Natriuretic Effect of Calcium-Channel Blockers in Hypertensives G. Gopal Krishna, MD, Louis J. Riley, Jr, MD, Gisela Deuter, BSN, Shiv C. Kapoor, PhD, and Robert G. Narins, MD • This double-blind, randomized, crossover trial characterizes the acute natriuretic response to calcium-channel blockers (CCB) and investigates the role of hemodynamic and hormonal factors in mediating the natriuresis. Thirteen male subjects with essential hypertension received a single oral 20-mg dose of nifedipine or 120 mg of diltiazem. Renal functional and hemodynamic measurements were performed prior to and hourly for 4 hours following medication. Subjects then received these medications for 4 weeks at which time the above studies were repeated. Urinary sodium excretion increased within 60 minutes of CCB administration and the natriuresis was sustained for 4 hours. Cumulative sodium loss during the 4 hours of study was greater with nifedipine (43 ± 12 mmol) than with diltiazem (18 ± 6 mmol) (P < 0.05). Despite natriuresis, urinary potassium excretion was decreased by both agents. Even though both drugs decreased the mean arterial pressure, inulin and paraaminohippurate (PAH) clearances were not altered. Plasma aldosterone concentrations decreased, plasma catecholamine concentrations increased, whereas plasma-renin activity was unchanged with both drugs. Body weight, glomerular filtration rate (GFR), renal plasma flow, plasma-renin activity, plasma aldosterone, and catecholamine concentrations were unchanged following 4 weeks of therapy. The acute natriuretic response after 4 weeks of therapy was similar to the response noted after the first dose. This study concludes that CCB are acutely natriuretic. Despite systemic hypotension, renal hemodynamics are unaltered during CCB therapy. Suppression of aldosterone as well as direct tubular effects of these drugs may mediate the natriuresis. Chronic therapy with CCB does not modify the acute natriuretic response to these agents. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Calcium-channel blockers; hypertension; sodium; potassium; blood pressure; aldosterone; catecholamines.
C
ALCIUM-CHANNEL blockers (CCB) have received wide acceptance as effective antihypertensive agents. I These drugs reduce transmembrane calcium influx thereby lowering the cystosolic free-calcium concentration. 2 Although CCB are potent vasodilators, unlike other vasodilators they do not cause sodium retention. Indeed, long-term therapy with CCB produces no alterations in blood volume. 3-5 Acute studies in experimental animals and humans suggest that CCB induce natriuresis in the face of systemic hypotension. 6 However, the mechanism ofthe natriuretic effect ofCCB is unknown. Natriuresis observed in isolated perfused kidneys suggests that these drugs may exert a direct tubular effect.6 The importance of hormonal and renal hemodynamic factors in mediating the natriuresis is unknown. The effect of chronic
From the Department of Medicine. Temple University School of Medicine. Philadelphia. PA. Supported in part by Marion Merrell Dow Inc.. Kansas City. MO. Dr Krishna received the New Investigator Research Award from the US Public Health Service (R23HL37372) during the study period. Portions of this work were presented at the 22nd annual meeting ofthe American Society ofNephrology and published in abstract form. Address reprint requests to G. Gopal Krishna. MD. Renal Electrolyte Section. University of Pennsylvania. 700 Clinical Research Bldg. 422 Curie Blvd. Philadelphia. PA 19104-6144. © 1991 by the National Kidney Foundation. Inc. 0272-6386/91/1805-0005$3.00;0 566
therapy with CCB on the renal response to these medications is also not well characterized. Accordingly, we investigated the role of hemodynamic and hormonal factors in mediating the natriuretic response to CCB using two structurally dissimilar agents. We studied the acute response to these agents following the first dose and subsequently after 4 weeks of therapy with the same drug. METHODS
Study Subjects Thirteen otherwise healthy men with essential hypertension ranging in age from 21 to 65 years were entered into the study. After obtaining a detailed history and physical examination, appropriate laboratory studies were performed to exclude secondary causes of hypertension, cardiovascular, cerebrovascular, renal, hepatic, metabolic, and endocrine disorders. Subjects were recruited who maintained diastolic blood pressures ranging between 95 to 114 mm Hg after discontinuing all antihypertensive medications for at least 2 weeks. An average of three supine and three upright readings was obtained to determine eligibility. SUbjects were instructed to ingest diets that provide 150 mmol of sodium and 80 mmol of potassium daily for 5 days. After verification of external sodium and potassium balance, subjects were admitted to the General Clinical Research Center (GCRC) of Temple University Hospital for clearance studies. The study protocol was approved by the Research Review Committee of Temple University, and informed consent was obtained.
