Reprinted from CuinicaL CARDIOPULMONARY PrysioLoGy Copyright © 1960 by Grune & Stratton, Inc. Printed in the Linited States of America — 17 — Pathogenesis of Organic Changes in Chronic Hypertension and Hemodynamic Effects of Antihypertensive Agents By EDWARD D. FREIS, M.D. Senior Medical Investigator, Veterans Administration Hospital; Associate Professor of Medicine, Georgetown University School of Medicine, Washington, D. C. HE characteristic hemodynamic abnor- mality in hypertension is the increase of total peripheral vascular resistanee. All other possible factors such as cardiac output, total blood volume and blood viscosity are normal in uncomplicated essential hypertension, but when unduly elevated might produce a rise of blood pressure. Except in rare instances, as im patients with pheochromocytoma, the cause of the vascular constriction is unknown. Despite the present ignorance concerning the etiology of chronic hypertension, there is con- siderable evidence to suggest that the patho- genesis of organic complications is connected directly to the elevation of arterial pressure. The characteristic pathologic lesion is hyper- plasia of the intima of the arterioles. It was considered previously that this change, as a primary process, produced the increased periph- eral resistance, resulting in hypertension, the Impression having been gained from autopsy examination of patients dying in the advanced stages of the disease. It is known that proliferation and fibrosis of the arterial intima are not found early in the course of benign essential hypertension. Biop- sies of muscle and also of kidney as well as autopsies in young hypertensives dying of other causes fail to reveal structural changes in the intima of the arterioles. Arteriolosclerosis, therefore, 1s a late development. In the early stages, the constriction is functional a narrowing due to smooth muscle con- traction. This functional constriction often can be seen in the optic fundi of patients with significant. hypertension of relatively short du- ration. More interesting, the spasm may sub- side when the blood pressure is reduced. Byrom has shown this reversal to occur in the me- 295 ningeal arterioles of hypertensive rats.’ Relaxa- tion of arteriolar spasm has been seen in the optic fundi in patients with short-lived hyper- tension such as acute nephritis or toxemia of pregnancy when the blood pressure was reduced with antihypertensive agents or following re- covery from the acute hypertensive state. Reversal of fundic arteriolar spasm may also oceur in young adults with chronic essential hypertension after their blood pressures have been controlled at normotensive levels with antihypertensive agents. Since the sclerosis of arterioles follows the hypertension by some years, it seems possible that the condition is produced by the hyper- tension per se or by the associated arteriolar spasm. Evidence supporting this concept has been supplied by Wilson and Byrom.! They induced hypertension in the rat. by constricting one renal artery with a partially oecluding clamp. As a result, distal to the elamp there occurred not only reduetion of blood flow but also of blood pressure. A severe hypertension, however, developed in the remainder of the animal, including the arterial branches of the opposite kidney. In the animals who died of severe hypertension, typical arterioloselerotic and arteriolonecrotic lesions were found in the vessels of the opposite or high-pressure kidney, whereas in the low-pressure kidney distal to the clamp the arterioles appeared quite normal. Some instances of hypertension associated with narrowing of a renal artery in man suggest that human arterioles react. similarly. lor ex- ample, in patients with hypertension second- ary to partial thrombosis or other forms of narrowing of one renal artery, intimal prolifer- ation of arterioles is found in the opposite kid- ney but seldom m the involved kidney. Bland 296 CLINICAL CARDIOPULMONARY PHYSIOLOGY described an unusual instance of hypertension apparently due to thrombosis of a main branch of one renal artery. Approximately one-half of the kidney was supplied with low blood flow and pressure, the other with blood under high pressure. Histologic examination revealed hy- perplastic arterioles on the hypertensive side and normal-appearing arterioles on the hypo- tensive side. Since the hypotensive side was not infarcted, it must have received some blood supply even though this was limited. Thus, if there were any unknown circulating or neurogenic toxic substance acting on arteriolar walls to damage them one would expect this factor to act on both portions of the kidney. Indeed, since the side distal to the thrombosed artery was the seat of the disorder, one would expect. the arterioles to be, if anything, more diseased in that