For any given frequency of sympathetic nerve stimulation, a greater vasoconstrictor response is observed in spontaneously hypertensive rats (SHR) compared to normotensive Wistar Kyoto control rats (WKY). This enhanced noradrenergic neurotransmission in SHR is due in part to some unknown defect in the control of norepinephrine exocytosis, such that for a given impulse frequency a greater quantity of norepinephrine is released from noradrenergic varicosities in SHR than in WKY. Sympathetic nerve stimulation increases the production rate of prostaglandins (PGs) by postjunctional elements and PGE-2, PGD-2 and, less potently, PGI-2 inhibit neurotransmitter release. Therefore, a PG negative feedback loop controlling norepinephrine release may be operative. In a recent study Martineau et al. (25) determined, using highly specific methodology, that in vivo synthesis of PGE-2 and PGI-2 is markedly depressed in SHR. Defective synthesis of PGs in SHR could interrupt the PG negative feedback loop controlling norepinephrine release and account for the enhanced neurotransmission characteristic of SHR. In pilot experiments the activity of the PG negative feedback loop in SHR and WKY was assessed by examining the consequences of interrupting the PG feedback loop by blocking PG biosynthesis. In WKY, inhibition of PG biosynthesis increased by 100% the vascular response to sympathetic nerve stimulation, without influencing the response to exogenous norepinephrine. In contrast in SHR, blockade of PG biosynthesis did not influence the vascular response to either sympathetic nerve stimulation or norepinehrine. The implication from this experiment is that in WKY the PG negative feedback loop controlling norepinephrine release is functional; whereas, in SHR this system is defective. The goal of this proposal is to further assess the hypothesis that the PG negative feedback loop controlling norepinephrine release is defective in SHR. To achieve this goal the in vivo activity of the PG negative feedback loop controlling norepinephrine release will be determined and compared in SHR and WKY using four different approaches: 1) The effects of cyclooxygenase inhibition on vascular responses to sympathetic nerve stimulation will be determined in the in situ blood perfused mesentery and kidney of SHR and WKY. 2) The effects of cyclooxygenase inhibition on the neuronal spillover of norepinephrine will be measured in the mesentery and kidney of SHR and WKY. 3) The effects of PGE-2, PGD-2 and PGI-2 on noradrenergic neurotransmission will be assessed in the mesentery and kidney of SHR and WKY. 4) The effects of sympathetic nerve stimulation on PGE-2 and 6-keto-PGF-1Alpha biosynthesis will be determined in the mesentery and kidney of SHR and WKY.
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