Vasodilators and Vasoconstrictors

VASODILATORS AND VASOCONSTRICTORS, VASODILATING AND VASOCONSTRICTING AGENTS. Numerous medicinal substances (poisons) at therapeutic and especially toxic doses cause changes in the lumen of the vascular bed, however only a small number of them are applied in medicine for this purpose. Such a narrowing of the concept of "vascular" agents is determined by a number of reasons, namely: the predominant or selective action of these agents on vessels, the necessity of intervention in the pathologically altered state of the lumen of vessels of individual organs, regions, or the whole organism, the time of onset, the force and duration of the required effect. The given basic conditions of action of vascular agents allow them to be distributed into groups according to various signs. The most widespread classification is by the point of application of action of vasodilators and vasoconstrictors. Basically, vasodilators and vasoconstrictors are divided into 2 groups: centrally and peripherally acting agents. In this case, a number of medicinal substances will be referred to both in that and in the other group, since they simultaneously exert influence both on the vasomotor center and directly on the vascular network. In turn, in both groups, stimulant and depressant agents are distinguished, exerting a resorptive and local effect (including reflexively). With such a classification, the tissue elements on which a given agent exerts its influence are not sufficiently emphasized, as a result of which subgroups of vascular agents of direct action on the vascular wall (its cells), on the endings of vasomotor nerves and cells of the vasomotor center have to be created. In the further review of vascular agents, they can be divided into the following groups: 1) resorptively acting vasoconstricting or vasodilating on the vasomotor center, ganglia of the autonomic nerves or on the vascular network (on the endings of vasomotor nerves, the muscle of arterioles, the wall of capillaries); 2) locally acting vasoconstricting or vasodilating on the vascular network (its elements) and indirectly (reflex or humoral) influencing the vasomotor center and vessels of various vascular areas. I. Resorptively acting agents embrace the vast majority of medicinal substances applied with the aim of influencing the lumen of vessels. In turn, they can be divided into subgroups by the point of application of action. 1. Agents exciting the vasomotor center. A whole series of agents acting in an exciting manner on the entire central system belongs here; however, agents that selectively excite only the vasomotor center are not available (beta-phenethylamine due to a number of side effects has not acquired therapeutic significance). The chief among these agents are caffeine, camphor, and strychnine. All these agents to a greater or lesser extent simultaneously increase the secretion of adrenaline by the adrenal glands, which strengthens their vasoconstrictive effect. Caffeine and camphor are also characterized by a direct dilating action on the vessel wall. Excitation of the vasomotor center of the medulla oblongata, in essence, comes down to increased activity of only the vasoconstrictor center, since the existence of a center of vasodilating nerves is not yet physiologically proven. Increased activity of the vasomotor center is most vividly reflected in the vessels of the abdominal cavity (the area of the celiac nerves) — these vessels constrict earlier than others and to a greater extent; on the contrary, the lumen of the pulmonary, cerebral, coronary, and hepatic vessels changes to a significantly lesser extent, since apparently these vascular areas do not receive such powerful impulses from the center. With caffeine, the exciting action occurs quite soon (after 10-15 minutes with subcutaneous administration), is vividly expressed, lasts for the next 2-3 hours and almost never leaves behind (even with large doses) a stage of depression of the vasomotor center. Thanks to the simultaneous direct dilating action of caffeine on vessels, a struggle of two influences occurs: central vasoconstrictive and peripheral vasodilating. As a result, the vessels of the intestine constrict, to a lesser extent the stomach, spleen, and uterus. The vessels of the kidneys, reacting generally not parallel to the reaction of other vessels of the celiac nerve area, respond differently to caffeine (see Caffeine). The vessels of the skin and muscles under the influence of caffeine dilate to a small extent, mainly due to the predominance of its peripheral action, as well as due to intensified blood flow from the constricted vessels of abdominal organs. The coronary, pulmonary, and to a lesser extent hepatic vessels