Role of nitric oxide in the internal anal sphincter of Hirschsprung's disease

It is not clear what contribution the internal anal sphincter (IAS) makes to the impaired motility observed in patients with Hirschsprung's disease (HD). Nitric oxide (NO) has recently been shown to be a neurotransmitter in the nonadrenergic noncholinergic (NANC) inhibitory nerves in the human gut. To clarify the physiologic significance of NO in the IAS of HD (aganglionosis), we investigated the enteric nerve responses on lesional (aganglionic) and normal IAS muscle strips above the dentate line. Lesional and normal IAS muscle strips above the dentate line were derived from patients with HD (10 cases) and patients who underwent rectal amputation for low rectal cancer (12 cases). A mechanographic technique was used to evaluate in vitro muscle responses to electrical field stimulation (EFS) before and after treatment with various autonomic nerve blockers, N(G)-L-nitroarginine, and L-arginine. The following results were obtained: (1) Cholinergic nerves are mainly involved in the regulation of enteric nerve responses to EFS in the normal IAS. (2) The aganglionic IAS of patients with HD was more strongly innervated by cholinergic nerves than the normal IAS (p < 0.05). (3) NANC inhibitory nerves were found to act on the normal IAS but had no effect on the enteric nerves in patients with aganglionosis. (4) NO was found to act on normal IAS, but no effect was observed in the aganglionic IAS. These findings suggest that innervation of the cholinergic nerves and a loss of NO mediation of NANC inhibitory nerves play an important role in the impaired motility observed in the IAS with HD.     

Responses of muscle strips from the internal anal sphincter in Hirschsprung's disease to drugs and electrical field stimulation

Responses of isolated muscle strips from the rat and the dog internal anal sphincter (IAS) to drugs and electrical field stimulation (EFS) were investigated in vitro for the purpose of clarifying a manner of neural control of IAS. Also, responses of muscle strips from IAS of the patients with Hirschsprung's disease were compared with those of muscle strips from human control IAS. Muscle strips from the dog and human IAS as normal control showed contractions to norepinephrine (NE), which were abolished in the presence of phentolamine and relaxations to isoproterenol. EFS (less than 1 msec) induced relaxations of the muscle strips. These responses to EFS were not affected by either one of phentolamine, propranolol and atropine but were inhibited by tetrodotoxin. Muscle strips from IAS in Hirschsprung's disease contracted to both NE and EFS, the responses of which were abolished in the presence of phentolamine. But no relaxation to EFS of muscle strips from IAS in Hirschsprung's disease was observed. These findings revealed that normal IAS is pharmacologically innervated by alpha-adrenergic excitatory nerve, beta-adrenergic inhibitory nerve and non-adrenergic, non-cholinergic inhibitory nerve and suggested that IAS in Hirschsprung's disease is also affected by alpha-adrenergic excitatory nerve but inhibitory neural control is absent.     

Differential effect of nitric oxide synthase inhibition on sigmoid colon longitudinal and circular muscle responses to nicotine and nerve stimulation in vitro

BACKGROUND: Nicotine has been shown to release nitric oxide from nerves in human sigmoid colon. This effect has been used to investigate the innervation and functional relationship of the longitudinal and circular muscle layers. METHODS: Strips of longitudinal and circular muscle were obtained from 19 patients with colorectal cancer. The strips from ten patients were subjected to electrical field stimulation (EFS) in vitro using stimulus parameters for selective stimulation of nerves. The effect of nicotine 1-10 micromol/l on EFS responses was then measured in the presence and absence of a nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME) 200 micromol/l. The effect of nicotine on spontaneous activity was investigated in the muscle strips from the other nine patients. RESULTS: Both longitudinal and circular strips responded to EFS with contraction. The time to achieve a peak contractile response (time to peak; TTP) was significantly longer (P<0.001) in circular strips. L-NAME reduced the mean(s.e.m.) TTP in circular muscle from 23.3(2.0) to 17.2(1.5) s (P=0.007) and altered its pattern of response to resemble that of longitudinal muscle. Nicotine 10 micromol/l reduced the contraction to EFS in circular (P<0.001) but not in longitudinal (P=0.347) muscle. The nicotine-induced reduction in circular muscle contraction was blocked by L-NAME 200 micromol/l (P=0.005). CONCLUSION: These findings suggest that nitric oxide release on neural stimulation is greater in circular than in longitudinal muscle.     

