The Antihypertensive Effect of Verapamil at Extremes of Dietary Sodium Intake

The Antihypertensive Effect of Verapamil at Extremes of Dietary Sodium Intake JOHN P. NICHOLSON, M.D.; LAWRENCE M. RESNICK, M.D.; and JOHN H. LARAGH, M.D.; New York, New York Restricting sodium intake is a primary recommendation for patients with hypertension, including those receiving drug treatment. Few studies, however, have examined the impact of different levels of sodium intake on the effectiveness of antihypertensive drugs. We administered two courses of verapamil to 13 patients with essential hypertension during a low-sodium (NaCI, 9 meq/d) and high-sodium (212 meq/d) diet. Overall, verapamil was an effective antihypertensive agent, but expressed its greatest potency in the lower-renin, sodium-sensitive subgroup (change in systolic/diastolic blood pressure, 18.8/ 17.7 in sodium-sensitive patients compared with 11.4/ 8.7 in sodium-insensitive patients; p < 0.05). Moreover, the antihypertensive efficacy of verapamil was not blunted by the high-sodium intake. Thus, dietary sodium restriction may not be necessary or appropriate in the treatment of essential hypertension with verapamil; salt-induced cellular calcium uptake may be involved in the phenomenon of sodium sensitivity. From Cornell University Medical College, The New York Hospital; New York, New York. THE INFLUENCE OF dietary sodium on the pathogenesis and therapy of essential hypertension remains undefined. Why, how, and when changes in dietary sodium will affect blood pressure in hypertensive people remain largely unexplained. Data suggest that dietary sodium may be a factor in some patients with essential hypertension, but not all (1-3). Although it is difficult to raise blood pressure in normotensive patients by increasing sodium intake (4, 5), blood pressure in certain hypertensive patients may change significantly by increasing or restricting sodium (6). Thus, the blood pressure of as many as 45% of hypertensive patients appears to be sensitive to dietary sodium (7, 8). The mechanism by which increased dietary sodium intake raises blood pressure in these patients is also poorly understood. One current hypothesis (9) proposes a defect in sodium-linked cellular calcium transport, perhaps mediated in part via a hormonal inhibition of Na+-K+ adenosine triphosphatase. Primary abnormalities of calcium metabolism have also been suspected in the pathogenesis of essential hypertension. Directly measured intracellular calcium levels in platelets from patients with essential hypertension are elevated compared with those from normotensive persons (10). The hypotensive effect of calcium influx antagonist drugs in hypertensive patients further implicates calcium-dependent mechanisms in hypertension (11). These calcium antagonists exert their pharmacologic effect by retarding the influx of ionic calcium through a calcium channel in the cell membrane of arterial smooth muscle cells, thereby reducing available cytosolic calcium. Because cellular uptake of sodium and calcium may be linked (9), we wondered whether the hypotensive effect of calcium channel blockers might be affected by Annals of Internal Medicine. 1987;107:329-334. 1987 American College of Physicians 329

Table 1. Clinical and Laboratory Characteristics of Thirteen Patients with Essential Hypertension Before Admission Patient Age Sex Race Blood Plasma Renin Urinary Serum Serum Blood Urea Pressure Activity Sodium Potassium Creatinine Nitrogen yrs mm Hg ng/ml /h meq/24 h mmol/l mg/dl mg/dl 1 59 M W 140/100 2.6 102 3.5 1.1 15 2 58 M W 168/94 3.6 103 4.2 1.0 10 3 49 F W 169/100 0.29 116 4.1 1.1 15 4 56 M W 150/96 1.7 111 4.2 1.0 19 5 51 F B 220/130 1.3 100 3.6 1.0 17 6 58 M W 148/106 2.7 48 4.3 1.1 13 7 24 M W 148/108 15.0 54 3.5 0.9 16 8 36 M W 150/120 3.4 95 4.0 1.0 14 9 43 M W 190/118 0.51 74 3.9 1.4 18 10 63 M W 160/95 3.5 181 4.5 0.9 11 11 44 