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1. Addition of noradrenaline (5 microM), UK-14,304 (0.1 microM) or phenylephrine (100 microM) to the serosal surface of sheets of rat jejunum mounted in Ussing type chambers decreased resting transepithelial short circuit current (SSC). These responses were inhibited by the selective alpha 2-adrenoceptor antagonist idazoxan (0.5-5.0 microM) but were not significantly affected by the alpha 1-adrenoceptor antagonist corynanthine (100 microM). 2. All three agonists caused a dose-related reduction of SSC which had been elevated by prior addition of theophylline (4 mM). UK-14,304 was 8.1 times more potent than noradrenaline and 76.2 times more potent than phenylephrine. Idazoxan (10 nM-1 microM) caused rightward, parallel displacements of the concentration-response curves for noradrenaline and UK-14,304; PA2 values were 7.87 and 8.02 respectively. Dose-response curves to noradrenaline were unaffected by prazosin (1 microM). 3. The reduction by noradrenaline (10 microM) of SCC which had been elevated by theophylline (4 mM) was not significantly affected by tetrodotoxin (5 microM), suggesting that noradrenaline reduces SCC in rat jejunum via a direct mucosal mechanism. 4. The resting SCC was markedly reduced in chloride-free PSS and under these conditions, noradrenaline did not elicit any further fall in SCC. In bicarbonate-free physiological salt solution (PSS) the resting SCC and the noradrenaline-induced fall in SCC were not significantly different from those in normal PSS. It is concluded that the decrease in SCC observed with noradrenaline, UK-14,304 and phenylephrine is mediated via stimulation of postjunctional alpha 2-adrenoceptors.

Intraluminal pressure changes were recorded from guinea-pig stomachs in vitro. Bradykinin (Bk) (0.4-9.6 nM) was generally found to produce a biphasic response (relaxation followed by contraction) in bathing solutions containing 1.1 mM calcium chloride. In bathing solutions containing 5.2 mM calcium chloride a relaxation without contraction was the most common observation. Relaxations to Bk were unaffected by selective concentrations of tetrodotoxin (5.6 microM), phentolamine (5.0-50.0 microM) and propranolol (5.0-50.0 microM). During virtually complete desensitization to Bk produced by 3 cumulative doses of 6.4 nM, relaxations to vagal stimulation were only reduced by 24.2% and those to adrenaline (2.0 microM) by 25.9%, indicating that Bk is unlikely to be the inhibitory transmitter released during vagal stimulation. Relaxations to ATP (10 microM) were reduced by 89.4% suggesting that Bk and ATP share a common step in the production of relaxation.

Cromakalim alone at 1 microM had no effect and at 10 microM hyperpolarized the rat aorta. The rat aorta was depolarized by KCl (20 mM), noradrenaline (0.3 microM) and 5-hydroxytryptamine (1 microM). In the presence of depolarization with KCl, noradrenaline or 5-hydroxytryptamine, cromakalim at 1 and 10 microM hyperpolarized the rat aorta. Thus the antispasmogenic actions of modest concentrations of cromakalim is compatible with potassium channel opening.

Dose response curves have been constructed from pressor responses to bolus injections of noradrenaline (NA) in the perfused mesenteric bed of the rat. Prazosin (1.0-50 nM) caused a shift to the right of these dose response curves and significantly depressed the maximum obtainable response without any significant change in slope, whereas corynanthine exhibited classical competitive antagonism. When perfused with calcium-free solution, the pressor responses to NA were of shorter duration and the maximum obtainable response was reduced by 26.9 +/- 3.1%. When perfused with calcium-free solution the antagonistic effect of corynanthine was unchanged but that of prazosin was enhanced such that 5.0 nM of prazosin now caused a much greater depression of the maximum NA-induced pressor responses and a marked reduction in slope of the dose response curve. Corynanthine (10 microM) was able to reverse these antagonistic effects of prazosin. These observations are consistent with the suggestion that prazosin selectively antagonizes NA-induced calcium release.

Strychnine (10(-5)-3 x 10(-4) M) increased the amplitude and duration of the spontaneous electrical and mechanical activity of the rat isolated portal vein. Similar effects were seen with tetraethylammonium and 4-aminopyridine. This stimulant action of strychnine was unaffected by tetrodotoxin (3 x 10(-7) M) or prazosin (5 x 10(-8) M) but was significantly reduced by verapamil (3 x 10(-8) M). On the isolated aorta, only inhibitory actions of strychnine were observed, yet tetraethylammonium and 4-aminopyridine had excitatory actions. It is suggested that the stimulant actions of strychnine on the portal vein are likely to be due to a reduction in potassium conductance and/or an increase in calcium conductance of the smooth muscle cell membrane.

