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Early and adequate transfusion, prevention of infection and improved supportive measures are responsible for the survival of an untold number of casualties whose injuries would formerly have been rapidly fatal. But the very survival of persons seriously injured raises new problems in traumatotherapy, among which anuria assumes increasing significance. This report summarizes clinically relevant observations made during an experimental study of post-traumatic renal injury. The effects of trauma on renal function vary widely, according to the nature, severity and duration of the injury. Hemorrhage which does not cause prolonged hypotension usually results in temporary anuria, which is corrected by transfusion and which has no more significant sequel than the transitory appearance in the urine of casts, protein and red blood cells. Prolonged shock from hemorrhage or skeletal trauma may be followed by oliguria or anuria which does not respond to transfusion and culminates in uremia, although no specific renal lesion

Traumatic shock is thought of as an acute state from which no threatening residues persist. As regards recovery ofrenal function, doubt was cast on this view by reports from the scene of the Messina earthquake and by detailed studies of cases of post-traumatic uremia occurring in the German Army in World War I. 1 Crush syndrome was rediscovered, named and studied on a wider scale during the London blitz. 2 Similar cases have been reported from the accidents of civilian life. 3 Many others, civil and military, have probably gone undiagnosed because fatal shock and sepsis have probably overshadowed the defect of renal function. Typically, the syndrome is initiated by crush of a limb or occlusion of its arterial supply for several hours. Release from debris or restoration of blood flow is followed by swelling, with whealing at the sites of compression. The limb becomes hard, paralyzed and anesthetic. Loss

1. Isolated dogs' kidneys have been perfused with defibrinated blood under hemodynamic conditions similar to those in the body. Under these circumstances blood flow, urine secretion, and oxygen consumption are well maintained, but urea clearance is low. Renal venous blood collected initially and at the end of 3 or more hours of perfusion exhibited no difference in vasoconstriction properties when perfused along with renin or renin-activator through an isolated rabbit's ear. 2. Reduction of pulse pressure by constricting the renal artery may be performed without reducing mean pressure significantly. Impairment of urea clearance and rate of urine secretion follow, and oxygen consumption is slightly reduced. 3. After an hour or more of perfusion with reduced pulse pressure, gradual rise in mean renal arterial pressure distal to the clamp and reduction of blood flow occur. 4. Renal venous blood collected after about one hour of perfusion with reduced pulse pressure differs from that collected before reduction of pulse pressure in that it causes intense vasoconstriction when perfused with renin-activator through an isolated rabbit's ear. 5. Perfusion of a dog's hind leg under similar circumstances does not cause this change in the venous blood to occur.

1. Extracts of human blood plasma, ascitic and cerebrospinal fluids have been shown to contain a substance or substances which have a prolonged and powerful pressor action when injected into test animals. 2. The chemical properties of the substance suggest those of an organic base. It is extracted with alcohol, soluble in water and acetone, extracted from water by chloroform, and probably is but slightly heat-stable. The plasma colloids seem to hold the substance in a bound state since it does not appear in the ultrafiltrate and is liberated on coagulation of the colloids by alcohol. Coagulation alone of the blood does not cause the substance to be formed. 3. Its action suggests that its pressor effect is brought about by mediation of the central nervous system. This inference was drawn from the following observations. (a) The functional intactness of the central nervous system is essential in order that pressor responses be obtained. Unanesthetized animals exhibit greater vascular responses than do anesthetized. (b) Pithing animals completely abolishes the response. Progressive ablation of the brain to the level of the hind brain does not alter the response, but below this level, injury abolishes the activity of the extract. (c) Some substance in the extract sensitizes the mechanism responsible for the carotid sinus reflex. (d) There is no parallelism between the response to peripherally acting drugs and pressor extracts. (e) Removal of the adrenal glands does not affect its character. 4. The rise in blood pressure appears to be due especially to constriction of the arteries in the splanchnic region. 5. Assay of the pressor extracts is made difficult because of the dependence of the vascular response on the functional state of the central nervous system. The carotid sinus reflex and stimulation with carbon dioxide-air mixtures have proved most useful means for the estimation of this functional state. It has been pointed out that the vascular responses to extract, stimulation of the carotid sinus, and inhalation of carbon dioxide-air vary greatly during the course of an experiment on anesthetized animals. This natural history of the vascular responses has been described. 6. No evidence has been produced by the method employed that the amount of this pressor substance is increased in the blood or spinal fluid of patients with hypertension of varied pathogenesis (nephritic hypertension, essential hypertension, malignant hypertension, eclampsia, and pituitary basophilism).

