, perfusion of the loop with hyperosmolal (1200 mOsm × kg^-1 of PEG solution) 0.20 M HC1 produced a greater reduction of the maximal response to pentagastrin (91% inhibition) than perfusion with 0.20 M HC1 (64%), suggesting that HC1 and hyperosmolal solution inhibit secretion by different mechanisms. The maximal acid response to histamine was more resistant to inhibition than that to pentagastrin; 0.20 M HC1 inhibited secretion by 43%, 1200 mOsm × kg^-1 of PEG solution by 42%, and hyperosmolal 0.20 M HC1 by 60%. The results suggest that HC1 and hyperosmolal solution also inhibit histamine-stimulated secretion by different mechanisms. The anatomical sites of the mechanisms remain to be established.     

大鼠重症急性胰腺炎发病机制中p38丝裂原活化蛋白激酶的作用研究

目的探讨p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38 MAPK)特异性抑制剂SB203580对大鼠重症急性胰腺炎(SAP)的保护作用。方法以胆胰管逆行注射5%牛磺胆酸钠建立SD大鼠SAP模型。将45只SD大鼠随机分为3组,假手术组(SO组,n=15);SAP组(SAP组,n=15);SB203580治疗组(SB组,n=15)。术后3、6、12 h处死大鼠并取血。对胰腺进行病理组织学评分,测定大鼠腹水量。检测血清淀粉酶,ELISA法测定血清IL-6和IL-10水平。并采用免疫组化法观察大鼠胰腺组织p38 MAPK下游靶点P-ATF2表达情况。结果 SO组胰腺组织存在P-ATF2弱表达,SAP组各时间点P-ATF2表达水平明显升高(P<0.01),SB组各时间点表达水平较SAP组下降明显(P<0.01)。SAP组6、12 h时间点IL-6水平,3、6 h时间点IL-10水平,血清淀粉酶,腹水量明显高于SB组(P<0.05)。SAP组各时间点胰腺组织病理学积分显著高于SB组,差异有统计学意义(P<0.05)。结论阻断p38 MAPK信号传导通路可以明显缓解大鼠重症急性胰腺炎的病情。预示此信号传导通路可以为SAP的治疗提供一个有价值的标靶。