Acute Studies After an overnight fast, subjects voided and received a water load of 20 mL/kg body weight. Following an intravenous
American Journal of Kidney Diseases, Vol XVIII, No 5 (November), 1991: pp 566-572
567
CALCIUM-CHANNEL BLOCKERS AND NATRIURESIS
loading dose of inulin and paraaminohippurate (PAH), continuous infusions of each were maintained to attain plasmainulin concentrations of20 mgJdL and plasma-PAH concentrations of2 mg/dL. The urine volume was measured hourly and was replaced orally with equal volumes of water. Subjects remained supine during the entire study period except for voiding and obtaining upright blood pressure. Blood samples were collected at hourly intervals for measurement of inulin, PAH, sodium, and potassium. After obtaining two baseline clearances from 9 AM to II AM, subjects received either 120 mg of diltiazem or 20 mg of nifedipine orally in a doubleblind, randomized, crossover design. The doses of medications administered represent commonly used therapeutic doses of both drugs. Following the administration of the CCB, urine was collected hourly for 4 hours. Blood pressure was recorded hourly by obtaining three readings in the supine position at I-minute intervals and three readings in the upright position. Blood samples were collected for measurement of calcium, phosphorus, plasma-renin activity, plasma aldosterone, and total catecholamines before and 4 hours following the administration of the study drug. Plasma samples for hormone assays were immediately frozen and kept at -70°C until the time of assay. Cumulative urinary sodium excretion was calculated as the increase over the baseline values during the 4 hours after drug administration.
Chronic Studies Following completion of the acute studies, subjects were discharged and instructed to take the study drugs at doses titrated to maintain a diastolic blood pressure less than 90 mm Hg. These drugs were maintained at doses of diltiazem between 60 mg and 120 mg or nifedipine between 20 mg and 30 mg and were administered every 8 hours. During the 4week study period, the total daily dose of diltiazem averaged 226 ± 13 mg (mean ± SEM), and the dose of nifedipine averaged 63 ± 2 mg. During this period subjects were asked to maintain constant sodium (150 mmol/d) and potassium (80 mmol/d) intake. Patients returned weekly for blood pressure monitoring. At the end of 4 weeks, 24-hour urine samples were collected to verify external sodium balance. The subjects were then readmitted to the GCRC to repeat the acute studies as described previously. Following a 2- to 4-week washout period, each subject reentered the protocol to receive the alternate medication and repeat the acute and chronic studies. Thus, in each subject we investigated the hemodynamic, hormonal, and renal responses following acute and chronic dosing of both diltiazem and nifedipine.
Blood Pressure Measurement All blood pressure readings were obtained manually from the same arm using a mercury sphygmomanometer. Korotkoff sounds I and V were used as determinants of systolic and diastolic blood pressures, respectively. All the blood pressure readings obtained for each time period were averaged to obtain a single value. The mean arterial pressure was calculated as [(systolic pressure - diastolic pressure)/3) + diastolic pressure.
Biochemical Assays The methods used in the assays have been described in previous publications from our laboratory.7.9 Plasma and urine
sodium and potassium concentrations were measured with a flame photometer (Instrumentation Laboratory, Lexington, MA). Plasma-renin activity was measured by radioimmunoassay and expressed as ng/(L' s) of generated angiotensin I. Plasma aldosterone was measured using an 1251-a1dosterone assay kit (Diagnostic Products, Los Angeles, CAl. Plasma catecholamines were measured with a radioenzymatic assay (Upjohn Diagnostics, Kalamazoo, MI). Inulin and PAH were measured using standard chemical analysis and are expressed as mL/s· 1.73 m 2.