M H 180/126 1.2 34 3.5 0.9 15 12 33 M W 140/104 1.6 125 4.2 0.9 15 13 46 M W 158/114 5.0 156 4.0 1.0 12 varying dietary sodium intake. Therefore, we examined the influence of two widely different dietary sodium intakes on the blood pressure response to the calcium channel influx antagonist, verapamil. We found that, unlike what is thought to occur with other antihypertensive drugs, this form of antihypertensive therapy is not adversely affected by a more liberal salt intake. Methods PATIENT POPULATION Thirteen patients with essential hypertension (11 men, 2 women) without concurrent medical illness were recruited from the Hypertension Center of The New York Hospital-Cornell Medical Center. Four of the patients had low renin hypertension, 8 had normal, and 1 had high-renin hypertension as denned previously (12). All patients were medication free for 3 weeks and were then admitted to the Clinical Research Center. Each patient gave written consent to the protocol as approved by the Institutional Human Rights and Research Committee. STUDY DESIGN Patients were randomly allocated to constant metabolic diets of either 9 or 212 meq/d of sodium and 60 meq/d of potassium. After 5 days on each dietary regimen, 120 mg of verapamil was administered orally three times a day for 3 days. Before and after verapamil therapy on both high and low sodium intakes, fasting venous blood for plasma renin activity was collected at 0800 h (supine) and again at 1000 h after the patients had ambulated for 2 hours. Twenty-four-hour urinary sodium excretion and body weight were measured daily. Nurses measured blood pressure by sphygmomanometer four times a day with patients in both supine and upright positions. Patients whose average daily supine and upright diastolic blood pressure on day 5 of a high-sodium intake were statistically significantly higher than on day 5 of a low-sodium diet were classified as salt sensitive. Patients whose average supine and upright diastolic blood pressure decreased, did not change, or were not statistically significantly higher were classified as salt insensitive. Urinary sodium values were measured by flame photometry, whereas plasma renin activity levels were measured by radioimmunoassay as reported previously (13). DATA HANDLING All data are expressed as mean + SE and differences were evaluated by Student paired r-tests when appropriate. Linear regression analysis was done using the Pearson correlation coefficient. Differences were considered significant when the p values were less than 0.05. Results Demographic and clinical characteristics for the group are shown in Table 1. Average blood pressure for the 13 patients before admission was 163 + 6/108 + 4 (range, 140 to 220/94 to 130). Average plasma renin activity for the group was 3.3 + 1.0 ng/ml.h (range, 0.29 to 15.0) with an average 24-hour urinary sodium excretion of 99+11 meq/d (range, 34 to 181). Sodium-sensitive patients had lower basal plasma renin activity values compared with sodium-insensitive patients (1.8 + 0.5 compared with 4.5 + 1.8 ng/ml h;p < 0.05), yet sodium-sensitive patients did not differ from sodium-insensitive patients with regard to age (50+3 compared with 46 + 3 years;p, not significant). All patients had normal serum potassium values as well as normal renal function on the basis of creatinine and blood urea nitrogen values. Blood pressure responses to low- and high-sodium diets are shown in Table 2. For the group there was no quantitative difference in blood pressure responses to either the high- or low-sodium intake. The average standing and supine blood pressures on the low-sodium diet were 163 + 4/105 + 3 and 155 + 6/106 + 4 mm Hg, and on the high-sodium diet 165 + 5/104 + 4 and Table 2. Blood Pressure Responses to s in Sodium Intake in Thirteen Patients Before and After Calcium Blockade Supine 163 ± 4/105 ± 3 Upright 155 ± 6/106 ± 4 145 ± 4V94 ± 3 140 ± 4 /98 ± 3 11.4/10.6 8.8/6.8 165 ± 5/104 ±4 160 ± 5/107 ± 4 146 ± 4f/90 ± 3 137 ± 3f/93 ± 3f 11.6/12.7 13.8/12.1 * p<0.01 compared with values before verapamil. tp<0.001 compared with values before verapamil. 330 September 1987 Annals of Internal Medicine Volume 107 Number 3

