The effect of cold-stress on alpha₂ modulation of transmitter release and transmitter uptake in the rat caudal artery Public Deposited

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  • The level of postganglionic sympathetic nerve activity is important in determining the tone of vascular smooth muscle, and subsequent maintenance of normal blood pressure. It is generally agreed that receptors located on postganglionic nerve terminals (pre-junctional alpha₂ receptors) are important in the modulation of neurotransmitter (norepinephrine) release from these nerves. This pre-junctional membrane is also the major site for the termination of the action of the neurotransmitter by re-uptake. These studies investigated the effects of a physiological elevation in sympathetic nervous system activity by cold-stress on these two important deter minants of adrenergic function. The effect of the alpha,, agonist clonidine on vascular adrenergic neuroeffector transmission was investigated in caudal arteries from the rat tail. Caudal arteries were isolated and their responses to electrical stimulation of the adrenergic nerves and/or to clonidine were assessed. Clonidine was found to act as a partial agonist at alpha₁ post-junctional receptors at concentrations above those used for investigation of alpha₂ prejunctional receptors. Concentrations of clonidine used to selectively stimulate pre-junctional receptors had no effect on basal perfusion pressure, but did facilitate the vascular response to exogenous nor epinephrine in the caudal artery of the non-stressed rat. Clonidine was able to inhibit the response to electrical stimulation in arteries from non-stressed rats in a frequency-dependent manner. It was concluded that clonidine, acting as an agonist on alpha₂ pre-junctional receptors, decreased the vascular response to electrical stimulation. Rats subjected to cold-stress show increased sympathetic nerve activity in the caudal artery as evidenced by levels of tyrosine hydroxylase. Caudal arteries from cold-stressed rats displayed similar responses to exogenous norepinephrine and clonidine as those seen in arteries from non-stressed rats, indicating that cold-stress did not alter the functional vascular response of post-junctional alpha, receptor. Clonidine was able to inhibit the vascular response to electrical stimulation in cold-stress arteries qualitatively in the same way as that seen in non-stressed arteries but with a quantitatively smaller degree of inhibition. Regression analysis of these data showed the log frequency-inhibition curve of cold-stressed arteries to be parallel and shifted to the left when compared with the non-stressed curve. These data were interpreted to mean that cold-stress treatment had induced a down-regulation or subsensitivity of the alpha₂ receptors located on the postganglionic nerves of caudal arteries throughout the range of frequencies tested. When arteries were electrically stimulated at a constant frequency and the inhibition of the repsonse to varying clonidine concentrations was measured, the responses to electrical stimulation in cold-stressed arteries were inhibited to a significantly smaller degree than the responses in non-stressed arteries. Both log dose-inhibition curves were somewhat sigmoidal and the cold-stress curve displayed competitive inhibition when compared with the non-stressed curve in a Lineweaver-Burke analysis. These data were interpreted to mean that cold-stress had induced the down-regulation of alpha₂ receptors by causing a change in the affinity of the alpha₂ receptor for clonidine. The mean contractile responses of arteries to electrical stimulation were slightly lower in arteries from cold-stressed rats when compared with arteries from non-stressed rats. Arteries from cold-stressed rats were able to take up ³H-norepinephrine to a greater extent than arteries from non-stressed rats. This action was significant at high frequencies of stimulation while at lower frequencies of stimulation the difference was not significant. Therefore, these observations are unlikely to provide a full explanation for the mostly insignificant parallel shift of the frequency-response control curve of the cold-stress arteries, since the magnitudes of the changes in norepinephrine uptake following cold-stress are frequency-dependent, and not parallel. These studies demonstrate that an elevation of sympathetic nervous system activity results in significant changes in the release and re-uptake of the adrenergic transmitter norepinephrine which may play important roles in both pysiological and pathological processes.
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