Excerpt To the Editor:Part 2 of The American College of Physicians' Ethics Manual (1) is first-rate throughout. Even I cannot find fault with it. I come from the school where a researcher was large...

The combined effect of clofibrate and a fat-modified diet was determined in 17 hyperlipidemic patients: 7 type IIA, 7 type IV, 2 type VI(IIB), and 1 type III. Control serum lipid levels and lipoprotein patterns and their alteration with a fat-modified diet had been determined previously 1/2 to 2 years for 3 patients, and 6 to 10 years for 14 patients. Two grams of clofibrate a day (0.5 gm four times daily) was taken along with the fat-modified diet for 2 to 6 months by 5 patients and for 2 years by 13 patients. The effect of clofibrate and a fat-controlled diet was also determined in 10 normolipidemic men who were subjects of an 18-day test in which the polyunsaturated fat diet was quantitatively prepared and eaten along with 2 gm clofibrate a day (0.5 gm four times daily). The effect of clofibrate on serum cholesterol levels was a further mean reduction in type IIA patients by 19 %, in type III by 23%, in type IV by 12%, in type VI by 7%, and in normolipidemic subjects by 8%. The extent of the additional serum cholesterol reduction with clofibrate in individual hyperlipidemic patients varied from +10% to minus 44% and was not related directly to the type of hyperlipidemia. The extent of reduction appeared related directly to the level of minus S 40-70 (similar to Sf 12-20) lipoprotein fraction in the control serum sample. Serum triglyceride levels were unaffected in type IIA and normolipidemic subjects. Serum triglyceride levels did not change consistently in the 2 type VI patients, rising by 11% in 1 and dropping by 31% in the other. Serum triglyceride levels were significantly (p = 0.001) and consistently reduced by 39% only in type IV patients.

A 48 year old male patient presented with xanthomatosis, hyperbeta lipoproteinemia and hyper-IgA globulinemia; these two serum components occurred as a "complex." The patient has subsequently been studied for 22 years (1952 to 1974). His serum cholesterol and triglyceride levels have been consistently and excessively high despite efforts to regulate them by means of diet or diet and drugs. Serum immunoglobulin A (IgA) concentration ranged from 1,400 to 3,400 mg/dl compared with a normal value of 156 plus or minus 92 mg/dl. The metabolism of lipoproteins, judged by vitamin A turnover studies was slow. Peripheral atherosclerosis became evident 15 years after beginning the study whereas cinecoronary arteriography concurrently demonstrated only minimum changes. Xanthomas exhibited marked regression only during the last 6 years, after 16 years of diet and the addition of clofibrate for 7 years. Beta lipoprotein and IgA globulin determined by immunofluorescent and immunoelectrophoretic technics were demonstrated in the atherosclerotic material obtained from the patient's arterial wall. They were also found in the plasma cells of the bone marrow. The IgA globulin-beta lipoprotein complex in the serum was broken with difficulty. The patient's isolated IgA globulin, free of lipoprotein, formed a firm complex when mixed with beta lipoprotein prepared from normal human serum. Initially, IgA globulin studies showed presence of both kappa and lambda light chains in normal proportion. But after 18 years, the IgA globulin has become monoclonal, type lambda. The plasma cells of the bone marrow have become progressively more atypical and immature. No clinical indications of multiple myeloma have been found. It is concluded that association of lipoproteins with IgA globulin in the serum of this patient with hyperlipidemia, hyper-IgA globulinemia did not prevent the development of atherosclerotic lesions and the deposition of lipids and lipoproteins in the plaques. It is possible that the lipoprotein-immunoglobulin association may have retarded the process, since it became manifest only after many years of known hyperlipidemia.