Figure 1. Plasma renin activity and verapamil-induced changes in blood pressure on high- and low-sodium diets. Circles show low sodium, 9 meq/d; triangles show high sodium, 212 meq/d. 160 ± 5/107 + 4 mm Hg, respectively. However, six patients' blood pressures each rose significantly on highcompared with low-sodium intake (average percent change for systolic/diastolic blood pressure was 9.9%/ 6.8% [upright], p < 0.05; 11.9%/7.5% [supine], p < 0.05), and these patients were sodium sensitive. The blood pressure for the other seven patients did not rise on high compared with low sodium (sodium-insensitive patients) (average percent change for systolic/diastolic blood pressure was 3%/ 6.6% [upright], p, not significant; 1.8%/ 3.7% [supine], not significant). Intervention with verapamil, 120 mg three times a day, on either high- or low-sodium intake produced significant antihypertensive responses. A marked reduction in blood pressure occurred in both the supine and upright positions, for both diastolic and systolic pressures. Altogether, there was a significant positive relationship between basal plasma renin activity and the hypotensive efficacy of verapamil (r = 0.72; p < 0.01) (Figure 1). The reductions in blood pressure induced by verapamil on highand low-sodium diets were similar. Indeed, the high-sodium diet may even have enhanced the response (percent change systolic pressure/diastolic pressure [high sodium] -13.8%/-12.1% compared with -8.8%/-6.8% [low sodium] in the upright position) (Table 2). Further, for the sodium-sensitive patients, the blood pressure response to verapamil, although significant on either sodium intake, was far greater on a higher sodium intake (percent change systolic pressure/diastolic pressure 18.3%/ 17.7% compared with 11.4%/ 8.7% in the upright position, p < 0.05), compared with that for the sodium-insensitive patients (Table 3). This finding was true despite a 1-kg weight gain in the sodium-sensitive group. The effect of dietary sodium intake and verapamil administration on the renin-angiotensin-aldosterone system for the group as a whole is shown in Table 4. As expected, plasma renin activity and urinary aldosterone excretion were suppressed on a high- compared with low-sodium intake (plasma renin activity, 2.8 + 0.8 compared with 9.5 + 2.0 ng/ml h, high compared with low sodium, p < 0.01; urinary aldosterone, 8.2 ±1.5 compared with 22 + 3.7 fxg/d, high compared with low sodium, p < 0.02). Verapamil therapy modestly elevated plasma renin activity on both sodium intakes. Interestingly, urinary aldosterone excretion with verapamil on the highsodium diet did not change (7.6 + 1.5 compared with 8.2 ± 1.5 jlig/d; p, not significant, comparing high sodium without or with verapamil), whereas on the low-sodium diet urinary aldosterone excretion did rise significantly with verapamil (32 ± 5.3 compared with 22 it 3.7 /xg/d, p < 0.02). These hormonal and metabolic indices were also different on high- and low-sodium intakes before and after verapamil therapy in sodium-sensitive as Table 3. Blood Pressure Response According to Sodium Sensitivity in Thirteen Patients Before and After Calcium Blockade Sensitive (n = 6) Supine 162 ± 7/103 ± 4 Upright 151 ± 10/106 ± 6 Insensitive (/? = 7) Supine 162 ± 5/106 ± 5 Upright 158 ±6/106 + 4 142 ± 6V92 ± 5 135±4 /94±4 147 ± 5 J/95 ± A% 145 ±6*/102± 3 12.8/10.5 8.2/10.2 9.4/9.7 8.4/3.8 178 ± 8t/H0± 5f 169±6t/H4± 5 157 ± 5/99 ± 5 155 ± 7/102 ± 5 149 ± 5^/93 ± 2 138 ± 6{/94 ± 6% 143 ± 5J/88 ± 4% 137 ±4{/92 ±4t 16.1/15.2 18.3/17.7 9.1/11.2 11.4/8.7 * p < 0.02 compared with values before verapamil. t p < 0.05 compared with low sodium. Xp < 0.005. p < 0.05 compared with sodium-insensitive patients. p < 0.05. Nicholson eta/. Verapamil and Dietary Sodium 331

