M H Weinberger

Sodium intake alters the effects of norepinephrine on blood pressure.

SUMMARY To examine the Interactions between sodium balance and the sympathetic nervous system, we studied eight normotensive men after high (800 mEq/day) and low (10 mEq/day) sodium intake. We measured blood pressure (BP), arterial, venous, and urinary norepinepfarine (NE) before and during incremental infusion of NE. We found significant direct, linear relationships (p < 0.001) between the dose of NE infused and arterial and venous NE levels, and with mean arterial BP at both levels of sodium balance. In addition, the sensitivity was greater and the threshold of pressor response to NE as well as the basal concentrations of NE in arterial and venous plasma significantly lower (p < 0.05) after the high sodium period. These observations expose heretofore unrecognized qualitative and quantitative interactions between sodium balance and NE that are capable of influencing BP in man.

Calcium channel blockade with nitrendipine. Effects on sodium homeostasis, the renin-angiotensin system, and the sympathetic nervous system in humans.

To test the hypothesis that the antihypertensive effect of the calcium channel blocking drug nitrendipine is in part related to natriuresis, we gave 16 subjects (8 normal, 8 hypertensive) placebo for 8 days followed by nitrendipine titrated to 20 mg twice daily for 8 days. The same diet was prepared for each meal for the entire study. Sodium intake was fixed for each subject and averaged 150 mEq/day. All urine was collected every day. Blood was drawn at the end of the placebo and nitrendipine periods for renin, aldosterone, and norepinephrine values. Nitrendipine caused a significant increase (p less than 0.05) in cumulative sodium excretion of 161 mEq over 7 days in the normal subjects and 103 mEq in hypertensive subjects. Potassium excretion was unaffected. In both hypertensive and normal subjects, plasma renin and plasma norepinephrine activity increased significantly (p less than 0.05), while plasma aldosterone levels did not change. Upright systolic blood pressure decreased significantly (p less than 0.05) in both groups, whereas upright diastolic blood pressure decreased only in hypertensive subjects. We conclude that blood pressure lowering effects of this drug may be in part related to natriuresis and that calcium channel blockade may dissociate plasma renin activity from that of aldosterone.

Blood pressure response to dietary sodium restriction in normotensive adults.

Sixteen healthy, normotensive husband-wife pairs participated in a study to investigate the effect of reduction of dietary sodium intake (goal less than or equal to 60 mEq/day) on blood pressure. Sodium excretion decreased from a control average of 152.7 +/- 10.1 (SE) mEq/day to 69.5 +/- 4.5 mEq/day (p less than 0.001). Results indicated significant decreases in both systolic (p less than 0.001) and diastolic (p less than 0.001) blood pressure after a period of sodium restriction. In the entire group, there was no significant change in potassium excretion (58.4 +/- 3.2 vs 54.6 +/- 3.5 mEq/day) or body weight (76.0 +/- 2.8 vs 75.3 +/- 2.7 kg). Although there was variability in the blood pressure response, the decrease in blood pressure was significantly correlated with the magnitude of sodium restriction (r = 0.36, p less than 0.03). These results indicate that the blood pressure response to sodium restriction may not be limited to individuals with hypertension and that the response is heterogeneous in normotensive subjects.

Norepinephrine in urine and plasma following provocative maneuvers in normal and hypertensive subjects.

SUMMARY Urinary norepinephrine (UNE) excretion rate and venous plasma norepinephrine (PNE) concentrations were studied in 266 normotensive and 107 essential hypertensive men and women under conditions of volume expansion with 2 liters of intravenous normal saline over 4 hours, and volume contraction with a 10 mEq sodium diet and 120 mg oral furosemide. The UNE excretion rate was correlated with age in normal women only. In men, and in hypertensives of both sexes, the relationship appeared to be biphasic. The PNE concentration was not correlated with age in the hypertensive subjects. Insufficient numbers of older subjects were available to exclude absolutely such a relationship among normals. The UNE and PNE were influenced by volume expansion and contraction in both normals and hypertensives; however, normals exhibited a correlation between UNE and blood pressure as well as consistent correlations between UNE and PNE, neither of which were observed in the hypertensives. Hypertensive women generally had greater UNE and PNE values than normal women or hypertensive men. Hypertensive women may have altered sympathetic activity.

Blood pressure response to potassium supplementation in normotensive adults and children.

To investigate the effect on blood pressure of a modest increase in dietary potassium intake, 38 healthy, free-living families were enrolled in a study involving 4 weeks of potassium supplementation. This was preceded by collection of five baseline measurements of blood pressure and urinary electrolyte excretion and followed by a 4-week recovery period. Although there was a significant increase in urinary potassium excretion during supplementation in both adults and children (p less than 0.001), there were no significant changes in systolic, diastolic, or mean arterial blood pressure. Height and weight increased significantly in children (p less than 0.001), and weight increased in adults (p less than 0.01) over the course of the study. Multivariate analysis of variance of blood pressure controlling for these confounding variables failed to reveal any effect of the potassium supplementation on blood pressure. These results suggest that increasing intake of dietary potassium alone in a healthy, free-living normotensive population is unlikely to have a discernible effect on blood pressure.