respond to caffeine with dilation (see Caffeine). In relation to the vessels of the brain, it is usually accepted (on the basis of experiments on animals) that caffeine has a vasodilating action, but plethysmographic measurement of the volume of the brain in a person with a skull defect did not show a change in volume even after intravenous administration of full therapeutic doses of caffeine. The therapeutic significance of the vascular action of caffeine is still disputed (see Caffeine). In relation to the influence of camphor on the vasomotor center, experimental material is still extremely insufficient. On the basis of experiments on an isolated kidney, which is connected with the organism only through the nervous system, Pilcher and Sollmann deny the exciting action on the center of therapeutic doses of camphor introduced into the vein of an animal; only with large (approaching convulsive) doses did they obtain a centrally conditioned constriction of the vessels of such a kidney. Speranskaya-Stepanova and Baranov (experiments from the laboratory of V. V. Savich), not excluding the possible central action of camphor, note under the influence of its intra-arterial administration an increase in blood pressure, which they attribute to its direct influence on the vascular wall under these conditions (with intravenous administration blood pressure fell). Other authors attribute to camphor a direct vasodilating action. This influence can explain the insignificant pressor effect of camphor — according to the experiments of Schwartz, blood pressure rises by only 10-20 mm Hg, according to other authors on normal people and patients with cardiovascular disease even 3 g of camphor subcutaneously do not change blood pressure. These data still do not resolve the participation of the vasomotor center in the effect. Even in the absence or small exciting resorptive action of camphor on the center, it is undeniable to recognize a significant reflex excitation of it with subcutaneous injections of camphor as an irritating agent. The latter modern pharmacologists attach increasing and increasing importance. Therapeutic effect from camphor in collapse — see Camphor. In accordance with the predominant exciting action of strychnine on the spinal cord, its influence on the medulla oblongata and vasomotor center in therapeutic doses is small. Although strychnine itself does not act directly on the vascular wall, nevertheless with its resorptive action one must also consider the peripheral action, owed to adrenaline, the secretion of which is intensified. As a vasoconstricting agent, strychnine cannot be useful in acute cases of vessel dilation. 2. Agents depressing the vasomotor center. Amyl nitrite, nitrite of sodium, and nitroglycerin, narcotic (chloroform, ether, alcohol, etc.) and soporifics of the fatty series (especially chloral hydrate), antipyretics, iohexbin, and partially morphine belong here. In addition, depression of the vasomotor center is observed to a certain extent with the action of other agents depressing the central nervous system. The action on the center is most vividly manifested with the application of nitrites of the fatty series and nitrites. Nitroglycerin, although it is a derivative of nitric acid, acts mainly by nitrites, into which it is transformed in the organism. This group of agents simultaneously exerts an even greater direct dilating action on vessels, so vividly expressed that in recent times many have begun to deny the central character of action, especially after the experiments of Pilcher and Sollmann (1915) on an isolated kidney with preserved central innervation. However, in experiments on an isolated rabbit ear with preserved central innervation (M. P. Nikolaev, 1928), the central depressing action of amyl nitrite, nitrite of sodium, and nitroglycerin turned out to be undeniable. The difference in the results of experiments must be explained by the character of action of substances of this group: first of all, dilation of the vessels of the face and head occurs, then of the upper half of the body and only with significantly larger doses do the vessels of the abdominal cavity, including the kidneys, dilate. Such a sequence of action some authors explain by the initial depression of only that part of the vasomotor center which governs the vessels of the upper half of the body. A more acceptable explanation seems to be this one by the peculiarities of innervation and reaction to medicinal substances of vessels of equal areas. Thus, Darwin first pointed out that the redness of the face caused by amyl nitrite corresponds exactly to the redness in various emotions over the occupied area of skin. Therapeutic application — see Amyl Nitrite and Nitroglycerin.

