Purines in Co-Transmission

The sub-types of alpha-adrenoceptors which mediate pressor responses to sympathomimetic agonists or to nerve stimulation in pithed rabbits have been classified according to the effects of "selective" antagonists and a comparison has been made, for the alpha2 subtype, with corresponding responses in the rat. In the rabbit the dose-response curve for phenylephrine was shifted to the right in parallel by prazosin (1 mg/kg) and was unaffected by rauwolscine (1mg/kg). The dose-response curve for noradrenaline was shifted to the right by prazosin (1 mg/kg) and was shifted to a smaller extent by rauwolscine (lmg/kg) or imiloxan (10 mg/kg). After rauwolscine, prazosin produced a rightward shift larger than when given alone. After prazosin, rauwolscine produced a rightward shift larger than when given alone. The responses to pressor nerve stimulation at low frequencies (1Hz) could be reduced by prazosin, rauwolscine or imiloxan but those at higher frequency could be reduced only by prazosin. These results indicate that the responses to noradrenaline or to nerve stimulation are mediated by both alpha1- and alpha2-adrenoceptors. Low doses or frequencies have a proportionately greater component which is alpha2. Responses to noradrenaline after prazosin (1 mg/kg), were sufficiently sensitive to rauwolscine to be considered as predominantly alpha2. A comparison was therefore made of prazosin-resistant pressor responses to noradrenaline in the rat and rabbit. Pressor responses to noradrenaline were produced by a lower dose per unit body weight in the rat whereas this was less marked for the alpha2-arenoceptor agonist guanabenz. In the rabbit pressor responses to noradrenaline were more susceptible to blockade by rauwolscine but were less sensitive to Wy 26703 than in the rat. This demonstrates that the alpha2- adrenoceptors mediating pressor responses in vivo, like those in other tissues in vitro, are different in rat and rabbit, with regard to sensitivity to antagonists. The fractions of alpha versus non-alpha components of vasopressor responses were assessed in the pithed rat preparation. Sympathetic pressor nerves exit from the spinal cord over most of the thoraco-lumbar outflows, the optimum region for evoking increases in systemic arterial blood pressure being T6 - T8. This region was therefore chosen for the study of the involvement of purinergic co-transmission in sympathetic nerve transmission. In the case of the vas deferens, maximal responses were obtained by stimulation at regions T13-L1 (McGrath, 1973). The involvement of purines in the pressor responses to stimulation of the spinal sympathetic outflow was investigated by the following methods. Firstly the position was found in the spinal column where the pithing rod electrode should be placed to give large responses suitable for investigating the relative involvement of the components within the response. This allowed determination of the optimum stimulatory parameters for the alpha-blocker-resistant component of the sympathetic pressor response which could be unmasked by giving combined alpha1- and alpha2-adrenoceptor blockade. Secondly a suitable protocol was developed for the use of the best P2'-purinoceptor desensitising agent available, alpha,beta-mATP. After desensitisation, its influence on nerve mediated responses was assessed. Finally responses to ATP and mATP were studied and compared with the responses obtained by sympathetic stimulation. These first two approaches have been used in the past but to limited success (Flavahan et al,1985), mainly due to the ineffective dosage of mATP employed. The P2-purinoceptor desensitising agent mATP was believed to be a very stable analogue of ATP (Delbro et al,1985). It was on this assumption that investigations were carried out on responses obtained to sympathetic nerve stimulation after 'desensitisation' with a single dose of mATP. However the stability and effectiveness of mATP in vivo could be much less that reports from in vitro studies suggest (Milner-White & Rycroft, 1983) since they take into account only one of the enzyme reactions which degrade ATP and none of the uptake or dissipating mechanisms which occur in vivo. Therefore it seemed possible that the limited success of other workers was due to the ineffectiveness of mATP rather than because there was little or no purinergic involvement. (Abstract shortened by ProQuest.)