Differential Effects of Nifedipine on Plasma Atrial Natriuretic Peptide in Normal Subjects and Hypertensive Patients M.D. Takashi Yamada, M.D., Ph.D., F.I.C.A. Toru Aizawa, M.D., Ph.D.
Satoshi
Shigematsu,
Nobuyuki Takasu, M.D., Ph.D. and
Zenji Shimizu, M.D., Ph.D.* NAGANO-KEN, JAPAN
Abstract The physiology of atrial naturiuretic peptide (ANP) secretion was studied in normotensive subjects and hypertensive patients both young and old. Basal plasma ANP concentration was least in young normotensives, intermediate in old normotensives and young hypertensives, and highest in old hypertensives. Nifedipine, a known stimulator of ANP secretion, acutely increased plasma ANP in young and old normotensive subjects but not in young hypertensive patients and half of the old hypertensive patients. Increase in serum ANP level in response to nifedipine did not augment its hypotensive effect. However, the increase of aldosterone in response to nifedipine-induced rise in plasma renin activity (PRA) seemed to be suppressed by elevated ANP.
Introduction A calcium channel blocker, nifedipine, lowers blood pressure by blocking calcium entry into the vascular smooth muscle.1.2 Three additional interesting actions of nifedipine have been described: (1) nifedipine augments renal excretion of sodium and water,3-6 (2) nifedipine augments secretion of atrial natriuretic peptide (ANP).7 (3) nifedipine elevates plasma renin activity (PRA) but inhibits subsequent elevation of aldosterone8-’° in response to the increased PRA. Since PRA and ANP secretion are largely influenced by agel’’’2 and hypertension,&dquo; these responses to nifedipine are expected to be uninfluenced by the age and blood pressure of patients. From the Department of Gerontology, Endocrinology, and Metabolism, School of Medicine, Shinshu University, Matsumotoshi ; and the *Department of Medicine, Hokushin General Hospital, Nakano-shi, Nagano-ken, Japan.
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Downloaded from ang.sagepub.com at Fachhochschule Osnabrück on April 15, 2015
41 The present study was designed to investigate possible differential effects of nifedipine on ANP secretion and the renin-aldosterone system in young and old subjects with normotension or hypertension. It also analyzed whether parameters such as cardio/thoracic (C/T) ratio, cardiac hypertrophy as judged by voltage criteria (S1 + RV,), and ST-T change are different in the patients with different ANP response to nifedipine. Patients and Methods Informed consent was obtained from the subjects. Seven young normotensive subjects (5 men, 2 women, aged seventeen to thirty-eight years), 9 old normotensive subjects (3 men, and 6 women, aged forty-four to sixty-five years), 8 young patients (4 men, 4 women, aged twenty-five to thirty-eight years) with essential hypertension, and 30 old patients (11 men, 19 women, aged forty-one to seventy-eight years) with essential hypertension were evaluated in this study. Patients treated for hypertension were not included, because of possible influence of previous treatment on the renin-aldosterone system and ANP. Diagnosis of essential hypertension was made by excluding secondary hypertension with appropriate tests. Blood pressure and blood samples were obtained from the individuals while they were standing upright, beginning two hours before the experiment. This maneuver was selected to analyze the ANP and renin-aldosterone system under normal physical conditions. Before and one hour after oral administration of 10 mg nifedipine, blood pressure and pulse rate were determined. Simultaneously, peripheral blood was obtained for the measurement of PRA, aldosterone, and ANP. Blood for PRA measurement was collected into chilled tubes containing liquid sodium EDTA. Plasma was separated in a refrigerated centrifuge and was stored at -20 °C until used. With the use of commercially available radioimmunoassay (RIA) kits, PRA and aldosterone were measured as reported previously.8 ANP was measured using RIA. 14,15 The C/T ratio in the chest x-ray and Si +RV5 in ECG were employed as indices of cardiomegaly, and ST-T change was assumed to be an index of myocardial damage.
Statistical Analysis When the measurements were repeatedly made in the same individual, statistical analysis of significance of difference between the results was performed by means of the paired t test. When the values were compared among different groups, Student’s t test was used. A p value less than 0.05 was considered statistically significant. Results
’
Increase of Plasma ANP Because of possible age- and hypertension-related differences in plasma ANP concentration, four different groups were analyzed as described above: young normotensive subjects, old normotensive subjects, young hypertensive patients, and old hypertensive patients. Old hypertensive patients were further divided into two groups (responders and nonresponders) depending on ANP response; those who showed any increase in plasma ANP level after administration of nifedipine were clas,sified as responders, those with no change or a decrease as nonresponders.