Dressed with essentially the same character of action, amyl nitrite, sodium nitrite, and nitroglycerin practically differ significantly from each other in the speed, duration, and strength of action (see corresponding articles). The effect of these agents is the greater the higher the blood pressure was before them. With repeated application, a relative tolerance to them is noted quite soon. In attacks of intermittent claudication and other diseases with spasm of the vessels of the lower extremities, this group of agents does not give an effect, while large doses are dangerous (see Amyl nitrite). The depressing action of volatile narcotic fatty series agents (chloroform, ether, etc.) on the vasomotor center is preceded by excitation of the center due to reflexes from sensitive nerve endings in the respiratory tract and in the oral cavity. Initial excitation of the center may also occur from the direct action of these substances, since it was observed (Gaskell and Irkhore, 1893) upon the introduction of chloroform directly into the blood vessels of the rabbit's brain (bypassing the heart). In the stage of anesthesia, vascular dilation is due mainly to depression of the vasoconstrictor center and partly to the direct dilating action of these agents on the vessel wall (see Chloroform and Chloral hydrate).- Upon the action of antipyrine group antipyretics on a febrile organism, dilation of cutaneous vessels occurs due to depression of the abnormally excited heat-regulating center, and through it - the vasomotor center (see Antipyretics). Vessels of other areas do not dilate, which is of essential importance for lowering body temperature.- Isoxsuprine possesses a selective depressing action on spinal vasomotor centers, causing dilation of the vessels of the skin, kidneys, and especially the genital organs. Vessels of other areas (for example, the spleen) it constricts. Besides the central action, isoxsuprine also has a peripheral action, since its dilating action is preserved even after cutting the nerves. It was proposed for lowering blood pressure in cases of hypertension, but observations (Lawrence and others) showed that it can cause further elevation of blood pressure with dangerous phenomena.- Morphine exerts a slight depressing action on the vasomotor center in therapeutic doses - hyperemia of cutaneous vessels occurs, apparently also of cerebral and coronary vessels. 3. Ganglionic poisons. The poisons of the nicotine group belong here. Of these, nicotine itself has only toxicological interest (see Nicotine), has no therapeutic value, while lobeline is applied for therapeutic purposes.- The action of lobeline on the vessels is analogous to that of nicotine, but is less pronounced. As a vascular agent, lobeline could not find application due to its significantly more pronounced depressing action on the heart (see Lobelia). 4. Agents acting on the endings of vasomotor nerves. In connection with the chief role of sympathetic innervation in the regulation of vascular tone, sympathicotropic agents (adrenaline, ephedrine, ergotoxin, ergotamine, etc.) have primary importance here. In some cases, especially experimentally, one can see vascular action of parasympathomimetic poisons (atropine, pilocarpine, etc.), but they have no practical significance in this respect. The vascular system is extremely sensitive to adrenaline and responds to it according to the character of sympathetic innervation - the small arteries of the abdominal cavity (intestine, kidneys, spleen, and other organs) constrict mainly, conversely, the vessels of the lungs, and in most cases also the coronary and possibly cerebral vessels dilate. The powerful vasoconstricting action of adrenaline is exclusively of peripheral origin, since it has no direct exciting action on the vasoconstrictor center, nor does it change the function of the adrenal gland, which represents a modified ganglion and has no sympathetic endings (Trendelenburg, Mansfeld). It is considered that adrenaline excites the so-called myoneural substances, i.e., a hypothetical intermediate substance between the end of nerves and the cell, not degenerating after cutting the nerve. Blood pressure generally rises, while in small doses in carnivorous animals and in people with signs of vagotonia (Csepai and others) a lowering of blood pressure is often observed. This fact has not yet received sufficient explanation. The action of adrenaline is brief (see Adrenaline), and often after constriction of the vessels their dilation occurs. Therapeutic significance of adrenaline - see Adrenaline. Paralysis of sympathetic endings in the vessels is not achieved even with very large quantities of adrenaline (7,000 times larger