Agonist-induced desensitization of liver alpha 1-receptors; implications for assessment of PI hydrolysis.
Alpha 1-adrenergic stimulation of phosphatidyl inositide (PI) hydrolysis was measured in liver slices and in cultured hepatocytes prelabeled with 3H-myoinositol. Incubation of cultured hepatocytes for 15 min with l-epinephrine stimulated the release of 3H-inositol phosphates with an EC50 of 0.28 +/- 0.19 microM and Emax representing 2.88 +/- 0.39% of incorporated radiolabel. Pretreatment of cultures with epinephrine resulted in reductions both in the maximum response and in the sensitivity to epinephrine. In liver slices, epinephrine elicited a similar maximum response (3.38 +/- 0.32%), but the sensitivity to epinephrine (EC50 = 2.27 +/- 1.27 microM) was considerably lower than for cultured cells. Prior treatment of liver slices with 200 microM l-epinephrine had no effect either on the maximum response to l-epinephrine or on the sensitivity to epinephrine. The affinity of alpha 1-adrenergic receptors for agonists was reduced 2.11 fold during incubation of liver slices for 60 min at 37 degrees C in the absence of added agonist (as is required for 3H-myoinositol labeling). Agonist affinity was not further reduced when 200 microM l-epinephrine was included in the incubation. It was concluded that alpha 1-adrenergic stimulation of PI hydrolysis in liver undergoes agonist-induced desensitization. It was also concluded that a limitation exists in the methodology for measuring PI hydrolysis in tissue slices prelabeled with 3H-myoinositol, in that this method assesses the activity of receptors in a desensitized state.
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Geriatric Research, Education and Clinical Center, Department of Veteran Affairs Medical Center, Gainesville, Florida.
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D000818:Animals; D002478:Cells, Cultured; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006868:Hydrolysis; D007294:Inositol / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011292:Premedication; D051381:Rats; D011916:Rats, Inbred F344; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*
D010716:Phosphatidylinositols; D011942:Receptors, Adrenergic, alpha; D007294:Inositol; D004837:Epinephrine