This study was undertaken to determine whether arginine vasopressin, infused or injected in doses within known physiological ranges, can alter pressor responses to injected or endogenously liberated catecholamines. In 8 pentobarbital-anesthetized dogs, 14 pithed rats, and 7 spinal cats, the pressor responses to catecholamine injections were definitely potentiated by administration of nonpressor doses of vasopressin. In eight dogs anesthetized with N2O-O2, readily reproducible pressor responses to bilateral carotid artery occlusion were subsequently potentiated by infusions of vasopressin. Vasopressin also potentiated both isometric and isotonic responses of 37 rat aortic strip preparations to norepinephrine or epinephrine added to the Krebs-bicarbonate bath. Vasopressin, in physiological dose ranges, potentiates pressor responses to catecholamines by a direct rather than a central action. Endogenously liberated vasopressin may play a role in the responsiveness of vascular smooth muscle to endogenously liberated catecholamines in dog, rat, and cat.

In 1933 Schmidt and Livingstone attempted to determine the cause of the marked fall of blood pressure which results when morphine sulphate is injected intravenously into the cat or the dog. They showed that. the phenomenon exhibited tachyphylaxis and that it was unaffected by ether, urethane, barbitone, or phenobarbitone. They were unable to arrive at any definite conclusions and could only suggest that " depression of the vasomotor centre plays some part in this effect, but most of it is due to dilatation of cutaneous and muscular blood vessels by direct action upon their walls." Sollmann and Pilcher (1917) reported that morphine evoked the triple response in the human skin, an observation which was confirmed by Lewis (1927). Since that time Nasmyth and Stewart (1950) have shown that the weals caused by morphine in human skin are reduced by antihistamine drugs. Feldberg and Paton (1950) reported that the intra-arterial injection of morphine into the isolated perfused gastrocnemius muscle of the cat caused the appearance of histamine in the effluent, and later (Feldberg and Paton, 1951) showed that the drug also released histamine from the cat's skin and that after its intravenous injection into the intact animal the plasma histamine was raised. They considered that the fall of blood pressure caused by the intravenous injection of morphine could not be wholly accounted for by the release of histamine.In this work we have shown that the effect is complex and that at least three factors which would affect the blood pressure are involved when morphine is injected intravenously. METHODSAnaesthesia.-All the rats from which records of blood pressure were taken were anaesthetized with urethane (7 ml./kg. of a 25 per cent (w/v) solution injected subcutaneously). Rats which received injections of morphine sulphate into the jugular vein 24 hours before records of blood pressure were taken from them were anaesthetized with ether while the vein was exposed.Cats were anaesthetized with ether followed by 80 mg./kg. of chloralose intravenously.Records of blood pressure.-All animals except decerebrate and spinal cats, from which records of blood pressure were taken, were heparinized. The apparatus described by Condon (1951) was used to record the blood pressure of the rats.

SUMMARY1. The influence of adenosine cyclic 3',5'-monophosphate (3',5'-AMP) and of drugs believed to increase or decrease its concentration in the tissues has been determined on the response of vascular and uterine smooth muscles to catecholamines. Generally, drugs believed to increase tissue content of 3',5'-AMP potentiated the responses and those believed to decrease it depressed them.2. The cardiovascular responses of dogs (with major vessels occluded in the chest) to carotid occlusion were potentiated by infusions of theophylline and sodium fluoride. Infusion of theophylline also potentiated the response of the occluded abdominal vessels to noradrenaline.3. Intravenous infusions of theophylline and sodium fluoride potentiated pressor responses to catecholamines in the pithed rat. Infusions of iminazole depressed the responses in two animals and was without effect in two others.4. In spinal cats intravenous infusions of theophylline potentiated pressor responses to catecholamines, but sodium fluoride was without effect.5. Contractions of the isolated rat aortic strip to noradrenaline were always potentiated by sodium fluoride and by theophylline, and depressed by iminazole, when they were recorded isometrically. Theophylline always potentiated the contractions, when they were recorded isotonically but sodium fluoride was mostly, and iminazole always, ineffective.6. 3',5'-AMP in concentrations from 041 to 20,g/ml. potentiated the responses of the isolated rat aortic strip to noradrenaline in thirty-eight experiments out of hundred. Concentrations from 10 to 500 ,ug/ml.

1 Noradrenaline (0.1-3.0 gM) inhibited the twitch responses to single pulse field stimulation of the isolated vas deferens of the mouse. The higher concentrations of noradrenaline (ca. 0.3-3.0 gM) were required to make the tissue contract. 2 Phentolamine (10 ,UM) abolished the contractor response to higher concentrations of noradrenaline and antagonized the inhibitory effect of lower concentrations on the twitch response. 3 Propranolol (10IM) potentiated both the contractor and the inhibitory effect ofnoradrenaline on the twitch response.4 Isoprenaline (0.1-3.0 uM) and salbutamol (1.0-3.0 gM) both inhibited the twitch response. Their effects were antagonized by propranolol (10 jiM), but not by practolol (10 jiM). SThe effects of uptakel and uptake2 blocking agents were determined. Cocaine (10 gM) reduced the size of the twitch response in 2 out of 4 experiments. Imipramine (0.18 ,uM) also reduced the size of the twitch, as did oestradiol (3.7 gM) and a combination of cocaine and oestradiol.6 Contractor responses to exogenous noradrenaline showed tachyphylaxis, but when this was not very marked, the response could be shown to be potentiated by uptake blocking agents. 7 The inhibitory effect of noradrenaline on the twitch response was greatly potentiated by cocaine (10 gM) and much less so by oestradiol (3.7 gM).8 It is concluded that the transmitter responsible for the twitch response is either an unknown substance released from the sympathetic neurone, or noradrenaline acting upon a receptor with none of the characteristics of known a-or fi-adrenoceptors. In either case, noradrenaline can inhibit the output, probably by stimulation of presynaptic a-adrenoceptors.

1 Noradrenaline (ID50, 0.75 pM) and clonidine (ID50, 2.8 nM) produced a dose-related inhibition of the twitch response of the isolated vas deferens of the mouse to electrical stimulation, their effectiveness decreasing as frequency of stimulation increased from 0.2 to 16 hertz. 2 Phenylephrine (1.0-3.0 pM) produced a dose-related contraction of the mouse isolated vas deferens and potentiated the responses to field stimulation. 3 Yohimbine (10 nM) antagonized the inhibitory effects of noradrenaline and clonidine, but had no effect on the motor activity of phenylephrine. At a concentration of 128 nM yohimbine potentiated the twitch response by 110% at 1 Hz, but its effectiveness decreased with increasing frequency of stimulation up to 16 hertz.4 Thymoxamine (0.3 gM) antagonized the effects of phenylephrine, but not those of clonidine.5 From a consideration of the known characteristics of pre-and postsynaptic a-adrenoceptors, it is concluded that the inhibitory effect of noradrenaline is produced by stimulation of the former and the effects of phenylephrine by stimulation of the latter.