Influence of perivascular peptides on endoneurial blood flow and microvascular resistance in the sciatic nerve of the rat.

1. A variety of vasoactive peptides has been identified in the axon terminals innervating vasa nervorum but their function is unknown. In mesenteric arterioles, substance P (SP) and calcitonin gene-related peptide (CGRP) have been postulated to have a role in tonic vasodilatation. 2. We explored the effect of epineurial capsaicin, SP, CGRP, spantide (SP antagonist), and hCGRP (8-37) (CGRP antagonist) on blood flow (EBF) and microvascular resistance (EMR) in the endoneurial compartment of the rat sciatic nerve, as measured by hydrogen clearance. 3. Epineurial capsaicin induced a prompt, intense and prolonged increase in EBF and lowering of EMR as compared to epineurial application of the carrier alone in a separate animal group. The hyperaemic response was also confirmed by studying serial clearance curves in individual animals. 4. Multifibre sciatic-tibial motor conduction was not changed by epineurial capsaicin. 5. When co-administered with capsaicin, hCGRP (8-37) completely blocked the hyperaemic response and increased EMR above the pooled control range. Spantide also blocked the capsaicin response. 6. When administered alone, both epineurial hCGRP (8-37) and spantide lowered EBF below and increased EMR above the control measurements in the same animals. 7. At 10(-5) M epineurial CGRP, but not SP lowered EMR. Vasodilatation from intra-arterial administration of CGRP was much greater and was more prolonged compared with that induced by SP. hCGRP (8-37), but not spantide reduced the intra-arterial response to CGRP. 8. The findings suggest that epineurial peptidergic terminals mediate a vasodilatory response (particularly through CGRP) that increases blood flow in the 'downstream' endoneurial compartment. Physiological peptide release (blocked by SP and CGRP receptor antagonism) may be important in maintaining tonic vasodilatation.