Rw Marshall

Suramin: a selective inhibitor of purinergic neurotransmission in the rat isolated vas deferens

The effects of the putative P2 purinoceptor antagonist suramin on contractile responses of the rat isolated vas deferens to electrical field stimulation and exogenously applied drugs (alpha,beta-methylene ATP and noradrenaline) were investigated. Suramin was devoid of agonist activity in the rat vas deferens. The response of the vas deferens to single pulse field stimulation was characteristically biphasic with a large first component peaking between 260-300 ms after the stimulus followed by a second smaller component peaking at about 650 ms post-stimulus. Suramin (100 nM-1 mM) selectively impaired the first, purinergic phase of the response to single pulse field stimulation but was without effect on the second, noradrenergic component. The response of the vas deferens to trains of electrical field stimuli (10 Hz for 10 s) was also biphasic. Suramin (1 microM-1 mM) reduced the first (less than 1 s) phase of the response by 30%, the second (greater than 5 s) plateau phase by 50% and inhibited the intermediate (2-4 s) phase by 80%. Dose-contact periods of 20 or 30 min respectively were sufficient to achieve equilibration of the inhibitory effects of suramin against the responses to single pulse field stimulation or trains of pulses. Following 30 min incubation with 1 mM suramin, the remaining first and second phase components of the response to trains of pulses were impaired and subsequently abolished by the alpha 1-adrenoceptor antagonist WB4101 establishing their noradrenergic origin. Suramin (300 microM) abolished responses of the vas deferens to alpha,beta-methylene ATP but was without effect on those to noradrenaline. Suramin (30 microM) induced a rightward shift in the concentration-response relationship to alpha,beta-methylene ATP that was associated with a significant 40% increase in the maximum response, but did not modify responses to noradrenaline. The inhibitory effects of suramin (3-300 microM) on responses of the vas deferens to approximate EC50 concentrations of alpha,beta-methylene ATP were reversible on repeated washout for 40-60 min. These results reveal suramin to be a useful pharmacological tool for the study of purinergic neurotransmission in rodent vasa deferentia.

Separation of putative α1A- and α1B- adrenoceptor mediated components in the tension response of the rat vas deferens to electrical field stimulation

1 The effects of the putative α1B‐adrenoceptor antagonist, chloroethylclonidine (CEC), on tension responses of the rat isolated whole vas deferens to single and multiple pulses of electrical field stimulation have been evaluated by use of a microcomputer system which enables the averaging of like‐responses throughout their time course. 2 CEC (10−7 to 3 × 10−6 m) selectively and in a concentration‐dependent manner blocked the noradrenergic component of the response to a single field stimulus in the absence or presence of nifedipine (10−5 m, which blocked the purinergic but not the noradrenergic component of the response). The concentration‐response curve of the vas to exogenously‐applied noradrenaline (NA) was unaffected by CEC (10−6 m) but was flattened by nifedipine (10−5 m). 3 The tension response to 10 Hz trains of pulses was biphasic, with an early (< 2 s) and a plateau (> 4 s) phase. We deduce from our pharmacological analysis that the early phase contains a putative α1B‐adrenoceptor component (susceptible to CEC or prazosin but not to nifedipine) and a P2‐purinoceptor component (susceptible to suramin or nifedipine) whereas the plateau phase contains an α1A‐adrenoceptor component (susceptible to prazosin or nifedipine but not to CEC) and a P2‐purinoceptor component (susceptible to suramin or nifedipine). 4 We suggest that the putative α1B‐adrenoceptors may be functionally confined to the synaptic region whereas the putative α1A‐adrenoceptors are excluded from this region. Trains of pulses would allow NA to accumulate and spill out beyond the synaptic region to reach and activate the putative α1A‐adrenoceptors.

Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis

Ulcerative colitis is a condition of nonsmokers in which nicotine is of therapeutic benefit.

Nicotine enemas for treatment of ulcerative colitis: a study of the pharmacokinetics and adverse events associated with three doses of nicotine

Background : Transdermal nicotine is of value in active ulcerative colitis but causes adverse events because of systemic absorption. Nicotine enemas may give rise to fewer adverse events.

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

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.

Human cognitive function following binedaline (50 mg and 100 mg) and imipramine (75 mg): Results with a new battery on tests

Abstract1. The effects of two single oral doses of binedaline (50 and 100 mg), imipramine (75 mg) and placebo were compared on a range of psychological tasks (logical reasoning, the Stroop test, and five-choice serial reaction) in healthy young volunteers.2. The tasks, together with a mood adjective check-list, were completed prior to drug administration and 1, 2, 4 and 8 h post-dose.3. Binedaline had no significant effect on any of the task parameters.4. Imipramine impaired performance on all but the Stroop test at 2 h after drug administration. At 1, 2 and 4 h, ratings on the “deactivation” dimension of the mood adjective check-list were significantly higher following imipramine when compared to placebo.5. The results are discussed in terms of some general considerations about the selection and scoring of tasks to be used in the screening of drugs.