portion. There is evidence to suggest that arteriolar smooth musele, like the smooth muscle of the ureter or gastrointestinal tract, reacts to stretching by further contraction. Many years ago, Baylis made this proposal, and more re- cently Folkow and others have shown that in vessels entirely freed of neurogenic or humoral influences elevation of pressure produce vascu- lar constriction, while reduction of pressure induces peripheral vascular relaxation.? Teleo- logically, this intrinsie response of vascular smooth muscle provides a second line of de- fense in case of exhaustion or failure of the moderator (carotid sinus and aortic arch) reflexes. It also is important to note in this connection that the moderator reflexes in hy- pertensive individuals are set at a higher level. In addition, it is apparent that the constriction of smooth muscle to pressure provides a mech- anism for the continuation of increased periph- eral resistance even after the initiating cause of the hypertension has been removed. This may explain why hypertension sometimes fails to regress following removal of a pheochromocy- toma, or a unilaterally diseased kidney, or following delivery in toxemia of pregnancy. Another important factor in the perpetuation of some hypertensions is the development of nephrosclerosis. ACCELERATED ATHEROSCLEROSIS OF Larce ARTERIES Many of the incapacitating or fatal compli- cations of hypertension are caused by the frequency of atherosclerosis of large arteries particularly in the cerebral and coronary blood vessels. The hypertensive patient is more prone to develop atherosclerosis than the normal in- dividual. The incidence of myocardial infare- tion has been found to be four to five times higher in hyperteusive males than in the gen- eral population and twenty times higher in hypertensive than in normotensive females.* It is well recognized also that the incidence of cerebrovascular atherosclerosis and thrombosis is unusually high in the hypertensive popula- tion. Some factor must be present in the hyper- tensives which accelerates the atherosclerotic process. This acceleration may be due to the high pressure existing in the arterial tree or to some other unknown factor present in hyper- tensive patients. In deciding between these two possibilities, it is pertinent to refer to the changes that may occur in the pulmonary arteries following long-standing and persistent pulmonary hypertension. Pulmonary hyperten- sion of long duration is found in certain forms of congenital heart disease, such as in patent ductus arteriosis with right-to-left shunt or in large interventricular septal defects in which the patients occasionally survive to adult life. The level of pulmonary pressure in such indi- viduals is several fold higher than is normal for that system. At autopsy, it is common to find in such patients extensive atherosclerosis of the pulmonary rather than the systemic arterial system. It is evident that if the acceleration of atherosclerosis were due to some circulating or neurogenic noxious factor it should affect both sides of the circulation. It would not spare the systemic circulation in pulmonary hypertension and the pulmonary circulation in systemic hypertension. The fact that the atherosclerosis is limited in each case to the areas of elevated pressure suggests strongly that the hyperten- sion is the aggravating factor. These observa- tions are not cited to imply that hypertension ORGANIC CHANGES IN CHRONIC HYPERTENSION 297 causes atherosclerosis but rather to indicate that the hydraulic effect of an increased pres- sure head existing within the arterial tree hastens and intensifies the process of lipid deposition. ConGestTivE Heart IatLbure It has been recognized for many years that the left ventricle responds immediately to an increased peripheral resistance by dilation and somewhat later by hypertrophy. The dilatation is purely a mechanieal response conditioned by the contractile properties of cardiac muscle. If the peripheral resistance is elevated, the ven- tricle fails to empty as completely as it had previously. As a result, the volume of residual blood increases in the ventricle producing fur- ther stretching of the myocardial fibers. Ac- cording to Starling’s law, cardiac output is proportional to diastolic fiber length; the greater the stretch the greater the subsequent. contraction. As a result, the output is restored to normal despite the clevated aortic pressure. It should be noted, however, that in order to maintain a@ normal output the contraction of the heart muscle is increased; this requires a greater expenditure of energy (increased work). As with any muscle subjected to prolonged work demands, the fibers hypertrophy and the ventricular wall thickens. Eventually, if the hypertension becomes more severe, or if the