Red-cell sodium-lithium countertransport and fractional excretion of lithium in normal and hypertensive humans.

To examine the relations between erythrocyte sodium-lithium countertransport and renal proximal tubular sodium handling, we measured countertransport, and then subjected 30 normal and 32 hypertensive subjects, both white and black, to provocative maneuvers of volume expansion and contraction. The fractional excretions of sodium and lithium were measured simultaneously. In agreement with previous studies, we found that countertransport in erythrocytes was elevated in hypertensive patients compared with normal subjects. We also observed that whites have a higher level of countertransport than blacks. In the basal state, we found that fractional sodium excretion of hypertensive patients was no different than in normal subjects, whereas the fractional lithium excretion of hypertensive persons was increased compared with normotensive values. Volume expansion with 2 1 0.9% saline administered intravenously during a 4-hour period provoked an exaggerated natriuresis and a greater increase in fractional lithium clearance in hypertensive patients compared with the control group. With volume expansion and contraction, fractional lithium clearance and countertransport were directly correlated. Our data suggest that hypertensive persons do not have increased proximal tubular sodium reabsorption compared with normal subjects. Further, the exaggerated natriuresis of hypertension is, in part, the result of increased distal solute delivery. The fact that our hypertensive patients were older may partially explain the discrepancies between this report and previous observations.

Rapid cyclic fluctuations of blood pressure associated with an adrenal pheochromocytoma.

We present a patient with an adrenal pheochromocytoma with an unusual pattern of periodic alternating hypertension and hypotension. Alpha-adrenergic blockade alone failed to affect this pattern, which was abolished only after fluid repletion. The efficacy of volume expansion in ultimately correcting the wide fluctuations of blood pressure implicates a possible reflex neurogenic mechanism for the cyclic changes in blood pressure attributable to intravascular volume contraction.

Influence of genetic variance on sodium sensitivity of blood pressure

SummaryTo examine the effect of genetic variance on blood pressure, sodium homeostasis, and its regulatory determinants, we studied 37 pairs of monozygotic twins and 18 pairs of dizygotic twins under conditions of volume expansion and contraction. We found that, in addition to blood pressure and body size, sodium excretion in response to provocative maneuvers, glomerular filtration rate, the renin-angiotensin system, and the sympathetic nervous system are influenced by genetic variance. To elucidate the interaction of genetic factors and an environmental influence, namely, salt intake, we restricted dietary sodium in 44 families of twin children. In addition to a modest decrease in blood pressure, we found heterogeneous responses in blood pressure indicative of sodium sensitivity and resistance which were normally distributed. Strong parent-offspring resemblances were found in baseline blood pressures which persisted when adjustments were made for age and weight. Further, mother-offspring resemblances were observed in the change in blood pressure with sodium restriction. We conclude that the control of sodium homeostasis is heritable and that the change in blood pressure with sodium restriction is familial as well. These data speak to the interaction between the genetic susceptibility to hypertension and environmental influences which may result in its expression.

Association of blood groups with essential and secondary hypertension. A possible association of the MNS system.

SUMMARY Persons participating in a 5-day diagnostic protocol were routinely typed for ABO, Rh, MNS, Kell, Kidd, Duffy, P, Haptoglobln, phosphoglucomutase-1 (PGM-1), and add phosphatase (AcP). The study population was composed of 164 nonnotensive whites, 34 normotensive blacks, 161 whites and 43 blacks with essential hypertension, and 52 whites with secondary forms of hypertension (18 atherosclerotic reoovascular hypertensives, 17 patients with fibromuscular disease, and 17 patients with primary aldosteronism). There were no significant differences in phentotype frequencies in ABO, Rh, Kidd, Kell, Duffy, P, Haptoglobin, PGM-1 or AcP in any of the comparisons. However, there was a significantly different distribution of MNS phenotypes in comparisons of essential and atherosclerotic renovascular hypertensives with nonnotensive controls. Essential hypertensives had a lower frequency of the S gene and a higher frequency of s in whites (X3 = 12.21, p < 0.005). Atherosclerotic renovascular hypertensives differed from the normotensive population in the frequencies of both MN (X1 = 4.34, p < 0.05) and Ss (X1 = 4.21, p < 0.05). The finding of disease-blood group associations supports the hypothesis that there may be significant physiological differences between individuals of different blood types.

Optimizing cardiovascular risk reduction during antihypertensive therapy.

The increasing understanding of the hemodynamic and metabolic effects of specific antihypertensive agents, and the recognition that not all effective blood pressure-lowering strategies have been demonstrated to have uniform or consistent benefit in reducting all forms of cardiovascular disease associated with hypertension has forced a critical reevaluation of the effects of specific antihypertensive drugs