Differential hyperpolarization to substance P and calcitonin gene-related peptide in smooth muscle versus endothelium of mouse mesenteric artery.

OBJECTIVE

We sought to define how sensory neurotransmitters substance P and calcitonin gene-related peptide (CGRP) affect membrane potential of vascular smooth muscle and endothelium.

METHODS

Microelectrodes recorded membrane potential of smooth muscle from pressurized mouse mesenteric arteries (diameter, ~150 µm) and in endothelial tubes.

RESULTS

Resting potential was similar (~ -45 mV) for each cell layer. Substance P hyperpolarized smooth muscle and endothelium ~ -15 mV; smooth muscle hyperpolarization was abolished by endothelial disruption or NO synthase inhibition. Blocking K channels (apamin + charybdotoxin) attenuated hyperpolarization in both cell types. CGRP hyperpolarized endothelium and smooth muscle ~ -30 mV; smooth muscle hyperpolarization was independent of endothelium. Blocking K channels prevented hyperpolarization to CGRP in endothelium but not smooth muscle. Inhibiting K channels with glibenclamide or genetic deletion of K 6.1 attenuated hyperpolarization in smooth muscle but not endothelium. Pinacidil (K channel agonist) hyperpolarized smooth muscle more than endothelium (~ -35 vs. ~ -20 mV).

CONCLUSIONS

Calcitonin gene-related peptide elicits greater hyperpolarization than substance P. Substance P hyperpolarizes both cell layers through K channels and involves endothelium-derived NO in smooth muscle. Endothelial hyperpolarization to CGRP requires K channels, while K channels mediate hyperpolarization in smooth muscle. Differential K channel activation in smooth muscle and endothelium through sensory neurotransmission may selectively tune mesenteric blood flow.