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R. G. SHANKS M.D., D.Sc Postgrad Med J: first published as 10.1136/pgmj.50.587.560 on 1 September 1974. Downloaded from Postgraduate Medical Journal (September 1974) 50, 560-561. Pharmacology of vascular control R. G. SHANKS M.D., D.Sc. Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Northern Ireland PROFESSOR Neil has discussed, in the preceding paper, replaces dopa as a precursor of noradrenaline with the physiological control of the circulation. This the result that methyl-noradrenaline is formed control depends for its proper functioning on the instead of noradrenaline. Methyl-noradrenaline is action of transmitter substances in various parts of described as a false transmitter, and as it has about the nervous system. These substances are drugs, for one hundredth the action of noradrenaline, the effect example, acetylcholine and noradrenaline, and have on the sympathetic system is greatly reduced. well defined pharmacological properties. The trans- These drugs reduce the effects of the sympathetic mitter substance in the brain, in the spinal cord and system and interfere with reflexes which involve an in the autonomic ganglia is acetylcholine. The final increase in sympathetic activity. The compensatory pathway of the transmission of nerve impulses in the cardiovascular responses to the Valsalva manoeuvre in autonomic system from the autonomic ganglia is are altered so that the tachycardia and increase Protected by copyright. the post-ganglionic fibre. The transmitter substance peripheral resistance, which result in the overshoot at sympathetic post-ganglionic nerve endings is in arterial pressure when the manoeuvre is stopped, noradrenaline and at parasympathetic endings, do not occur. acetylcholine. When noradrenaline is released from sympathetic As the sympathetic system, and drugs which nerve endings it activates a specialized part of the effect it, are probably of more relevance to this effector cell which has been termed the 'receptor', or present meeting, only this subject has been included adrenergic receptor. These can be stimulated by and in particular the effects of drugs on the arterial noradrenaline released from nerve endings or from side of the circulation. the adrenal medulla or other drugs administered, e.g. by intravenous injection. The sympathetic nervous system The sympathetic nervous system exerts powerful Receptors control on the arterioles in the peripheral circulation. Little is known about these receptors as they have Normally, tonic activity in these nerves maintains not been isolated biochemically or histologically. peripheral vascular resistance. Section or blockade They are a convenient basis by which to explain the http://pmj.bmj.com/ of these nerves to a particular region, e.g. the arm, mode of action of drugs affecting the adrenergic produces a marked dilatation of the blood vessels. nervous system. These receptors are part of the The effect of the sympathetic system is maintained effector cell as they do not disappear after degenera- through the continued release of noradrenaline from tion of the sympathetic nerve fibres. They can be the nerve ending. The action of noradrenaline is activated, not only by neuronally released nora- terminated by a combination of three processes- drenaline, but by other administered adrenergic the effect of mono-amine oxidase in the region of agonists. The receptors may be activated by a group the nerve ending, uptake of noradrenaline in the of drugs, including tyramine and ephedrine, which on September 28, 2021 by guest. noradrenaline pool in the nerve ending and carriage do not have a direct effect on the receptor but act to the liver in the blood where it is metabolized by through the release of noradrenaline from the catechol-o-methyl transferase. neuronal pool which then activates the receptor to initiate a response. Effect of drugs Adrenergic receptors were classified in 1948 by Many drugs have been developed which interfere Ahlquist into two separate groups which he desig- with these actions of noradrenaline. Guanethidine nated alpha and beta. Alpha adrenergic receptors inhibits transmission in the post-ganglionic sym- are present chiefly in the peripheral vessels in skin pathetic neurone and in addition depletes or reduces and in the kidney. They are activated selectively by the stores of noradrenaline at the nerve endings. phenylephrine and methoxamine. Beta adrenergic Reserpine has only the latter effect. Methyldopa receptors are present in the heart where they are Postgrad Med