The depressor action of dopamine and adrenaline

Dopamine is a pressor agent in the spinal cat, but causes a fall of blood pressure in the guinea-pig and rabbit under urethane anaesthesia. When guinea-pigs and rabbits are injected with reserpine, which depletes the vessel walls of noradrenaline, dopamine then becomes pressor. If an intravenous infusion of noradrenaline is given the depressor action returns. An intravenous infusion of vasopressin does not have this effect.

A strip of rabbit aorta is caused to contract by noradrenaline and by dopamine, but if dopamine is added at the height of a noradrenaline contraction it causes relaxation.

Adrenaline causes a fall of blood pressure in the cat under ether with vagi cut. However, in a reserpine-treated cat its action is pressor. The depressor action is restored during an infusion of noradrenaline. Noradrenaline has thus been shown to cause a vasomotor reversal of dopamine and of adrenaline.

     

Cactecholamines and the oedematous reaction to oestradiol in the rat uterus

The effect of catecholamines on the 4 h oedematous reaction to estradiol in the immature rat uterus was investigated. Isoprenaline was found to augment the reaction to suboptimal doses of estradiol (0.25--0.5 microgram/kg. This effect was reversed by d,l-propranolol. Adrenaline and noradrenaline were found to inhibit the reaction to oestradiol 2 microgram/kg. The effect of adrenaline was reversed by phenotalmine.     

UTERINE CONTRACTILITY AND ACTIONS OF CATECHOLAMINES IN LONGITUDINAL AND CIRCULAR UTERINE LAYERS FROM OVARIECTOMISED GUINEA-PIGS: THE EFFECTS OF OVARIAN STEROIDS

• 1 The influence of ovarian steroids upon responses to electrical stimulation and to activation of adreno-receptors in field-stimulated preparations of longitudinal and circular myometrium from ovariectomised guinea-pigs has been investigated. Adult virgin guinea-pigs were bilaterally ovariectomised and were (i) treated two weeks later with thrice-weekly injections of oestradiol cypionate for two weeks, or (ii) treated as in (i) then given oestradiol cypionate and progesterone for a further four days. Control groups of bilaterally ovariectomised and sham ovariectomised animals remained untreated.
• 2 Both myometrial layers from untreated ovariectomised guinea-pigs were atrophied. Responses to field stimulation in the circular myometrium were much smaller than those in the iongitudinal layer. Steroid pretreatment, most notably treatment with oestradiol and progesterone, were associated with decreased and increased responsiveness to electrical stimulation in the circular and longitudinal myometrial layers respectively.
• 3 Adrenaline and noradrenaline were consistently excitatory on preparations of circular myometrium from ovariectomised animals. Responses comprised either enhancement of electrically-evoked contractions, or, with the higher concentrations, the appearance of rapid contractions superimposed upon an increase in basal tone. The latter effects were also evident in preparations of circular myometrium from sham operated animals. In preparations of longitudinal myometrium from untreated ovariectomised animals noradrenaline consistentaly and adrenaline usually caused a simple enhancement of the magnitude of the evoked contractions. Phentolamine reduced the excitatory effects of both amines in both layers.
• 4 In circular myometrium from the oestrogen-treated group both catecholamines produced phentolamine-sensitive enhancement of electrically-evoked contractions, but did not cause high frequency contractions or increased tonus. Noradrenaline and adrenaline produced qualitatively similar phentolamine-sensitive effects in preparations of longitudinal myometrium from this group.
• 5 The co-administration of progesterone and oestradiol to oestradiol-treated animals led to a decrease in the excitatory potency of both amines on the circular layer compared to values obtained for the oestradiol-primed group: this effect achieved statistical significance in the case of noradrenaline. The effects of adrenaline and noradrenaline on the longitudinal layer were reversed to a propranolol-sensitive inhibition of the evoked contractions.
• 6 These findings, when contrasted with the results of an earlier study, in which identical treatments were given to non-ovariectomised guinea-pigs, indicate that the precise nature of the influence of treatments with ovarian steroid hormones upon responses mediated by longitudinal and circular myometrial adrenoreceptors depends upon the presence or absence of functional ovaries.

