Evidence from guinea-pig trachealis that Uptake2 of isoprenaline is enhanced by hyperpolarization of the smooth muscle

Previous studies (Bönisch et al. 1985; Trendelenburg 1986, 1987) have provided evidence that Uptake2 of catecholamines is inhibited by depolarization of cells. The aim of this study was to further examine the relationship between Uptake2 and membrane potential by testing the hypothesis that Uptake2 is, conversely, stimulated by hyperpolarization of cells. The effects of β-adrenoceptor agonists (isoprenaline and salbutamol) and β-adrenoceptor antagonists (propranolol and ICI 118,551) on Uptake2 of isoprenaline were examined in guinea-pig trachealis muscle, in which stimulation of β-adrenoceptors mediates hyperpolarization of the smooth muscle cells (Allen et al. 1985), and in rat heart, in which β-adrenoceptor agonists do not cause hyperpolarization. In guinea-pig trachealis muscle segments, propranolol and ICI 118,551 reduced Uptake2 (as measured by the steady-state rate of corticosterone-sensitive formation of 3-O-methylisoprenaline normalized for the isoprenaline concentration) in tissues incubated in 2.5–250 nmol/l 3H-isoprenaline (in the range over which isoprenaline causes hyperpolarization of the muscle), but not in 1 nmol/l 3H-isoprenaline (which does not hyperpolarize the muscle). The normalized rates were greater in tissues incubated in 25 nmol/l than 1 nmol/l isoprenaline, and were enhanced by 2.5 gmol/l salbutamol in tissues incubated in 1 nmol/l isoprenaline. In rat hearts perfused with 1 or 25 nmol/l 3H-isoprenaline and U-0521 to inhibit catechol-O-methyltransferase, the rate of Uptake2 of isoprenaline, normalized for the isoprenaline concentration, was unaffected by the isoprenaline concentration or the presence of propranolol, ICI 118,551 or salbutamol. The results of the study suggest that, in guinea-pig trachealis muscle, isoprenaline and salbutamol enhance Uptake2 due to β-adrenoceptor-mediated hyperpolarization of the muscle and that propranolol and ICI 118,551 decrease Uptake2 of isoprenaline by preventing this hyperpolarization of the smooth muscle, and not by directly inhibiting the Uptake2 transport process