The treatment of hypertension was discovered long before the mechanisms of the disease became known. Only recently has it been appreciated that blood pressure is controlled physiologically in many ways. Hypertension has suddenly achieved celebrity status. It is now recognized as the second leading cause of death in the United States. New programs have made the public aware of it and have prompted many individuals to have their blood pressure checked. Office diagnostic measures usually suffice to determine the presence of the disease. Treatment should generally be initiated with a slow-acting diuretic or with propranolol; other drugs may be added later. Treatment is a lifelong undertaking, and engaging the patient as a partner in the venture by means of home blood pressure measurements and an educational program contributes to its success. Treatment of hypertension is the first step in the prophylaxis of atherosclerosis.

(1978). Science, intuition, and medical practice. Postgraduate Medicine: Vol. 64, No. 5, pp. 217-221.

Arterial pressure, cardiac output, stroke volume, heart rate, and peripheral resistance have been recorded daily in eight trained, healthy dogs with implanted aortic flow probes and aortic catheters. After suitable control periods angiotensin II was infused for periods of from 2 to 29 days. The effects observed were considered under four categories: 1) The immediate effects consisted of rise of arterial pressure, decrease of cardiac output and heart rate, rise of peripheral resistance and increased pulse pressure. Within five days all values tended to return to control levels unless the infusion rate of angiotensin was increased. 2) A chronic phase followed and, during this period, cardiac output was normal while arterial pressure and peripheral resistance were elevated. 3) After infusions were stopped pressure and peripheral resistance rapidly declined to be low normal, while cardiac output and heart rate rose to above normal. 4) A transient "malignant" phase was elicited by very large increases in the rate of angiotensin infusion, during which cardiac output and stroke volume were diminished while arterial pressure and peripheral resistance were increased greatly. The hemodynamic changes resulting from prolonged angiotensin infusion were similar in some respects to those found by us during the onset of hypertension due to renal artery constriction in dogs. They differed, however, in that doses of angiotensin, which were great enough to induce arterial pressure elevations similar to those of chronic experimental renal hypertension, reduced stroke volume, and these higher pressures could not be maintained for more than a few days. Hypertension did not persist after discontinuing angiotensin even after 28 days of almost continuous infusion. There was a distinct tendency for the pressor response to diminish with passage of time; more angiotensin was required to maintain similar elevations of arterial pressure.

SummaryIn rats made hypertensive by clipping a renal artery or subcutaneous renin injections, removal of the clipped kidney or cessation of renin administration were followed by an abrupt fall in arterial pressure, which stabilized at a level higher than the control value. This was associated with healing of mesenteric arteritis, while hyaline lesions remained unaffected. The functional and pathologic changes caused by removal of the clip were prevented by administration of renin. These experiments provide additional evidence that renal and renin-induced hypertension may have the same pathogenesis.

Coronary disease is rare among the Navajo Indians. Their plasma proteins and lipids differ from those of the population of Cleveland in that albumin is low normal and α- and γ-globulin elevated; total cholesterol was much lower. Since the diet and living habits are not strikingly different from those of the control group, it is suggested that heredity, in this case, is the most likely explanation for the low incidence of coronary disease and low level of cholesterol. Neither in the control nor Navajo group did mean serum total cholesterol rise with age.

1. (1) A useful method for perfusing a dog's tail is described. 2. (2) Purified renin, which produces a marked rise in arterial pressure when injected into intact animals, has little or no constrictor action on the vessels of a dog's tail perfused with Ringer-Lockeacacia solution. The addition of small amounts of whole blood, plasma, laked erythrocytes, or plasma colloids to purified renin causes intense vasoconstriction in the perfused tail. 3. (3) Partially purified extracts of kidneys contain heart-stable and dialyzable substances that cause constriction of the blood vessels of the dog's tail. 4. (4) The injection of sufficient cocaine to make the blood vessels nonresponsive to tyramine does not inhibit the action of renin-plasma mixture. 5. (5) Plasma from dogs after bilateral nephrectomy and hypophysectomy activates renin. 6. (6) Experimental hypertension produced in dogs by clamping the renal arteries or applying cellophane to the renal parenchyma appears to increase the ability of plasma to activate renin. There is no strict parallelism between the mean arterial pressure of the hypertensive animals and activator content of the blood.

1. 1. Nicotine has been isolated as crystalline oxalate and picrate from the urine of persons who smoke. Its pharmacologic properties are the same as those of pure nicotine. 2. 2. Most of the nicotine disappears from the urine within three to four days after smoking has been discontinued. 3. 3. Nicotine appears to be the substance responsible for the marked pressor action of many urine specimens. Unless tobacco has been eliminated as a source of pressor substance in urine, conclusions relating urinary pressor substances to arterial disease may not justifiably be drawn.

