European Journal of Clinical Pharmacology © by Springer-Verlag 1979
Europ. J. clin. Pharmacol. 15,235-240 (1979)
Effect of Nifedipine on Plasma Renin, Aidosterone and Catecholamines in Arterial Hypertension O. Lederballe Pedersen, E. Mikkelsen, N. J. Christensen, H. J. Kornerup, and E. B. Pedersen Department of ClinicalPharmacology,Universityof Aarhus, Department of Internal MedicineI, Aarhus Amtssygehus, Departments of InternalMedicineC and M, Aarhus Kommunehospital,and Departmentof InternalMedicineand Endocrinology, Herlev Hospital, Denmark
Summary. Acute sublingual administration of nifedipine 10-20mg to 13 hypertensive patients caused a rapid decrease in blood pressure (BP) and a concomitant increase in heart rate (HR), plasma noradrenaline (NA) and plasma renin activity (PRA); there was no significant change in plasma adrenaline (A) or aldosterone (ALDO). Basal PRA was the major determinant of the rise in PRA, as a close correlation was present between the basal value and the increase caused by nifedipine ( r = 0.92, p < 0.001). The rise in PRA was also correlated with the plasma concentration of nifedipine after 60 min (r = 0.80, p < 0.01), but it was not correlated with the decrease in BP, the rise in HR or the increase in NA. Nifedipine 30-60 mg daily for 6 weeks caused a reduction in mean BP from 133 to 113 mmHg (p 95 mm Hg), and if side-effects permitted, the daily dose was raised to a maximum of 20 mg t. i. d. The patients were seen every second week. BP and H R were recorded after at least 10 min in the supine position and then after 1 min in the erect position. The measurements were made in the morning 1-2 h after ingestion of the nifedipine capsule. The patients were questioned about side-effects and they were weighed. Before starting therapy, and at the end of the study, blood samples were taken for determination of PRA,
o. LederballePedersen et al.: Effectof Nifedipinein Hypertension ALDO, NA, A and serum creatinine, sodium and potassium. They were collected from an indwelling cannula after 60 min of rest in the supine position and after at least an 8-h fast. Urine was collected for two 24-h periods before and after 6 weeks of nifedipine treatment for the determination of excreted catecholamines.
Analyses of Blood Samples PRA was measured by the method of Giese et al. (1970), using radio-immunological quantitation of angiotensin I (Ang I) after incubation of dialyzed plasma for 3 h at pH 7.4 and 37 °C. The results are expressed as ng Ang 1/80% ml/h. Plasma aldosterone concentration was measured using the method of Rask-Madsen et al. (1974); radioimmunoassay was performed on the residue from plasma prepared by extraction with dichloromethane, purification on silica gel columns and chromatographic separation on paper. The results are given as ng/100 ml. Plasma NA and A were measured by a sensitive double-isotope derivative assay (Christensen, 1973). The results are expressed as ng/ml. NIF was determined by the laboratories of Bayer AG, Leverkusen, Germany, according to the fluorometric method of R~msch (1979). Serum concentrations of creatinine, sodium and potassium, and urinary excretion of NA and A, were determined as routine procedures in the central laboratory of the Aarhus Amtssygehus.
Statistical Calculations Mean BP was calculated as diastolic BP + 1/3 pulse pressure. Forearm vascular resistance, calculated as mean BP divided by forearm blood flow, is expressed in arbitrary units. Correlations were calculated by linear regression analysis. Student's t-test was employed for comparison of paired data; the level of significance was set at p < 0.05. Results are given as mean + SEM.
Results
Acute Experiments Hemodynamic Parameters and Plasma Concentrations of Nifedipine. Fluctuations of some of the hemodynamic and biochemical parameters measured during the first 90 min after sublingual administration of nifedipine 20 mg to two patients are shown in Figure 1.
O. Lederballe Pedersen et ai.: Effect of Nifedipine in Hypertension
NIFEDtPINE, ng//ml
237
300
3O
.-
0 BP, mm Hg
200
4 .