hlood supply to the myo- ‘“ardium becomes compromised by atheroscle- rosis of the coronary arteries, or if the myocar- dial musculature becomes diseased through other causes, a point is reached in which fur- ther diastolic stretching leads to less effective rather than more effective contraction. HH was demonstrated by Starling and later amplified by Sarnoff that there are limits to the compen- satory powers of cardiac muscle. In every myocardium there is a critical point at which further stretching of the fibers leads to less effective contraction and the cardiac output falls. Onee this point is passed, additional m- creases in arterial pressure evoke progressively poorer contractions with a consequent rapid decline in output. If the heart 1s damaged from other causes such as coronary artery disease or myocardial fibrosis, this critical point occurs at lower aortic pressures than in an undamaged heart. It is logical to assume that the left ventricle will fail first and that pulmonary edema will result; and indeed this is often the case. At first, there will be only dyspnea on exertion, then paroxysmal nocturnal dyspnea and finally per- sistent chronic pulmonary edema or bouts of acute pulmonary edema requiring emergency therapy. It is possible, however, for right ventricular failure to occur and even predominate with the appearance of peripheral edema, high venous pressure and an enlarged liver. The reasons for this are not completely understood, but there are several possible explanations which prob- ably operate in concert to produce the right ventricular failure. First, it should be recalled that the myocardial musculature is a syneytium involving both ventricles. Damaye to the major or left ventricle can compromise the weaker or right ventricle, although the reverse seldom occurs. Second, the reduetion of left ventricular output lowers the driving force that keeps the blood circulating and results in a tendency for blood to collect on the venous side of the cireu- lation. Third, reduction of arterial pressure secondary to the fall of cardiac output stimu- lates the aortic and carotid sinus nerves to produce peripheral vasoconstriction involving postarteriolar as well as arteriolar small vessels. By this means, much of the blood normally distributed in the small vessels is shunted into the central venous system where it tends to accumulate because of the ineffective cardiac output. Finally, the disordered cireulation stimulates secondary reactions, possibly in- volving aldosterone secretion. This may com- promise salt and water excretion in the kidney, thus favoring salt. retention and edema. It seems probable, as pointed out a number of years ago on the sequence of events following severe myocardial infarction, that the body has only a limited number of response patterns to stress. Indeed, most important for survival of the species are the reactions following hemor- rhage; the wounded animal must fight or flee if he is to survive and propagate. After hemor- rhage, as the cardiae output falls, the baro- receptors are stimulated to constrict small 298 CLINICAL CARDIOPULMONARY PHYSIOLOGY peripheral vessels of all types in order to shunt blood into the central circulation. At the same time, the heart rate increases. In the healthy individual subjected to blood loss, these reac- tions are advantageous, but with a low output. as in heart failure they only add to the burdens of an already overworked myocardium. In addition, the reduction of cardiac output or possibly of arterial blood volume following hemorrhage or low output heart failure stimu- lates renal salt and water retention with resulting expansion of the extracellular fluid and plasma volumes. Within 48 hours following blood loss there develops a considerable expan- sion of plasma volume due to this mechanism. Unfortunately, the body does not scem_ to differentiate between a reduction of cardiac output due to blood loss and a reduction due to cardiac failure. The reaction which is so help- ful to the rapid restoration of blood volume following hemorrhage only adds to the burdens of the failing heart producing edema and fur- ther venous congestion. The salt and water retention mechanism restores blood volume and cardiac output in the healthy heart, thereby shutting off the stimulus to further salt reten- tion. In the failing heart, however, as these burdens further reduce the cardiac output, the stimulus to salt and water retention increases, thereby setting up a vicious cycle. OTHER COMPLICATIONS Dissecting aneurysm of the aorta which occurs almost exclusively in hypertensive pa- tients may also be a direet consequence of the elevated pressure. The aorta, being made up primarily of elastic tissue rather than smooth muscle, dilates in the presence of hypertension. Tt seems possible that