A new substance, Benzmalacene, was tested to determine whether it had hypocholesteremic effect in normotensive, hypertensive and hypercholesteremic patients. It proved effective. But after 4 months' treatment liver function began to deteriorate. It is strongly urged that drugs which interfere with cholesterol synthesis in the body be studied most carefully for long periods before widespread clinical trials to prevent atherosclerosis are attempted.

The hemodynamic changes accompanying experimental neurogenic hypertension due to sinoaortic denervation were measured in unanesthetized dogs for 3 weeks with chronically implanted arterial catheters and aortic flow transducers. Hypertension was modest, the average increase in mean arterial pressure being 31 ± 5 (SE) mm Hg. In about half of the dogs it was due predominantly to increase in cardiac output and in the others to increase in peripheral resistance; one factor or the other tended to maintain the hypertension in each dog throughout the experiments. Arterial pressure became extremely labile during the first few days after denervation and remained so during the entire experiment. This lability was closely correlated with environmental stimuli; rather minor distractions caused a sharp fall in pressure due variably to decrease in both cardiac output and peripheral resistance; greater distractions or physical activity caused a rise in pressure due usually to increase in peripheral resistance. Mean arterial pressures were higher when measured by transcutaneous puncture of a femoral artery, presumably because of the necessity of restraint and the discomfort associated with passage of a needle. Before sinoaortic denervation, arterial pressures fell to basal levels during sleep. After denervation, unexpectedly and for an undetermined cause, pressures rose to very high levels during sleep; the rises were consistently due to increase in peripheral resistance. Awakening was accompanied by a sharp fall in pressure and peripheral resistance.

Oral administration of chlorothiazide depresses glomerular filtration, increases blood urea, maintains sodium output in the face of decreased filtered sodium load, and paradoxically for a diuretic, in these and in tests done shortly after intravenous administration, increases the efficiency of water reabsorption.

Hypertension was induced in rats by constricting the aorta between the origins of the renal arteries. The left kidney, which became ischemic and atrophic ("endocrine kidney"), caused a malignant type of hypertension associated with weight loss, cardiac hypertrophy, hypertension, cardiac necrosis, nephrosclerosis of the right kidney, and arteritis. Amounts of pressor substances were increased in the left kidney and decreased in the right as compared with those in kidneys of normal rats. Aqueous extracts of ischemic kidneys, of kidneys contralateral to ischemic kidneys and of normal kidneys were prepared and the supernatant solutions were injected subcutaneously into test rats which had been uninephrectomized a few hours previously. Extracts of ischemic kidneys caused hypertension, cardiac hypertrophy, weight loss, and renal and vascular lesions mimicking the signs which result from renal ischemia. The extracts from the other kidneys were inactive. Administration of renin in doses roughly equivalent in pressor activity to the extracts of ischemic kidneys caused a rise in pressure, diuresis, and proteinuria but no lesions when given subcutaneously. It is proposed as a working hypothesis that renal hypertensive disease results not only from increased secretion of renin and formation of angiotensin but from simultaneous release from kidneys with reduced perfusion pressure of a substance which augments the enzymatic formation of angiotensin. This substance is presumably absent from normal kidneys and from semipurified renin preparations.

1. Extracts of kidneys have been prepared containing a substance which lowers arterial blood pressure for prolonged periods in patients with essential and malignant hypertension, and in hypertensive dogs and rats. 2. Several different chemical procedures are proposed for the preparation of the extract. The best one has not been decided upon. 3. The quantity of original fresh whole kidney required to yield enough extract to lower blood pressure from hypertensive levels (200 mm. Hg mean pressure) to normal levels is roughly 600 to 900 gm. in dogs within 4 to 8 days. In hypertensive patients the yield from 700 to 1000 gm. daily for several weeks may be necessary. 4. Lowering of the blood pressure too rapidly in animals results in a shock syndrome which may be fatal. If overdosage is avoided, no appreciable rise in blood urea nitrogen occurs, nor do other signs of toxicity appear. 5. Lowering of blood pressure to nearly normal levels has been accomplished in 60 hypertensive dogs, and in some of these it has been allowed to rise and was again reduced as many as five times. Similar results have been obtained with hypertensive rats. 6. Six patients with essential hypertension have been treated resulting in prolonged reduction of blood pressure. Clinically the patients appear improved. 7. Five patients with malignant hypertension have been treated, with reduction of the blood pressure in all instances. One patient was treated despite urea clearance of 5 per cent of normal. His blood pressure was sharply reduced, but death in uremia occurred. The second patient also exhibited sharp reduction of pressure and died after treatment was discontinued. The other three are much improved after treatment, as indicated by increase in vision and mental activity, loss of dyspnea, improvement in the electrocardiogram, etc. 8. The length of time the blood pressure remains lowered varies greatly in both animals and man. The trend is usually upwards after discontinuing treatment for 4 to 6 days. 9. Increasing experience with this treatment suggests that it is of value in the management of hypertension, but it is yet in the experimental stage.

