Pharmacological characterization of arteriolar smooth muscle located vanilloid receptor‐1 (TRPV1)

Abstract

Earlier we found a functional TRPV1 expression in arteriolar smooth muscle cells, suggesting a new drug target to regulate microvascular diameter. We characterized the vascular smooth muscle located TRPV1 mediated vasoconstriction to establish its pharmacological properties. Vascular diameter of isolated, pressurized skeletal (m. gracilis) muscle arterioles possessing spontaneous myogenic tone was measured upon treatment by various TRPV1 agonists. First, capsaicin responses were investigated in detail. Application of TRPV1 knock out mice and AMG9810 (a specific competitive inhibitor) confirmed the involvement of TRPV1. Then potency, efficacy, kinetics of action, receptor desensitization was determined for a set of agonists to establish SAR. Some of the tested TRPV1 agonists evoked substantial constrictions (capsaicin, MSK-195, JYL-79), while others were without effect (resiniferatoxin, JYL-273), but generarly leading to a complete desensitization of arteriolar TRPV1 (with the exception of capsaicin). Potency of the applied agonists was also tested on a nociceptive test (eye -wiping) suggesting that the arteriolar smooth muscle located TRPV1 has different structure-activity relationship than the sensory neuron located receptor. Funding: TÁMOP-4.2.1.B-09/1/KONV-2010-0007