P37620-HETE-induced activation of TRPV1: a novel pathway influencing blood pressure and coronary resistance

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A novel vasoconstrictor pathway involving the neuronal non-selective cation channel, transient receptor potential vanilloid 1 (TRPV1) and the arachidonic acid-derived vasoconstrictor, 20-hydroxyeicosatetraenoic acid (20-HETE) has recently been proposed. It has been demonstrated that both pressure- and 20-HETE-induced vasoconstriction of mesenteric arteries are near-abolished after treatment with the TRPV1 antagonist, capsazepine (Scotland et al. 2004, Circ Res. 95:1027-1034.). The aim of this study was to determine whether this pathway might influence blood pressure (BP) and coronary artery resistance.


Changes in BP in response to 20-HETE (0.07-2.1 μmol/kg) were determined in conscious wildtype (WT) and TRPV1 knockout (KO) mice. In isolated, perfused hearts changes in coronary perfusion pressure (CPP) in response to 20-HETE (10 nmol) or the classical TRPV1 activator, capsaicin (1 nmol) were determined. Responses were measured in the absence or presence of TRPV1 antagonist, capsazepine (3 μmol/l, in vitro) or NK1 receptor antagonist, RP 67580 (in vivo 0.4 mg/kg, i.v.; in vitro 1 μmol/l), to determine the contribution of substance P (a neuropeptide released from C-fibre nerve endings after TRPV1 activation).


20-HETE caused dose-dependent increases in mean arterial pressure (MAP) in WT mice that were substantially attenuated in KO mice (P=0.0002, n=8). In WT mice RP 67580 reduced 20-HETE-induced elevations in MAP (max 80% reduction, P=0.027, n=5). Both 20-HETE and capsaicin caused increases in CPP (by 17 ± 7 and 26 ± 4 mmHg, respectively, n=7), which were abolished by capsazepine (20-HETE, P < 0.05 and capsaicin, P < 0.001, n=7) and in hearts from KO mice. Blockade of substance P receptors (n=7) resulted in significant reductions in 20-HETE (P < 0.05) and capsaicin-induced (P < 0.01) increases in CPP.


These findings suggest that activation of TRPV1 by 20-HETE results in elevations of BP, which is likely due to increased peripheral resistance. Both BP and CPP elevations in response to 20-HETE are attenuated by NK1 receptor antagonism, indicating that the release of substance P from C-fibre nerve endings, underlies the vasoconstrictor effects of 20-HETE. These findings identify a novel pro-hypertensive pathway; the targeting of which may prove a useful strategy in the therapeutics of hypertension.


This work was funded by The Wellcome Trust

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