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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).

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.

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.

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 synthetic octapeptide angiotonin evoked systolic and diastolic pressure responses in anesthetized and unanesthetized dogs identical with those due to a natural, largely decapeptide, angiotonin, and responses to both angiotonins were modified in the same manner by a variety of procedures. Infusion of synthetic angiotonin caused hypertension sustained for the durations of the infusions and tachyphylaxis was not observed. Induced tachyphylaxis to a crude renin preparation was accompanied by loss of response to both synthetic and natural angiotonin but not to norepinephrine.

Arterial pressure response to serotonin depends largely upon four main actions of the drug: direct vasoconstriction, a von Bezold-like reflex, transient ganglion blockade and peripheral inhibition of neurogenic vasoconstriction. The relative prominence of these actions differs depending upon the dose of serotonin, species tested and degree of pre-existing neurogenic vasoconstriction.

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.

1. The chlorine content of Woods Hole sea water has been examined over a three-week period and shown not to vary within any large range.2. Analyses of the sea salt are presented.

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.

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.

Chylomicrons were separated by low and high speed ultracentrifugation from lipemic sera of human subjects in the absorptive phase. The final chylomicron preparation was free from other serum components and contained a small constant amount of protein, approximately 2 per cent of the chylomicron fraction. Electrophoresis, immunochemical analysis, and absorption experiments identified the protein component as derived from a mixture of beta and alpha1 serum lipoproteins. Large aliquots of an emulsion of serum freed of chylomicrons and coconut oil were incubated at 37°C. for 2 hours and ultracentrifuged as in the preparation of chylomicrons. The fat particles now showed the presence of minute amounts of beta and alpha1 serum lipoproteins in almost the same proportion as found in chylomicrons. "Finger prints" of delipidized samples of chylomicrons and particles from serum-coconut oil emulsion gave similar, although not identical patterns. The data on "clearing factor" activity corroborated the finding that serum alpha1 lipoproteins are contained in chylomicrons and particles from serum-coconut oil emulsion. These two lipide particles, partially delipidized, were both able to activate a "clearing factor" system in vitro, a property exhibited only by intact or partially delipidized alpha1 serum lipoproteins. Clearing activity was satisfactorily determined by using an emulsion of coconut oil mixed in agar as a substrate to give an opaque gel, in which the diffusing enzyme showed its activity by areas of clearing. The results obtained by this technique were in agreement with those based on fall in optical density and non-esterified fatty acid production. Chemical analysis of serum chylomicrons showed a concentration of cholesterol and phospholipides higher than could be accounted for by the attached beta and alpha1 serum lipoproteins. On the basis of these results the assumption is made that in the blood stream small amounts of serum lipoproteins, by a process of adsorption, form a complex with the absorbed triglycerides, cholesterol, and phospholipides, to produce chylomicrons.

We have shown the side groups of angiotensin that are necessary for biological activity. Additional evidence is given that angiotensin decapeptide has little or no biological activity and exerts its effect only through the octapeptide. Even though none of the analogues of angiotensin have inhibitory action on the parent compound, the information obtained from studying these compounds could lead to the synthesis of inhibitors.

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.

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.

The results of these experiments indicate that the carotid and aortic baroceptor mechanisms are reset to the hypertensive pressure levels of animals with chronic perinephritic hypertension. Thus, seemingly, the buffer reflexes tend to maintain, rather than prevent, the chronic phase of renal hypertension and are, presumably, an important component in the mechanism of chronic renal hypertension.

Tachyphylaxis to angiotensin and some analogues has been demonstrated on spirally cut arterial strips from cat, dog, sheep and rat, and on venous strips from rabbit and cat. Rabbit and guinea pig arteries do not appear to become tachyphylactic. A free C-terminal carboxyl group of angiotensin is necessary for binding with receptor sites and development of tachyphylaxis. Tachyphylaxis seems to represent saturation of receptor sites. It can be reversed by plasma fractions rich in angiotensinase A, possibly by metabolizing the N-terminal part of angiotensin directly from the bound state. Dowex 50 can also reverse it, probably by physical adsorption and stronger binding of angiotensin. Angiotensinase A does not metabolize βaspartyl 1 -angiotensin and does not reverse tachyphylaxis to this peptide. A possible scheme of interaction between peptide and receptor site is presented.

