Structure-activity relationships of vanilloid receptor agonists for arteriolar TRPV1

Br J Pharmacol. 2012 Mar;165(6):1801-1812. doi: 10.1111/j.1476-5381.2011.01645.x.


Background and purpose: The transient receptor potential vanilloid 1 (TRPV1) plays a role in the activation of sensory neurons by various painful stimuli and is a therapeutic target. However, functional TRPV1 that affect microvascular diameter are also expressed in peripheral arteries and we attempted to characterize this receptor.

Experimental approach: Sensory TRPV1 activation was measured in rats by use of an eye wiping assay. Arteriolar TRPV1-mediated smooth muscle specific responses (arteriolar diameter, changes in intracellular Ca(2+)) were determined in isolated, pressurized skeletal muscle arterioles obtained from the rat and wild-type or TRPV1(-/-) mice and in canine isolated smooth muscle cells. The vascular pharmacology of the TRPV1 agonists (potency, efficacy, kinetics of action and receptor desensitization) was determined in rat isolated skeletal muscle arteries.

Key results: Capsaicin evoked a constrictor response in isolated arteries similar to that mediated by noradrenaline, this was absent in arteries from TRPV1 knockout mice and competitively inhibited by TRPV1 antagonist AMG9810. Capsaicin increased intracellular Ca(2+) in the arteriolar wall and in isolated smooth muscle cells. The TRPV1 agonists evoked similar vascular constrictions (MSK-195 and JYL-79) or were without effect (resiniferatoxin and JYL-273), although all increased the number of responses (sensory activation) in the eye wiping assay. Maximal doses of all agonists induced complete desensitization (tachyphylaxis) of arteriolar TRPV1 (with the exception of capsaicin). Responses to the partial agonist JYL-1511 suggested 10% TRPV1 activation is sufficient to evoke vascular tachyphylaxis without sensory activation.

Conclusions and implications: Arteriolar TRPV1 have different pharmacological properties from those located on sensory neurons in the rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / pharmacology
  • Animals
  • Arterioles / drug effects
  • Arterioles / physiology*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • CHO Cells
  • Calcium / physiology
  • Capsaicin / pharmacology
  • Coronary Vessels / cytology
  • Coronary Vessels / drug effects
  • Coronary Vessels / physiology
  • Cricetinae
  • Cricetulus
  • Dogs
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / blood supply
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / physiology
  • Rats
  • Rats, Wistar
  • Sensory Receptor Cells / physiology
  • Structure-Activity Relationship
  • TRPV Cation Channels / agonists*
  • TRPV Cation Channels / antagonists & inhibitors
  • TRPV Cation Channels / deficiency
  • TRPV Cation Channels / physiology*
  • Vasoconstriction / drug effects
  • Vasoconstrictor Agents / chemistry
  • Vasoconstrictor Agents / pharmacology*


  • 3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide
  • Acrylamides
  • Bridged Bicyclo Compounds, Heterocyclic
  • TRPV Cation Channels
  • TRPV1 receptor
  • Vasoconstrictor Agents
  • Capsaicin
  • Calcium