Substance P and vasoactive intestinal peptide in rat small-bowel isografts

BACKGROUND: It is established that substance P (SP) is released by stimulation of nonadrenergic noncholinergic (NANC) excitatory nerves and vasoactive intestinal peptide (VIP) by stimulation of NANC inhibitory nerves. To evaluate the function of peptidergic nerves such as SP and VIP in small-bowel isografts, we examined the enteric nerve responses to SP and VIP in the isografted rat jejunum, using the normal rat jejunum as a control. METHODS: Orthotopic entire small bowel transplantation (SBT) with portocaval drainage was performed from Lewis rats to Lewis rats. Grafted tissue specimens were obtained 130 days after SBT (n = 9). As controls, normal segments of the jejunum were obtained from untransplanted Lewis rats (n = 22). A mechanograph was used to evaluate in vitro jejunal responses to electrical field stimulation of the enteric nervous system before and after treatments with various autonomic nerve blockers and neuropeptides (SP and VIP). RESULTS: SP concentration-dependently mediated the contraction reaction of NANC excitatory nerve in the isografted jejunum and to a lesser extent in the normal jejunum. In addition, there were significant diferences in the percentages showing contraction at 1 x 10(-8) and 1 x 10(-6)g/mL SP between the normal and isografted jejunal muscle strips (P < .05, respectively). VIP concentration dependently mediated the relaxation reaction of NANC inhibitory nerve in the normal jejunum and to a lesser extent in the isografted jejunum. In addition, there was a significant difference between the relaxation frequencies of the normal and those of isografted jejunal muscle strips at 1 x 10(-6) g/mL SP (P < .01). CONCLUSIONS: Contraction reactions of SP were observed in both the normal and isografted jejunum but were increased in the isografted jejunum. Relaxation reactions of VIP were also observed in both the normal and isografted jejunum but were decreased in the isografted jejunum. The increase of the effects of SP via NANC excitatory nerves and the decrease of the effects of VIP in mediating NANC inhibitory nerves may be largely related to the peristaltic abnormalities seen in the isografted LEW rat jejunum.     

Direct measurement of acetylcholine release in detrusor smooth muscles isolated from rabbits

In the present study, we measured acetylcholine (ACh) released from rabbit detrusor smooth muscle strips induced by electrical field stimulation (EFS) using high-performance liquid chromatography coupled with microdialysis procedure. There were frequency- and duration-dependent increases in contractile response and ACh release. There was a significant, but not simple correlation between EFS-induced contraction and ACh release. Atropine caused a decrease and increase in the contractile response and ACh release, respectively. Pretreatment with propranolol increased ACh release, but pretreatment with phentolamine had no significant effect. These results demonstrate that this method is applicable to direct measurement of ACh release by EFS, and that neurotransmitters other than ACh may relate to EFS-induced contraction. In addition, it is suggested that there are prejunctional inhibitory muscarinic receptors and beta-adrenoceptors, which contribute to ACh release induced by EFS in the rabbit detrusor smooth muscles. Received: 20 January 1998 / Accepted: 17 April 1998     

Mechanism of action of botulinum toxin on the internal anal sphincter

BACKGROUND: Botulinum toxin is an effective treatment for anal fissure. Manometric studies support an apparent action of botulinum toxin on the internal anal sphincter (IAS). This aim of this study was to establish the underlying mechanism. METHODS: Porcine IAS strips were suspended in a superfusion organ bath and allowed to equilibrate. Electrical field stimulation (EFS) was applied with parameters that induced nitrergic relaxation followed by noradrenaline-mediated contraction. These responses were compared before and after addition of botulinum toxin. RESULTS: All strips developed myogenic tone, which was slightly increased following the addition of botulinum toxin. EFS-induced nitrergic relaxation was unaffected by toxin treatment. However, EFS-induced contraction was significantly reduced by toxin treatment. 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), a nicotinic agonist, caused muscle strip contraction, which was blocked by guanethidine, implying the presence of sympathetic ganglia within the IAS. Botulinum toxin significantly attenuated DMPP-induced contraction. CONCLUSION: In the treatment of anal fissure the major effect of botulinum toxin on the IAS is blockade of sympathetic (noradrenaline mediated) neural output. This is probably a postganglionic action, involving a reduction in noradrenaline release at the neuromuscular junction. Botulinum toxin has no significant effect on nitrergic transmission, which is probably not vesicular in nature.     