than the smallest effective doses). The active principle of the plant Ephedra vulgaris (Kuzmicheva grass), the alkaloid ephedrine, in many ways resembles the action of adrenaline, but apparently besides exciting sympathetic nerve endings it also exerts a direct action on the cell. The vasoconstricting action of ephedrine occurs upon introduction into the mouth, under the skin, and into the vein. Vessels in the area of the splanchnic nerves constrict most strongly, but the volume of the spleen always increases, while the kidneys on small doses react with slight dilation of the vessels and only on large doses respond with significant constriction of the vascular wall. Besides its influence on sympathetic endings, ephedrine excites ganglia and increases the secretion of adrenaline by the adrenal glands. Clinical studies (Csepai and Dole-schall) showed that after the introduction of ephedrine the action of adrenaline is intensified. The elevation of blood pressure under the influence of ephedrine occurs to a lesser extent than from adrenaline, but lasts significantly longer (1-2 hours). Ephedrine was tried in states of hypotonia, in shock, and in circulatory insufficiency during operations (by SO-100 mg orally repeated after a few hours), but it proved unsuitable for maintaining blood pressure in cases of prolonged hypotension, since the effect upon repeated administration of ephedrine is significantly less than the initial one. In individual observations, an increase in systolic and diastolic blood pressure was noted upon the intake of patients with Addison's disease of an aqueous tincture from Ephedra vulgaris (5-10%), but the effect here is still less than from ephedrine. Ephedrine found the greatest application in attacks of bronchial asthma and as a locally acting vasoconstrictive agent (see Ephedra vulgaris).- On the active principles of ergot, ergotoxin, and ergotamine - see Ergot. 5. Agents acting on the muscles of arterioles. Partially about these agents has already been mentioned above (caffeine, camphor, nitrites, isoxsuprine, etc.). Here it is especially necessary to emphasize the vasodilating action of theobromine (resp. diuretin) due to its important significance. Similar to caffeine, by dilating vessels due to their direct action on them, these substances at the same time do not possess the characteristic exciting action of caffeine on the vasomotor center, due to which they give a reliable vasodilating effect.- Introduced in 1913 into therapy by Pal (Pal) papaverine (one of the opium alkaloids) won itself a reputation as a means relaxing vascular spasms and lowering elevated (but not normal) blood pressure. Its central action is insignificant, its peripheral manifestation is mainly in the area of the splanchnic nerves. Upon subcutaneous introduction of the hydrochloride salt of the alkaloid (0.04-0.06 per injection) or upon oral administration of approximately the same doses, favorable results were noted in hypertension, angina pectoris, and other states of angiospasm. The action lasts several hours, with small doses the effect is insignificant. Upon intravenous introduction, large doses are very dangerous - cases of collapse and even fatal outcome have been described (Saxl). Instead of papaverine, in recent times (especially in America) benzyl benzoate began to be applied as an antispasmodic agent in hypertension, but so far the results obtained are contradictory. Upon ordinary oral intake (20% alcoholic solution of 1-10 ³ in cold water 3-4 times a day) it often causes dyspeptic phenomena, sometimes vomiting and diarrhea. On blood pressure in cases of arterial hypertension it did not exert a noticeable influence (Gruber). In recent years, various organopreparations have acquired special significance as vasodilating agents. Among them, the first place should be given to the preparation Padutin (German), or Angioxyl (French authors), containing the hormone kallikrein {Kraut, Frey, 1925). This hormone is apparently formed in the pancreas, and is also present in active form in urine; in the blood, liver, kidneys, and other tissues it is for the most part in a bound form with a second substance (polypeptide), which inactivates it. It differs from insulin both chemically and biologically: kallikrein represents a colloidal substance, easily destroyed by acids and boiling, insoluble in 80° alcohol. Possesses a brightly expressed ability to lower blood pressure due to its peripheral action on the blood vessels: under its influence the vessels of the brain, lungs, heart, skin, and muscles dilate significantly; at the same time an increase and acceleration of heart contractions, an increase in minute volume and speed of circulation are noted.