     

Importance of calcium in the actions of some drugs that stimulate the isolated hypodynamic frog heart

Infusions of adrenaline failed to produce a significant increase in the adrenaline and noradrenaline content of cat uterus and kidney and of rat uterus and spleen, using normal and reserpine-treated animals. The adrenaline content of extracts of the organs was assayed on the isolated rat uterus, which was stimulated electrically; the noradrenaline content was assayed on the blood pressure of the pithed rat. The tissues studied contained relatively small quantities of adrenaline and this was not decreased by reserpine. Our results show a difference between the stores of adrenaline and noradrenaline in these tissues; the noradrenaline stores are larger, they are depleted by reserpine, and they are increased by an infusion of noradrenaline.     

Effect of the vascular endothelium on noradrenaline-induced contractions in non-pregnant and pregnant guinea-pig uterine arteries.

1. The effect of pregnancy on noradrenaline-mediated contraction of guinea-pig uterine artery rings with both intact and denuded endothelium was investigated. 2. Noradrenaline (25 nM-100 microM) induced concentration-dependent contraction of non-pregnant and pregnant guinea-pig uterine arterial rings with intact endothelium with similar pD2 and maximal response values (non-pregnant: pD2 = 5.85 +/- 0.02, maximal response = 121 +/- 8.2%; pregnant: pD2 = 5.81 +/- 0.04, maximal response = 122 +/- 9.1%). Removal of endothelium did not affect noradrenaline-induced contractions in non-pregnant guinea-pig uterine artery (pD2 = 5.97 +/- 0.02, maximal response = 119 +/- 8.6%). In contrast, in arteries from pregnant guinea-pigs, removal of endothelium shifted concentration-response curve for noradrenaline to the left, without affecting maximal response value (pD2 = 6.36 +/- 0.03, maximal response = 120 +/- 9.0%). 3. The pKA values for noradrenaline were: 5.76 +/- 0.09 and 5.82 +/- 0.10 for non-pregnant guinea-pig uterine artery with intact and denuded endothelium, respectively and 5.74 +/- 0.09 and 5.72 +/- 0.07 for pregnant guinea-pig uterine artery with intact and denuded endothelium, respectively. 4. The receptor occupancy-response relationship for noradrenaline was linear for all types of vessels, except for pregnant guinea-pig uterine artery with denuded endothelium, since half-maximal response to noradrenaline was obtained with 44.8 +/- 6.9% (non-pregnant guinea-pig uterine artery with intact endothelium), 43.3 +/- 6.1% (non-pregnant guinea-pig uterine artery with denuded endothelium) and 44.3 +/- 6.3% (pregnant guinea-pig uterine artery with intact endothelium) receptor occupancy. In pregnant guinea-pig uterine artery with denuded endothelium, occupancy-response relationship for noradrenaline was non-linear since half-maximal response to noradrenaline was obtained with 19.7 +/- 3.3% receptor occupancy. 5. NG-monomethyl-L-arginine (100 microM) and indomethacin (10 microM) did not affect concentration-response curve for noradrenaline in guinea-pig uterine arteries, regardless of pregnancy status or endothelial condition. 6. In quiescent preparations, the alpha-adrenoceptor antagonists, prazosin (5-50 nM) and yohimbine (1-10 microM) produced parallel rightward shifts of the curves for noradrenaline and the slopes of the Schild plots were not significantly different from unity.(ABSTRACT TRUNCATED AT 400 WORDS)     

The role of the adrenal glands and of alpha- and beta-adrenergic receptors in bronchodilatation of guinea-pig lungs in vivo

Adrenaline, aminophylline, isoprenaline, noradrenaline, papaverine and phenylephrine exerted non-specific bronchodilator effects in guinea-pig lungs in vivo. The descending order of bronchodilator potency was isoprenaline > adrenaline > noradrenaline > phenylephrine. These agents also exerted a bronchoconstrictor effect, the descending order of bronchoconstrictor potency being phenylephrine > noradrenaline > adrenaline > isoprenaline. Bronchodilator activity could be antagonized by either α- or β–adrenergic receptor antagonists. The bronchodilator action of aminophylline, papaverine, phenylephrine and noradrenaline was partly mediated via the adrenal gland.     

