Pharmacology of vanilloids at recombinant and endogenous rat vanilloid receptors

• Published in: Biochemical pharmacology Vol. 65; no. 1; pp. 143 - 151
• Main Authors: Ralevic, Vera, Jerman, Jeffrey C, Brough, Stephen J, Davis, John B, Egerton, Julie, Smart, Darren
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 2003; Elsevier Science
• Subjects: Alkaloids - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Cells, Cultured; Diterpenes - pharmacology; Drug Interactions; Humans; Indicators and Reagents; Isovelleral; Medical sciences; Mesenteric Arteries - drug effects; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Olvanil; Pharmacology. Drug treatments; Phenols - pharmacology; Phorbol Esters - pharmacology; PPAHV; Receptors, Drug - drug effects; Receptors, Drug - metabolism; Recombinant Proteins - drug effects; Recombinant Proteins - metabolism; Resiniferatoxin; Ruthenium Red - pharmacology; Scutigeral; Sensory Receptor Cells - drug effects; Sesquiterpenes - pharmacology; Vanilloid VR1 receptor; Isovelleral; PPAHV; Resiniferatoxin; PPAHV, phorbol 12-phenyl-acetate 13-acetate 20-homovanillate; Olvanil; Vanilloid VR1 receptor; Scutigeral; Agonist; Rat; Capsaicin; Ligand; Rodentia; Central nervous system; Dorsal ganglion; Vasodilation; Vertebrata; Mesenteric artery; Vasomotricity; Mammalia; Neuron; Animal; Sensory nerve; Circulatory system; Vanilloid receptor; Calcium Cations
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(02)01451-X

This study compared the actions of members of five different chemical classes of vanilloid agonists at the recombinant rat vanilloid VR1 receptor expressed in HEK293 cells, and at endogenous vanilloid receptors on dorsal root ganglion cells and sensory nerves in the rat isolated mesenteric arterial bed. In mesenteric beds, vanilloids elicited dose-dependent vasorelaxation with the rank order of potency: resiniferatoxin⪢capsaicin=olvanil>phorbol 12-phenyl-acetate 13-acetate 20-homovanillate (PPAHV)>isovelleral. Scutigeral was inactive. Responses were abolished by capsaicin pretreatment and inhibited by ruthenium red. In VR1-HEK293 cells and dorsal root ganglion neurones, Ca
2+ responses were induced by resiniferatoxin>capsaicin=olvanil>PPAHV; all four were full agonists. Isovelleral and scutigeral were inactive. The resiniferatoxin-induced Ca
2+ response had a distinct kinetic profile. Olvanil had a Hill coefficient of ∼1 whilst capsaicin, resiniferatoxin and PPAHV had Hill coefficients of ∼2 in VR1-HEK293 cells. The capsaicin-induced Ca
2+ response was inhibited in a concentration-dependent manner by ruthenium red>capsazepine>isovelleral. These data show that resiniferatoxin, capsaicin, olvanil and PPAHV, but not scutigeral and isovelleral, are agonists at recombinant rat VR1 receptors and endogenous vanilloid receptors on dorsal root ganglion neurones and in the rat mesenteric arterial bed. The vanilloids display the same relative potencies (resiniferatoxin>capsaicin=olvanil>PPAHV) in all of the bioassays.