Mark S. Pecker

The captopril test for identifying renovascular disease in hypertensive patients

To develop a screening test for identifying renovascular hypertension, the blood pressure and plasma renin activity responses to an oral test dose of captopril were studied in 246 quietly seated hypertensive patients. The following criteria were developed that exploit the hyperresponsiveness of renin secretion in renovascular hypertensive patients: a 60-minute post-captopril plasma renin activity of 12 ng/ml per hour or more and an absolute plasma renin activity increase of 10 ng/ml per hour or more, along with a 150 percent increase in plasma renin activity (or a 400 percent increase if the baseline plasma renin activity was below 3 ng/ml per hour). Retrospectively, the test identified, among 200 hypertensive patients without evidence of renal dysfunction, all 56 patients with proved renovascular disease. In this group, false-positive results occurred only in two of 112 patients with essential hypertension and in six with secondary hypertension. Nine untreated patients had blood pressure levels of less than 160/100 mm Hg. The test was neither as sensitive nor specific in the 46 patients with renal insufficiency. This study demonstrates that the renin response to oral captopril is a useful screening test for identifying patients with unilateral or bilateral renovascular disease. Since the test also characterizes the renin dependency of the hypertension, it may have other diagnostic and therapeutic uses.

On the renal basis for essential hypertension: nephron heterogeneity with discordant renin secretion and sodium excretion causing a hypertensive vasoconstriction-volume relationship.

We propose herein that there are two functionally abnormal nephron populations in essential hypertension: (1) a group of ischemic nephrons with impaired sodium excretion which chronically hypersecrete renin. Numerically, these ischemic nephrons comprise a minor subgroup since most patients with essential hypertension exhibit no overt evidence of renal insufficiency. (2) In reaction to this, a more numerous group of normal nephrons appears in adaptive hypernatriuresis. They have an increased distal sodium supply and consequently, a chronically suppressed renin secretion. One difference between patients with renovascular hypertension and those with essential hypertension is the intermingling of these two populations of nephrons. In our hypothesis, the adapting hyperfiltering normal nephrons accomplish the hypernatriuresis in response to saline infusion, that is characteristic of all essential hypertension. However, the unsuppressed secretion of renin, that arises from the ischemic nephron population attenuates this compensatory natriuresis in the following ways: (1) by inappropriately acting on the hyperfiltering nephrons to enhance proximal tubular sodium reabsorption; (2) by activating TGF-mediated afferent constriction in these nephrons, and (3) simultaneously, the reactive secretion of renin from ischemic nephrons is diluted by non-participation of the adapting hypernatriuretic nephrons so that plasma renin settles at a level which is insufficient to fully compensate GFR in the ischemic nephrons. These adaptive responses provide a basis for the observation that the inhibition of renin activity with converting enzyme inhibitors in essential hypertension increases renal blood flow and sodium excretion. They also explain why converting enzyme inhibitors can effectively reduce blood pressure, even when renin levels are not absolutely elevated, since any circulating renin imposed upon the adapting hypernatriuretic nephrons inappropriately impairs their sodium excretion. In addition, the theory explains why basal renin secretion is either not suppressed or inadequately suppressed in patients with essential hypertension. As a result, whole kidney homeostatic function is compromised because individual nephrons are responding to their individual stimuli to fulfil their individual need, rather than acting in concert with other nephrons. The net effect of this uncoordinated response is to shift total renal function so that systemic arterial hypertension is sustained by abnormal sodium retention for the inappropriately high plasma renin level, or vice versa.(ABSTRACT TRUNCATED AT 400 WORDS)

