EurJ Clin Pharmacol (1990) 39:435-439

© Springer-Verlag 1990

Co-dergocrine mesylate inhibits the increase in plasma catecholamines caused by nifedipine in essential hypertension R. Kirsten 1, K. Nelson 1, G. Weidinger 2, and D. Welzel 2 Department of Clinical Pharmacology, University of Frankfurt, Frankfurt am Main and 2 Clinical Research, Sandoz AG, Ntirnberg, FRG Received: August 8, 1989/Accepted in revised form: May 21, 1990

Summary. Co-dergocrine mesylate (Cod), which inhibits norepinephrine secretion by stimulating presynaptic dopamine receptors, and has no known metabolic side effect, has an additive antihypertensive effect to that of Nifedipine (Nif). Plasma norepinephrine, epinephrine, renin activity and aldosterone have been measured after acute administration of Nil and Cod alone and in combination to 18patients with a diastolic blood pressure > 105 m m H g in a cross-over, randomized, double-blind study. Every patient received 4 mg Cod then 20 mg Nif, placebo then 20 mg Nil and 4 mg Cod then placebo. The second treatment was always given 1 h after the first medication. Blood pressure was measured before and every 15 rain during the study period. Blood for measurement of catecholamines, aldosterone and renin activity was collected before medication, l h after the first dose and 90 rain after the second treatment. Blood pressure was significantly lower (P < 0.05) where Cod preceded Nil. Cod caused a significant decrease in plasma norepinephrine from 293 to 202 pg. mland in epinephrine from 67 to 55 pg.m1-1. The Nif-induced increase in norepinephrine from a pre-treatment value of 293 pg. ml- 1 with preceding Cod to 331 pg-m1-1 was much less than the increase with placebo as premedication, from 284 to 440 pg-ml 1. Nif caused an increase in renin activity but no increase in aldosterone. Nif-related side effects, such as flushing and headache, occurred in 6 patients of whom 5 had no received Cod as premedication. Due to the stabilizing action of Cod on catecholamines and on the side effects of Nif, Cod may be preferable to other antihypertensives in augmenting the antihypertensive action of Nif. Key words: co-dergocrine mesylate, hypertension; aldosterone, catecholamines, nifedipine, renin side effects The antihypertensive effect of nifedipine is partly abolished by reflex stimulation of the sympathetic nervous system, indicated by an increase in circulating norepinephrine [2, 8, 13, 14, 20]. Since co-dergocrine mesylate can

inhibit norepinephrine secretion by stimulating peripheral presynaptic dopamine receptors [6] the combination of the two drugs might prove clinically useful. Studies have shown that the antihypertensive effect of calcium antagonists can be increased by diuretics, methyldopa, and alpha- and beta-adrenoceptor blocking agents [7, 11, 18, 24, 25]. However, some of those agents induce negative metabolic effects on urea, glucose, potassium or lipids [3, 4, 19, 29]. It should be reasonable, therefore, to employ a combination of co-dergocrine mesylate and nifedipine, as both antihypertensive drugs lack metabolic side -effects. The present study was designed to examine whether co-dergocrine mesylate combined with nifedipine had an additive antihypertensive effect. A further object was to measure catecholamine and aldosterone concentrations and renin activity after acute administration of nifedipine and co-dergocrine alone and in combination to hypertensive patients.

Patients and methods

Patients' 18 patients (3 f, 15 m) with a diagnosis of moderate essential hypertension and a mean diastolic blood pressure > 105 mmHg (Korotkov V), measured in triplicate in the supine position, were admitted to the study. Two patients were smokers and hypertension had been pretreated in 17 cases (J3-blockers9, calcium antagonists 4, cq-blockers 2, others 2) for an average period of 10 y. The mean age of the patients was 59.4 (8) y, their mean height was 175 (7.9) cm and their mean weight was 83.4 (11.8) kg. Pregnant or lactating women, patients with renal impairment or with diseases that might influence the absorption or metabolism of the drugs were excluded from the study. The patients were informed of the nature of study and gave their informed consent to participation in it.

