Harold S. Solomon

Increased sodium-lithium countertransport in red cells of patients with essential hypertension.

This paper describes experiments showing that one of the pathways of sodium transport across the red-cell membrane, sodium-lithium countertransport, is faster in patients with essential hypertension than in control subjects. This transport system accepts only sodium or lithium and is not inhibited by ouabain. The maximum rate of transport shows inherited differences. The mean maximum rate of sodium-lithium countertransport was found to be 0.55 +/- 0.02 (mean +/- S.E.M.) mmol (liter of red cells X hour)(-1) in a group of 36 patients with essential hypertension and 0.24 +/- 0.02 in 26 control subjects (P less than 0.001). The first-degree relatives of eight patients with essential hypertension and 10 control subjects had mean maximum rates of sodium-lithium countertransport of 0.54 +/- 0.05 and 0.23 +/- 0.02, respectively. Five patients with secondary hypertension had normal mean maximum rates of sodium-lithium countertransport. The relation between heritability of red-cell sodium-lithium countertransport and essential hypertension should be investigated further.

Senescence and the Renal Vasculature in Normal Man

The xenon washout technique and the renal blood flow response to vasoactive agents or alterations in sodium intake were used to characterize the effect of aging on the renal vasculature in 207 normal human subjects ranging in age from 17 to 76 years. A highly significant, progressive reduction in the mean blood flow, the rapid-component flow rate, and the percent of flow into the rapid-flow (cortical) compartment accompanied advancing age. Because 133Xe measures flow per unit tissue mass, the results indicated a larger reduction in flow than in mass—the anticipated finding if flow reduction is primary in the genesis of atrophy. Age also reduced the vasodilation consequent to administration of acetylcholine or a sodium load; this finding is consistent with a fixed lesion of the vessels. Responses to angiotensin were not modified by age. Thus, offsetting factors of increased ratio of wall to lumen thickness and smooth muscle atrophy are precisely matched. The findings in this study agree with earlier hypotheses based on morphology that suggest a primary vascular process in the development of age-related renal changes.

Renal vascular tone in essential and secondary hypertension: hemodynamic and angiographic responses to vasodilators.

The renal vascular response to graded doses of acetylcholine, dopamine and phentolamine, assessed by xenon washout and selective arteriography was used to define the relative contribution of fixed and reversible vascular abnormalities to increased renal vascular resistance in patients with essential or secondary hypertension. The increase in blood flow induced by acetylcholine and dopamine was blunted strikingly in patients with advanced nephrosclerosis, chronic pyelonephritis and polycystic kidney disease and was normal in the kidney contralateral to a significant renal artery stenosis. Conversely, the response to both was potentiated in 9 of 13 (69%) patients with mild essential hypertension. Equivalent potentiation of the response to acetylcholine was induced in normal subjects by increasing renal vascular tone pharmacologically with angiotensin. Phentolamine infused into the renal artery also increased renal blood flow significantly in 6 of 9 (67%) patients with mild essential hypertension, but in none of 15 normal subjects, over a dose reange that paralleled that for alpha-adrenergic blockade. Changes in the selective renal arteriogram were in excellent accord: potentiated response to acetylcholine, phentolamine or dopamine was associated with reversal of the small vessel abnormalities visualized in the arteriogram. The reduced blood flow response in advanced nephrosclerosis or parenchymal disease was associated with a reduced angiographic change during dilator infusion. The results suggest a quantitatively important, functional renal vascular abnormality--perhaps mediated by the sympathetic nervous system--in many patients with mild essential hypertension. Conversely the renal vascular abnormality associated with advanced nephrosclerosis or renal parenchymal disease is largely fixed and is probably due to organic changes.

