Evidence favoring the existence of two high molecular weight precursor forms of dog kidney renin.

Extraction of canine renal cortical tissue at pH 7.4 in the presence of the protease inhibitors diisopropylfluorophosphate (0.2 mM), Na2EDTA (7.8 mM), sodium tetrathionate (7.8 mM). N-ethyl maleimide (7.8 mM) yielded renin activity in two high molecular weight (HMW) forms, 65,000 (65K) and 55,000 (55K). Serial gel filtration chromatography of such extracts stored at 4 C showed that over the course of 2 days, activity at both 65,000 and 55,000 decreased almost entirely, while low molecular weight (LMW) activity at 41,000 (41K), not present immediately after extraction, had appeared in the extracts, The renin activity of the extract doubled over the first 24 h of storage and remained stable over the next 24 h. The activity of all three renin forms was comparably inhibited by antirenin antibodies. Our results support the concept that HMW renin(s) is a biological precursor of 41K renin. The new finding of a renin form intermediate in apparent molecular weight between 65K and 41K renin suggests that proteolytic processing of HMW to LMW renin may involve more than one step. The fact that in vitro conversion of HMW to LMW renin will occur under these conditions but takes place slowly may provide a technique for the future study of the precise manner in which HMW is converted to LMW renin.

Serial renin-angiotensin studies in spontaneously hypertensive and Wistar-Kyoto normotensive rats. Transition from normal- to high-renin status during the established phase of spontaneous hypertension.

To characterize the renin-angiotensin system in the Aoki-Okamoto spontaneously hypertensive rat (SHR) more fully, serial measurements of plasma renin activity (PRA), plasma renin concentration (PRC), renin reactivity (as relative index of circulating modifiers of the renin reaction) and renin substrate concentration were made in 6- to 64-week-old SHR and in age-matched Wistar-Kyoto normotensive rats (WKY). In the evolving phase of SHR hypertension (6 and 13 weeks of age), PRA was comparable to WKY control values, whereas mature SHR with established hypertension developed, between 13 and 35 weeks of age, a high-PRA state persisting through 64 weeks of age. In 64-week-old SHR, increased plasma volume (3.54 +/- 0.91 in SHR vs. 3.18 +/- 0.90 ml/100 g body weight in WKY, p less than 0.025), together with increased PRA (24.9 +/- 3.8 in SHR vs. 13.1 2.2 ng AI/ml plasma/hr in WKY, p less than 0.025), suggest that volume decrease cannot explain increased PRA. In 42-week-old SHR, PRA was incompletely suppressed by deoxycorticosterone acetate plus 1% saline orally for 4 days: 4.9 +/- 1.2 in SHR vs. 0.6 +/- 0.8 ng angiotensin I/ml plasma/hr in WKY, p less than 0.001. Modestly increased renin reactivity of plasma was observed in SHR at all ages studied, supporting the ubiquity of increased circulating accelerators (or decreased inhibitors) of the renin reaction in hypertensive states. However, elevated renin reactivity did not account for the transition from normal to high PRA observed in mature SHR, nor did renin substrate concentration, which was consistently lower in SHR than in age-matched WKY. Temporal patterns of, and strain differences in PRA were closely paralleled by variations in PRC but not by other reaction components. Significant elevation of serum creatinine in old SHR support the presence of renal injury. We conclude that PRA and PRC are normal in evolving SHR hypertension and progress to abnormally elevated levels after hypertension is established. We postulate that "high-renin" hypertension may develop as a consequence of the hypertensive state per se, perhaps due to nephrosclerotic vascular disease.

Renin reactivity, renin activity and renin concentration in patients with normal and low renin essential hypertension.

Renin activity, concentration, substrate and reactivity were determined in normal subjects as well as in hypertensive subjects with suppressed and normal plasma renin activity. Renin substrate measurements were similar in all groups. Renin reactivity, a measure of circulating modifiers of the renin reaction, was significantly increased in both hypertensive groups. Reactivity was significantly greater in the normal renin hypertensive group than the low renin hypertensive group. Renin concentration was significantly suppressed in both hypertensive groups, but to a greater degree in the low renin hypertensives. These findings suggest that plasma renin concentration may be suppressed in most hypertensive subjects. Furthermore, plasma renin activity may be "normalized" in most hypertensive subjects by the effect of circulating modifiers of the renin reaction. While renin reactivity in the plasma of low-renin hypertensive subjects is accelerated to a lesser degree than that of the normal-renin hypertensives, this finding alone does not explain the low plasma renin activity.

Renin-renin substrate kinetic constants in the plasma of normal and estrogen-treated humans.