Table 4. The Effect of Sodium Intake and Verapamil on the Renin-Angiotensin-Aldosterone System in Thirteen Patients Plasma renin activity, ng/ml h Upright 9.5 ± 2.0 14.5 ± 2.3 2.8 ± 0.8* 3.2 + 0.8 Supine 4.7 ± 1.2 6.5 ± 1.3 1.4 ±0.5* 1.5 ±0.3 Urinary sodium excretion, meq/d 20 + 4 11 ±4 226+ lit 204 ± 11 Urinary aldosterone excretion, pg/d 22 ± 3.7 32 ± 5.3t 8.2+ 1.5* 7.6 ± 1.5f * p < 0.02 compared with low sodium. fp < 0.001. tp < 0.05. compared to sodium-insensitive patients (Table 5). Discussion The nature and prevalence of sodium sensitivity in essential hypertension is an important issue therapeutically because sodium restriction has been widely recommended for all essential hypertensive persons and even for normotensive persons (14). Additionally, diuretic-induced sodium depletion has also been advocated widely as a primary component of drug therapy for essential hypertension (2). This practice dates back to the time when most antihypertensive agents (such as ganglion blocker vasodilators and anti-adrenergic agents) produced salt and water retention, tending to neutralize their action; however, few studies have critically evaluated the blood pressure effects of changing salt intake in conjunction with the more modern agents (15), most of which (betablockers, converting enzyme inhibitors, and calcium channel blockers) do not induce salt and water retention. Because some current hypotheses link the ability of dietary sodium to affect blood pressure with its ability to alter calcium metabolism and cellular calcium transport (9, 16, 17), we sought to determine the effects of a changing dietary sodium intake on the blood pressure, hormonal, and metabolic responses to verapamil. Our data confirm the antihypertensive efficacy of verapamil (18, 19), and also show that it was as effective on high- as on low-sodium intakes. Indeed, in the 6 of 13 patients who were sodium sensitive, the reduction in pressure was greatest on the higher-sodium intake. This finding was surprising because it has not been reported for other antihypertensive agents, and because it suggests that the popular approach of advocating dietary sodium restriction may not be necessary or even appropriate in verapamil-treated patients. Moreover, because significant sodium restriction is often hard to achieve and may be counterproductive during times of physiologic stress, monotherapy with calcium channel antagonists without concomitant sodium restriction may be an appealing alternative. Why is verapamil's antihypertensive efficacy not blunted on a higher-sodium intake, especially in the sodiumsensitive patient? Even though the sodium-sensitive patient has higher pretreatment blood pressures on higher-sodium levels, this finding cannot quantitatively explain the profound blood pressure response to verapamil. For example, for an approximately 10-mm Hg difference between sodium-sensitive and sodium-insensitive patients on a high-sodium diet, verapamil-induced responses were 75% (supine systolic) and 100% (upright diastolic) greater in sodium-sensitive compared with sodium-insensitive patients (Table 3). Therefore, other explanations for similar or even enhanced verapamil effects on high salt intake may be more likely. Specifically, contributions of renal sympathetic nerve activity, the renin-aldosterone system, and linked cellular transport of calcium and sodium should be considered. Guanethidine blockade increases sodium excretion (20), and renal nerve stimulation can increase proximal tubular sodium reabsorption, an effect blocked by phentolamine (20). Futhermore, renal sodium handling in hypertension may be abnormal (21), perhaps mediated by Table 5. The Effect of Sodium Intake and Verapamil on Renin-Angiotensin-Aldosterone According