The starfish (Asterias forbesii) egg is unusual in that it is very resistant to cytolysis by Quillaja saponin but possesses little resistance to hypotonic solutions (Page and Clowes1). Inasmuch as the point of attack of saponin and hypotonic solutions is quite unknown, the fact that the effect of hypotonic solutions is related to the fixing action of saponin in different kinds of protoplasm becomes of much interest. Such a selective increase in resistance to hypotonic solutions is conferred by saponin as the following experiments demonstrate.

Increased vasomotor discharge induced by bleeding caused renal release of renin in anesthetized dogs whether or not there was measurable change in either arterial pressure or total renal blood flow. Release of renin was prevented by ganglion blockade or local anesthesia of the renal nerves. Hemorrhage-induced release of renin occurred more consistently in dogs fed a low-sodium diet than in those fed a standard kennel diet. Stimulation of sympathetic vasomotor discharge by occlusion of the common carotid arteries, while renal perfusion pressure was kept constant, also caused release of renin, as did infusions of norepinephrine, tyramine, or DMPP. Isoproterenol, angiotensin, vasopressin, serotonin, or acetylcholine infused into the renal artery did not cause release of renin. It is concluded that neural stimuli are capable of causing release of renin in the absence of gross change in renal perfusion pressure or flow.

In a majority of experiments on both dogs and cats, hypotensive doses of tetraethylam-monium chloride or mecamylamine caused no change or moderate increase in efferent electric activity in the largely preganglionic thoracic portion of the splanchnic nerve, and caused complete and prolonged elimination of efferent activity in the postganglionic inferior cardiac and renal nerves. Both drugs failed to suppress changes in splanchnic nerve activity that were elicited refiexly. These results imply strongly that both ganglion-blocking drugs, in dosage used intravenously to induce hypotension, act mainly through their peripheral effects rather than through one on central vasomotor synapses. In both dogs and cats, reserpine caused slowly progressive and marked diminution in efferent splanchnic nerve activity, which supports the hypothesis that the central action of this agent contributes to its hypotensive effect.

1. The oil of the sea urchin egg (Arbacia punclulata) has an I2 number of 146-148 and saponification value of approximately 606. The star fish (Asterias forbesii) egg oil I2 number is about 110-115 and saponification value 318.8.2. Steam distillation of the eggs by the Dyer method suggests along with the Kottstorfer number that the fatty acids of the Arbacia egg are of a lower order than those of the Asterias egg.3. Qualitatively there appears to be more kephalin in the Arbacia egg and more lecithin in the Asterias. The Asterias egg appears to contain more KOH decomposable sulphur compounds than the Arbacia egg.4. Qualitatively large quantities of soaps were found.

1. Alcoholic extracts of the plasma of rabbits obtained from arterial or venous blood differ from those of human plasma in having a marked depressor action on the blood pressure of anesthetized cats. This action is unantagonized on atropinization. Extracts of the plasma of dogs, on the other hand, are almost without vascular effect. 2. Ultrafiltrates of the plasma of rabbits are actively vasodepressor, while those of human and dog plasma are without action. 3. Extracts of the plasma of rabbits reduce the renal volume greatly and they have a relatively weak dilator action on the arteries of the periphery. These effects resemble those of adenylic acid more than those of histamine. 4. It is possible that the pressor-depressor substances of the blood are species-specific. 5. Human plasma, ascitic and spinal fluid which have been allowed to stand, yield extracts that are depressor and in their pharmacological action resemble closely extracts prepared from red blood cells and acetic acid extracts of tissues. Their constrictor effect on the kidneys is marked. 6. Histamine, choline, and adenosine depress the level of the blood pressure more effectively than they constrict the volume of the kidneys, while the reverse is true when adenylic acid is employed.