生长激素释放肽ghrelin对小鼠结肠动力的影响

目的 探讨生长激素促分泌素受体(growth hormone secretagogue receptor,GHSR)内源性激动剂生长激素释放肽ghrelin对小鼠结肠动力的影响.方法 小鼠按随机数字法分组后,分别注射生理盐水和不同剂量ghrelin(20,50,100,200 ng/g),用炭末推进实验的方法观察ghrelin对小鼠结肠推进的影响,研究阿托品、NG-硝基精氨酸甲酯和D-Lys3-GHRP-6(GHSR阻断剂)对ghrelin(100 ng/g)引起的小鼠结肠推进改变的影响.将小鼠近端结肠环形平滑肌条安置在恒温灌流肌槽中并用SMUP-E生物信号处理系统记录肌条的自发收缩活动,观察不同浓度的ghrelin(0.01、0.1、1和10 μmol/L)对肌条自发收缩幅度的影响.结果 ghrelin能显著提高小鼠的结肠推进速度,有明显的量效关系.阿托品、NG-硝基精氨酸甲酯、D-lys3-GHRP-6均能显著抑制ghrelin促进结肠推进的作用(t=10.230,12.560,11.590,P＜0.05).ghrelin能显著增加小鼠近端结肠环形平滑肌的自发收缩幅度,河豚毒素预处理肌条后ghrelin不能显著增加肌条的自发收缩幅度.结论 ghrelin可以显著增加小鼠结肠的推进,可能是通过结肠肌间神经丛的硝基能神经和胆碱能神经上的GHSR而起作用.     

Alpha-adrenergic receptor blockade by phentolamine increases the efficacy of vasodilators in penile corpus cavernosum

Penile trabecular smooth muscle tone, a major determinant of erectile function, is highly regulated by numerous inter- and intracellular pathways. The interaction between pathways mediating contraction and relaxation has not been studied in detail. To this end, we investigated the functional effects of alpha adrenergic receptor blockade with phentolamine and its interaction with vasodilators (sildenafil, vasoactive intestinal polypeptide (VIP) and PGE1) that elevate cyclic nucleotides on penile cavernosal smooth muscle contractility. In organ bath preparations of cavernosal tissue strips contracted with phenylephrine, phentolamine significantly enhanced relaxation induced by sildenafil, VIP and PGE1. Sildenafil, VIP or PGE1 also significantly enhanced relaxation induced by phentolamine in cavernosal tissue strips contracted with phenylephrine. To study the effects of alpha adrenergic receptor blockade and modification of cyclic nucleotide metabolism during active neurogenic input, cavernosal tissue strips in organ bath preparations were contracted with the non-adrenergic agonist endothelin-1 and subjected to electrical field stimulation (EFS) in the absence or presence of phentolamine and/or sildenafil. EFS (5-40Hz) typically caused biphasic relaxation and contraction responses. Phentolamine alone enhanced relaxation and reduced or prevented contraction to EFS. Sildenafil enhanced relaxation to EFS at lower frequencies (< or = 5 Hz). The combination of phentolamine and sildenafil enhanced EFS-induced relaxation at all frequencies tested. EFS, in the presence of 10 nM phentolamine and 30 nM sildenafil, produced enhanced relaxation responses which were quantitatively similar to those obtained in the presence of 50 nM sildenafil alone. Thus, blockade of alpha-adrenergic receptors with phentolamine increases the efficacy of cyclic nucleotide-dependent vasodilators. Furthermore, phentolamine potentiates relaxation and attenuates contraction in response to endogenous neurotransmitters which are released during EFS. These findings suggest that antagonism of alpha-adrenergic signaling enables other independent relaxatory pathways to predominate within penile trabecular smooth muscle.     