Frey proposed that the unit of action of kallikrein be defined as the smallest amount of the preparation which, when injected intravenously into a dog, causes a noticeable increase in the amplitude of heart contractions, an increase in rhythm, and a fall in mean arterial pressure. The German preparation Padutin contains 7 units of kallikrein in 1 cm³ for oral administration of 10 drops three times a day; for intramuscular injections 1 cm³ contains 2 units and is applied as 7 cm³ twice a day; after 3 days the dose is increased to 1 ampoule (1 cm³) per injection. It has been tested in a number of clinics and proved non-toxic even with prolonged (for months) administration of large doses. Especially good results were obtained in angiospasm, hypertension, in the initial stages of arteriosclerosis, in intermittent claudication, Raynaud's disease, in many forms of gangrene (except diabetic and others), in necroses, poorly healing wounds and ulcers, and other diseases associated with disorders of peripheral circulation. A prolonged effect was obtained with prolonged use of the preparation (for months). The nature of the action of kallikrein allows it to be considered a hormone regulating vascular tone (Dale, 1932). Along with this, preparations of other organs with a vasodilatory action are currently on sale. In our Union, Myol of Prof. Schwartzman (Odessa) has become known. Myol is obtained from striated muscles and is analogous to the German preparation Lacarnol. It is applied orally and, more effectively, parenterally. Doses: orally 15-25 drops 2-3 times a day, intramuscularly 7-10 drops 2-3 times a day. The active principle of Lacarnol is adenine and adenylic acid (Rothmann)—normal intermediate products of nuclear metabolism in the cell. Unlike kallikrein, preparations of this group act mainly on coronary, not peripheral, vessels. Clinically, a good and sometimes prolonged (up to 2-10 months) success is often noted in angina pectoris. Sometimes success was also seen in vasomotor disorders of cerebral circulation, in intermittent claudication, etc. There is still no complete agreement on the evaluation of the efficacy of preparations of this type in various diseases, but the fact that their action can be obtained by a number of other preparations is undeniable. Abroad, alcoholic extracts from the liver, giving a prolonged lowering of elevated blood pressure (Major), enjoy special popularity. The so-called cardiac hormone of Gaberlandt, obtained not only from the Kisch-Flack nodes but also from the liver and muscles, is closely related to this. Its action is extremely reminiscent of adenylic acid. When these preparations are applied, side effects are sometimes noted (drowsiness, unpleasant sensations in the head, buzzing in the ears, dizziness, sensation of heat, thirst, and sometimes shock-like phenomena). Since these phenomena are also noted with oral administration, dosing in each individual case must be cautious, especially since different preparations and their batches have different activity. The use of tissue substances in the form of various preparations for therapeutic purposes is of interest also from a general physiological point of view, since their increased formation is currently used to explain working and reactive hyperemia of muscles and a number of other physiological and pathological processes. In contrast to adrenaline, vasopressin (the hormone of the posterior lobe of the pituitary gland) and kallikrein, all these substances act only at the site of their formation and possibly participate in the creation of a certain vascular tone. However, when formed in excess, they can enter the bloodstream and cause certain pathological phenomena. From this point of view, organ preparations with a vasodilatory action can be considered as agents of replacement therapy and at the same time as agents giving, in appropriate doses, a transition to a pathological state. One of the hormones of the posterior lobe of the pituitary gland, contained in the preparation pituitrin, has long acquired significance as a vasoconstrictor agent. Upon intravenous, to a lesser extent upon subcutaneous (but not upon oral) administration, it exerts a direct vasoconstrictor action on most organs (except the kidneys, where the vessels dilate). This action is due to the contraction of the musculature of small arteries and does not depend on peripheral or central influence on the nervous system. The result is an increase in blood pressure—less strong but more prolonged than from adrenaline. In case the preparation is contaminated with histamine (see below), which unfortunately often occurs (see Pituitrin), the action is complicated by the capillary dilation caused by histamine. Possibly for this reason, pituitrin has not yet acquired wide significance as a vasoconstrictor agent. Some authors have seen good results from it in cases of collapse, toxic drop in blood pressure during peritonitis, during surgical shock and other conditions. However, the effect was observed far from all cases. The use of pituitrin is very dangerous in cases of pronounced damage to the heart muscle and in arteriosclerosis. It is possible that the improvement of the purification of the preparation from ballast substances and the obtaining of the hormone in pure form will expand its application as a vascular agent. Among substances exerting a direct action on the vascular wall, one should still mention a number of medicinal plants used for the purpose of increasing sweating (see Diaphoretics), garlic and iodine, which have acquired fame as agents against arteriosclerosis, which some authors are inclined to explain by their vasodilatory action (however, according to experimental data, many authors deny such action). The influence of hydrastinin on blood pressure (initial fall with subsequent rise) is due mainly to its action on the heart, but also to the constriction of arteries, thanks to its direct excitatory action on the smooth muscle of their walls. The use of salts of catarnin (stipticin, stiptol) as hemostatic agents (especially in uterine bleeding) does not find a satisfactory explanation (except for the contraction of uterine muscle), since they do not exert a direct action on the vascular wall or on the vasoconstrictor center (Falk, Marfou and Ronsse, Laidlaw and others, Pilcher and Sollmann). 