the distention and stretching of the aortic wall may compromise the patency of the capillaries feeding the media and thus lead to medial necrosis. The resultant, weakness of the aortic wall favors tearing or splitting in the presence of a constantly in- creased distending pressure or in a moment of extreme hypertensive overshoot. Very little is known about the mechanism of cerebral hemor- rhage. It is recognized, however, that hyperten- sion contributes to excessive bleeding during brain surgery. These considerations as to the pathogenesis of the various organic complications of hyper- tension are of more than academic interest. Tf it is true that the elevated pressure produces organic damage, then reduction of blood pres- sure in the early stages of the disease would retard or prevent the development of organic damage. The argument that effective antihy- pertensive therapy should be reserved only for the advanced patients who already have severe organic damage becomes illogical when viewed in the light of the basie considerations. PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS The basic mechanisms by which arterial pressure may be reduced are: (1) by decreasing cardiac oul put and (2) by reducing total periph- eral resistance. Most of the agents used today probably act. on both mechanisms. GANGLIONIC BLOCKING AGENTS The hemodynamic effects of the ganglion- blocking drugs ean be demonstrated most clearly by substituting a mechanical pump for the left ventricle? In an anesthetized dog, blood is diverted as it enters the Jeft atrium into a reservoir and then is pumped back into the animal via a T tube in the descending thoracic aorta. When hexamethonium is in- jected intravenously, there is first a fall in arterial pressure, indicating clearly a decrease in peripheral vascular resistance, since the pump is maintained at a constant output. There soon follows, however, a decrease in central venous pressure, pulmonary arterial pressure and a transient deerease in the volume of blood returned from the right heart through the pulmonary circulation to the reservoir. As a result of the temporary disparity between the output of the right heart and the pump’s constant: flow, the reservoir is depleted of sev- eral hundred milliliters of blood. Thus, the vas- cular volume or capacity of the dog must have increased sufficiently to accommodate the amount of blood transferred from the reservoir to the animal. Since this amount is too great to be explained on the basis of arteriolar dilation alone, it is apparent that the postarteriolar vessels must have dilated as well. ORGANIC CHANGES IN CHRONIC HYPERTENSION 299 In the intact animal or human,‘ the sequence of events appears to be as follows: As sympa- thetic vasoconstrictor discharges are inhibited by the blocking agent, some arteriolar dilation occurs which is followed quickly by postarterio- lar (capillary and venular) relaxation and pool- ing of blood in these small vessels. As a result, right heart filling pressure declines due to lack of adequate venous return, and the cardiac output falls. Thus, there is produced a further fall in arterial pressure. Since arteriolar relaxa- tion and reduced cardiac output are present, the calculated total peripheral resistance rela- tive to the cardiae output shows no significant change. In the presence of congestive heart failure, however, the cardiac output rises rather than falls after ganglion-blocking agents. This para- doxical response results from the combined beneficial effects of arteriolar relaxation (de- creased aortic pressure head reducing the work load) and pooling of blood volume peripherally (relief of central venous congestion). The effects of the inhibition of the sympa- theties are aggravated when the patient assumes the erect, position (failure of compensa- tory reflex vasoconstriction) and are counter- acted when he assumes the head down position, since gravity facilitates venous return. Simi- larly, blood loss cannot be compensated for by vasoconstriction, and severe hypotension can result. from only moderate depletions of total blood volume.’ With continued inhibition of the sympathetics, however, some homeostasis seems to return in time. This so-called ‘‘autono- mous tone” of the muscular blood vessels probably is due to the intrinsic property of smooth muscle to contract under stretch and to relax after the stretching force has been removed. Normally, the sympathetic reflexes rather than autonomous tone provide the quick adjustments required for cireulatory homeos- tasis during changes of body position. When the sympathetics no longer function effectively, as after surgical sympathectomy or ganglion- blocking drugs, the autonomous tone mecha- nism probably comes into play as a second line of defense. When the sympathetic tone is released, following ganglion-blocking agents there is also some redistribution of blood flow to the various areas of the body.