Functional evaluation of the grafted wall with porcine-derived small intestinal submucosa (SIS) to a stomach defect in rats

BACKGROUND: Small intestinal submucosa (SIS) represents a novel bio-scaffolding material that may be used to repair hollow-organ defects. However, it is unclear whether neurophysiologic responses return to SIS-grafted areas in the gut. We evaluated the functional recovery of a stomach defect grafted with the porcine-derived SIS. METHODS: Twelve rats had a full-thickness defect created in the stomach. SIS was secured to the gastric wall. After 6 months, muscle strips were harvested from within the grafted area to perform both a histologic and a functional study. Additional full-thickness muscle strips were harvested from the posterior in the same stomach as controls. A dose response curve was obtained with carbachol (CCH) or sodium nitroprusside (SNP). Activation of intrinsic nerves was achieved by electrical field stimulation (EFS). RESULTS: The response to CCH and amplitude in EFS showed tonic contraction in both controls and SIS strips in a concentration-dependent and frequency-dependent manner. The magnitude after each stimulation was significantly lower in SIS strips compared with controls (P < .01). However, the contraction ratio of EFS to ED(50) of CCH was not significantly different between the groups. Additionally, SNP produced relaxation in both strips in a concentration-dependent manner. Histologic findings revealed that an insufficient amount of smooth-muscle cells existed in the muscularis propria, whereas compensated growth was observed in the submucosa with nerve regeneration. CONCLUSIONS: This study demonstrates that SIS provides a template for nerve migration to the graft in the rodent stomach. Innervations showed a similar distribution to that observed in the controls. The clinical implications of such findings warrant additional investigation.     

Physiological studies on vasoactive intestinal peptide in rat small bowel isografts

BACKGROUND: Vasoactive intestinal peptide (VIP) is released by stimulation of nonadrenergic noncholinergic (NANC) inhibitory nerves. In order to evaluate the function of VIP in jejunal isografts, we examined the enteric nerve responses in isografted rat jejunum compared with normal jejunum. METHODS: Orthotopic entire small bowel transplantation (SBT) with portocaval drainage was performed from Lewis rats to Lewis rats. Grafted tissue specimens were obtained 130 days after SBT (n = 8). As controls, normal segments of the jejunum were obtained from nontransplanted Lewis rats (n = 20). A mechanograph was used to evaluate in vitro jejunal responses to electrical field stimulation (EFS) of the adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers and VIP. RESULTS: The isografted jejunum was more strongly innervated by excitatory nerves, especially NANC excitatory nerves, than the normal jejunum (P <.05). VIP mediated relaxation reactions of NANC inhibitory nerves in the normal but to a lesser extent in the isografted jejunum (P <.05). CONCLUSIONS: The increased NANC excitatory nerves and the decreased effects of VIP in mediating NANC inhibitory nerves may largely relate to the peristaltic abnormalities seen in the isografted LEW rat jejunum.     

Pre-junctional alpha2-adrenoceptors modulation of the nitrergic transmission in the pig urinary bladder neck

AIMS: To investigate the nitric oxide (NO)-mediated nerve relaxation and its possible modulation by pre-junctional alpha2-adrenoceptors in the pig urinary bladder neck. METHODS: Urothelium-denuded bladder neck strips were dissected, and mounted in isolated organ baths containing a physiological saline solution (PSS) at 37 degrees C and continuously gassed with 5% CO2 and 95% O2, for isometric force recording. The relaxations to transmural nerve stimulation (electrical field stimulation [EFS]) or exogenously applied NO were carried out on strips pre-contracted with 1 microM phenylephrine (PhE) and treated with guanethidine (10 microM) and atropine (0.1 microM), to block noradrenergic neurotransmission and muscarinic receptors, respectively. RESULTS: EFS (0.2-1 Hz, 1 msec duration, 20 sec trains, current output adjusted to 75 mA) evoked frequency-dependent relaxations which were abolished by the neuronal voltage-activated Na+ channel blocker tetrodotoxin (TTX, 1 microM). These responses were potently reduced by the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NOARG, 30 microM) and further reversed by the NO synthesis substrate L-arginine (L-ARG, 3 mM). The alpha2-adrenoceptor agonist BHT-920 (2 microM) reduced the electrically evoked relaxations, its effectiveness being higher on the responses induced by low frequency stimulation. BHT-920-elicited reductions were fully reversed by the alpha2-adrenoceptor antagonist rauwolscine (RAW, 1 microM). Exogenous NO (1 microM-1 mM) induced concentration-dependent relaxations which were not modified by BHT-920, thus eliminating a possible post-junctional modulation. CONCLUSIONS: These results indicate that NO is involved in the non-adrenergic non-cholinergic (NANC) inhibitory neurotransmission in the pig urinary bladder neck, the release of NO from intramural nerves being modulated by pre-junctional alpha2-adrenoceptor stimulation.     