6. Agents acting on capillaries. Among these agents, histamine is of the greatest interest, although practically it is applied mainly for the purposes of investigating the speed of blood circulation. Significant amounts of it are released in the intestine under the influence of bacteria: normal human feces contain from 5 to 7 mg of histamine per day. Probably it is formed in significantly larger amounts, but it is quickly destroyed in the intestine. In relation to its action on capillaries, histamine is of interest because it is contained in many extracts from organs and upon parenteral administration of these organ preparations gives its characteristic effect. It manifests itself as a rapidly occurring dilation of capillaries and an increase in the permeability of their walls; arterioles are constricted. Blood pressure drops significantly. Completely analogous phenomena were noted in anaphylactic, traumatic and peptone shock, which is why some are inclined to consider their cause the formation of histamine-like substances. Specific action on capillaries is also exerted by arsenic and antimony. Already small amounts of them cause dilation of cutaneous vessels; this action is combined with the trophic influence of arsenic and is used in therapy to improve tissue nutrition. Toxic doses of arsenic and antimony cause a sharp dilation of the capillaries of the mucous membrane of the digestive canal (see Arsenic and Antimony). There are experimental data allowing one to think that along with the direct action on the wall of capillaries, arsenic exerts a selective action on the sympathetic terminal apparatus of small arteries. II. Locally acting agents. This group includes medicinal substances that exert action on the vessels of the skin and mucous membranes upon direct application to them; moreover, with simultaneous irritation of sensitive nerve endings we can have a remote influence on other vascular areas (reflexively through the central nervous system or by way of axon reflexes); along with this, the formation at the site of application of the medicinal substance of products of intensified tissue activity or cellular breakdown can act on the whole organism humoral way. A typical locally constricting vessel agent is adrenaline, the application of which is especially valuable in combination with local anesthetics, in order to prevent their absorption and thereby strengthen and prolong the local effect (for example, solutions of novocaine or cocaine with adrenaline). Ephedrine possesses such action to a significantly lesser degree. Among anesthetics, cocaine causes constriction of small arteries due to its excitatory action on the endings of their sympathetic nerves. However, the vasoconstrictor action of cocaine is significantly inferior to adrenaline (see Cocaine). Besides such selective action on sympathetic nerve endings, constriction of vessels can also be obtained from agents acting directly on the cell itself.

This includes the action of astringent agents, both organic and metallic. By causing partial coagulation of proteins, they reduce the size of the adjacent tissues and the vascular wall, as a result of which the vessels constrict and are compressed by the surrounding tissue. Such an action is especially clearly manifested in inflamed tissues, which is why astringents have been used since ancient times as anti-inflammatory agents. At stronger concentrations, the same substances dilate the vessels, acting in an irritating manner. Many volatile oils containing terpenes, oxidized aromatic derivatives (turpentine, etc.), Spanish flies, and others are specifically employed for the purpose of local irritating action. Their local action manifests as vessel dilation. Such an action entails an increased influx of blood to the site of application of the medicinal substances and at the same time causes reflexes in other vascular areas. The specific localization of the site of application of these skin-irritating agents in diseases of internal organs found an explanation in Mackenzie's doctrine of visceral-sensory and visceral-motor reflexes (see Visceral Reflexes), which pass through those segments of the spinal cord that are directly connected with the affected organ and the site of application of the irritating agent on the skin (Ged zones). Thanks to such a reflex, one may expect reflex constriction of the vessels of the organ affected by the inflammatory process, a reduction in its blood filling, and tonic contraction of the corresponding muscular segment. It is possible that this action can also be explained by a purely humoral path - the formation at the site of application of the irritating agents of an increased amount of tissue substances, which are absorbed into the general circulation and exert a predominant action on the vascular system and the tissues of the affected organ. Such an action is accepted as the basis of the so-called non-specific parenteral therapy; it explains the identical result obtained from the application of chemically completely different substances (hypertonic salt solutions, proteins and their decomposition products, application of radiant energy, etc.); according to this view (Weichardt, Schittenhelm, and others), it is not the applied substances themselves that act, but the tissue substances and products of cellular decomposition formed at their site of application (subcutaneous, intramuscular injections) (see Protein Therapy).