TRPV1 mediation of local vasoconstrictor reflexes in spinal cord injured humans

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DESCRIPTION (provided by applicant): The arteriolar myogenic response and the venoarteriolar reflex (VAR) are local vasoconstrictor responses to increased intravascular pressure that involve local sensory afferents. Recent evidence suggests that these responses involve activation of the neuronal vanilloid receptor, TRPV1 on C-fibers causing local depolarization and neuropeptide release effects local vasoconstriction. The VAR occurs when venous pressure increases more than 25mmHg and causes a reduction in blood flow probably by distention of stretch receptors that results in an 'upstream' arteriolar vasoconstriction throug non-adrenergic local neuronal mechanisms that may also involve TRPV1. These local vasoconstrictor responses occur in able-bodied persons, but are of special importance in maintaining hemodynamic stability after spinal cord injury (SCI) where there is loss of baroreflex mediated sympathetic vasoconstriction; indeed, these vasoconstrictor responses may even be enhanced in SCI. This pilot project will test the hypothesis that TRPV1 receptors participate in the locally mediated vasoconstrictions by the myogenic response and venoarteriolar reflex in humans. In addition, we hypothesize that enhanced local vasoconstrictor responses found caudal to the level of injury in SCI is due to augmented TRPV1-mediated local neurovascular reflexes. Our specific aims to test our hypotheses in humans in vivo are: 1. Are TRPV1 receptors more prevalent in SCI than in able-bodied individuals? 2. Does blockade of TRPV1 receptors attenuate the myogenic response in SCI and able-bodied individuals and does this attenuation differ between groups? 3. Does blockade of TRPV1 receptors attenuate the venoarteriolar reflex in SCI and able-bodied individuals and does this attenuation differ between groups? Aims will be addressed in healthy able-bodied and SCI subjects in skin as this is a readily accessible tissue that manifests both the myogenic response and VAR. Skin biopsies from able-bodied persons and from sensate and insensate skin of SCI persons will be tested for TRPV1 receptor density in Aim 1. Aims 2 and 3 will be tested in the same groups by comparing the effects of local anesthesia and TRPV1 receptor antagonism on myogenic responses and the VAR during limb dependency and limb cuff inflation. Local anesthesia will be by EMLA and TRPV1 receptor blockade by local administration of capsazepine. Responses will be recorded by laser-Doppler flowmetry.