Study design After a2 week placebo phase, 18 patients were randomly assigned to one of three double-blind study periods. The patients ate a nonstandardized lunch prior to each study period and a canula was in-

436

R. Kirsten et al.: Co-dergocrine in hypertension

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Glutathion and EGTA were added to blood to be used for the determination of norepinephrine and epinephrine; blood for aldosterone assay was heparinized, and EDTA was added to blood for the measurement of renin activity, Blood was immediately centrifuged at 6,500 g for 15 s and the plasma frozen in liquid nitrogen. It was stored at - 40°C until analysed. Catecholamines were extracted from plasma by adsorbtion onto aluminum oxide. All reagents for the extraction procedure and the mobile phase for the HPLC determination of norepinephrine and epinephrine were purchased ready made (Catecholamine-Kit JWGE 88001, Waters, Millipore, Eschborn, FRG). The catecholamines were detected electrochemically (ESA Coulochem Detector-Mode15100A, Bedford, Massachusetts, USA) after separation on an ODS 18, 3 micron ultrasphere Altex column (Biotronic, Maintal, FRG). Aldosterone and renin activity were determined with radioimmunoassay kits from Biermann (Bad Nauheim, FRG) and New England Nuclear (Dreieich, FRG), respectively.

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Fig.2. Mean (SEM) plasma norepinephrine before, during and after co-dergocrine me@ate, nifedipine and placebo, n = 18. * = 2P < 0.05. Cod-Nif = co-dergocrine (Phase A) -nifedipine (Phase B) Pla-Nif = placebo (Phase A) -nifedipine (Phase B) Cod-Pla = co-dergocrine (Phase A) -placebo (Phase B) Before phase A F--------q After phase A After phase B serted in a cubital vein 0.5 h before hand. The patients maintained the supine position in a quiet room throughout the observation period (total 3.5 h beginning at 12.30 h and ending at 16.00 h). During each study period two drugs were administered. The period of 60 min after oral administration of the initial medication was designated. "Phase A", the 90 min period after the second oral treatment was designated as "Phase B". One dose schedule consisted of 4 mg co-dergocrine mesylate as a non-retarded tablet (Phase A) followed by a capsule of 20 mg non-retarded nifedipine (Phase B) 1 h later. The second dose schedule was placebo (Phase A) followed i h later

Blood pressure and heart rate between the 3 groups were compared at the start and end of "Phase B" using Student's paired t-test. For plasma parameters within each group the levels at the start and end of "Phase A" = start of "Phase B" and start "Phase B" versus end of "Phase B" were compared using the Wilcoxon-signedrank test. To ensure that the multiple level of testing for every parameter did not exceed the significance level o~= 0.05, the resulting 2 P-values were corrected by the Bonferronie-Holm-procedure (6 hypotheses each for systolic and diastolic blood pressure, heart rate and every plasma parameter). This procedure was stopped as soon as the first Bonferronie-Holm corrected 2 P-value exceeded the significance level of c~= 0.05. Values are expressed as mean (SEM).

Results D u r i n g the 2 w e e k wash o u t (placebo) phase of p r i o r antih y p e r t e n s i v e t r e a t m e n t the b l o o d pressure i n c r e a s e d f r o m 157/95 (17/9) to 173/110 (13/4) m m H g . C o - d e r g o c r i n e m e s y l a t e caused a decrease in b l o o d p r e s s u r e c o m p a r e d to p l a c e b o (Fig. 1). T h e systolic b l o o d p r e s s u r e was significantly lower 60 rain after a d m i n i s t r a t i o n of m e d i c a t i o n , b u t the diastolic b l o o d p r e s s u r e was n o t significantly d e c r e a s e d at that time. A f t e r a d m i n i s t r a t i o n of n i f e d i p i n e (Phase B), b o t h systolic a n d diastolic b l o o d pressure w e r e d e c r e a s e d c o m p a r e d to placebo. T h e y were also significantly lower w h e n c o - d e r g o c r i n e mesylate administration preceded nifedipine administration, c o m p a r e d to p l a c e b o a d m i n i s t r a t i o n followed b y

R. Kirsten et al.: Co-dergocrine in hypertension

437

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Fig.4. Mean (SEM) plasma renin activity before, during and after codergocrine mesylate, nifedipine and placebo, n = 18. * = 2P < 0.05. Cod-Nil = co-dergocrine (Phase A) -nifedipine (Phase B) Pla-Nif = placebo (Phase A) - nifedipine (Phase B) Cod-Pla = co-dergocrine (Phase A) -placebo (Phase B) Before phase A [ [ After phase A After phase B nifedipine administration. Therefore, an additive effect on the reduction in blood pressure was observed when codergocrine mesylate preceded nifedipine administration. The heart rate after nifedipine monotherapy increased slightly from 75 to 7 8 b e a t s . m i n - L It remained unchanged after premedication with co-dergocrine mesylate (73 vs. 72 beats-min-1). In the two groups to whom co-dergocrine mesylate was administered in Phase A, a significant decrease in norepinephrine from 293 (19) and 284 (18) pg.m1-1 to 202 (22) and 216 (18) p g - m l - 1 (Fig. 2) occurred. A similar decrease in epinephrine from 67 (5) and 61 (4) p g - m l - ~to 55 (4) and 54 (5) pg.ml 1 (Fig.3) occurred as well after co-dergocrine mesylate. Nifedipine administered in Phase B caused a significant increase in norepinephrine. The rise from a pre-treatment value of 293 (19) pg-ml 1