The renin-renin substrate Michaelis constant (Km) and maximal velocity (Vmax) were determined in the plasmas of normal subjects. The mean Km was 0.7 microgram/ml. Under these conditions, the in vitro reaction of renin with physiologic concentrations of renin substrate will proceed at only 70% of its maximal velocity. Following estrogen administration, Km doubled to a value of 1.3 microgram/ml. Vmas increased by 81%. Analysis of the changes induced in the in vitro reaction velocity demonstrated that estrogen-induced acceleration of the renin reaction is dependent upon both an increase in renin substrate concentration as well as an increase in Vmas. The latter appears to be quantitatively more important. These findings suggest the emergence of modifying factors in the renin-renin substrate interaction following estrogen administration.

Adrenocorticotropin-cortisol axis abnormalities in hemodialysis patients.

The ACTH-cortisol axis was studied in 15 hemodialysis patients. Basal plasma cortisol concentrations were found to be elevated and ACTH to be in the high normal range. Cortisol responded normally to exogenous ACTH, but neither cortisol nor ACTH were suppressed in response to oral dexamethasone. 11-Deoxycortisol and ACTH concentrations did not rise normally in response to either oral or iv metyrapone. We conclude that standard testing of the ACTH-cortisol axis in dialysis patients yields results suggesting Cushing's syndrome.

Do diuretics have antihypertensive properties independent of natriuresis?

To ascertain whether diuretics have an antihypertensive effect independent of natriuresis, 12 stable patients on maintenance hemodialysis underwent a crossover evaluation with hydrochlorothiazide, 50 mg daily, metolazone, 5 mg daily, or placebo in 4-wk treatment periods for 6 mo. Compliance was assured by pill counts and serum drug concentrations. All patients had daily urine less than 100 ml. Pre- and postdialysis blood pressure, body weight, plasma volume, and plasma renin activity were monitored. Over the 6-mo study period there were no statistically significant changes in any parameter related to diuretic therapy. It is concluded that a functioning kidney with the ability to respond to diuretics with a natriuresis is necessary for the antihypertensive action of diuretics. Direct vascular effects of diuretics to lower peripheral resistance could not be demonstrated in this unique patient population.

Mechanisms in hypokalemia: clinical correlation.

Hypokalemia is seen most often with the use of diuretics and in patients with emesis. Other common clinical settings in which it may be significant include corticosteroid therapy, antibiotic usage, diarrhea, diabetic ketoacidosis, or psychiatric illness. Occasionally the cause may be obscure. In such situations the determination of urine potassium and arterial pH may prove helpful. Subclassification of hypokalemia into such categories as "acidosis", "alkalosis", "extra-renal", or "renal" loss is then possible. The cases discussed demonstrate the utilization of these methods to define the etiology and to understand the pathophysiology in hypokalemia.

Intravenous diazoxide therapy in hypertensive crisis.

Ninety-one doses of diazoxide were administered intravenously to 41 patients with hypertensive crises. Diastolic blood pressure was reduced from an average of 139 to 98 mm Hg within 10 minutes. On the basis of a retrospective analysis of the response of diastolic blood pressure, it was possible to determine within 10 minutes of injection whether a second dose would be required. Therapy was judged to be effective in 38 of 41 patients; 35 percent of injections were ineffective. Concomitant administration of furosemide was not shown to have a beneficial antihypertensive effect. Mean blood urea nitrogen was 59.5 mg/100 ml initially and was not significantly different 2 weeks after therapy. None of the patients demonstrated clinical evidence of diazoxide-induced deterioration of coronary circulation. Electrocardiograms obtained 2 weeks after diazoxide therapy failed to show evidence of new ischemic changes. Only 9 percent of patients complained of side effects, and these were transient and relatively innocuous. It is concluded that diazoxide is both safe and efficacious in the management of hypertensive crises.

A plasma inhibitor of the renin-antirenin reaction and the in vitro generation of angiotensin I.

In the course of studies designed to develop a radioimmunoassay system for the detection of renin, we have identified in human plasma a potent inhibitor that interferes with the renin-antirenin reaction. Utilizing gel filtration, this renin-antirenin inhibitory activity was found to have the same molecular size as renin substrate. However, it could be separated from renin substrate by ion-exchange chromatography. When fractions containing this activity were tested in an in vitro system containing renin and renin substrate, they were found to inhibit the generation of angiotensin I.

Physician revolutionaries of 1776--patriots, opportunists, or both?