Action of dexamphetamine on 5-hydroxytryptamine receptors

Dexamphetamine contracted isolated preparations of rat stomach, dog retractor penis, rabbit aorta, rabbit uterus and all sections of guinea-pig ileum. Adrenaline inhibited rat stomach and all but the terminal 10 cm of guinea-pig ileum, but contracted dog retractor penis, rabbit aorta, rabbit uterus and the terminal portion of the guinea-pig ileum. 5-Hydroxytryptamine contracted all five preparations. Responses to dexamphetamine and 5-hydroxytryptamine were not blocked in preparations protected by a high concentration of either drug during exposure to phenoxybenzamine in a dose which usually caused block. Responses to dexamphetamine and 5-hydroxytryptamine were blocked in preparations protected by adrenaline. Responses to dexamphetamine in dog retractor penis, rabbit aorta and rabbit uterus were not reduced in preparations from animals treated with reserpine or after cocaine, indicating that the contraction is not mediated by released noradrenaline. It is concluded that dexamphetamine acts directly on 5-hydroxytryptamine receptors in these smooth muscles and therefore cannot be regarded as a true sympathomimetic amine.     

The nature of the adrenoceptors in the post-partum rat uterus

1. Uteri were removed from rats 0.5 h to 8 days after parturition and were suspended in Locke solution at 37 degrees C.2. The agonists isoprenaline, adrenaline, noradrenaline and phenylephrine produced an inhibition of the post-partum rat uterus.3. In the presence of propranolol, the agonists noradrenaline, adrenaline, and phenylephrine had an excitatory effect on the post-partum rat uterus. This excitatory effect was blocked by phenoxybenzamine indicating that it is mediated through alpha-adrenoceptors.4. These excitatory alpha-adrenoceptors could be demonstrated for 5-6 days after parturition. By the 7th-8th days their existence was no longer apparent.5. Excitatory alpha-adrenoceptors were also demonstrated in the late pregnant rat uterus.     

The effect of adrenaline, noradrenaline and isoprenaline on the guinea-pig uterus

The actions of adrenaline, noradrenaline and isoprenaline were compared on the isolated guinea-pig uterus. In uteri from immature animals (200 to 350 g) adrenaline caused relaxation which changed to a biphasic effect and finally to a contraction in the course of an experiment (6 to 8 hr). Noradrenaline always caused contraction and isoprenaline relaxation. In uteri from oestrogen-treated animals adrenaline and noradrenaline caused contraction and isoprenaline caused relaxation. Isoprenaline potentiated the contraction produced by adrenaline and reversed the adrenaline relaxation to a contraction. The change of the pharmacological action of adrenaline was not related to the Na⁺ and K⁺ content of the uterus, which remained constant throughout an experiment involving repeated application of the amines. Nor could it be related to a change in the glycogenolytic effect of adrenaline estimated by determinations of total glycogen of the muscle which, however, may not reflect a momentary change in rate of breakdown.     

Effects of oestradiol and progesterone on the in vitro production of prostaglandin F2alpha by the guinea-pig uterus.

1 The effects of oestradiol and progesterone on the production of F 2alpha by the guinea-pig uterus in vitro have been studied. 2 Ovariectomized guinea-pigs were treated with oestradiol benzoate, progesterone, or a combination of these hormones. The uteri were homogenized and incubated and the prostaglandin F2alpha produced was measured by radiommunoassay or combined gas chromatography-mass spectrometry (g.c.-m.s.). Oestradiol treatment or progesterone followed by oestradiol caused a significant increase in prostaglandin F2alpha synthesis compared with control values, whereas progesterone treatment caused no significant increase. 3 The uteri from guinea-pigs on day 7 of the oestrous cycle were split into four parts, and each part homogenized and incubated either alone or in the presence of oestradiol-17beta, progesterone, or a combination of these hormones. Prostaglandin F2alpha was measured by g.c.-m.s. Oestradiol was found to increase prostaglandin F2alpha synthesis by the uterus whereas progesterone had no effect. However, progesterone did inhibit the response to oestradiol. 4 Oestradiol treatment of the guinea-pig uterus causes an increase in capacity to produce prostaglandin F2alpha in vitro. The role of progesterone is difficult to interpret.     

