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The effects of compounds with alpha 2-agonist and alpha 2-antagonist properties on human forearm blood flow and on isolated human arterial segments have been studied. The findings from these studies in vivo and in vitro did not provide evidence in support of the hypothesis that postsynaptic alpha 2-receptors mediate smooth muscle contraction in the tissues under investigation. The constriction of the forearm vascular bed in response to low intra-arterial doses of idazoxan (RX 781094), an alpha 2-antagonist, provides evidence for a physiological role for a presynaptic alpha 2 autoregulatory mechanism. The variability of the forearm vascular responses to higher doses of idazoxan highlights the pitfalls that may have misled previous authors in their interpretation of the results of similar studies. A U-shaped dose-response curve to compounds with mixed alpha 2- and alpha 1-antagonist properties may be constructed, which emphasizes the importance of the dose-dependent selectivity of these antagonists at alpha 2- and alpha 1-receptors. The effect of idazoxan on the responses of arterial segments in vitro to exogenous catecholamines was dependent on the integrity of the endothelium, and provides evidence that alpha 2-receptors may mediate release of the endothelium-derived relaxing factor.

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1 The ability of histamine to inhibit the overall contractile ('twitch') response of the isolated vas deferens of the mouse to electrical field stimulation (64 V pulse, 1 ms pulse width, frequency 0.2 Hz) was studied in nine inbred mouse strains. The strains were also characterized in terms of the potency of the histamine H2-receptor antagonist cimetidine in its inhibition of histamine-mediated effects. An apparently bimodal inter-strain variation (8-10 fold) in both characteristics was encountered, with three strains (SWR, A2G and C57BL/1OScSn) relatively sensitive (S) to both agonist and antagonist actions, and six (C3H, A, C57/BL6, DBA/2, Balb/C and 129/Sv) relatively insensitive (IS). 2 These strain differences were independent of extracellular calcium concentration in the range 1.25 -5 mM, and also independent of the frequency of tissue stimulation over the range 0.2 -6.4 Hz.3 Representative S (SWR and A2G) and IS (DBA/2 and C3H) mouse vasa were also characterized in terms of their sensitivity to the agonist actions of dimaprit and the antagonist actions of tiotidine. In the S strain tissues, dimaprit produced 50% inhibition of the twitch response at 4.6-1.8pM (mean+s.d.) and was able to elicit complete inhibition of the twitch response at concentrations greater than 100 JM, whereas 48.7 ± 11.9 JIM dimaprit was required to produce 50% inhibition of the twitch response in tissues from IS mice. In addition, the agonist actions of dimaprit were incomplete in the latter tissues, the drug eliciting no more than 75% inhibition of the twitch response at concentrations in the range 300-1000 JIM. Tiotidine produced competitive antagonism of the actions of both histamine and dimaprit, the strain differences being of the same magnitude as those observed for cimetidine.4 Mating of a representative S (SWR) and IS (129/Sv) strain produced F, mice with intermediate histamine and cimetidine sensitivities relative to the parental strains. A backcross of male F1 to female IS mice produced progeny displaying a range of histamine and cimetidine sensitivities representative of those seen in tissues from F1 and IS parental animals, however, the data were not bimodal. Thus, the backcross data provided no evidence to support single gene inheritance of histamine sensitivity and might suggest that more than one gene is responsible for these differences between S and IS mice.

1 Salbutamol (1.0 tM) and isoprenaline (1.2 nM) significantly increased the fractional release of tritiated noradrenaline from driven left atria but phentolamine (101LM) failed to do so. Butoxamine (4.0pM) blocked the increase in overflow produced by isoprenaline. Isoprenaline (1.2 nM), phentolamine (10.0 pIM) and salbutamol (1.0 jM) 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 (0.04-4.0iM) and isoprenaline (0.11-9.OnM) were inhibited by practolol (4.01M) and by butoxamine (4.0 jM). The chronotropic effects were inhibited only by practolol (4.01M). 5 Both inotropic and chronotropic effects of noradrenaline (3.0-200nM) were antagonized by practolol (4.0 pM), but not by butoxamine (4.01M). Thus both functions appeared to be mediated by P1-adrenoceptors when noradrenaline was the agonist. 6 Inotropic responses to salbutamol (0.45-7.51pM) were inhibited by both practolol (4.0 MM) and by butoxamine (4.01M), but chronotropic responses were anatgonized only by butoxamine (4.0 pm). Thus salbutamol acts on both hi-and 32-adrenoceptors to produce an inotropic response but only on 032-adrenoceptors to produce its chronotropic response.7 It is concluded that both h1-and 32-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 released from sympathetic neurones.