EXISTENCE OF A β3-ADRENOCEPTOR AND ITS FUNCTIONAL ROLE IN THE HUMAN URETER

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Abstract
We tried to determine the β-adrenoceptor (AR) subtypes distributed in the human ureter and to clarify their functional role in ureteral relaxation. 1) Effects of β-AR agonists on either spontaneous or KCl-induced contractions of the human ureter and the antagonism by β-AR antagonists on isoprenaline (a non-selective β-AR agonist)-induced effects were evaluated in vitro. 2) Displacement by β-AR antagonists of [3H]-dihydroalprenolol binding to a membrane preparation derived from human ureteral smooth muscle was evaluated. 3) A reverse transcription polymerase chain reaction assay was performed to determine the expression of the mRNA for β1-, β2- and β3-ARs in human ureteral smooth muscle. 1) Isoprenaline and procaterol (a β2-AR agonist) concentration-dependently suppressed both spontaneous and KCl-induced contractions of the human ureter. The β3-AR agonists, CGP-12177A and CL-316243, also suppressed these ureteral contractions, but dobutamine (a β1-AR agonist) had little relaxing effect. The rank order of relaxing potency for the catecholamines was isoprenaline > adrenaline > noradrenaline. ICI-118,551 (a β2-AR antagonist) only partially antagonized the isoprenaline-induced relaxation. 2) Propranolol (a non-selective β-AR antagonist) and ICI-118,551 concentration-dependently displaced [3H]-dihydroalprenolol binding to the membrane with Ki values of 1.5 × 10−9 M and 6.3 × 10−9 M, respectively, while metoprolol (a β1-AR antagonist) was less effective in this assay. 3) β1-, β2- and β3-AR mRNAs were all expressed in human ureteral smooth muscle. The present results provide the first evidence that the β3-AR subtype is distributed in human ureteral smooth muscle and that it, and β2-AR, mediate the ureteral relaxation induced by adrenergic stimulation.