in the group with preceding co-dergocrine to 331 (55) pg-m1-1 was much less than that occurring with placebo as premedication, from 284(17) to 440 (57) pg- ml- 1. In all three groups receiving either co-dergocrine mesylate or placebo, a significant decrease both in renin activity and aldosterone concentration was observed (Figs. 4 and 5). Nifedipine in Phase B, caused an increase in renin activity but no increase in aldosterone. As with norepinephrine, the increase was not as pronounced after premedication with co-dergocrine, 1.40 (0.21) n g A n g I - m l - 1. hcompared to 1.88 (0.31) ngAngI, m1-1- h 1after premedication with placebo. Side effects, such as flushing (n = 2), headache (n = 3) and dizziness (n = 1), occurred in 6 patients. They were found solely after nifedipine administration and 5 of the patients had not received co-dergocrine mesylate as premedication.

Discussion Nonretarded (conventional formulation) co-dergocrine mesylate caused a maximum decrease in blood pressure after i h with a gradual increase in blood pressure thereafter [1]. The maximum concentration as well as the maximum fall in blood pressure produced by the nifedipine formulation used were also expected to occur l h after administration [23]. Premedication with co-dergocrine mesylate greatly enhanced the fall both in systolic and diastolic pressure after nifedipine. The augmentation indicates that co-dergocrine mesylate counteracted the stimulation of the sympathetic nervous system apparent after nifedipine. The effect of co-dergocrine mesylate was comparable to that observed by Sluiter et al. [25] with the combination of nifedipine and the alphal-adrenoceptor blocker, prazosin, and to that reported by Daniels et al.

R. Kirsten et al.: Co-dergocrine in hypertension

438 [7], who combined nifedipine with the cardioselective 13adrenoceptor blocker, atenolol. Several studies, including the present one, have reported increased catecholamine concentrations after nifedipine [8, 17], and it is thought that the antihypertensive effect of nifedipine may partly be abolished by this rise [2, 8, 13, 14, 20]. Therefore, combining nifedipine with other antihypertensive agents, such as prazosin [25], atenolol [7], methyldopa [11] or captopril [5], has been the object of many studies in the attempt directly to counteract the increase in catecholamines, or indirectly by decreasing the dose of nifedipine by augmenting its antihypertensive action. Of the augmenting antihypertensive agents, none has been shown directly to cause a decrease in circulating catecholamines. However, there was a significant decrease both in norepinephrine and epinephrine after codergocrine mesylate, which could fully compensate the nifedipine-induced increase (Figs. 2, 3). Since it has been postulated that depressed central dopaminergic activity might be a pathophysiological factor in essential hypertension [21, 27], an agent such as co-dergocrine mesylate, which stimulates presynaptic dopamine receptors [6], thereby reducing catecholamine secretion, might be a very suitable augmenting agent. The reason for the small (18%) but significant decrease in epinephrine was not apparent. Petersen et al. [22] has also reported a greater fall in blood pressure decrease after giving co-dergocrine and nifedipine to healthy volunteers for 3 days. Nifedipine significantly increased the plasma norepinephrine level, but it remained unchanged after simultaneous administration of co-dergocrine. Renin activity was also reduced by the combined therapy. A variety of studies in man and experimental animals has demonstrated that the sympathetic nervous system plays a regulating role in renin secretion [9]. Sympathetic activation, such as exercise [16], psychic stress [15] or upright tilting [26], leads to enhanced renin activity [28]. The nifedipine-induced stimulation of the sympathetic nervous system (55% increase in norepinephrine) here was paralled by an increase of 57% in renin activity (1.19 (0.17) before versus 1.88(0.31) n g A n g I . m l - h -1 after nifedipine). The rise was in good agreement with values reported by Sluiter et al. [25] and Lederballe Pedersen et al. [17], who found an increase from 1.24 (0.27) before nifedipine to 1.86 (0.41) n g A n g I 80% ~- m l . h - 1 after it. Premedication with co-dergocrine abolished the increase. Hiramatsu et al. [12] found no increase in renin activity after nifedipine in older hypertensive patients (58 (4) y) but there was an increase in younger patients (24 (2) y). This may be due to long standing dietary differences between European and Japanese populations, since the basal renin values in young hypertensive patients in Japan were 2.41 (0.32) ngAngI-ml i. h-1 and 0.68 (0,13) n g A n g I - m l - l - h ~ in older patients. There was no increase in the aldosterone concentration after nifedipine, as reported elsewhere [12, 17]. The significant decreases in renin and aldosterone activity (Fig.4 and 5) 1 h after co-dergocrine and placebo may be attributed to two factors. For logistic reasons the