The aortae of dogs may be constricted or occluded at the arch without the development of arterial hypertension proximal to the occlusion. Hypotension of moderate to marked degree occurs distal to the occlusion, and is usually more marked a few hours after clamping than later. the return toward normal of the pressure distal to the clamp was attributed, among other causes, chiefly to the development of collateral circulation and acute and chronic thining of the vessel walls within the clamp. After several days the pressure in the femoral artery may fall progressively, without simultaneous reduction of carotid pressure. The oxygen content of the blood does not appear to be reduced significantly until a great reduction of femoral pressure has occurred. The failure to produce, in dogs, hypertension proximal to a clamp constricting the aorta at or near the site where aortic coarctation occurs in human beings is attributed to the ready development in dogs of an extensive collateral circulation. Hypertension of renal origin occurs when the aorta is closed a few centimeters below the origin of the renal vessels, and, in addition, constricted or closed in the thorax at a level corresponding to the dome of the diaphragm. Removal of the kidneys reduces or abolishes this hypertension. The hemodynamic changes are sufficiently similar to suggest the possibility that the hypertension of human coarctation is of renal origin, and that the manner in which collateral circulation develops differentiates the response to constriction of the aorta in dogs and men.

High spinal cord section caused reduction of stroke volume, cardiac output, aortic pressure, and increase in heart rate. Peripheral resistance was little changed. With time, arterial pressure and heart rate recovered to near control levels; stroke volume, cardiac output, and peripheral resistance tended to increase. Recovery of arterial pressure was due either to increase in peripheral resistance or increase in cardiac output. Elimination of essentially all efferent sympathetic activity caused little or no decrease in peripheral resistance; the small decrease in arterial pressure was accounted for by decrease in stroke volume and cardiac output. Atropine given well after recovery from operation increased heart rate, cardiac output, and aortic pressure while stroke volume decreased. The increase in blood pressure was due to increased cardiac output. Tetraethylammonium chloride given after atropine showed that cardiovascular denervation was essentially complete. Induction of experimental renal hypertension caused marked rise in peripheral resistance without change in stroke volume, heart rate, and cardiac output. Since cardiovascular denervation was complete, the hypertension was of humoral origin.

1. Tachyphylaxis occurs when renin is repeatedly injected into dogs and cats regardless of whether they are normal, anesthetized, pithed, hepatectomized, suprarenalectomized, nephrectomized, or eviscerated. 2. The pressor response to renin in brief experiments is independent of the height of the arterial pressure or the presence of the suprarenals. Evisceration and large doses of ergotamine reduce the response. It is largely uninfluenced by pithing, intracisternal injection of renin, cocaine, strychnine, caffeine, and infusion of sodium bicarbonate or hydrochloric acid. It may be slightly increased by large blood transfusions or hepatectomy but the result is short lived. 3. There is no parallelism between the pressor responses to carotid sinus stimulation, adrenine, and tyramine on the one hand and renin on the other. 4. Section of the brain may be followed by depressor responses to renin. 5. Intracisternal injection of renin elicits no significant rise in blood pressure or other circulatory manifestations. 6. Continuous infusion of renin produces a prolonged rise of arterial pressure in normal and chronically suprarenalectomized dogs, but the pressure ultimately falls despite continued infusion. 7. Tachyphylaxis develops in the isolated rabbit's ear perfused with blood and small doses of renin. The same blood perfused through a second ear causes no vasoconstriction when renin is added. Addition of renin-activator restores the ability of renin to cause constriction. 8. Renin alone causes no vasoconstriction when perfused with Ringer's solution, but renin plus renin-activator restores activity. Tachyphylaxis does not develop when Ringer's solution is employed instead of recirculating blood. 9. Blood from animals made tachyphylactic by repeated injections of renin is lacking in activator and also fails to cause vasoconstriction in the rabbit's ear when renin and renin-activator are added. 10. Renin-activator is lost and tachyphylaxis develops more slowly during continuous infusion of renin. Blood pressure may fall after a period of renin infusion despite the pressure in the blood of excess renin. Injection of partially purified activator restores the activator content of the blood as demonstrated in the rabbit's ear, but no rise in arterial pressure occurs.