The effect of precursors of noradrenaline on the response to tyramine and sympathetic stimulation

Previous observations have shown that the effects of sympathetic stimulation and of tyramine were absent in the organs of animals treated with reserpine, but that they were restored by an infusion of noradrenaline. Observations are described showing that an infusion of adrenaline did not restore the pressor action of tyramine in the cat or in the rat, but that in the rat the pressor action was restored by an infusion of dopamine, or of (—)-dopa, or of m-tyrosine,or of phenylalanine. Observations are also described showing that the effect of postganglionic stimulation of the fibres to the nictitating membrane and to the iris was restored by an infusion of dopamine or of (—)-dopa; it was restored less well by an infusion of noradrenaline. An infusion of noradrenaline did not restore the action of tyramine on the denervated iris or on the denervated vessels of the cat's foreleg. An infusion of noradrenaline appeared to increase the effect of sympathetic stimulation of the hypogastric nerves to the uterus of the virgin cat about as much as an infusion of adrenaline. An infusion of noradrenaline restored the constrictor action of nicotine on the perfused vessels of the rabbit ear.     

Chronic administration of morphine in cats: effects on adrenal and urinary catecholamines.

Adrenaline and noradrenaline levels in the adrenal glands and the excretion of both bioamines in urine of adult cats were investigated after chronic administration of morphine and nalorphine-induced withdrawal. After 7 days of daily consecutive morphine treatment, a significant increase in the adrenal noradrenaline content and a drop in adrenaline content were observed. After 2 weeks of daily injection of morphine, no significant changes were observed in the adrenal catecholamine level. One month of treatment with the opioid caused a significant increase in the adrenal content of both adrenaline and noradrenaline. Urinary excretion of catecholamines was significantly increased during the 4 weeks of treatment. In animals subjected to spontaneous or induced withdrawal with nalorphine, the adrenal content of catecholamines was altered and the ratio adrenaline/noradrenaline in the adrenal gland was shifted towards noradrenaline. A first injection of morphine produced an excitant manic response characterized by hyperexcitement and aggressive behaviour; animals chronically treated with the drug showed a progressively diminished response to this effect of the drug. It is concluded that physical dependence on morphine is reached by cats chronically treated with morphine and that this effect of the drug influences adrenomedulllary function in a different fashion depending on the stage of morphine treatment.     

Interactions between cocaine, tyramine and noradrenaline at the noradrenaline store

In the cat, the pressor actions of noradrenaline and of adrenaline were generally reduced and that of tyramine was increased during infusions either of noradrenaline or of adrenaline. The increase in the response to tyramine after an infusion of noradrenaline was prevented by cocaine, methyl phenidate and pipradrol. Pipradrol, unlike its isomer azacyclonol, increased the responses to catechol amines but reduced that to tyramine. Cocaine did not prevent the increase in the noradrenaline content of cat kidney and uterus after an infusion of noradrenaline. In the pithed rat, cocaine increased the pressor response to noradrenaline but antagonized that to tyramine. Treatment of the rat with reserpine prevented the effect of cocaine on the response to tyramine but did not modify the potentiation of the response to noradrenaline. Prolonged treatment with cocaine did not lower the tissue noradrenaline levels and did not prevent the noradrenaline depletion by reserpine. It is suggested that interactions between cocaine, tyramine and noradrenaline occur at the point where noradrenaline enters its tissue store.     

Adrenergic receptors in the guinea-pig trachea

The effects of adrenaline, noradrenaline and isoprenaline have been investigated on the guinea-pig isolated trachea in the presence of propranolol hydrochloride 10^?5 and 10^?6 g/ml. Adrenaline and noradrenaline were both shown to produce contractions of the tissue. The relative order of potency of the catecholamines (adrenaline > noradrenaline > isoprenaline), together with the antagonism exhibited by phenoxybenzamine, suggests that the contractions were due to α-adrenergic receptor involvement.     

The mode of action of caffeine on catecholamine release from perfused adrenal glands of cat.