J: first published as 10.1136/pgmj.50.587.560 on 1 September 1974. Downloaded from Pharmacology of vascular control 561 responsible for inotropic and chronotropic responses, The intra-arterial injection of noradrenaline and and in the bronchi and blood vessels in skeletal phenylephrine decreases blood flow to the hand in muscle where activation relaxes smooth muscle. normal subjects. A similar response occurs after Beta adrenergic receptors are selectively stimulated acute division of the sympathetic fibres to an arm by isoprenaline and orciprenaline. These drugs have and also after chronic degeneration of the nerves. no effect on the alpha adrenergic receptors. Adrena- In contrast, ephedrine and methylamphetamine line and noradrenaline activate both alpha and beta decrease flow but have no effect after acute or receptors. chronic interruption of the sympathetic fibres as Thus the effect of any adrenergic drug depends on these drugs depend for their action on the presence the type of receptor which it activates and on the of intact stores of noradrenaline at the sympathetic distribution of these receptors. Isoprenaline will nerve endings. increase heart rate, dilate the bronchi and increase The administration of isoprenaline into the forearm blood flow as it activates beta adrenergic brachial artery has little effect on blood flow to the receptors which are present in these three sites. hand but produces a marked increase in forearm blood flow. A similar effect is obtained with orci- Drugs and adrenergic receptors prenaline. This vasodilator action of both drugs is This classification of adrenergic receptors has been inhibited by propranolol. vindicated by the development of drugs which The blood vessels in the skeletal muscles also selectively block either alpha or beta adrenergic contain alpha adrenergic receptors as the injection receptors. Drugs, such as phenoxybenzamine, the of adrenaline and noradrenaline decreases forearm ergot alkaloids, phentolamine and dibenamine, blood flow. When these receptors are blocked by the which have been available for many years, block prior administration of phentolamine, both drugs alpha adrenergic receptors but not beta receptors. increase forearm blood flow through activation of Protected by copyright. These drugs will inhibit the vasoconstrictor action beta adrenergic receptors. of phenylephrine, adrenaline and noradrenaline but Thus the effect of adrenergic drugs on the peri- not the inotropic, chronotropic or peripheral vaso- pheral blood vessels depends on a number of inter- dilator action of isoprenaline or adrenaline. related factors including the type of receptor in the The first drug, which would selectively block beta vessels in each particular vascular bed, the receptor adrenergic receptors, was dichloroisoprenaline which type activated by the drug and the effects of any was described by Powell and Slater in 1958. Since other concurrently administered drug. Although then many other drugs with this property have been these effects have been elucidated for the arterial side discovered. These include pronethalol, propranolol of the circulation to the limbs, much less informa- and oxprenolol. These drugs block the effects of tion is available about the venous side and about isoprenaline on beta adrenergic receptors. Practolol organs such as the liver and kidney. selectively antagonizes the effects of isoprenaline on beta adrenergic receptors in the heart (beta 1) but References not those in the smooth muscle of the bronchi or AHLQUIST, R.P. (1948) A study of the adrenotropic receptors. http://pmj.bmj.com/ blood vessels in skeletal muscle (beta 2). American Journal of Physiology, 153, 586. BRICK, I., HUTCHISON, K.J., MCDEVITT, D.G., RODDIE, IC. The effects of drugs on the peripheral circulation & SHANKS, R.G. (1968) Comparison of the effects of I.C.I. in man has been studied using venous occlusion 50172 and propranolol on the cardiovasular responses to plethysmography to measure blood flow to hand or adrenaline, isoprenaline and exercise. British Journal of forearm. The former reflects changes in skin blood Pharmacology and Chemotherapy, 34, 127. to muscle. POWELL, C.E. & SLATER, I.H. (1958) Blocking of inhibitory flow and the latter changes in blood flow adrenergic receptors by a dichloro analog of isoproterenol. The drugs can be administered either by injection Journal of Pharmacology and Experimental Therapeutics, into the brachial artery or by intravenous injection. 122, 480. on September 28, 2021 by guest..
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