β-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects

Although beta-adrenergic-blocking drugs suppress the renin system (RAAS), plasma angiotensin II (Ang II) responses during beta-blockade have not been defined. This study quantifies the effects of beta-blockade on the RAAS and examines its impact on prorenin processing by measuring changes in the ratio of plasma renin activity (PRA) to total renin. In normotensive (N = 14) and hypertensive (N = 16) subjects, blood pressure (BP), heart rate, PRA, plasma prorenin, plasma total renin (prorenin + PRA), ratio of PRA to total renin (%PRA), plasma Ang II, and urinary aldosterone were measured before and after 1 week of beta-blockade. Plasma renin activity, Ang II, and urinary aldosterone levels were similar for normotensive and hypertensive subjects. Plasma renin activity correlated with Ang II. Total renin, which is proportional to (pro)renin gene expression, was lower in hypertensive subjects and was inversely related to BP. Beta-blockade decreased BP and heart rate in both groups, with medium- and high-renin hypertensive subjects responding more frequently than those with low renin. Beta-blockade consistently suppressed PRA, Ang II, and aldosterone. Total renin was unchanged, thus, %PRA fell. These results indicate that beta-blockers suppress plasma angiotensin II levels, in parallel with the marked reductions in PRA and urinary aldosterone levels in normotensive and hypertensive subjects. The suppression of Ang II levels was comparable to that produced during angiotensin converting enzyme (ACE) inhibition. However, by reducing prorenin processing to renin, beta-blockers do not stimulate renin secretion, unlike ACE inhibitors and Ang II receptor antagonists. This unique action of beta-blockers has important implications for the treatment of cardiovascular disease.

Relation of plasma renin to end organ damage and to protection of K+ feeding in stroke-prone hypertensive rats.

We studied the effects of regular diet (0.35% NaCl/1.1% potassium), high sodium diet (4% NaCl/0.75% potassium), or high sodium and high potassium diet (4% NaCl/2.11% potassium) on blood pressure, plasma renin activity, renal and cerebrovascular lesions, and incidence of stroke and mortality in male stroke-prone spontaneously hypertensive rats (SHRSP). In the first 4 weeks, the rise in blood pressure was higher in high NaCl than in high NaCl/high potassium or regular diet groups. However, by 8 and 12 weeks, the blood pressure in all three groups was similar. After 4 weeks of diet, plasma renin activity was similar in the three groups (3.4 +/- 0.8, 4.1 +/- 0.9, and 5.2 +/- 1.6 ng/ml/hr, in high NaCl, high NaCl/high potassium, and regular diet groups, respectively) and were not related to sodium excretion. After 8 weeks, plasma renin activity was significantly increased only in the high NaCl group (13.7 +/- 3.7 ng/ml/hr), and by 12 weeks plasma renin activity was significantly higher in the high NaCl group (25.3 +/- 3.6 ng/ml/hr) than in the high NaCl/high potassium (11.1 +/- 2.9 ng/ml/hr) or in the regular diet (7.8 +/- 4.6 ng/ml/hr) groups. Moderate to severe renal vascular lesions were first detected in the high NaCl group by 8 weeks of diet. At 12 weeks, renal vascular damage index (RVDI), estimated histologically, was significantly higher in the high NaCl group (RVDI = 79 +/- 14) than in the high NaCl/high potassium (RVDI = 40 +/- 11) and regular diet (RVDI = 7.8 +/- 4.6) groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary Sodium and Essential Hypertension: Some Myths, Hopes, and Truths

Rigorous sodium deprivation can lower the blood pressure of some patients with essential hypertension (at best, 30% to 50% of patients). In the rest, sodium depletion is ineffective and, in some instances, can raise the blood pressure and cause adverse clinical effects. In normal persons, it is difficult to affect blood pressure even with drastic changes in salt intake; for the blood pressure to rise even slightly, it may be necessary to consume more than 800 meq/d. There is no evidence to indicate that a widely applied, moderate reduction of salt intake could prevent the development of hypertension. The evidence suggesting that such moderate salt intake would significantly lower blood pressure in the patients with sodium-sensitive essential hypertension is weak. Human hypertension comprises a heterogeneous spectrum of abnormal vasoconstriction-volume interactions. Sodium deprivation, like other forms of therapy, should be applied only to those patients in whom its effectiveness has been established.

Control of blood pressure and end-organ damage in maturing salt-loaded stroke-prone spontaneously hypertensive rats by oral angiotensin II receptor blockade