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w
t -5’ s
W
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Satoshi
Shigematsu,
Nobuyuki Takasu, M.D., Ph.D. and
Zenji Shimizu, M.D., Ph.D.* NAGANO-KEN, JAPAN
Abstract The physiology of atrial naturiuretic peptide (ANP) secretion was studied in normotensive subjects and hypertensive patients both young and old. Basal plasma ANP concentration was least in young normotensives, intermediate in old normotensives and young hypertensives, and highest in old hypertensives. Nifedipine, a known stimulator of ANP secretion, acutely increased plasma ANP in young and old normotensive subjects but not in young hypertensive patients and half of the old hypertensive patients. Increase in serum ANP level in response to nifedipine did not augment its hypotensive effect. However, the increase of aldosterone in response to nifedipine-induced rise in plasma renin activity (PRA) seemed to be suppressed by elevated ANP.
Introduction A calcium channel blocker, nifedipine, lowers blood pressure by blocking calcium entry into the vascular smooth muscle.1.2 Three additional interesting actions of nifedipine have been described: (1) nifedipine augments renal excretion of sodium and water,3-6 (2) nifedipine augments secretion of atrial natriuretic peptide (ANP).7 (3) nifedipine elevates plasma renin activity (PRA) but inhibits subsequent elevation of aldosterone8-’° in response to the increased PRA. Since PRA and ANP secretion are largely influenced by agel’’’2 and hypertension,&dquo; these responses to nifedipine are expected to be uninfluenced by the age and blood pressure of patients. From the Department of Gerontology, Endocrinology, and Metabolism, School of Medicine, Shinshu University, Matsumotoshi ; and the *Department of Medicine, Hokushin General Hospital, Nakano-shi, Nagano-ken, Japan.
40
Downloaded from ang.sagepub.com at Fachhochschule Osnabrück on April 15, 2015
41 The present study was designed to investigate possible differential effects of nifedipine on ANP secretion and the renin-aldosterone system in young and old subjects with normotension or hypertension. It also analyzed whether parameters such as cardio/thoracic (C/T) ratio, cardiac hypertrophy as judged by voltage criteria (S1 + RV,), and ST-T change are different in the patients with different ANP response to nifedipine. Patients and Methods Informed consent was obtained from the subjects. Seven young normotensive subjects (5 men, 2 women, aged seventeen to thirty-eight years), 9 old normotensive subjects (3 men, and 6 women, aged forty-four to sixty-five years), 8 young patients (4 men, 4 women, aged twenty-five to thirty-eight years) with essential hypertension, and 30 old patients (11 men, 19 women, aged forty-one to seventy-eight years) with essential hypertension were evaluated in this study. Patients treated for hypertension were not included, because of possible influence of previous treatment on the renin-aldosterone system and ANP. Diagnosis of essential hypertension was made by excluding secondary hypertension with appropriate tests. Blood pressure and blood samples were obtained from the individuals while they were standing upright, beginning two hours before the experiment. This maneuver was selected to analyze the ANP and renin-aldosterone system under normal physical conditions. Before and one hour after oral administration of 10 mg nifedipine, blood pressure and pulse rate were determined. Simultaneously, peripheral blood was obtained for the measurement of PRA, aldosterone, and ANP. Blood for PRA measurement was collected into chilled tubes containing liquid sodium EDTA. Plasma was separated in a refrigerated centrifuge and was stored at -20 °C until used. With the use of commercially available radioimmunoassay (RIA) kits, PRA and aldosterone were measured as reported previously.8 ANP was measured using RIA. 14,15 The C/T ratio in the chest x-ray and Si +RV5 in ECG were employed as indices of cardiomegaly, and ST-T change was assumed to be an index of myocardial damage.
Statistical Analysis When the measurements were repeatedly made in the same individual, statistical analysis of significance of difference between the results was performed by means of the paired t test. When the values were compared among different groups, Student’s t test was used. A p value less than 0.05 was considered statistically significant. Results
’
Increase of Plasma ANP Because of possible age- and hypertension-related differences in plasma ANP concentration, four different groups were analyzed as described above: young normotensive subjects, old normotensive subjects, young hypertensive patients, and old hypertensive patients. Old hypertensive patients were further divided into two groups (responders and nonresponders) depending on ANP response; those who showed any increase in plasma ANP level after administration of nifedipine were clas,sified as responders, those with no change or a decrease as nonresponders.
Downloaded from ang.sagepub.com at Fachhochschule Osnabrück on April 15, 2015
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