Statistical Methods All data are expressed as mean ± SEM. The effect of the study drug was analyzed by repeated measures analysis of variance. JO When a significant treatment effect was detected, post-drug values were compared with basal values by a paired t-test. The response noted with the two study drugs were compared with a paired t-test or signed-rank test, as applicable. I I Two-tailed P-values less than 0.05 were considered significant.
RESULTS
Initial Effect of CCB
Following 20 mg of nifedipine, systolic blood pressure decreased from prestudy levels of 147 ± 2 mm Hg to a nadir of 126 ± 3 mm Hg at 2 hours (P < 0.001) and remained significantly reduced at 4 hours (Fig 1). Diastolic pressure reached its nadir at 1 hour, and remained lower than prestudy measurements at 4 hours (Fig 1). The 20-mg dose of nifedipine decreased both systolic and diastolic blood pressures more than 120 mg of diltiazem. Despite the decrease in systemic arterial pressure, no changes in inulin or PAH clearances were noted with either nifedipine or diltiazem (Table 1). The basal values for inulin and PAH clearances are similar to those previously reported from our laboratory in hypertensives and normotensives. 9, '2.13 An increase in urinary sodium excretion over basal values (P < 0.02) was noted by 1 hour after nifedipine administration (Fig 2). Peak values were noted at 3 hours and the natriuresis persisted through the 4th hour of study. With diltiazem, a significant increase in urinary sodium excretion was noted by the 2nd hour (P < 0.02) with peak values occurring at 4 hours (P < 0.005). The cumulative increase in sodium excretion over baseline values with nifedipine (43 ± 12 mmol/4 h) was significantly (P < 0.05) greater than that noted after diltiazem (18 ± 6 mmol/4 h). Despite the significant increase in urinary sodium excretion, urinary potassium excretion declined over the study period. Indeed, the mean excretion rates for potassium over the 4-hour study period were
KRISHNA ET AL
568
sodium, potassium, phosphorus, and ionized calcium were unchanged by the treatments.
150
...
DILTIAZEM
~
140
130 NIFEDIPINE
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BASELINE
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DILTIAZEM
*
80
*. B
70
BASELINE
30
,
,
,
,
60
120
180
240
TIME (minutes)
Fig 1. Changes in systolic (top panel) and diastolic (bottom panel) blood pressure following nifedipine (D) and diltiazem (.) administration. Baseline values represent the average of measurements made during the 2 hours preceding drug administration. The * indicates significant (P < 0.05) decrease from prestudy values and • indicates significant (P < 0.05) difference compared with corresponding values noted during nifedipine administration.
significantly lower than basal values for both nifedipine (68 ± 10 v 58 ± 7 tLmol/min, P < 0.05) and for diltiazem (72 ± 10 v 60 ± 9 tLmol/min, P < 0.05). Urinary excretion rates for phosphorus were significantly higher than basal values following nifedipine administration (0.45 ± 0.05 v 0.57 ± 0.05 mg/min, P < 0.05). Although urinary phosphorus excretion increased following diltiazem administration, the values did not reach significance (0.52 ± 0.05 v 0.58 ± 0.06 mg/min, P < 0.1). Plasma-renin activity was unchanged following both nifedipine and diltiazem whereas plasmaaldosterone concentration was significantly reduced and catecholamine concentration significantly increased by both agents (Fig 3). Plasma