1. Plasma from the renal vein, femoral artery or vein of normal dogs and plasma from the femoral artery, femoral and antecubital veins of man cause little or no vasoconstriction when added in small amounts to blood from a bilaterally nephrectomized dog used as perfusing medium in an isolated rabbit's ear. 2. Plasma from the femoral vessels and antecubital vein of patients with essential hypertension, malignant hypertension, and chronic nephritic hypertension causes marked vasoconstriction under the same circumstances. The plasma of dogs made hypertensive either by constriction of the parenchyma by the scar of silk perinephritis or by constriction of the renal artery by a clamp also causes pronounced vasoconstriction. 3. Plasma from the renal vein of normal dogs produces little or no vasoconstriction, but that of hypertensive dogs elicits vasoconstriction but usually not so marked as that elicited by plasma collected from peripheral vessels. A sample of renal venous plasma from one hypertensive patient caused severe vasoconstriction, not quite so intense as that produced by the peripheral vein plasma. 4. Since renin is liberated into the renal vein in large amounts in hypertensive dogs and reacts with renin-activator to produce angiotonin and since the conditions of the experiment are such as to enhance greatly the sensitivity of the ear preparation to angiotonin, it is believed that the vasoconstriction is the result of the presence of angiotonin in the peripheral blood. 5. Since vasoconstriction occurs under the same experimental conditions with plasma from both hypertensive patients and dogs, this is considered cogent evidence in favor of the view that the chemical mediator of both is similar and is possibly angiotonin. 6. A method is presented which is believed will distinguish between plasma from patients with normal blood pressure and that from those with hypertension, and between plasma from normal dogs and that from dogs with experimental renal hypertension.

The effects of long-term treatment with propranolol, a beta-adrenergic blocking drug, were determined in 19 hypertensive patients (five with renal arterial disease, two with renal parenchymal disease, and 12 with essential hypertension) whose vascular disease was of mild to moderate severity. The drug reduced arterial pressure in 16 patients during 32 weeks of treatment (average); daily dose was 180 mg (average). No side effects required discontinuance of treatment. Orthostatic hypotension did not occur, an unusual finding for an antihypertensive drug which acts to inhibit autonomic neural function. In seven patients, hemodynamic studies, performed during treatment (after 10 months, average), confirmed reduction of arterial pressure and heart rate, and demonstrated associated diminution of cardiac output and increased peripheral resistance.

Certain chemical and pharmacological properties of sodium nitroprusside, a cheap, readily available chemical, have been described. It is a powerful hypotensive agent when given intravenously tohypertensive patients. It is no more effective than the sodium thiocyanate into which it is converted when given by mouth. Prolonged infusion has proved highly effective in the treatment of hypertensive encephalopathy.

Comment and SummaryThe increased pressor responsiveness to adrenaline caused by injection of Et4N is shown to be associated with an increase in renal vasoconstriction. The depressor response to injection of “Isuprel,” the N-isopropyl homologue of adrenaline, is shown to be associated with renal vasodilation. The depressor, cardioaccelerator and renal vasodilator effects of injection of “Isuprel” are augmented by prior injection of tetraethylammonium. On the assumption that the effects of tetraethylammonium are due to blockinq of autonomic ganglia,4 we conclude that inhibition of these ganglia increases vascular responsiveness to typical vasoconstrictor and vasodilator sympatheticomimetics.

