The influence of drugs on the overflow of noradrenaline and the identification of receptors in guinea-pig atria.

1 Salbutamol (1.0 microM) and isoprenaline (1.2 nM) significantly increased the fractional release of tritiated noradrenaline from driven left atria but phentolamine (10 microM) failed to do so. Butoxamine (4.0 microM) blocked the increase in overflow produced by isoprenaline. Isoprenaline (1.2 nM), phentolamine (10.0 microM) and salbutamol (1.0 microM) failed to increase the overflow of tritiated noradrenaline from spontaneously beating atria. 2 Spontaneously beating atria were therefore used to identify the receptors mediating chronotropism and inotropism. 3 There was no clear relationship between inotropism and chronotropism. 4 The inotropic effects of both dobutamine (0.04-4.0 microM) and isoprenaline (0.11-9.0 nM) were inhibited by practolol (4.0 microM) and by butoxamine (4.0 microM). The chronotropic effects were inhibited only by practolol (4.0 microM). 5 Both inotropic and chronotropic effects of noradrenaline (3.0-200 nM) were antagonized by practolol (4.0 microM), but not by butoxamine (4.0 microM). Thus both functions appeared to be mediated by beta 1-adrenoceptors when noradrenaline was the agonist. 6 Inotropic responses to salbutamol (0.45-7.5 microM) were inhibited by both practolol (4.0 microM) and by butoxamine (4.0 microM), but chronotropic responses were antagonized only by butoxamine (4.0 microM), Thus salbutamol acts on both beta 1-and beta 2-adrenoceptors to produce an inotropic response but only on beta 2-adrenoceptors to produce its chronotropic response. 7 It is concluded that both beta 1- and beta 2-adrenoceptors can mediate chronotropism and inotropism in guinea-pig isolated atria. Determination of the postsynaptic effects of drugs should be carried out on spontaneously beating rather than driven atria to obviate modification of the responses by noradrenaline release from sympathetic neurons.