Data Obtained on Day 28 Body weight did not change significantly during the 4-week study period with either nifedipine (88.2 ± 4.0 kg v 88.7 ± 3.8 kg) or diltiazem (89.0 ± 4.0 kg v 89.4 ± 4.0 kg). Significant decreases in systolic and diastolic pressures were noted following both nifedipine and diltiazem (Table 2) . Basal inulin and PAR clearances and urinary sodium excretion rates were similar to those noted on day 1. An increase in sodium excretion and a decrease in potassium excretion were noted over the 4-hour period following both nifedipine and diltiazem. As noted on day 1, the cumulative increment in sodium excretion over the 4-hour study period with nifedipine (42 ± 5 mmol/4 h) was significantly (P < 0.01) greater than that noted with diltiazem (13 ± 1 mmol/4 h). Thus, chronic therapy with CCB did not modify the acute natriuretic response to these agents. Basal values for plasma-renin activity, aldosterone, and total catecholamines were also similar to those on day 1. A significant decrease in plasma aldosterone concentration and an increase in catecholamine concentration was observed following nifedipine and diltiazem whereas plasmarenin activity was unchanged (Table 3). The return of these measurements to baseline values just before the next dose of CCB strongly suggests that these drugs do not exert a sustained effect on these hormones. Chronic therapy did not alter the plasma concentrations of sodium, potassium, phosphorus, or ionized calcium. z
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C
ALCIUM-CHANNEL blockers (CCB) have received wide acceptance as effective antihypertensive agents. I These drugs reduce transmembrane calcium influx thereby lowering the cystosolic free-calcium concentration. 2 Although CCB are potent vasodilators, unlike other vasodilators they do not cause sodium retention. Indeed, long-term therapy with CCB produces no alterations in blood volume. 3-5 Acute studies in experimental animals and humans suggest that CCB induce natriuresis in the face of systemic hypotension. 6 However, the mechanism ofthe natriuretic effect ofCCB is unknown. Natriuresis observed in isolated perfused kidneys suggests that these drugs may exert a direct tubular effect.6 The importance of hormonal and renal hemodynamic factors in mediating the natriuresis is unknown. The effect of chronic
From the Department of Medicine. Temple University School of Medicine. Philadelphia. PA. Supported in part by Marion Merrell Dow Inc.. Kansas City. MO. Dr Krishna received the New Investigator Research Award from the US Public Health Service (R23HL37372) during the study period. Portions of this work were presented at the 22nd annual meeting ofthe American Society ofNephrology and published in abstract form. Address reprint requests to G. Gopal Krishna. MD. Renal Electrolyte Section. University of Pennsylvania. 700 Clinical Research Bldg. 422 Curie Blvd. Philadelphia. PA 19104-6144. © 1991 by the National Kidney Foundation. Inc. 0272-6386/91/1805-0005$3.00;0 566
therapy with CCB on the renal response to these medications is also not well characterized. Accordingly, we investigated the role of hemodynamic and hormonal factors in mediating the natriuretic response to CCB using two structurally dissimilar agents. We studied the acute response to these agents following the first dose and subsequently after 4 weeks of therapy with the same drug. METHODS
Study Subjects Thirteen otherwise healthy men with essential hypertension ranging in age from 21 to 65 years were entered into the study. After obtaining a detailed history and physical examination, appropriate laboratory studies were performed to exclude secondary causes of hypertension, cardiovascular, cerebrovascular, renal, hepatic, metabolic, and endocrine disorders. Subjects were recruited who maintained diastolic blood pressures ranging between 95 to 114 mm Hg after discontinuing all antihypertensive medications for at least 2 weeks. An average of three supine and three upright readings was obtained to determine eligibility. SUbjects were instructed to ingest diets that provide 150 mmol of sodium and 80 mmol of potassium daily for 5 days. After verification of external sodium and potassium balance, subjects were admitted to the General Clinical Research Center (GCRC) of Temple University Hospital for clearance studies. The study protocol was approved by the Research Review Committee of Temple University, and informed consent was obtained.