* Renal blood flow is reduced at first, but, due to the remarkable autonomy of the renal vasculature, adjustments are made promptly to restore blood flow to control levels. Essentially, the same adjustment oecurs in the brain. The hepatic-portal blood flow decreases whereas the flows of the calf and forearm increase immediately. In the hands and feet, however, if there has been vasocon- striction by, e.g., placing the subjcet. in a cold room, the increase in blood flow is approxi- mately tenfold. The other effects of ganglionic blockade are related to inhibited {ransmission of nervous impulses through all autonomic ganglia, parasympathetic as well as sympa- thetic. SaLtT-Resrrictep Diets anp SALURETIC AGENTS Since it is our belief that low sodium diets and saluretic agents such as chlorothiazide pro- duce similar hemodynamic effects, they will be discussed under the same heading. Vhe con- siderations are limited to the effeets of diets, such as the rice diet, which are restricted to 200 mg. of sodium per day or less. It should be mentioned that diets more liberal in sodium content do not produce a degree of salt deple- tion necessary to induce a reduction of blood pressure. Salt depletion can be accomplished more effectively and quickly with a saluretic agent, such as chlorothiazide, than with a sodium-re- stricted diet. If a nonedematous, hypertensive patient is given orally 1.0 to 1.5 Gm. of chloro- thiazide per day, there will occur a prompt diuresis of sodium and chloride, and, to a lesser extent, potassium.> During the first 48 to 72 hours, approximately 250 to 350 mEq. of so- dium and chloride are sost from body stores, i.e., over and above the daily intake. If the chloro- thiazide is maintained beyond this period, the depletion of body stores of salt levels off and the patient comes into balance with his intake. However, he does not regain the original losses. If the salt ingestion is mcreased, the extra amount is excreted unless the intake is pushed to excessive levels (approximately 25 Gm. per day). 300 CLINICAL CARDIOPULMONARY PHYSIOLOGY The excreted salt appears to be derived primarily from the total extracellular fluid space. The patient characteristically loses 1 to 2 kilos of body weight and | to 2 L. of extra- cellular fluid as measured by thiocyanate, radiosodium or radiosulfate dilution spaces. The serum concentrations of sodium and chlo- ride do not change significantly indicating that the elimination of extracellular salt and water is proportionate. The serum concentration of potassium usually falls slightly, but this reduc- tion frequently is progressive unless potassium supplements are administered. Included in the extracellular fluid space is the plasma volume which is reduced by about 15 per cent from its original level. All of these effeets occur approximately within the first 48 hours, during which time the blood pressure also falls. The reduction in plasma volume and extracellular fluid space usually is maintained for periods of at least one month with the con- tinued administration of chlorothiazide in the dosage of 500 mg. twice daily. The hemody- namie importance of the plasma volume deple- tion is indicated by the fact that restoration of plasma volume loss alone, without added salt, as by infusion of 500 ml. of 6 per cent dextran in glucose and water, usually returns the blood pressure to the previous or pretreatment level. Normotensive, nonedematous individuals also exhibit a similar saluretic response and reduction of extracellular fluid and plasma volumes. However, unlike the hypertensive patients, there is no reduction of basal blood pressure. Nevertheless, altered vascular reac- tivity in that the degree of blood pressure elevation following infusions of pressor agents such as norepinephrine usually is reduced and the hypotensive response to depressor agents is increased. This altered vascular responsive- ness can be reversed by restoring the plasma volume with salt-free dextran. Several important considerations emerge from these observations. First, there is a labile pool of extracellular fluid and plasma volume which can be eliminated either by effective saluretic agents or by severely restricted salt intake. Parenteral mercurials also produce a de- pletion of plasma volume with an alteration in vascular reactivity. Second, the reduction of plasma volume alters vascular reactivity in both the normo- tensive and hypertensive individual but re- duces basal blood pressure only in the hyperten- sive. Our experience indicates that individuals with basal diastolic blood pressures in the region of 90 mm. Hg or above react to chloro- thiazide with a fall of basal blood pressure, whereas those with