Renal Vascular Responses to Angiotensin and Norepinephrine in Normal Man: EFFECT OF SODIUM INTAKE

The effect of sodium intake on renal vascular responses to angiotensin and norepinephrine infused intra-arterially was assessed in normal man by xenon washout. In subjects on an unrestricted diet, the dose of angiotensin inducing a 50% reduction in mean blood flow (ED50) was 38.2 ± 12.6 ng/min, a hundredfold lower dose than that for norepinephrine. Sodium restriction reduced the sensitivity to angiotensin tenfold: the ED50 rose to 378 ± 12 ng/min. This diet, conversely, potentiated responses to norepinephrine: the threshold dose fell from 37 ± 10 to 3.6 ± 1.9 ng/min. Thus, the reduction in sensitivity to angiotensin induced by sodium restriction was not a nonspecific effect on the vascular smooth muscle. Sodium restriction also reduced the variability in the vascular response to angiotensin, and a close correlation was found between urine sodium content and angiotensin responsiveness. The blood vessels of the normal human kidney are remarkably sensitive to angiotensin: the threshold dose is approximately 1 ng/min for intra-arterial infusion. Circulating angiotensin may be a mediator of renal vascular tone, but circulating catecholamines probably play a minimal role.

Na Countertransport and Cotransport in Human Red Cells: Function, Dysfunction, and Genes in Essential Hypertension

We describe in this paper studies on the modes of operation of ouabain-insensitive sodium transport systems in red cells of normotensive and hypertensive patients. We have extensively investigated the properties of Na countertransport and cotransport in order to clarify whether they are two different proteins or one transport protein with two modes of operation. Several criteria of discrimination between the two pathways are described: They differ in their affinity for Na and Li, sensitivity to several inhibitors, changes in cell volume, and chloride replacement by nitrate. We propose that there are two different transport systems. We have found elevated countertransport in red cells of hypertensive patients in France and in the United States. However, the cotransport system was found elevated in patients in Boston but reduced in patients in Paris. Studies of the modes of operation of the Na-K cotransport system indicate that it can promote K accumulation using an inward sodium gradient. This mode might be more efficient than Na extrusion at the physiological level of Na and K gradients. We interpret our findings of elevated Na-K cotransport in American hypertensive patients as an increased number of transport units functioning as K accumulators. It remains to be determined whether the reduced affinity for internal sodium of the outward cotransport is a defective outward cotransport or else a modulation of this transport system to favor K accumulation.

Determinants of dropout rate among hypertensive patients in an urban clinic

Noncompliance with follow-up is a serious problem in the management of hypertension. A retrospective cohort study examined dropout rates and their determinants among 249 randomly selected outpatients with essential hypertension from the medical clinic of an urban teaching hospital. Data were abstracted from hospital records and a subset of dropouts was interviewed. A lifetable analysis revealed that patients who were initiating therapy or who had been under therapy for less than six months had a 50% chance of remaining in care two years later, while 70% of patients who had been under therapy for more than six months at entry were still in care after this period. Patients who were less severely ill by several indicators were the most likely to drop out. It is hypothesized that the low perceived severity of illness, coupled with the costs and inconvenience of care and the lack of physician enthusiasm for the treatment of mild hypertension leads to noncompliance with follow-up.

Abnormal Adrenal Responsiveness and Angiotensin II Dependency in High Renin Essential Hypertension

Adrenal responsiveness to angiotensin II (AII) and the diastolic blood pressure responses to saralasin were studied in 19 patients with high renin essential hypertension (HREH) on a 10-meq Na(+)/100 meq K(+) diet. The increment in plasma renin activity (PRA) between supine and upright positions was used as an estimate of the acute stimulation of the adrenal gland by endogenous AII; the normal increment in plasma aldosterone divided by the increment in PRA was >3.8. 7 of 19 had abnormal upright posture responses with significantly greater mean PRA increments (24+/-6 ng/ml per h) and significantly smaller plasma aldosterone increments 47 +/- 16 ng/dl) (P < 0.036) compared to the increments observed in HREH patients with normal adrenal responsiveness (PRA = 15 +/- 1 ng/ml per h; plasma aldosterone = 87 +/- 17 ng/dl). When AII was infused at doses of 0.1-3 ng/kg per min, only patients with normal posture responses had normal plasma aldosterone increments; plasma aldosterone levels failed to significantly increase even at the highest infusion rate in the patients with the abnormal upright posture responses. The AII competitive inhibitor, saralasin (0.3-30 mug/kg per min) was then infused to study the occurrence of angiotensinogenic hypertension in both HREH subgroups. The mean decline in diastolic blood pressure to saralasin in the subnormal adrenal responsive patients (-15 +/- 3 mm Hg) was significantly greater than in the normal adrenal responsive group (-3 +/- 2 mm Hg) (P < 0.02).It is concluded that patients with HREH are not a homogeneous population; approximately one-third have AII-dependent hypertension. In these patients, the mechanism responsible for the elevated renin and blood pressure could be a compensatory increase secondary to decreased adrenal responsiveness to AII. In the remainder, the high PRA levels have little, if any, causal role in the pathogenesis of the hypertension but could reflect a marker of other pathophysiologic processes.

