Influence of sodium intake on the reliability of active renin as a measure of the renin-angiotensin system in essential hypertension.

Plasma renin activity (PRA), active renin (AR), prorenin, and angiotensinogen were assessed in 486 hypertensive and 175 normotensive subjects with a sodium intake of 10 or 200 mEq/d during supine and upright posture and after infusion of angiotensin II. PRA and AR levels were compared in hypertensive subjects in each condition. With low sodium intake, particularly while upright, there was a significant correlation between PRA and AR. In upright subjects with low sodium intake who had a PRA of 2.4 ng/mL per hour or less (1.85 nmol.L-1.h-1 or less), the correlation was also strong. With high sodium intake, the correlation was weaker. With intermediate sodium excretion, the correlation was intermediate. Prorenin was less predictive of PRA than was AR, and angiotensinogen had a marginal role. Using PRA during sodium restriction while upright as the standard for determining renin status, the precision of AR for predicting renin status was excellent. AR may be used for surrogate assessment of the renin-angiotensin system activity when the system is activated.

Renal response to captopril reflects state of local renin system in healthy humans.

BACKGROUND: Heightened activity of the renin-angiotensin system has been linked to the development of both essential hypertension and diabetic nephropathy. Blunting of the renal vasoconstrictor response to Ang II, specifically when it is corrected by angiotensin converting enzyme (ACE) inhibition, is a feature which we have employed as a marker for activation of the intrarenal RAS. In this study we tested the hypothesis that variation in the renal vasodilator response to ACE inhibition in healthy humans reflected the variation in angiotensin-mediated renal vasoconstriction provoked by a low-salt diet. METHODS: We studied 20 healthy people (ages 19 to 57; 15 males) who were in balance on a low sodium diet. Ang II was infused for 45 minutes (3 ng/kg/min), followed by 25 mg captopril and a repeat Ang II infusion; PAH clearance was measured at the end of each interval. RESULTS: All subjects responded to captopril with a rise in renal plasma flow (range 43 to 242, mean 118 + 12 ml/min/1.73 m2). Individual vasodilator response to captopril was a strong inverse predictor of the precaptopril vasoconstrictor response to Ang II (P = 0.006, r = -0.59). There was a stronger, positive correlation of the vasodilator response to captopril and enhancement of Ang II responsiveness after captopril (r = 0.57). Plasma renin activity was significantly correlated with captopril response among the large responders (P = 0.003; r = 0.83), but not at all among those with little response. CONCLUSION: These results suggest substantial variation in angiotensin-mediated control of the renal circulation in healthy individuals on a low sodium intake. Variation in the vasodilator response to captopril, correlated with responses to Ang II, provides a measure of that control.

Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1.

Increased plasma renin activity (PRA) has been associated with an increased risk of myocardial infarction (MI), whereas angiotensin-converting enzyme (ACE) inhibition appears to reduce the risk of recurrent MI in patients with left ventricular dysfunction. These observations may be partially explained by an interaction between the renin-angiotensin system (RAS) and fibrinolytic system. To test this hypothesis, we examined the effect of salt depletion on tissue-type plasminogen activator (tPA) antigen and plasminogen activator inhibitor-1 (PAI-1) activity and antigen in normotensive subjects in the presence and absence of quinapril (40 mg BID). Under low (10 mmol/d) and high (200 mmol/d) salt conditions there was significant diurnal variation in PAI-1 antigen and activity and tPA antigen. Morning (8 AM through 2 PM) PAI-1 antigen levels were significantly higher during low salt intake compared with high salt intake conditions (ANOVA, F=5.8, P=0.048). PAI-1 antigen correlated with aldosterone (r=0.56, P<10(-7)) during low salt intake. ACE inhibition significantly decreased 24-hour (ANOVA for 24 hours, F=6. 7, P=0.04) and morning (F=24, P=0.002) PAI-1 antigen and PAI-1 activity (F=6.48, P=0.038) but did not alter tPA antigen. Thus, the mean morning PAI-1 antigen concentration was significantly higher during low salt intake than during either high salt intake or low salt intake and concomitant ACE inhibition (22.7+/-4.6 versus 16. 1+/-3.3 and 16.3+/-3.7 ng/mL, respectively; P<0.05). This study provides evidence of a direct functional link between the RAS and fibrinolytic system in humans. The data suggest that ACE inhibition has the potential to reduce the incidence of thrombotic cardiovascular events by blunting the morning peak in PAI-1.

Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism.

There are anecdotal reports of early cerebrovascular complications occurring in patients with glucocorticoid-remediable aldosteronism (GRA). The issue has never been systematically evaluated. In this study, we retrospectively reviewed the International Registry for GRA to see if there was an association between cerebrovascular complications and GRA. We searched the records of 376 patients from 27 genetically proven GRA pedigrees for premature death or cerebrovascular complications. Each case was subsequently verified through the referring physician, or autopsy reports. The number of complications occurring in patients with proven GRA were compared to GRA negative subjects from the same pedigrees. There were 18 cerebrovascular events in 15 patients with proven GRA (n=167) and none in the GRA negative group (n=194; P<.001). There were an additional 15 events in 15 subjects that were suspected of having GRA based on clinical history. Seventy percent of events were hemorrhagic strokes; the overall case fatality rate was 61%. The mean (+/- SD) age at the time of the initial event was 31.7+/-11.3 years. In total, 48% of all GRA pedigrees and 18% of all GRA patients had cerebrovascular complications, which is similar to the frequency of aneurysm in adult polycystic kidney disease. GRA is associated with high morbidity and mortality from early onset of hemorrhagic stroke and ruptured intracranial aneurysms. Screening for intracranial aneurysm with magnetic resonance angiography is advised for patients with genetically proven GRA.

Increased urinary free cortisol: a potential intermediate phenotype of essential hypertension.

We evaluated urinary cortisol excretion as a potential intermediate phenotype of essential hypertension in 153 white patients with essential hypertension and 18 normotensive white control subjects. Analyses were controlled for dietary sodium and gender to adjust for potential confounding effects of these variables on cortisol excretion. Urinary cortisol excretion measured on both high- and low-salt diets was significantly related to hypertension by repeated measures ANCOVA (P=.02). Additional determinants of urinary free cortisol included dietary sodium intake and gender; cortisol excretion was significantly higher in men (P=.0006) and during a high-sodium diet (P=.0001). Maximum likelihood analysis showed urinary cortisol to have a bimodal distribution on both 200-mmol (P<.01) and 10-mmol (P<.002) sodium diets in hypertensive subjects. On the low-salt diet, the mean urinary cortisol in normotensive subjects (108.7+/-44.7 nmol/d) was similar to the mean of hypertensive subjects in the low mode (127.2+/-43.0 nmol/d). The high mode comprised 31.2% of the hypertensive population and had a mean urinary cortisol of 224.3+/-93.8 nmol/d. Subjects with the highest urinary free cortisol showed the least sensitivity of blood pressure to dietary sodium loading (P<.05). These data suggest that there is an association between salt-resistant hypertension and high urine cortisol levels. This association may have a genetic basis.