Table 2 summarizes the apparent motivations of the five physician signers. While religion played a role and each individual had his own other motivations, patriotic feelings for the evolving nation were probably a major factor which has been down-played in the past. It was an exciting and heady time for the citizens of the colonies. It was not difficult to get caught up in the excitement. The last word belongs to James Thacher from Massachusetts. Thacher is an example of the best of the apprentice-physicians of the late eighteenth century. Self-taught in matters of culture, he completed his apprenticeship in his twenty-first year on the eve of the Revolution. Deciding to join the army as a military surgeon, he wrote "...I am too young to possess a maturity of judgment, but yet unable to resist the impulse of enthusiasm which characterizes the time". His remarkable experiences as a military physician were chronicled during the entirety of the war and upon the publication of this work early in the following century, he penned the following, which perhaps says it best and for the most: "Should posterity inquire why their ancestors, destitute of military education or experience, abandoned their peaceful abodes to encounter the perils of uncertain warefare, let them be told it was not to execute the mandates of a tyrant in subjugating their fellow men, but it was in defence of our most precious rights and privileges; it was a display of that genuine patriotism and true glory which it is evermost honourable to venerate and cherish".

The future of medicine.

Speculation about the future of medicine is risky. Few would have predicted five years ago the sweeping changes that have occurred. Nonetheless, an analysis and projection of current trends would suggest that further substantial changes await us. These include, among other things, a return of double-digit inflation in health care, an increase in governmental oversight, an opportunity for both patients and physicians to reestablish their influence, a strain upon traditional medical ethics, and no resolution to the issues involving the uninsured. Taken together, these projections suggest a real need for physicians to be involved in helping to assure that those positive developments come to pass and that those unfavorable do not.

Some treatment-withholding implications of no-code orders in an academic hospital.

To identify treatment-withholding intentions for 56 VA medicine inpatients who received a no-code order, 31 resident physicians who wrote the orders completed a checklist on which they indicated the interventions they intended to withhold from each patient. Review of patients' charts indicated that 24 (43%) contained no documentation of treatment limitation plans beyond the no-code order. To identify the general interpretations of no-code orders, "cross-covering" physicians indicated on a questionnaire the likelihood that they would withhold specific interventions from patients they were covering who had received a no-code order. Both the intention and interpretation of no-code orders were characterized by variability, and interpretation of the orders was characterized by uncertainty as well. Because of these discrepancies, we suggest a no-code order which provides greater specificity for individual patients.

Epidemiology of no-code orders in an academic hospital.

Relatively little is known about the circumstances in which decisions not to resuscitate, documented by no-code orders, are made. By review of medical records and interviews with house staff officers, we studied all medical service patients for whom no-code orders were written and those patients who received cardiopulmonary resuscitation (CPR) between October and December 1980 in the Portland Veterans Administration Medical Center. Among 1,780 patients admitted, 56 (3.1%) received no-code orders. All decisions were reportedly made by groups of individuals usually including the intern (98% of cases) and resident (93%), but not attending physician (39%). Many patients (43%) were disoriented or obtunded at the time of the no-code decision and 80% of oriented patients did participate in the decision.Thirty-seven of the 56 no-code patients died during the study. Comparing these with 20 patients who experienced cardiac arrest and did receive CPR, cancer, dementia, incontinence, non-ambulatory, divorced-separated and unemployed statuses were all more prevalent among no-code patients (P<.05).No-code orders in this Veterans Administration teaching hospital were relatively common and appeared to be made collectively. Participation of patients and attending physicians in the decisions, however, was limited.

In vitro determinants of plasma renin activity in serially-studied inbred dogs with neonatally induced coarctation hypertension: renin reactivity, renin substrate, and renin concentration.

Increased renin activity of plasma, suggesting an excess of circulating accelerators and/or deficit of inhibitors of the renin reaction, has been reported in a number of hypertensive states; however, its contribution to genesis and/or maintenance of hypertension is unknown. To longitudinally assess the evolution of plasma renin reactivity in relation to blood pressure in neonatally-induced coarctation hypertension, we have made serial observations in 6 coarcted dogs and in 7 littermate controls over 1-12 months post-aortic-banding during varied steady-state sodium intake. Measurements of renin activity (defined as the increment of angiotensin I-generation rate following addition of exogenous renin to plasma), renin substrate concentration (RS), and plasma renin activity (PRA), together with calculation of plasma renin concentration (PRC) (as PRC = PRA divided by renin reactivity) provided estimates of the three major determinants of PRA. RS values were adjusted for variability due to assay-control and to age via covariate analysis. Results indicate no difference in adjusted RS between coarcted and control dogs, thus obviating the influence of RS differences on renin reactivity results. Renin reactivity and PRC in coarcted dogs were also comparable to control values. Furthermore, responses of RS, renin reactivity and PRC to dietary sodium manipulation were similar in coarcted and control animals. We conclude that circulating modifiers of the renin reaction play no role in the genesis or in the first-year maintenance of neonatally-induced coarctation hypertension.