to Sodium Sensitivity in Thirteen Patients Sodium sensitive (72 = 6) Plasma renin activity, ng/ml h Supine 3.7 ± 1.1 6.1 ±6.6 1.2 ± 6.6 1.4 ±0.5 Upright 8.2 ± 2.0 16 ± 4.4* 2.2 ± 0.7* 2.9 ± 0.7 Urinary aldosterone excretion, meq/d 21 ± 3 32 ±9 9±2 6±2 Weight, kg 68 ± 1.8 68 ± 1.9 69 ± 2.0 69 ±2.1 Sodium insensitive (n = 7) Plasma renin activity, ng/ml h Supine 5.6 ± 1.0 6.8 ± 1.9 1.5 ±0.8* 1.4 ±0.5 Upright 10.5 ± 3.4 13.4 ±2.7 3.2 ± 1.3* 3.9 ± 1.6 Urinary aldosterone excretion, meq/d 24 ± 7 32 ±7 7±2f 9 ±2 Weight, kg 84 ± 4.9 83 ± 4.8 84 ± 4.6 83 ± 4.5 * p < 0.01 compared with low sodium, fp < 0.001 compared with low sodium. 332 September 1987 Annals of Internal Medicine Volume 107 Number 3

inappropriately increased renal alpha-adrenergic activity (22). Verapamil may reverse this renal tubular sodiumsensitive adrenergic component, being itself an alpha2-antagonist (23, 24). Indeed, consistent with the natriuretic effect of verapamil (25, 26), no significant weight gain was seen during verapamil therapy on either high- or low-sodium diets, either in sodium-sensitive or sodiuminsensitive patients. In addition, plasma renin activity, independently of dietary sodium intake, was predictive of the blood pressure response to verapamil (Figure 1). Sodium-sensitive patients on their free living diets, but not at the extremes of sodium intake in this study, had approximately half the basal plasma renin activity as that of the salt-insensitive patients. It has been reported that the abnormal setting of plasma renin activity in low-renin hypertension also predicts the clinical response to dietary or diuretic sodiumdepletion therapy (26). Others (27-29) have similarly reported that lower plasma renin activity values are predictive of greater blood pressure responses to verapamil and nifedipine. The lack of a significant aldosterone response to verapamil, especially on high-sodium intake, may also help explain why sodium loading does not blunt verapamil-induced hypotension. Furthermore, the hypertension of patients with primary aldosteronism, exhibiting extremely low plasma renin values, shows a remarkable sensitivity to calcium channel blockade (30). Lastly, these results may also be understood in the context of certain molecular hypotheses relating calcium to salt-dependent hypertension. Lower serum ionized calcium values seen in salt-sensitive and low-renin essential hypertensive persons (17, 31) appear to be the "mirror image" of increased intracellular cytosolic free-calcium levels previously reported (10), suggesting a sodium volume-induced maldistribution of calcium between extracellular and intracellular sites (32). Additionally, salt loading may also increase nitrendipine receptors on cell membranes (33), indicating a salt-induced increase in potential-dependent calcium channels. Therefore, under salt-loaded conditions, blood pressure (reflective of cytosolic free calcium) would show an enhanced dependence on extracellular calcium, and would be more responsive to calcium channel antagonists, as seen here. If this were true in the renal tubule as well, then the equal or even enhanced blood pressure and natriuretic response to calcium channel blockade under low-renin and high dietary sodium conditions might all be explained in the setting of the same mechanism inhibition of salt-induced cellular calcium uptake from the extracellular space. Regardless of mechanism, the idea that the antihypertensive action of calcium channel blockers is not opposed by a liberal sodium intake is now gaining additional support. Since this relationship was first seen (34), other preliminary reports of studies using verapamil, nifedipine, or nitrendipine (35, 36) also indicate that dietary sodium depletion is not necessary and may even oppose the antihypertensive action of calcium channel antagonists. Under conditions of metabolic balance, verapamil as an antihypertensive