Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Supersensitivity is defined as the phenomenon in which the amount of a drug required to produce a given biological response is decreased. Supersensitivity is characterized by a shift of the drug concentration effect curve to the left. Removal of endogenous stimulation can produce supersensitivity. Postsynaptic supersensitivity occurs in the rat vas deferens following seven days of denervation and is not accompanied by an increase in receptor number or a change in inositol phosphate stimulation. The increase in sensitivity extends to a number of unrelated contractile agonists including epinephrine, ACh and angiotensin. There is no change in sensitivity to neurokinin A. This proposal studies the development and mechanism of supersensitivity in the denervated rat vas deferens, an established model of sensitivity changes. One vas deferens is denervated through a midline incision under anesthesia; the contralateral tissue serves as a paired control. The project utilizes several techniques to probe differences between denervated vas deferens and their contralateral controls.Our studies concentrate on the intracellular protein kinase C (PKC) system. Isolated tissue experiments will assess functional differences. Control and denervated vas will be contracted using the Alpha 1- adrenergic agonist norepinephrine and the tachykinin neurokinin A. The importance of intracellular PKC will be assessed using PKC stimulator phorbol-12,13 dibutyrate (PDBu) and the PKC inhibitor H-7. Receptor bindings studies with [3 H]-PDBu will determine changes in PKC in purified membranes, specifically KD and number of binding sites. Electrophysiological experiments will compare the effects of adrenergic agonist and neurokinin A on resting membrane potential and action potential characteristics in control and supersensitive tissues. Supersensitivity accompanies a number of diseases (hypertension, ulcerative colitis) and drug treatments. Its understanding in this animal model may provide insight into supersenitivity in humans.
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