The role of nitrergic system on the contractility of colonic circular smooth muscle in Hirschsprung's disease.

The contribution of nitrergic tone on the contractility of colonic smooth muscle in Hirschsprung's disease (HD) was investigated. METHODS: Ganglionic and aganglionic bowel specimens were taken from 8 patients with HD during pull-through operations and electrical field stimulation (EFS)-induced isometric contractions of the circular smooth muscle were recorded in vitro. Isolated circular muscle strips prepared from colonic segments of sex- and age-matched patients (n = 3) who underwent surgery for nonmotility-related colonic diseases formed the control group. Statistical analysis was performed by two way analysis of variance and unpaired Student's ttest. RESULTS: The amplitude of spontaneous rhythmic activity was lower in aganglionic segments than in ganglionic ones. The amplitudes of contractile responses were significantly greater in aganglionic segments. In ganglionic preparations, N(omega)-nitro-L-arginine (L-NNA) addition into the medium increased the contractile responses to the level of aganglionic preparations. This increase was completely blocked by L-arginine application. Neither L-NNA nor L-arginine produced any change in aganglionic segments. A relaxation phase was detected in both ganglionic and aganglionic segments. In ganglionic preparations, this relaxation phase was completely inhibited by L-NNA and restored by L-arginine, whereas no effect was detected in aganglionic ones. Responses obtained from the control group were similar to the ganglionic segments of HD patients. CONCLUSIONS: In normal colon and as well as in ganglionic segments of HD, the evoked contractile activity and relaxations are under the tonic influence of the nitrergic system. Aganglionic segments totally lack the nitrergic activity in both evoked contraction and relaxation responses, while still maintaining an inefficient relaxation capacity under unknown mechanisms.     

Effect of hypothyroidism on the nitrergic relaxant responses of corpus cavernosal smooth muscle in rabbits

BACKGROUND: The incidence of hormonal dysfunction as a cause of impotence remains controversial. However, several recent studies have reported evidence of hormonal abnormalities in 25-35% of impotent men. Hypothyroidism has been reported to occur in 6% of impotent men. METHODS: In the present study, we examined nitrergic responses in hypothyroidism in rabbit corpus cavernosum and compared them with controls. RESULTS: Carbachol-induced relaxation responses and electrical field stimulation (EFS)-induced frequency-dependent relaxations decreased significantly in hypothyroid rabbits. Papaverine and sodium nitroprusside (SNP)-induced relaxation responses did not change significantly in hypothyroid rabbits. The contraction responses of phenylephrine and EFS-induced frequency-dependent contractions were significantly decreased in the hypothyroid group. CONCLUSIONS: We can speculate that the reduction of relaxant responses to EFS and carbachol in hypothyroid rabbits can depend on a decreased release of nitric oxide (NO) from nitrergic nerves and endothelium or a reduction of muscarinic receptor density. Also, decreases in contraction responses may depend on diminished adrenoceptor density.     

Pro-erectile effect of vardenafil: in vitro experiments in rabbits and in vivo comparison with sildenafil in rats

