Bowel dysfunction is a common non-motor symptom in Parkinson’s disease (PD). The main contractile neurotransmitter in the GI tract is acetylcholine (ACh), while nitric oxide (NO) causes the relaxation of smooth muscle in addition to modulating ACh release. The aim of this study was to characterise functional and neurochemical changes in the isolated ileum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset, an established model of PD motor dysfunction. While NO-synthase inhibitor L-NAME concentration dependently augmented the neurogenically-evoked contractions and inhibited the relaxations in normal tissues, it had no effects on the MPTP ileum. Immunohistochemical analyses of the myenteric plexus showed that ChAT-immunoreactivity (-ir) was significantly reduced and the density of the enteric glial cells as shown by SOX-10-ir was increased. However, no change in TH-, 5-HT-, VIP- or nNOS-ir was observed in the MPTP tissues. The enhancement of the neurogenically-evoked contractions and the inhibition of the relaxation phase by L-NAME in the control tissues is in line with NO’s direct relaxing effect on smooth muscle and its indirect inhibitory effect on ACh release. The absence of the relaxation and the inefficacy of L-NAME in the MPTP tissues suggests that central dopaminergic loss dopamine may eventually lead to the impairment of NO signal coupling that affects bowel function, and this may be the result of a complex dysregulation at the level of the neuroeffector junction.

SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts AL6 9AR 1 SK&F 95654 inhibited the guanosine 3':5'-cyclic monophosphate (cyclic GMP)-inhibited phosphodiesterase (cGI-PDE) with an IC50 value of 0.7 g1M. The IC50 values were greater than 100 1M for the other four phosphodiesterase isoenzymes tested. The R-enantiomer of SK&F 95654 (IC50 = 0.35 1M) was a more potent inhibitor of cGI-PDE than was the S-enantiomer (IC50 = 5.3 LM). 2 In the guinea-pig working heart, SK&F 95654 produced a positive inotropic response without altering heart rate. 3 Oral administration of SK&F 95654 to conscious dogs caused dose-dependent increases in left ventricular dpldtM,, in the range 10-50 tg kg-'. These positive inotropic responses were maintained for 3 h without simultaneous changes in heart rate or blood pressure. The peak effects on left ventricular dp/dtma, were similar for orally and intravenously administered compound, indicating good oral bioavailability. 4 SK&F 95654 caused a potent inhibition of U46619-induced aggregation in both a human washed platelet suspension (WPS) (ICm = 70 nM) and in human platelet-rich plasma (PRP) (IC50 = 60 nM), indicating that the compound shows negligible plasma binding. 5 The R-enantiomer of SK&F 95654 was twenty fold more potent as an inhibitor of platelet aggregation than was the S-enantiomer. The similarity of this ratio to that obtained on the cGI-PDE suggests that SK&F 95654 inhibits platelet aggregation via its effects on cGI-PDE. This was also indicated by studies which showed that SK&F 95654 increased adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels and activated cyclic AMP-dependent protein kinase in human platelets. 6 Collagen-induced aggregation of rat PRP was also inhibited by SK&F 95654 (ICso = 65 nM). The effects of SK&F 95654, administered intravenously, on ex vivo platelet aggregation were studied in the conscious rat. At 1 mg kg-', SK&F 95654 inhibited aggregation for at least 4 h post dose and was more potent than the two other cGI-PDE inhibitors studied (siguazodan and SK&F 94120). 7 In contrast to its potent effects on heart and platelets, SK&F 95654 caused only a modest relaxation of histamine-or U46619-induced bronchoconstriction in the anaesthetized, ventilated guinea-pig. 8 Taken together, these results indicate that SK&F 95654 may be a suitable agent for the treatment of congestive heart failure.

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