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Background: Postoperative ileus (PI) is a common surgical complication treated mainly with supportive measures. Tachykinins control gastrointestinal motility and modulate somatic and visceral pain sensation; therefore, the effect of tachykinin receptor antagonists in a rat model of PI using NK1–3 antagonists, SR140333, SR48968, and SR142801, was investigated. Materials and methods: Intestinal transit was measured as Evans blue migration after varied nociceptive stimuli: skin incision (SI), laparotomy (LAP), or laparotomy plus gut manipulation (L + M) in anesthetized rats. Results: Diethyl ether anesthesia and SI did not influence the intestinal transit of the dye in comparison to untreated animals—UN: 61.17 ± 5.47, 62.10 ± 8.30, and 56.70 ± 4.10 cm, respectively. In contrast LAP and L + M have significantly reduced intestinal motility to 26.40 ± 2.07 and 9.70 ± 1.15 cm, respectively. SR140333 (3–30 μg/kg), SR48968 (1–30 μg/kg), and SR142801 (3–10 μg/kg) reversed the additional inhibitory effects of gut manipulation subsequent to LAP dose-dependently, the dye transit returning with the use of the most effective antagonist doses up to 25.28 ± 1.08, 21.70 ± 0.19, and 25.0 ± 1.34 cm. The combinations of submaximal doses of NK1 and NK3, NK2 and NK3 and NK1, and NK2 and NK3 antagonists were not more effective than a single-agent regimen. On the other hand SR140333 and SR48968 (NK1 + NK2 antagonists) acted additively, the intestinal transit reaching 26.60 ± 0.85 cm. SR140333, SR48968, and SR142801 have not affected the intestinal passage in UN rats or those undergoing SI or LAP. Conclusions: SR140333, SR48968, and SR142801 exert a salutary action on suppressed gut motility following surgical manipulation of the gut, the combination of NK1 and NK2 antagonists being most beneficial. [Copyright &y& Elsevier]

Abstract: The activity of short porcine galanin (Gal) analogues was tested in vitro using rat jejunal and colonic smooth muscle strips. Peptides evoked concentration-dependent tissue contractions yielding typical response curves in concentration range from 0.3nM to 300μM, with a characteristic fall-down effect at the supramaximal concentrations. Gal(1–15) was less potent than Gal(1–29). Furthermore, [d-Trp2]Gal(1–15), [endo-Trp2,Cle4]Gal(1–15), [d-Leu4]Gal(1–15), [des-Leu4]Gal(1–15), [Hse6]Gal(1–15), [Dab14]Gal(1–15), [Dpr14]Gal(1–15) or [Arg14]Gal(1–15) showed a considerable decrease in potency compared to Gal(1–15) in jejunal and/or colonic smooth muscle cells. Functional evidence confirmed that the integrity of both N- and C-terminals must be preserved in order to preserve a full excitatory myogenic potential of the peptide in rat jejunum and colon. Besides, amino acids located in positions 2, 4, 6 and 14 play a crucial role in recognition and activation of molecular domains responsible for Gal action in the intestinal smooth muscle. [Copyright &y& Elsevier]

The effects of heme oxygenase (HO) inhibitors, zinc-protoporphyrin-IX (ZnPP-IX), and tin protoporphyrin-IX (SnPP-IX) and their interactions with L-arginine/nitric oxide synthase (NOS) and cyclooxygenase (COX) pathways were investigated in postoperative ileus in rats. Intestinal transit was measured as Evans blue migration after skin incision, laparotomy or laparotomy plus gut evisceration and handling. Laparotomy and small intestinal manipulations increased blood plasma nitrites/nitrates level 1.88-fold. Nω-nitro-L-arginine methyl ester, indomethacin, a selective COX-1 blocker (resveratrol) and COX-2 antagonists (nimesulide, DuP-697, NS-398) reversed the additional inhibitory effects of gut manipulation subsequent to laparotomy. In contrast, N-(3-(aminomethyl)benzyl)acetamidine or S-methylisothiourea, highly selective inducible NOS blockers, remained ineffective. ZnPP-IX and SnPP-IX overturned the effects of laparotomy on dye propulsion, but were only partially effective after laparotomy and gut handling attenuating the additional inhibitory influences of gut manipulation, the intestinal transit reaching 89.21%, 92.87%, 53.46%, and 48.56% of respective controls transit. Salutary effects of L-NAME, ZnPP-IX, and SnPP-IX were dose-dependent, L-arginine or hemin (HO substrate) sensitive. Administration of indomethacin and resveratrol subsequent to SnPP-IX reversed the inhibitory effects of laparotomy and manipulation, amounting to 93.91% and 87.43% of controls. On the other hand, L-NAME injected after SnPP-IX abolished the salutary effects of the latter, study dye migration reached 25.18% of control rat. Therefore we demonstrated that nitric oxide, carbon monoxide, and prostanoids play a role in the pathogenesis of postoperative ileus albeit in different mechanisms. Laparotomy stimulated HO activity, whereas gut manipulation led to an excessive constitutive NOS stimulation accompanied by augmented prostanoid synthesis by COX-1. Unaffected synthesis of either NO or CO enables a return of gastrointestinal transit during postoperative period, whereas a pharmacological blockade of two complementary metabolic pathways provides a most effective measure against postoperative ileus development. [Copyright &y& Elsevier]