Objective: To study the effects of renin-angiotensin system blockade by a novel non-peptide angiotensin II receptor antagonist, losartan, on development of hypertension and acceleration of end-organ damage in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). Design and methods: One hundred and eighty-one male SHRSP were fed a 4% sodium diet from 6 to 18 weeks of age. Seventy-eight SHRSP were treated orally with losartan, 30 mg/kg per day. One hundred and three rats constituted untreated controls. Blood pressure, plasma renin activity (PRA), renal function and end-organ damage were monitored during the transition to malignant hypertension. Results: Losartan prevented a blood pressure rise during the first 4 weeks of salt loading. Thereafter, blood pressure rose slowly in losartan-treated rats; however, at each time-point studied blood pressure was significantly lower in losartan-treated rats than in control rats. Losartan treatment increased PRA during the first 4 weeks, but this effect was not sustained. Thereafter, PRA decreased to control (week 0) levels. In contrast, 2 weeks after high-sodium feeding started, untreated SHRSP failed to suppress PRA appropriately; thereafter, PRA rose significantly. Losartan affected renal pathophysiology by blunting the decline in glomerular filtration rate, controlling proteinuria and preventing or delaying the appearance of malignant nephrosclerosis. Losartan treatment significantly increased survival and completely prevented cerebrovascular infarcts. Conclusions: The results indicate that angiotensin II blockade markedly reduces both hypertension and end-organ damage in chronically salt-loaded SHRSP and that the renin—angiotensin system may play an important role in the development of hypertensive cardiovascular disease in SHRSP.

The Incidence and Predictors of Job Burnout in First-Year Internal Medicine Residents: A Five-Institution Study

Purpose Job burnout is prevalent among U.S. internal medicine (IM) residents and may lead to depression, suboptimal patient care, and medical errors. This study sought to identify factors predicting new burnout to better identify at-risk residents. Method The authors administered surveys to first-year IM residents at five institutions twice between June 2008 and June 2009, linking individual pre- and postresponses. Surveys measured job burnout, sleepiness, personality traits, and other characteristics. Burnout was defined using the most commonly identified definition and another stricter definition. Results Of 263 eligible residents, 185 (70%) completed both surveys. Among 114 residents who began free of burnout and completed both surveys, 86 (75%) developed burnout, with no differences across institutions. They were significantly more likely to report a disorganized personality style (9 versus 0; 11% versus 0%; P = .019) and less likely to report receiving regular performance feedback (34 versus 13; 63% versus 87%; P = .057). Using a stricter definition, 50% (78/156) of residents developed burnout. They were less likely to plan to pursue subspecialty training (49 versus 63; 78% versus 93%; P = .016) or have a calm personality style (59 versus 70; 77% versus 90%; P = .029). There were no significant associations between burnout incidence and duty hours, clinical rotation, demographics, social supports, loan debt, or psychiatric history. Conclusions This study identified a high burnout incidence. The associations observed between burnout incidence and personality style, lack of feedback, and career choice uncertainty may inform interventions to prevent burnout and associated hazards.

Plasma atrial natriuretic factor in essential hypertension: Relation to cardiac size, function and systemic hemodynamics

To evaluate determinants of elevated plasma atrial natriuretic factor levels in patients with hypertension, immunoreactive plasma atrial natriuretic factor in 54 normal subjects and 40 untreated hypertensive patients was compared with echocardiographic measurements of cardiac size, function and systemic hemodynamics. In normal subjects, plasma atrial natriuretic factor was related to age, systolic blood pressure and left atrial and ventricular chamber sizes, but only age and ventricular size were independent predictors. In untreated hypertensive patients, atrial natriuretic factor was directly related to age, atrial size, systolic pressure, peripheral resistance and ventricular systolic performance; age, atrial size and peripheral resistance were independent predictors. Eight patients with elevated atrial natriuretic factor values (greater than 25 fmol/ml) were significantly (p less than 0.01) older and had greater atrial and ventricular size and higher systolic pressure and function than normal subjects or patients with normal natriuretic factor levels. Plasma atrial natriuretic factor was inversely related to peak diastolic filling rate in normal subjects (r = -0.59; p less than 0.001), whereas it was positively related to the proportional contribution of atrial systole to left ventricular filling in hypertensive patients (r = 0.77; p less than 0.001). These findings suggest that in normal subjects, impairment of ventricular relaxation with age may contribute to atrial natriuretic factor secretion by increasing left atrial afterload; the correlation with left ventricular size may reflect physiologic fluctuations in plasma volume. In patients with uncomplicated hypertension, left atrial enlargement and consequent stronger atrial contraction contributed to increased atrial natriuretic factor release, whereas no independent relation existed with left ventricular hypertrophy or systolic function. Because ventricular relaxation was normal and ventricular size and systolic performance were increased in hypertensive patients with high atrial natriuretic factor levels, the observed increase in left atrial size and atrial contribution to ventricular filling might reflect a primary increase in venous return in this subset of hypertensive patients.