agent is equally effective at extremes of dietary sodium intake. Lower plasma renin activity values predicted a better blood pressure response to verapamil therapy. Although longer-term outpatient studies are required, these data suggest that verapamil is likely to be especially effective in low-renin, sodium-sensitive forms of essential hypertension. This study also suggests that the use of verapamil for treating at least some forms of essential hypertension may not require or warrant accompanying dietary sodium restriction. Calcium channel blockade may thus provide the theoretical and practical advantages of lowering blood pressure without causing or requiring undue sodium-volume depletion, and thus maintaining tissue perfusion as pressure is reduced. ACKNOWLEDGMENTS: Presented in part at the American Federation for Clinical Research National Meeting, Washington, D.C., 4-7 May 1984. Requests for reprints should be addressed to John P. 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21. DIBONA GF. Neurogenic regulation of renal tubular sodium reabsorption. Am J Physiol 1977;233:F73-81. 22. PETTINGER WA, GANDLER T, SANCHEZ A, SARVEDRA JM. Dietary sodium and renal alpha 2 -adrenergic receptors in Dahl hypertensive rats. Clin Exp Hypertens [A]. 1982;4(4-5):819-28. 23. CAVERO I, SHEPPERSON F, LEFEVRE-BORG F, LANGER SZ. Differential inhibition of vascular smooth muscle responses to alphap and alpha2- adrenoreceptor antagonists by diltiazem and verapamil. Circ Res. 1983;52(2pt2):I69-76. 24. MOTULSKY HJ, SNAVELY MD, HUGHES RJ, INSEL PA. Interaction of verapamil and other calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors. Circ Res. 1983;52:226-31. 25. BELL AJ, LINDNER A. Effects of verapamil and nifedipine on renal function and hemodynamics in the dog. Renal Physiol. 1984;7:329-47. 26. VAUGHAN ED JR, LARAGH JH, GAVRAS I, et al. Volume factor in low and normal renin essential hypertension: treatment with either spironolactone or chlorthalidone. Am J Cardiol. 1973;32:523-32. 27. ERNE P, BOLLI P, BERTEL O. Factors influencing the hypotensive effects of calcium antagonists. Hypertension. 1983;5(4 pt 2):II97-102. 28. BUHLER FR, HULTHEN UL, KIOWSKI W, BOLLI P. The place of the calcium antagonist verapamil in antihypertensive therapy. / Cardiovasc Pharmacol. 1982;4 (Suppl 3):S350-7. 29. MOLLER FB, BOLLI P, ERNE P, BLOCK LH, KIOWSKI W, BUHLER FR. Antihypertensive therapy with the long-acting calcium antagonist nitrendipine. J Cardiovasc Pharmacol. 1984;6 (Suppl 7) :S 1073-6. 30. NADLER JL, HSUEH W, HORTON R. Therapeutic effect of calcium channel blockade in primary aldosteronism. / Clin Endocrinol Metab. 1985;60:896-9. 31. RESNICK LM, LARAGH JH, SEALEY JE, ALDERMAN MH. Divalent cations in essential hypertension: relations between serum ionized calcium, magnesium, and plasma renin activity. N Engl J Med. 1983;309:889-91. 32. RESNICK LM. Uniformity and diversity of calcium metabolism in hypertension: a conceptual framework. Am J Med. 1987;82(lB):16-26. 33. GARTHOFF B, BELLEMANN P. Effects of salt loading and nitrendipine treatment on dihydropyridine receptors in hypertensive rats. In: Proceedings of the Eleventh Meeting of the Society of International Hypertension. Heidelberg; 1986: Abstract 335. 34. NICHOLSON JP, PICKERING TG, RESNICK LM, LARAGH JH. The hypotensive effect of calcium channel blockade with verapamil is enhanced by increased dietary sodium intake [Abstract]. Clin Res. 1984;32:245A. 35. MORGAN T, ANDERSON A, WILSON D, MYERS J, MURPHY J, NOWSON C. Paradoxical effect of sodium restriction on blood pressure in people on slow-channel calcium blocking drugs [Letter]. Lancet. 1986;1:793. 36. NICHOLSON JP, RESNICK LM, DIFABIO B, JAMES GD, JENNIS R, LAR AGH JH. Sodium restriction and the antihypertensive effect of nitrendipine [Abstract]. Clin Res. 1986;34:404A. 334 September 1987 Annals of Internal Medicine Volume 107 Number 3