Effects of nadolol on hemodynamic and hemostatic responses to potential mental and physical triggers of myocardial infarction in subjects with mild systemic hypertension

Although beta-adrenergic blocking agents are known to reduce the risk of myocardial infarction, the mechanism of this protective effect is not well understood. The recent demonstration that beta blockers selectively blunt the increased morning risk of myocardial infarction suggests that these agents block the pathophysiologic consequences of stressors concentrated in the morning. We determined the effect of nadolol on the hemodynamic and hemostatic responses to mental stress and isometric exertion (handgrip), 2 potential triggers of infarction. The study was conducted in 15 subjects with mild systemic hypertension, using a placebo-controlled, double-blind, crossover design. Nadolol reduced systolic pressure and heart rate after mental stress. Poststress systolic pressure was 139 +/- 4 mm Hg during therapy with nadolol versus 161 +/- 4 mm Hg during placebo administration (p < 0.05). Heart rate increased to 61 +/- 2 during nadolol therapy versus 89 +/- 5 beats/min during placebo therapy (p < 0.05). The systolic pressure increase was similar during therapy with nadolol and placebo (29 +/- 2 vs 33 +/- 2 beats/min, p = NS); however, heart rate increase was less during nadolol therapy (4 +/- 1 vs 12 +/- 4 vs beats/min, p < 0.01). The responses to handgrip and their modification during nadolol therapy were similar to those observed after mental stress. Neither platelet aggregability nor fibrinolytic potential was altered by nadolol. Thus, nadolol modified hemodynamic indexes without altering the hemostatic indexes measured. This hemodynamic effect may contribute to the decrease in morning cardiovascular events by beta-adrenergic blockers and their well-documented cardioprotective effect.

Hemodynamic and hemostatic responses to morning and evening exertion in systemic hypertension and implications for triggering of acute cardiovascular disease.

The increased morning frequency of cardiovascular disease onset has created concern that morning exertion promotes greater risk than evening exertion. The physiologic responses to isometric exercise (handgrip) in the morning (9 A.M.) versus the evening (6:30 P.M.) were compared in 15 subjects with mild hypertension. Isometric exercise produced similar increases at both times of the day (morning vs evening) in systolic arterial pressure (31 +/- 4 vs 35 +/- 4 mm Hg, p = NS) and heart rate (7 +/- 1 vs 8 +/- 1 beats/min, p = NS). It also produced similar increases in fibrinolytic activity (reduction in euglobulin clot lysis time) at both times of the day (-53 +/- 27 vs -53 +/- 21 minutes). However, because basal fibrinolytic activity was lower in the morning than in the evening (euglobulin clot lysis time 364 +/- 45 vs 220 +/- 33 minutes, p < 0.01), peak fibrinolytic activity after stress was also lower in the morning (312 +/- 44 vs 176 +/- 27 minutes, p < 0.01). The present study demonstrates that in subjects with hypertension, the hemostatic and hemodynamic responses to handgrip are not greater during morning versus evening exertion. This finding, plus the overall benefits of regular exercise and the low absolute risk of an event during exercise, suggests that timing of exertion is not of critical importance. However, to obtain a definitive answer to this question, further studies are needed using different potential triggers and subject populations.

Effect of Sustained-Release Verapamil on the Morning Systemic Arterial Pressure Surge During Daily Activity in Patients With Systemic Hypertension

In a placebo-controlled study of 13 subjects with systemic hypertension, sustained-release verapamil reduced the morning surge in systolic pressure by 10.2 mm Hg (p = 0.04), diastolic pressure by 11.1 mm Hg (p = 0.008), and heart rate by 3.3 beats/min (p = 0.17). Blunting of the morning hemodynamic surge may be a mechanism by which verapamil could reduce the risk of plaque disruption and acute coronary events in the morning.