Strophanthidin inotropy: Role of intracellular sodium ion activity and sodium-calcium exchange

The relation among the ratio of extra- and intra-cellular sodium ion activities (aoNa/aiNa), contractile force and action of strophanthidin was studied in cardiac Purkinje fibers when transmembrane Na+ and Ca2+ gradients were changed. The aiNa, contractile force and action potential were simultaneously measured. Simultaneous reduction of [Na+]o and [Ca2+]o to 80.8 and 1.08 mM respectively, decreased aiNa from 8.0 +/- 1.1 mM (mean +/- S.D., n = 17) to 6.0 +/- 0.9 mM (n = 17) whereas contractile force transiently increased and then recovered toward the level similar to that in Tyrode solution. Reduction of [Ca2+]o alone increased aiNa by 1.7 +/- 0.4 mM (n = 5) and decreased contractile force by 87 +/- 5% (n = 5). Raising osmolarity of Tyrode solution with sucrose increased both aiNa and contractile force. Substitution of sucrose with Na+ (high [Na+] solution) increased aiNa by 1.2 +/- 0.3 mM (n = 5) and decreased contractile force by 31 +/- 9% (n = 5). Strophanthidin (2 X 10(-7) M) increased aiNa by 0.4 +/- 0.1 mM (n = 6) and contractile force by 24 +/- 8 (n = 6) in a low [Na+] - [Ca2+] solution. These changes were smaller than those in Tyrode solution (1.1 +/- 0.3 mM); 96 +/- 32%, n = 6). On the other hand, strophanthidin increased aiNa and contractile force more in a low [Ca2+] (2.7 +/- 0.5 mM; 220 +/- 24%, n = 5) or a high [Na+] (2.3 +/- 0.9 mM; 164 +/- 37%, n = 5) solution than in Tyrode solution. In the solutions containing the altered [Na+]o and/or [Ca2+]o, the increases in aiNa and force by strophanthidin were parallel. Therefore, the parallel increase in aiNa and contractile force due to strophanthidin depends on the initial level of aiNa, suggesting the dependence of digitalis inotropy on the rate of Na+ extrusion by the Na+ -K+ pump. The results also indicate that the ratio of aoNa/aiNa is an important and powerful factor in the control of contractile force. Presumably this is mediated through the Na+ -Ca2+ exchange.

Effect of norepinephrine and cyclic AMP on intracellular sodium ion activity and contractile force in canine cardiac Purkinje fibers.

The effect of norepinephrine on the Na+-K+ pump was investigated by simultaneously measuring intracellular sodium ion activity (a1Na) and contractile force of canine cardiac Purkinje fibers driven at 1.0 Hz in K+-free solution, high K+ solution, and in the presence of tetrodotoxin. In Tyrode solution containing 5.4mM [K+]o, 10-6 M norepinephrine decreased a1Na, whereas in K+-free solution 10-6 M norepinephrine did not lower a1Na. 16.2 mM [K+]o decreased a1Na from 8.8 ±0.9 mM to 6.5 ± 0.5 mM (mean ± SD, n = 5). Exposure to 10-6 M norepinephrine in the presence of high [K+]o, further decreased a1Na by 0.7 ± 0.4 mM. This further decrease was prevented by exposure to 2.5 × 10-6 M strophanthidin (n = 4). Blockade of the fast sodium channel with 5 × 10-6 M tetrodotoxin lowered a1Na from 8.5 ± 1.3 mM to 7.4 ± 1.1 mM (n = 4). Exposure to 10-6 M norepinephrine in the presence of tetrodotoxin further lowered a1Na by 0.9 ± 0.2 mM. We also studied the effects of the analogues of adenosine 3′:5′-cyclic monophosphate, N6, 2′-0-dibutyryladenosine 3′:5′-cyclic monophosphate, and 8-(4-chlorophenylthiol)-adenosine 3′:5′-cyclic monophosphate on a1Na and twitch tension. Both analogues lowered to a1Na and increased twitch tension mimicking the effects of norepinephrine. Our results support the hypothesis that norepinephrine lowers a1Na by stimulating the Na+-K+ pump in this tissue. This stimulation appears to be mediated by adenosine 3′: 5′-cyclic monophosphate and does not appear to be due to intercellular K+ accumulation. The results also are consistent with the hypothesis that lowering a1Na by norepinephrine or cyclic AMP plays a role in the control of contractile force in cardiac Purkinje fibers.