Since vascular responsiveness to adrenaline, noradrenaline, renin and angiotonin is reduced by suppression of thyroidal function in normotensive dogs, it was a possibility that in neurogenic and renal hypertensive animals suppression of thyroidal function might be associated with decrease in arterial pressure. This possibility was not confirmed, hypertension persisting unaltered in both groups of hypertensive animals over long periods of observation. Changes in vascular reactivity were slight in comparison with those associated with the athyroid state in normotensive dogs.

At least four mechanisms contribute to the increased responsiveness to pressor drugs caused by ganglioplegic agents: 1) Elimination of parasympathetic reflexes alone was found to have a prominent effect on pressor responsiveness, especially to norepinephrine. 2) Elimination of sympathetic compensatory reflexes caused the expected increase in responsiveness. 3) Tetraethylammonium had a direct effect on blood vessels of the dog's perfused hind limb that resulted in sensitization to norepinephrine, though not to angiotensin; this direct effect of the ganglioplegic was similar to that produced by surgical denervation. 4) Tetraethylammonium caused enhancement of response to epinephrine but not to norepinephrine in pithed cats and this effect seems best explained by a blocking action of the ganglioplegic on adrenergic vasodilator receptors. Because of the participation of these different mechanisms, ganglioplegics and surgical denervation do not necessarily affect pressor responsiveness in the same manner. Additionally, the different mechanisms involved account for the various degrees of augmentation of response to different pressor drugs since the latter have their major actions on different portions of the cardiovascular system. Responsiveness may vary greatly during a single experiment and also from day to day; this variability is due in large part to the nervous system since it is abolished by cervical section of the spinal cord.

1. Both renin and angiotonin in small doses cause constriction of the arterioles in the ears of normal rabbits, as seen directly with the microscope. Capillaries appear unaffected while venules exhibit slight or no constriction with small doses and moderate constriction with large doses. The flow of blood through the tissues is not reduced except when very large doses are administered. Tyramine and methylguanidine sulfate in isopressor amounts act somewhat similarly. 2. Isopressor amounts of epinephrine and pitressin, by contrast, elicit severe vasoconstriction of arterioles lasting longer than that due to angiotonin, and flow of blood is sharply reduced or abolished altogether. The degree of venular constriction was also greater, while the capillaries remained unaffected. 3. The vasoconstrictor action of angiotonin on peripheral vessels in moat chambers in normal rabbit's ears is indistinguishable from that of renin, except that it is more rapid.

The effects of caudal and spinal anesthesia on arterial pressure in hypertension are similar despite the fact that in the former, voluntary muscles are not paralyzed. During anesthesia marked decreases in pressure were observed in forty of the forty-three patients. Blood pressure was persistently decreased by lumbodorsal sympathectomy and ganglionectomy in twelve of these patients. The three patients whose arterial pressures were not decreased by anesthesia were similarly unaffected by operation. It is concluded that the blood pressure response to spinal and caudal anesthesia has no more than negative value in the selection of patients for sympathectomy. The discrepancy between the effects on arterial pressure of spinal or caudal anesthesia and sympathectomy may be due to the great difference in time during which the effects are observed or to a difference in the denervation which each of them causes.

Systemic pressor responses occurred consistently 5 to 15 minutes following reduction of renal perfusion pressure and were accompanied by the appearance of pressor material in renal vein blood. The pressor material is probably angiotensin formed from renin released by the kidney, since its activity was not affected by protein precipitation, was eliminated by incubation with chymotrypsin, and since it caused enhanced pressor responses to tyramine, all of which are characteristic of angiotensin. Activity was unaffected by pharmacologic blockade of response to norepinephrine and serotonin. Its renal origin is indicated by the greater amount of pressor activity in renal venous than in arterial blood throughout the systemic pressor responses. Smaller amounts of pressor material, also with properties of angiotensin, were found in thoracic duct lymph. They did not contribute materially to the systemic pressor response since external drainage of all lymph did not modify the response, and since the time course of the response correlated with an increase in pressor activity in renal vein blood but not in lymph. The late appearance of angiotensin in thoracic duct lymph is probably due to renin secretion by the kidney into renal lymph rather than transfer from circulating blood; activity did not appear in lymph when renin was infused intravenously in amounts that caused rises in systemic pressure comparable to those produced by reduction of renal perfusion pressure. The results indicate that during short periods of reduced renal perfusion pressure, renin is released in larger amounts in blood than in lymph.