Acute Studies After an overnight fast, subjects voided and received a water load of 20 mL/kg body weight. Following an intravenous
American Journal of Kidney Diseases, Vol XVIII, No 5 (November), 1991: pp 566-572
567
CALCIUM-CHANNEL BLOCKERS AND NATRIURESIS
loading dose of inulin and paraaminohippurate (PAH), continuous infusions of each were maintained to attain plasmainulin concentrations of20 mgJdL and plasma-PAH concentrations of2 mg/dL. The urine volume was measured hourly and was replaced orally with equal volumes of water. Subjects remained supine during the entire study period except for voiding and obtaining upright blood pressure. Blood samples were collected at hourly intervals for measurement of inulin, PAH, sodium, and potassium. After obtaining two baseline clearances from 9 AM to II AM, subjects received either 120 mg of diltiazem or 20 mg of nifedipine orally in a doubleblind, randomized, crossover design. The doses of medications administered represent commonly used therapeutic doses of both drugs. Following the administration of the CCB, urine was collected hourly for 4 hours. Blood pressure was recorded hourly by obtaining three readings in the supine position at I-minute intervals and three readings in the upright position. Blood samples were collected for measurement of calcium, phosphorus, plasma-renin activity, plasma aldosterone, and total catecholamines before and 4 hours following the administration of the study drug. Plasma samples for hormone assays were immediately frozen and kept at -70°C until the time of assay. Cumulative urinary sodium excretion was calculated as the increase over the baseline values during the 4 hours after drug administration.
Chronic Studies Following completion of the acute studies, subjects were discharged and instructed to take the study drugs at doses titrated to maintain a diastolic blood pressure less than 90 mm Hg. These drugs were maintained at doses of diltiazem between 60 mg and 120 mg or nifedipine between 20 mg and 30 mg and were administered every 8 hours. During the 4week study period, the total daily dose of diltiazem averaged 226 ± 13 mg (mean ± SEM), and the dose of nifedipine averaged 63 ± 2 mg. During this period subjects were asked to maintain constant sodium (150 mmol/d) and potassium (80 mmol/d) intake. Patients returned weekly for blood pressure monitoring. At the end of 4 weeks, 24-hour urine samples were collected to verify external sodium balance. The subjects were then readmitted to the GCRC to repeat the acute studies as described previously. Following a 2- to 4-week washout period, each subject reentered the protocol to receive the alternate medication and repeat the acute and chronic studies. Thus, in each subject we investigated the hemodynamic, hormonal, and renal responses following acute and chronic dosing of both diltiazem and nifedipine.
Blood Pressure Measurement All blood pressure readings were obtained manually from the same arm using a mercury sphygmomanometer. Korotkoff sounds I and V were used as determinants of systolic and diastolic blood pressures, respectively. All the blood pressure readings obtained for each time period were averaged to obtain a single value. The mean arterial pressure was calculated as [(systolic pressure - diastolic pressure)/3) + diastolic pressure.
Biochemical Assays The methods used in the assays have been described in previous publications from our laboratory.7.9 Plasma and urine
sodium and potassium concentrations were measured with a flame photometer (Instrumentation Laboratory, Lexington, MA). Plasma-renin activity was measured by radioimmunoassay and expressed as ng/(L' s) of generated angiotensin I. Plasma aldosterone was measured using an 1251-a1dosterone assay kit (Diagnostic Products, Los Angeles, CAl. Plasma catecholamines were measured with a radioenzymatic assay (Upjohn Diagnostics, Kalamazoo, MI). Inulin and PAH were measured using standard chemical analysis and are expressed as mL/s· 1.73 m 2.
Statistical Methods All data are expressed as mean ± SEM. The effect of the study drug was analyzed by repeated measures analysis of variance. JO When a significant treatment effect was detected, post-drug values were compared with basal values by a paired t-test. The response noted with the two study drugs were compared with a paired t-test or signed-rank test, as applicable. I I Two-tailed P-values less than 0.05 were considered significant.