Phenylephrine (PE) and Guanfacine (GU) produced maximum contractions of rat isolated aorta which were 96.8 +/- 1.3% and 96.0 +/- 2.8% respectively of the maximum responses induced by noradrenaline (NA). The responses produced by maximum concentrations of NA following 2 min incubation of the preparations with 3.0 mM EGTA were 38.1 +/- 1.2% of the maxima achieved in normal Krebs. PE produced maximum EGTA-resistant responses which were significantly less than those seen with NA; GU produced EGTA-resistant responses which were significantly less than those to PE. The concentration response curves to NA and PE were shifted to the right by incubation with EGTA. The curve for PE was shifted by a significantly greater degree than that for NA. Amidephrine, UK-14,304 and St-587 produced only nominal EGTA-resistant responses even though one of these (UK-14,304) produced contractions in normal Krebs which were almost 70% of the maximum achieved by NA. The log dose ratio for all agonists (except amidephrine) were similar following the addition of 5 nM prazosin. Amidephrine had no effect in the presence of this concentration of prazosin. It is concluded that all agonists tested were acting on alpha 1-adrenoreceptors. Prazosin (5 nM) but not corynanthine (2.5 microM) slowed the rate of rise of contraction of all agonists tested. It is proposed that the rate of rise of agonist/receptor combinations is an important determinant of alpha-adrenoreceptor agonist induced EGTA-resistant responses in rat aorta.

alpha-Adrenoceptor antagonists have been compared for their effects on dose-response curves of fast and slow components of contraction of the rat aorta to noradrenaline (NA). All agents caused a competitive antagonism of the slow component of contraction to NA. The order of potency was: prazosin greater than WB4101 = doxazosin greater than tiodazosin greater than phentolamine greater than corynanthine greater than trimazosin greater than rauwolscine. For the fast component, doxazosin, prazosin, tiodazosin and WB4101 caused some depression of the maximum response. Doxazosin (25 nM) and prazosin (25 nM) produced a complete and unsurmountable antagonism of the maximum fast component. Phentolamine, corynanthine, trimazosin and rauwolscine all competitively antagonized the fast component. The degree of antagonism of the fast component by prazosin and its analogues appeared to be directly related to the potency of individual agents for the slow component. WB4101, which was equipotent with doxazosin and more potent than tiodazosin was less effective than either in reducing the fast component. The antagonism of the fast component by prazosin or doxazosin was easily reversed by washing and prevented by phentolamine (2.5 microM). Neither prazosin nor doxazosin in concentrations of up to 2.5 microM has any effect on contractions of the aorta to 5-hydroxytryptamine (5-HT, 0.25-250 microM) or caffeine (20mM). It is concluded that the ability of some alpha-adrenoceptor antagonists to produce a non-competitive antagonism of the fast component of contraction is (a) dependent upon blockade of alpha-adrenoceptors; (b) unrelated to selectivity for alpha 1-adrenoceptors; (c) related to potency and structure. 8 EGTA (3.0 mM) caused a selective suppression of the slow component of contraction to NA. Both doxazosin and prazosin caused a non-competitive antagonism of EGTA-resistant contractions to NA whereas corynanthine showed competitive antagonism. These observations, together with those above imply that prazosin and doxazosin non-competitively antagonize alpha-adrenoceptorinduced release of calcium in the rat aorta, but competitively antagonize alpha-adrenoceptor-induced calcium entry.

The pharmacological characteristics of post-junctional alpha-adrenoceptors mediating contractions of the longitudinal smooth muscle of the rat isolated portal vein have been examined. Responses to the noncumulative addition of either noradrenaline, or the selective alpha 2-adrenoceptor agonist UK-14,304, were equally sensitive to a low concentration (0.005 mumol/l) of prazosin. Idazoxan (0.1 mumol/l-0.5 mumol/l), a selective alpha 2-adrenoceptor antagonist, was less potent than prazosin against both agonists. The combination of 0.1 mumol/l idazoxan and 0.125 mumol/l prazosin failed to produce a greater inhibition of responses to UK-14,304 than 0.125 mumol/l prazosin alone. A study involving the effect of various antagonists against a single concentration producing a submaximal response to UK-14,304, provided evidence for a prazosin-resistant component of responses which was sensitive to phentolamine. This component could, therefore, be attributed to an alpha-adrenoceptor. However, this particular response could not be ascribed to stimulation of an alpha 2-subtype since the selective alpha 1-adrenoceptor antagonist, corynanthine, produced greater inhibition than the selective alpha 2-adrenoceptor diastereoisomer rauwolscine.

1. The cervical sympathetic trunk of the isolated rat superior cervical ganglion was stimulated with short bursts of repetitive pulses. At room temperature with rates of stimulation of 4 Hz and above, the ganglionic action potentials were reduced in size.2. Amphetamine (2.7 x 10(-5)M), which caused some depression of transmission during stimulation at 0.1 Hz, caused a partial reversal of the depression of transmission occurring with rates of stimulation above 4 Hz.3. This action of amphetamine was mimicked by adrenaline (3 x 10(-5)M) and noradrenaline (9.6 x 10(-5)M) but not by isoprenaline (1.8 x 10(-5)M) and was unaffected by propranolol (1.4 x 10(-5)M) but was abolished by prior application of phenoxybenzamine (5.8 x 10(-6)M). Furthermore, this action of amphetamine was unaltered in ganglia taken from rats pretreated with reserpine (single dose of 6 mg/kg, 16 h before dissection).4. Amphetamine had no effect on the surface potentials of the ganglion or on changes in these potentials produced by concentrations of carbachol (5. x 10(-6)M to 5.5 x 10(-3)M).5. It is concluded that amphetamine has a direct action on alpha-adrenoceptors situated at presynaptic sites.