OBJECTIVES: To assess pro-erectile responses to vardenafil, a new selective PDE5 inhibitor, in vitro in isolated rabbit corpora cavernosa, and in vivo in anaesthetized rats. METHODS: Rabbit cavernosal strips were precontracted with 10 microM phenylephrine. Dose-response relaxation curves to cumulative dosings of vardenafil (1 nM-10 microM) were constructed alone and in the presence of 10 mM L-NAME. Relaxation responses to electrical field stimulation (EFS) (2 Hz, 2 ms, 10 V) were compared in control preparations and in the presence of vardenafil (1-10 nM). Male Sprague-Dawley rats were anaesthetized with urethane and prepared for measurement of blood pressure and intracavernous pressure. Erectile responses (ICPmax/dBP x 100) to cavernous nerve submaximal stimulation (10 Hz, 1 ms, 0.45-1.6 V) were determined before, and 3, 10 and 23 min after i.v. administration of saline, vardenafil or sildenafil (0.1, 1 mg/kg). RESULTS: Vardenafil was effective in relaxing precontracted rabbit cavernosal strips (IC50 54 +/- 18 nM). This relaxing activity was partially antagonized with 10 mM L-NAME, increasing the IC50 to 620 +/- 81 nM. Vardenafil significantly increased (more than 4 times) relaxation of precontracted rabbit cavernosal strips to EFS at 10 nM. In anaesthetized rats, erectile responses were significantly facilitated 3 and 13 min after 0.1 and 1 mg/kg vardenafil was administered. In contrast, 1 mg/kg sildenafil only significantly increased erectile responses at 3 min post-injection. CONCLUSIONS: Vardenafil relaxes rabbit corpus cavernosum in vitro and is effective at a lower dose than sildenafil in facilitating erectile responses to cavernous nerve stimulation in anaesthetized rats.     

Does the distal rectal muscle in anorectal malformations have the functional properties of a sphincter?

Smooth muscle strips from the distal rectum of 11 patients who underwent surgery for imperforate anus and cloacal malformations, were studied in vitro to assess the motility response to electrical field stimulations (EFS) and to pharmacological stimulation with adrenergic and cholinergic agonists. EFS induced a nonadrenergic, noncholinergic inhibition in most strips. Acetylcholine caused either a modest contraction, no response, or a relaxation. Following atropine administration, acetylcholine caused a nonadrenergic and tetrodotoxin-resistant relaxation. The alpha-adrenergic agonist phenylephrine induced contractions in all strips. The response was abolished by alpha-adrenoceptor blockade with phentolamine, but was resistant to atropine and tetrodotoxin. beta-Adrenergic stimulation caused a relaxation that was abolished by propranolol. Function of the distal rectal smooth muscle, resected during correction of anorectal malformations, shows similarities to the function reported previously on normal anal smooth muscle evaluated in vitro.     

Endothelial and neuronal-derived nitric oxide mediated relaxation of corpus cavernosal smooth muscle in a rat, in vitro, model of erectile function

We set out to establish a simple, reproducible, rat in vitro model of erectile function and to use this to demonstrate the functional importance of both neuronal- and endothelial-derived nitric oxide within this animal. Two corpora cavernosal smooth muscle strips were harvested from sexually mature male Wistar rats and mounted in an organ bath for measurement of isometric tension. Following contraction with noradrenaline the strips were relaxed by the addition of either acetylcholine or sodium nitroprusside. Electrical field stimulation was performed in the presence of atropine and guanethidine. Relaxation responses were repeated in the presence of methylene blue, L-arginine, L-NNA and haemoglobin +/- L-arginine. Methylene blue abolishes the relaxation to acetylcholine and EFS; L-NNA and haemoglobin cause a significant impairment in the relaxation response. L-arginine reverses the effect of haemoglobin. In conclusion, the inhibitory, relaxant stimulus of rat corpora cavernosa is due to both neuronal nitric oxide and endothelial-derived nitric oxide released in response to cholinergic stimulation.     