1 Adrenaline and noradrenaline secretion induced by caffeine was investigated in the perfused cat adrenal glands. 2 Caffeine (10-80 mM) caused a dose-dependent increase in both adrenaline and noradrenaline secretion when applied for 1 min and 10 min after replacing Ca2+ with 10(-5)M EGTA in the perfusion solution. The ratio of adrenaline to noradrenaline was about 1:1. Mg2+ and/or Ca2+ inhibited the response to caffeine. 3 When caffeine (40 mM) was repeatedly applied in the absence of extracellular Ca2+, the secretory response almost disappeared but only at the second challenge with caffeine. However, the response was partially restored after readmission of Ca2+ (2.2 mM) and was augmented after the readmission of Ca2+ with ouabain (10(-5) M). 4 Caffeine-induced secretion of adrenaline and noradrenaline increased with the increase in the preloaded concentration of Ca2+ and attained a maximum at 16 mM Ca2+. 5 During perfusion with Ca2+-free Locke solution containing hexamethonium (10(-3)M), acetylcholine (10(-4)M) caused increases in both adrenaline and noradrenaline secretions with a ratio of about 1:2. The secretory responses were partially inhibited by preceding stimulation with exposure to caffeine (80 mM). 6 These results suggest that caffeine mobilizes Ca2+ from an intracellular storage site that may not be entirely the same as that linked to muscarinic receptors, and causes an increase in both adrenaline and noradrenaline secretion from cat adrenal chromaffin cells.     

Adrenaline activation of prejunctional beta-adrenoceptors in guinea-pig atria.

1. Adrenaline in a concentration of 1.0 microM depressed the stimulation-induced efflux of tritium from the guinea-pig atria incubated with [3H]-noradrenaline, whereas adrenaline in a concentration of 0.5 nM significantly enhanced the stimulation-induced efflux of tritium. This enhancement was blocked by metoprolol (0.1 microM) and thus appears to be mediated by beta-adrenoceptors. 2. In guinea-pig atria incubated with unlabelled adrenaline and then with [3H]-noradrenaline, both catecholamines were released by field stimulation. In such atria metoprolol, practolol, oxprenolol or propranolol decreased the stimulation-induced efflux of tritium. These effects did not occur if the atria were incubated with unlabelled noradrenaline and then with [3H]-noradrenaline, suggesting that neuronally released adrenaline activates prejunctional beta-adrenoceptors. 3. The effect of oxprenolol in decreasing the release of tritium from guinea-pig atria, incubated with unlabelled adrenaline and then with [3H]-noradrenaline was greater in the presence of phentolamine. This may reflect the alpha-adrenoceptor blocking activity of oxprenolol.     

Effects of thyroidectomy and L-thyroxine on adrenaline and noradrenaline concentrations in the adrenal glands and plasma of rats during the pro-oestrous phase of the oestrous cycle and pregnancy.

1 The influence of thyroidectomy upon the adrenaline and noraddrenaline content of adrenal glands and plasma in mature female rats in pro-oestrus and in pregnant rats was studied. 2 Adrenal adrenaline and noradrenaline declined significantly after thyroidectomy in pro-oestrous and pregnant females but the effects were more marked in pregnant females. 3 Plasma adrenaline increased by 160% after thyroidectomy in pro-oestrous females but similar treatment resulted in 85% decrease in plasma adrenaline of pregnant rats. The loss of thyroid increased plasma noradrenaline significaantly in both groups of females. 4 The administration of L-thyroxine of thyroidectomized females increased adrenal noradrenaline stores of both the groups. The effects of L-thyroxine in pro-oestrous females resulted in decreased adrenaline stores of the adrenals but the pregnant group showed an increase. Plasma noradrenaline increased after treatment of pro-oestrous and pregnant-thyroidectomized females with L-thyroxine. 5 The thyroidectomized females in pro-oestrous phase receiving L-thyroxine showed a return to the control values for plasma adrenaline but in pregnant females whose plasma adrenaline had declined after thyroidectomy no such change occurred. 6 Considering the variations in total catecholamines in plasma and adrenals, it was observed that the loss of thyroid hormones results in an increase in total catecholamine storyage and output in the blood. The results provide evidence that the thyroid-catecholamine interrelation is significantly affected by pregnancy.     

Effects of ethanol and salsolinol on catecholamine function in LS and SS mice

Adrenal and urinary levels of adrenaline and noradrenaline were determined in rats subjected to severe ethanol intoxication for periods of up to 96 hours, in rats undergoing withdrawal and in a post-withdrawal period, and in controls. Adrenaline and noradrenaline content of adrenal glands fell markedly to less than eight and twenty percent, respectively, after four days of intoxication. Noradrenaline content, but not adrenaline content, had recovered after a subsequent four day period of recovery. The depletion in adrenal catecholamine levels was coincident with increases in urinary adrenaline and noradrenaline levels over the first 48 hours of intoxication. Urinary catecholamine levels remained higher than control values for the next 48 hours of intoxication. Adrenal glands were larger after 12 hours of intoxication, although there was no increase in dry weight. At later times adrenal enlargement was associated with increased dry weight and protein content. This increase in mass was found to be of cortical origin. These results demonstrate that severe ethanol intoxication promotes an intense stimulation of the rat adrenal gland with enhanced synthesis and release of catecholamines, and cortical hypertrophy.     