Hemodynamic changes associated with diastolic hypertension were investigated using 50° head-up for 52 untreated hypertensive patients not in cardiac failure, and for 17 normotensive subjects. Normals responded to tilt with±10 mm Hg change in mean arterial pressure. Twenty-four hypertensives responded similarly; the remainder had either orthostatic hypertension (18) or orthostatic hypotension (10). During tilt, cardiac output reduction of each hypertensive group was greater than normal, but only orthostatic hypertensives responded with exaggerated increase in peripheral resistance. When supine, orthostatic hypotensives had lower cardiac indices and higher peripheral resistances than orthostatic hypertensives. When the three hypertensive groups were compared with respect to clinical features, orthostatic hypertensives had the least severe vascular disease; orthostatic hypotensives were the opposite extreme, and normal responders were intermediate. These findings suggest that neurogenic activity is highest in mild hypertension and in the more severe forms of the disease, it is least.

Contractile responses of vascular smooth muscle strips (rabbit aorta) to angiotensin, vasopressin and serotonin are potentiated by amounts of metanephrine, ephedrine or tyramine that produce no contractions by themselves. Epinephrine and norepinephrine contractions of aortic strips are not potentiated. Phentolamine and bretylium prevent this potentiating effect of meta-nephrine and ephedrine; the effect of tyramine is blocked by bretylium but only partially by high doses of phentolamine. Contractions of strips pretreated with reserpine are not potentiated except when repleted with norepinephrine. It is suggested as a working hypothesis that low doses of metanephrine release storage norepinephrine which acts on the contractile machinery to potentiate its response to other stimulating agents.

The plasma protein pattern of patients with uncomplicated essential hypertension showed only slight variations from the normal while that of patients with severely malignant hypertension showed marked shifts. The fibrinogen and ß-globulins were usually elevated beyond the normal range and the albumin decreased. In less severely malignant hypertension, the changes were less marked. In dogs with experimental renal hypertension, the γ-globulin level was greatly elevated, and in one animal exhibiting the malignant syndrome ß-globulin and fibrinogen were also increased. Elevation of ß-globulin seems in some manner associated with the occurrence of severe vascular disease.

The hemodynamic events, during onset of experimental renal hypertension, and during its progression to the chronic state, were recorded in 19 trained quiet dogs for 20 to 30 minutes daily for four to forty-two days. This was made possible by implanting a flow probe around the root of the aorta, and a catheter in the aortic arch for connection to an external pressure gauge. Continuous graphic recordings of blood pressure, cardiac output, stroke volume, heart rate, and peripheral resistance were made daily during a period of training to obtain control values, and after hypertension was initiated by partial occlusion of a renal artery and unilateral nephrectomy. The average mean arterial pressure in 34 unanesthetized dogs in this study was 85 mm Hg (range, 68 to 116 mm Hg). This is about 30% below values previously reported by others in unanesthetized dogs. These low pressures were ascribed to lack of restraint, to training, and to the natural posture of the dogs. At onset of hypertension a sharp rise in arterial pressure was accompanied by a decrease of cardiac output and heart rate, and by a large abrupt increase of peripheral resistance. After one to four days, the continued rise of arterial pressure was associated with return of cardiac output and heart rate toward normal. Peripheral resistance eventually stabilized at a level above that of the initial large rise. A chronic state of hypertension was reached by ten to twenty days after the initial rise of pressure. At this time cardiac output and heart rate were restored to normal, while peripheral resistance remained elevated. Studies lasting for as long as forty-two days did not show further changes. If the renal arterial constriction was severe, a third, "malignant" phase ensued with extreme elevation of diastolic pressure, reduction of cardiac output, and greatly increased peripheral resistance. This terminated in uremic death after a few days.