Ghrelin及其合成肽生长激素释放肽6对小鼠胃动力的影响和机制

目的探讨生长激素促分泌素受体（GHS-R）内源性激动剂ghrelin及其合成肽生长激素释放肽6（GHRP．6）对小鼠胃动力影响及机制。方法小鼠随机分组后，分别注射生理盐水、ghrelin（20、50、100和200μg／kg）及GHRP-6（20、50、100和200μg／kg），用灌食酚红的方法研究ghrelin和GHRP-6对小鼠胃排空的影响，并研究阿托品、一氧化氮合成酶抑制剂左旋．硝基精氨酸甲基酯（L-NAME）和GHS．R阻断剂D．lys3-GHRP-6对ghrelin和GHRP-6引起小鼠胃排空改变的影响。小鼠胃底环形平滑肌条安置在恒温灌流肌槽中，并用SMUP-E生物信号处理系统记录肌条的自发收缩活动，观察不同浓度的ghrelin（0．01、0.1．0和10．0μmol／L）和GHRP-6（0．01、0．1、1．0和10．0μmol／L）对肌条自发收缩活动的影响。结果GHRP-6和ghrelin注射剂量在50、100和200μg／kg时，均能显著提高小鼠的胃排空（P〈0．05）。阿托品、L-NAME和D-lys3-GHRP-6均能显著抑制GHRP-6或ghrelin促进胃排空的作用（P〈0．05）。GHRP-6和ghrelin浓度在0．1、1．0和10．0μmol／L时，均能显著增加小鼠胃底环形平滑肌条的自发收缩幅度（P〈0．05）；在河豚毒素同时存在的情况下，GHRP-6或ghrelin均不能显著增加肌条的自发收缩幅度（P〉0．05）。结论GHRP-6和ghrelin均可显著增加小鼠的胃排空．其机制可能是通过肌间丛神经系统的硝基能神经和胆碱能神经上的受体而起作用。     

The evaluation of the effects of renal failure on erectile dysfunction in a rabbit model of chronic renal failure

OBJECTIVE: To determine whether chronic renal failure (CRF) reduces nitrergic relaxant responses in a rabbit model. MATERIALS AND METHODS: Ten rabbits underwent surgery to induce uraemia (CRF rabbits) and a further 10 a sham operation (controls). Corpus cavernosal tissue was prepared and used in organ-chamber experiments, with relaxation assessed against a background of pre-contraction with phenylephrine. At the plateau of contraction, relaxation responses to cumulative concentrations of carbachol or sodium nitroprusside (SNP), to test endothelium-dependent and -independent relaxations, respectively, were assessed. Before electrical-field stimulation (EFS), the tissue was treated with an adrenergic nerve blocker and a muscarinic receptor blocker to eliminate the adrenergic and cholinergic components, and to determine the relaxation responses to the stimulation of nonadrenergic, noncholinergic (NANC) nerves. The relaxation responses in corporal strips obtained from CRF rabbits were compared with those from controls. RESULTS: When tissues were contracted with KCl, tensions were similar in all groups. The impairment in concentration-dependent relaxation with carbachol was significant in CRF rabbits, but SNP- and papaverine-induced concentration-dependent relaxation responses were no different among the groups. EFS-induced frequency-dependent relaxations were significantly lower in CRF rabbits than in controls. CONCLUSION: CRF inhibits the NANC-mediated relaxation of rabbit corpus cavernosum smooth muscle. Changes in NANC-mediated and carbachol-induced (endothelium-dependent) relaxation of corporal smooth muscle in the rabbit are probably caused by uraemia and subsequently, hyperthyroidism, hyperparathyroidism or low testosterone levels in CRF. These results also suggest that if vasoactive agents are to be used for treating erectile dysfunction in uraemic patients, direct-acting vasodilators and phosphodiesterase inhibitors will be useful.     

Chronic extrinsic denervation of the small bowel: effect on adrenergic and cholinergic contractile mechanisms in canine ileal circular muscle

BACKGROUND: Small bowel transplantation necessitates chronic extrinsic denervation and is often followed by enteric dysfunction. Our aim was to study canine ileal contractile activity after extrinsic denervation. METHODS: In vitro dose responses to cholinergic and adrenergic agonists were evaluated in canine ileal muscle strips in control subjects and after jejunoileal extrinsic denervation (EX DEN) at 0, 2, and 8 weeks after operative preparation. RESULTS: Spontaneous activity and the increased activity after tetrodotoxin (enteric nerve blockade) did not differ between groups. Response to acetylcholine and bethanechol did not differ at any time in the control or EX DEN group. In contrast, the EX DEN group demonstrated a procontractile hypersensitivity to norepinephrine at 2 and 8 weeks that was not seen in the control group. This adrenergic hypersensitivity in the EX DEN group was insensitive to intramural neural blockade with tetrodotoxin. CONCLUSIONS: Extrinsic denervation does not affect basal contractile activity, augmented contractile activity to intramural neural blockade, nor response to cholinergic agonists. However, it induces a procontractile adrenergic hypersensitivity in canine ileal circular muscle mediated at the level of the smooth muscle and not at the enteric nervous system.