Purinoceptor-mediated contractility of the perfused uterine vasculature of the guinea-pig: influence of oestradiol and pregnancy

1. The effects of ATP, the stable ATP analogues alpha,beta-methylene ATP (alpha,beta-mATP), 2-methylthioATP (2meSATP) and adenosine tetraphosphate (ATP4), the pyrimidine nucleotide uridine 5'-triphosphate (UTP) and the alpha1-adrenoceptor agonist phenylephrine were examined on the isolated perfused uterine vasculature of dioestrous, oestradiol-treated, dexamethasone-treated and late-pregnant guinea-pigs. 2. The alpha1-adrenoceptor agonist phenylephrine elicited concentration-dependent vasoconstriction from preparations of perfused uterine vasculature from dioestrous, estradiol-treated and late-pregnant guinea-pigs. The mean maximal response to phenylephrine was unaffected by treatment of dioestrus guinea-pigs with oestradiol or dexamethasone, but was reduced in preparations from late-pregnant animals. 3. In perfused uterine arteries from dioestrous animals, the pyrimidine UTP, but not ATP4 and ATP, elicited vasoconstrictor responses. In preparations from oestradiol-treated animals, all three agonists elicited vasoconstriction, with a rank order of potency of ATP4 = UTP > ATP, whereas in preparations from late-pregnant animals this order of potency was ATP4 > UTP = ATP. In preparations from dexamethasone-treated animals, the vasoconstriction was similar to that seen in dioestrous animals. Vasoconstrictor responses to ATP4 were significantly greater in preparations of uterine vasculature from oestradiol-treated and pregnant animals than in preparations from dioestrous animals or dexamethasone-treated animals. 4. In preparations from dioestrous, oestradiol-treated, pregnant and dexamethasone-treated animals, alpha,beta-mATP was approximately two to three orders of magnitude more potent than 2meSATP. Compared with preparations from dioestrous animals, the maximal responses to alpha,beta-mATP were significantly greater in tissues from oestradiol-treated and pregnant animals. In preparations from dioestrous animals, the P2 purinoceptor antagonist suramin (100 micro mol/L) inhibited the responses to alpha,beta-mATP, but not those to ATP4. 5. The present study has demonstrated that pregnancy, but not the steroid treatment of dioestrous guinea-pigs with oestradiol or dexamethasone, reduces the sensitivity of the guinea-pig isolated perfused uterine vasculature to phenylephrine. In contrast, preparations from pregnant or oestradiol-treated guinea-pigs respond to ATP4 and to alpha,beta-mATP with significantly greater constrictions than those of dioestrous or dexamethasone-treated animals. These data indicate that the sensitivity of the uterine vasculature to adrenoceptor and purinoceptor agonists is differentially regulated by oestradiol and pregnancy, but not by the synthetic glucocorticoid dexamethasone.     

EFFECTS OF CATECHOLAMINES ON PREGNANT RAT UTERUS

• 1 The effects of noradrenaline (NA), adrenaline (Adr) and isoprenaline (Iso) have been studied on pregnant rat uterus, at various stages of gestation - on the 10th and 20th days of pregnancy and on the first day post-partum.
• 2 The three catecholamines were inhibitory in all stages of gestation, with the same order of potency as observed in non-pregnant uteri (ie Iso > Adr > NA). However, mean pD₂ values for the catecholamines tended to decrease as gestation progressed.
• 3 In 20 day pregnant and 1 day post-partum uteri, in the presence of propranolol, NA and Adr produced consistent α-adrenoreceptor mediated motor responses.
• 4 It is concluded that in the rat uterus, a form of pregnancy reversal occurs, in that there is a decrease in β-adrenoreceptor responsiveness, and an increase in α-adrenoreceptor responsiveness towards the end of gestation, and immediately post-partum.