diastolic levels of 85 or lower are not responsive. Since the fall of blood pressure may occur even in patients with only mild elevations of diastolic blood pressure, it is concluded that a basic difference exists between mildly hypertensive and normotensive individuals. We have interpreted our results to indicate that in all hypertensives, including those with only moderate elevations, a pressor mechanism or stimulus of some type is opera- tive. Chlorothiazide reduces the blood pressure in such a group by decreasing the vascular reactivity to this stimulus. A third implication is that the studies show an important relationship between total blood volume and vascular reactivity. It is probable that. when the venous system is well filled a stimulus to vascular contraction produces a greater venous return to the heart than when the venous system is poorly filled. According to Crosley and also Dunstan, the cardiac output in hypertensive patients is reduced by chloro- thiazide. It is a general property of muscle cells that the greater the initial tension the greater the contraction. Thus, other things being equal, a decrease in blood volume would reduce vas- cular tone. This reduction of vascular tone does not occur following hemorrhage, because the baroreceptor reflexes initiate sympathetic vaso- constriction, and the total blood volume is restored rapidly through hemodilution. Follow- ing chlorothiazide, however, these compensa- tory reactions are not prominent. There is no tachycardia or other evidences of compensatory vasoconstriction in the hypertensive as con- trasted to the normotensive subject after chlor- thiazide. Finally, the studies of salt restriction and saluretic agents provide no evidence that so- dium plays an important etiologic role in hypertension. The effect of sodium seems to he secondary rather than primary, permissive rather than causative. The administration of an excessive amount of salt does not elevate the ORGANIC CHANGES IN CHRONIC HYPERTENSION 301 blood pressure of nonedematous normotensive or hypertensive subjects. It appears that a depletion of sodium ion induced either by diet or by potent saluretic agents reduces blood pressure in hypertensive patients. However, the hypotension occurs primarily because the salt loss is associated with a reduction of plasma volume, The unimportance of the sodium ion per se is indicated by the fact that the blood pressure can be restored simply by replenish- ing the plasma volume with salt-free dextran solutions. The role of salt, therefore, appears to be permissive. Its presence is required to main- tain a normal expansion of plasma volume. This expansion permits normal vascular reac- tivity to the unknown pressor mechanism operative in hypertension. Salt. loss and result- ing plasma volume depletion reduce this vascu- lar reactivity. Hydralazine Hydralazine or Apresoline produce hemody- namic effects which are unique among the an- tihypertensive agents. Pyrogenic substances produce similar hemodynamic changes, but hydralazine does not induce fever. Either hy- dralazine or pyrogenic substances produce a marked decrease in total peripheral vascular resistance while at the sume time approximately doubling the cardiac output.* The heart rate also accelerates. Renal, splanchnic, cerebral and coronary blood flows inerease, whereas flow remains essentially unchanged in the extremi- ties. Teleologically, the increased circulatory rate, particularly through the kidneys, heart and liver, aids in the rapid detoxification and elim- mation of noxious produets associated with febrile infections and with the mobilization of body defenses. This represents another reaction pattern of the body useful for survival of the species which is advantageous in the treatment of hypertensive patients. The increase in cardiac output counteracts the marked arteriolar relaxation induced by hydralazine, so that the percentage of fall in systolic pressure is not as great as the fall in diastolic. Therefore, when hydralazine is ad- ministered alone, the most significant redue- tions oecur in the diastolic pressure. However, it is readily seen that if the venous return to the heart is impaired by the addition of gan- glion-blocking agents or chlorothiazide the cardiac output cannot increase effectively, and the peripheral dilating effects of hydralazine then become relatively unopposed. For this reason, hydralazine is far more effective when used in combination with other drugs which reduce cardiac output, particularly chlorothia- zide. The tachyeardia and palpitation produced by hydralazine sometimes is disturbing to the patient. If this is troublesome, Rauwolfia, which produces some bradyeardia and also dulls apprehension, provides a worthwhile counter- agent. In high dosages, hydralazine may pro- duce a syndrome