Europ. J. clin. Pharmacol. 15,235-240 (1979)
Effect of Nifedipine on Plasma Renin, Aidosterone and Catecholamines in Arterial Hypertension O. Lederballe Pedersen, E. Mikkelsen, N. J. Christensen, H. J. Kornerup, and E. B. Pedersen Department of ClinicalPharmacology,Universityof Aarhus, Department of Internal MedicineI, Aarhus Amtssygehus, Departments of InternalMedicineC and M, Aarhus Kommunehospital,and Departmentof InternalMedicineand Endocrinology, Herlev Hospital, Denmark
Summary. Acute sublingual administration of nifedipine 10-20mg to 13 hypertensive patients caused a rapid decrease in blood pressure (BP) and a concomitant increase in heart rate (HR), plasma noradrenaline (NA) and plasma renin activity (PRA); there was no significant change in plasma adrenaline (A) or aldosterone (ALDO). Basal PRA was the major determinant of the rise in PRA, as a close correlation was present between the basal value and the increase caused by nifedipine ( r = 0.92, p < 0.001). The rise in PRA was also correlated with the plasma concentration of nifedipine after 60 min (r = 0.80, p < 0.01), but it was not correlated with the decrease in BP, the rise in HR or the increase in NA. Nifedipine 30-60 mg daily for 6 weeks caused a reduction in mean BP from 133 to 113 mmHg (p 95 mm Hg), and if side-effects permitted, the daily dose was raised to a maximum of 20 mg t. i. d. The patients were seen every second week. BP and H R were recorded after at least 10 min in the supine position and then after 1 min in the erect position. The measurements were made in the morning 1-2 h after ingestion of the nifedipine capsule. The patients were questioned about side-effects and they were weighed. Before starting therapy, and at the end of the study, blood samples were taken for determination of PRA,
o. LederballePedersen et al.: Effectof Nifedipinein Hypertension ALDO, NA, A and serum creatinine, sodium and potassium. They were collected from an indwelling cannula after 60 min of rest in the supine position and after at least an 8-h fast. Urine was collected for two 24-h periods before and after 6 weeks of nifedipine treatment for the determination of excreted catecholamines.
Analyses of Blood Samples PRA was measured by the method of Giese et al. (1970), using radio-immunological quantitation of angiotensin I (Ang I) after incubation of dialyzed plasma for 3 h at pH 7.4 and 37 °C. The results are expressed as ng Ang 1/80% ml/h. Plasma aldosterone concentration was measured using the method of Rask-Madsen et al. (1974); radioimmunoassay was performed on the residue from plasma prepared by extraction with dichloromethane, purification on silica gel columns and chromatographic separation on paper. The results are given as ng/100 ml. Plasma NA and A were measured by a sensitive double-isotope derivative assay (Christensen, 1973). The results are expressed as ng/ml. NIF was determined by the laboratories of Bayer AG, Leverkusen, Germany, according to the fluorometric method of R~msch (1979). Serum concentrations of creatinine, sodium and potassium, and urinary excretion of NA and A, were determined as routine procedures in the central laboratory of the Aarhus Amtssygehus.
Statistical Calculations Mean BP was calculated as diastolic BP + 1/3 pulse pressure. Forearm vascular resistance, calculated as mean BP divided by forearm blood flow, is expressed in arbitrary units. Correlations were calculated by linear regression analysis. Student's t-test was employed for comparison of paired data; the level of significance was set at p < 0.05. Results are given as mean + SEM.
Results
Acute Experiments Hemodynamic Parameters and Plasma Concentrations of Nifedipine. Fluctuations of some of the hemodynamic and biochemical parameters measured during the first 90 min after sublingual administration of nifedipine 20 mg to two patients are shown in Figure 1.
O. Lederballe Pedersen et ai.: Effect of Nifedipine in Hypertension
NIFEDtPINE, ng//ml
237
300
3O
.-
0 BP, mm Hg
200
4 .