RESULTS
Initial Effect of CCB
Following 20 mg of nifedipine, systolic blood pressure decreased from prestudy levels of 147 ± 2 mm Hg to a nadir of 126 ± 3 mm Hg at 2 hours (P < 0.001) and remained significantly reduced at 4 hours (Fig 1). Diastolic pressure reached its nadir at 1 hour, and remained lower than prestudy measurements at 4 hours (Fig 1). The 20-mg dose of nifedipine decreased both systolic and diastolic blood pressures more than 120 mg of diltiazem. Despite the decrease in systemic arterial pressure, no changes in inulin or PAH clearances were noted with either nifedipine or diltiazem (Table 1). The basal values for inulin and PAH clearances are similar to those previously reported from our laboratory in hypertensives and normotensives. 9, '2.13 An increase in urinary sodium excretion over basal values (P < 0.02) was noted by 1 hour after nifedipine administration (Fig 2). Peak values were noted at 3 hours and the natriuresis persisted through the 4th hour of study. With diltiazem, a significant increase in urinary sodium excretion was noted by the 2nd hour (P < 0.02) with peak values occurring at 4 hours (P < 0.005). The cumulative increase in sodium excretion over baseline values with nifedipine (43 ± 12 mmol/4 h) was significantly (P < 0.05) greater than that noted after diltiazem (18 ± 6 mmol/4 h). Despite the significant increase in urinary sodium excretion, urinary potassium excretion declined over the study period. Indeed, the mean excretion rates for potassium over the 4-hour study period were
KRISHNA ET AL
568
sodium, potassium, phosphorus, and ionized calcium were unchanged by the treatments.
150
...
DILTIAZEM
~
140
130 NIFEDIPINE
A 120
BASELINE
30
,
....,
,
,
60
120
180
240
110
100
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*
DILTIAZEM
*
80
*. B
70
BASELINE
30
,
,
,
,
60
120
180
240
TIME (minutes)
Fig 1. Changes in systolic (top panel) and diastolic (bottom panel) blood pressure following nifedipine (D) and diltiazem (.) administration. Baseline values represent the average of measurements made during the 2 hours preceding drug administration. The * indicates significant (P < 0.05) decrease from prestudy values and • indicates significant (P < 0.05) difference compared with corresponding values noted during nifedipine administration.
significantly lower than basal values for both nifedipine (68 ± 10 v 58 ± 7 tLmol/min, P < 0.05) and for diltiazem (72 ± 10 v 60 ± 9 tLmol/min, P < 0.05). Urinary excretion rates for phosphorus were significantly higher than basal values following nifedipine administration (0.45 ± 0.05 v 0.57 ± 0.05 mg/min, P < 0.05). Although urinary phosphorus excretion increased following diltiazem administration, the values did not reach significance (0.52 ± 0.05 v 0.58 ± 0.06 mg/min, P < 0.1). Plasma-renin activity was unchanged following both nifedipine and diltiazem whereas plasmaaldosterone concentration was significantly reduced and catecholamine concentration significantly increased by both agents (Fig 3). Plasma
Data Obtained on Day 28 Body weight did not change significantly during the 4-week study period with either nifedipine (88.2 ± 4.0 kg v 88.7 ± 3.8 kg) or diltiazem (89.0 ± 4.0 kg v 89.4 ± 4.0 kg). Significant decreases in systolic and diastolic pressures were noted following both nifedipine and diltiazem (Table 2) . Basal inulin and PAR clearances and urinary sodium excretion rates were similar to those noted on day 1. An increase in sodium excretion and a decrease in potassium excretion were noted over the 4-hour period following both nifedipine and diltiazem. As noted on day 1, the cumulative increment in sodium excretion over the 4-hour study period with nifedipine (42 ± 5 mmol/4 h) was significantly (P < 0.01) greater than that noted with diltiazem (13 ± 1 mmol/4 h). Thus, chronic therapy with CCB did not modify the acute natriuretic response to these agents. Basal values for plasma-renin activity, aldosterone, and total catecholamines were also similar to those on day 1. A significant decrease in plasma aldosterone concentration and an increase in catecholamine concentration was observed following nifedipine and diltiazem whereas plasmarenin activity was unchanged (Table 3). The return of these measurements to baseline values just before the next dose of CCB strongly suggests that these drugs do not exert a sustained effect on these hormones. Chronic therapy did not alter the plasma concentrations of sodium, potassium, phosphorus, or ionized calcium. z
o ~ a:
u >< w
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is.E
go
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550 NIFEDIPINE
450
350
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