Evaluation of the dexamethasone suppression test for the diagnosis of glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism (GRA) is a rare form of inherited hypertension caused by a characteristic gene duplication. With the advent of definitive genetic testing for GRA, the performance of the traditional screening test for GRA, the dexamethasone suppression test (DST), can be evaluated. We compared the DST to direct genetic testing in 24 patients referred for genetic screening for GRA (12 GRA positive and 12 GRA negative) based on clinical and biochemical findings, DST, and family history. Plasma aldosterone was measured before and after oral dexamethasone administration to determine the extent to which aldosterone was suppressed by glucocorticoids in each patient group. The results of the DST in these subjects were also compared to those in 19 historical patients with primary aldosteronism [4 bilateral hyperplasia and 15 aldosterone-producing adenoma (APA)] reported previously. The DST differentiated GRA-positive from GRA-negative patients with 92% sensitivity and 100% specificity. Cutoffs based on the post-DST plasma aldosterone level (< 4 ng/dL) or percent suppression compared to baseline (> 80%) were equally effective in correctly diagnosing GRA (only one GRA-positive patient would have been incorrectly diagnosed). However, DST in 15 APA patients revealed that 33% had greater than 80% suppression of aldosterone, and 1 had aldosterone levels below 4 ng/dL. We conclued that a post-DST aldosterone level below 4 ng/dL will correctly diagnose GRA patients with high sensitivity and specificity. Suppression compared to baseline can be misleading, as evidenced by the results in APA patients and referred subjects who genetically screened negative.

Impaired potassium-stimulated aldosterone production: a possible explanation for normokalemic glucocorticoid-remediable aldosteronism.

Unlike other forms of primary aldosteronism, recent prospective studies have paradoxically revealed that glucocorticoid-remediable aldosteronism (GRA) is usually characterized by normal potassium (K+) levels. To evaluate this paradox we studied 10 GRA subjects and 14 healthy controls in two protocols: 1) the renal K+ excretory response to acute oral administration of 50 mmol K+ chloride and to fludrocortisone, 0.2 mg p.o. q12 h x 4 doses; and 2) the aldosterone response to administration of 50 mmol K+ chloride. The K+ excretion rate (KER) in GRA subjects (n = 6) at baseline (45.6 +/- 8.3 microEq/min), after K+ (134 +/- 34.2 microEq/min), and after fludrocortisone (100 +/- 35.0 microEq/min) was not significantly different than that seen in the control (n = 8) subjects (54.9 +/- 19.0, 154 +/- 35.5, 112 +/- 45.8 microEq/min, respectively). Thus the renal kaliuretic response to K+ ingestion and exogenous mineralocorticoid is normal in GRA. Serum aldosterone increased from 5.0 +/- 3.8 at baseline to a maximum of 13.1 +/- 6.6 ng/dL 60 min after K+ ingestion in control subjects (n = 7), but failed to increase in GRA subjects (n = 14), going from 8.7 +/- 3.8 (baseline) to 8.8 +/- 5.4 ng/dL at 60 min (P = 0.004 vs. control). The blunted aldosterone response to K+ in GRA in association with the sharp diurnal decline in aldosterone in this ACTH-regulated syndrome probably results in a milder degree of hyperaldosteronism compared with other forms of primary aldosteronism, thereby producing volume expansion with minimal renal K+ wasting.

Glucocorticoid-remediable aldosteronism.

Although GRA is said to be one of the least common of the mineralocorticoid-excess states, it is probably underdiagnosed. Moreover, recent advances in our understanding of its pathogenesis has greatly broadened the understanding of this disorder. The development of direct genetic testing for GRA has simplified the diagnostic approach to GRA and will likely increase the detection of many previously undiagnosed cases. Since appropriate treatment can often result in normalization of this refractory form of hypertension, a high index of suspicion should be maintained for this diagnosis when a patient is diagnosed with mineralocorticoid-induced hypertension. It is only through early detection and institution of directed treatment that the morbidity and mortality associated with GRA can be reduced.

Primary aldosteronism.

The mineralocorticoid-excess state caused by primary aldosteronism usually causes hypokalemia and moderate to sever hypotension. A directed approach to the patient with suspected primary aldosteronism is essential. Appropriate use of biochemical and diagnostic imaging studies can identify the etiology of the primary aldosteronism in an efficient and noninvasive way in most cases. Precision in defining the etiology of the mineralocorticoid-excess state logically leads to therapeutic strategies that usually cure or improve the hypertensive state.