indistinguishable from dis- seminated lupus erythematosus. This does not. occur, however, when dosages are maintained below 200 mg. per day. When properly admin- istered, hydralazine is an extremely useful antihypertensive agent. OTuER ANTUIYPERTENSIVE AGENTS Little is known about the hemodynamic effects of Rauwolfia serpentina. When injected parenterally in animals, reserpine, the active alkaloid of Rauwolfia, produces a eentral de- pression of sympathetic vasoconstrictor re- flexes. When given orally in man, it is doubtful that the drug reduces baxal blood pressure. It appears more likely that, following Rauwolfia, the patient becomes less emotionally reactive, and as a result the transient elevations of blood pressure caused by fear and apprehension be- come less frequent and severe. Since these elevations often occur as the result of subcon- selous or conscious fears associated with the visit to the doctor’s office, Rauwolfia may give a false overestimation of antihypertensive po- tency when evaluated under such conditions. When evaluated under more critical conditions, notably in hospitalized patients, the drug in customary dosage has little if any antihyper- tensive effect on basal blood pressure. The considerations of Rauwolfia are not meant. to imply that the drug and its active alkaloid reserpine have no place in the treat- ment of hypertensive patients. By the paren- teral route in dosages of 2 to 5 mg., reserpine is an active antihypertensive drug. By the oral route in far smaller dosages, it may be a useful 302 CLINICAL CARDIOPULMONARY PHYSIOLOGY adjunct in the total management of the pa- tient. Psychic factors are important; certain emotions, particularly fear (but probably not anger unassociated with fear) and anxiety, tend to oppose the antihypertensive effectiveness of most blood pressure-reducing drugs. Reserpine is a particularly useful sedative in such patients. It should be mentioned, however, that the drug also is potentially harmful, since serious and long-lasting mental depressions as well as other disturbing side effects can occur following prolonged use. Therefore, it is safer to admin- ister other sedative drugs, such as the barbit- urates or meprobamatc, whenever these will provide the desired psychic effects. In regard to the so-called nonsedative, antihypertensive al- kaloids of Rauwolfia, such as rescinnamine, when given orally in the advised dosages, this author has merely found a placebo-like action. The Veratrum alkaloids stimulate still an- other type of hemodynamic reaction pattern used by the body for survival. This occurs when blood loss poses limitations for violent activity or when fear and other forms of psychic shock become overwhelming in the face of a challenge which cannot be met either by de- fense or flight. In this situation, a sudden vasodilation occurs with a marked fall of blood pressure, the heart rate slows and the pulse becomes almost imperceptible; a deathly pallor ensues and consciousness is lost as the individ- ual falls to the ground in a faint. This reaction is a prominent protective device of cold-blooded animals who affect all the appearances of death when caught in a position that permits no successful escape. In man, the residual of this reaction is called vagovagal syncope. The efferent arm of the reflex response as mentioned above travels out over the vagus nerve to produce bradyeardia and over un- known pathways to produce peripheral vasodi- lation. The afferent arm may originate as fol- lows: in the cortex under the impact of some intense emotional shock, in the carotid sinus or in afferent vagal nerve endings distributed to the lungs and myocardium. The Veratrum alkaloids stimulate these afferent nerve endings and so initiate a reflex vasodilation and brady- cardia. Syncope, however, rarely occurs, but. nausea and vomiting, due to stimulation of the emetic center, is common. Thus, the drug does not entirely reproduce the picture of vagovagal syncope. Of all known antihypertensive agents, the hemodynamic responses produced by the Ver- atrum alkaloids are the most physiologic. The cardiac output remains unchanged while the total peripheral resistance falls.? Blood flowing to various body areas may fluctuate initially but soon reverts to the pretreatment level. There is no interference with postural and other homeostatic reflex adjustments. Unfortunately, Veratrum has been less satisfactory than other agents in long-term therapy for the fol- lowing reasons: (1) a narrow spread between the hypotensive and the emetic dose and (2) the developement of tolerance to the antihyper- tensive effect. Considerable progress has been made in the control of hypertension during the past 10 years and further advances are to be expected in the future. 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