patients could not be required to remain 2 h in the supine position before the medication phase began. This means that the initial renin and aldosterone values after only 30 min in the supine position were probably not true basal values. The diurnal renin rhythm may also have been involved [10]; plasma renin activity reaches a minimum in the late afternoon and the observation period began at 13.00 h and ended at 16.00 h. A further factor in the choice of a suitable augmenting agent for nifedipine is the nature of any side effects. Alpha-adrenoceptor blockers, 13-adrenoceptor blockers and methyldopa are all potential inductors of metabolic side effects [3,19, 29], whereas co-dergocrine mesylate has not been shown to induce them. Due to the small number of patients used, no final conclusion can be drawn about subjective tolerance of nifedipine after comedication with co-dergocrine mesylate. However, since 5 out of 6 patients who noticed adverse side effects had received nifedipine alone, the tolerance of nifedipine may well be improved by combining it with codergocrine. The catecholamine and side effect stabilizing action of co-dergocrine mesilate on nifedipine may make it superior to other agents in augmenting the antihypertensive effect of nifedipine.

References 1. Abisch E, Humbert H (1983) Die Pharmakokinetik yon Hyderginspecial, in: Bock KD (ed) Hochdrucktherapie im Alter mit Hydergin: Neue Gesichtspunkte, Narnberger Expertengespr~ich.Schattauer, Stuttgart, p 71 2. Agabiti-Rosei E, Muiesan ML, Romanelli G, Beschi M, Castellano M, Muiesan G (1988) Reversal of cardiac hypertrophy by long-term treatment with calcium antagonists in hypertensive patients. J Cardiovasc Pharmaco112 [Suppl 6]: $75-$78 3. Amery A, Brixko R Clement D, De Schaepdryver A, Fagard R, Forte J, Henry JF, Leonetti G, O'Malley K, Strasser T, Birkenh~ger W, Bulpitt M, Deruyttere M, Dollery C, Forette E Hamdy R, Joossens JM Lund-Hohansen R Petrie J, Tuomilehto J, Williams B (1985) Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancet I: 1349-1370 4. Ames RP (1986) The effects of antihypertensive drugs on serum lipids and lipoproteins. Drugs 32: 260-278, 335-337 5. Brouwer RM, Bolli R Erne R Conen D, Kiowski W, BiJhler R (1985) Antihypertensive treatment using calcium antagonists in combination with captopril rather than diuretics. J Cardiovasc Pharmacol 7 [Suppl 1]:88-91 6. Clark BJ, Bucher T, Waite R (1985) Analysis of cardiovascular effects of co-dergocrine (Hydergine). J Pharmaco116 [Suppl III]: 101-111 7. Daniels AR, Opie LH (1986) Atenolol plus nifedipine for mild to moderate systemichypertension after fixed doses of either agent alone. Am J Cardio157:965-970 8. Daul A, Bock KD, Wang XL, Brodde OE (1985) Effects of nifedipine and co-dergocrine mesylate (Hydergine) on alphar and ~32-adrenoceptors in circulating blood cells of essential hypertensive patients. Hochdruck 6:48 9. Davis JO, Freeman RH (1976) Mechanisms regulating renin release. Physiol Revs 56:1-56 10. Gordon RD, Wolf LK, Island DR Liddle GW (1966) A diurnal rhythm in plasma renin activity in man. J Clin Invest 45: 1587-1592

R. Kirsten et al.: Co-dergocrine in hypertension 11. Guazzi MD, Fiorentini C, Olivari MT, Bartorelli A, Necchi G, Polese A (1980) Short- and long-term efficacy of a calcium antagonistic agent (nifedipine) combined with methyldopa in the treatment of severe hypertension. Circulation 61:913-919 12. Hiramatsu K, Yamagishi F, Kubota T, Yamada T (1982) Acute effects of the calcium antagonist, nifedipine, on blood pressure, pulse rate, and the renin-angiotensin-aldosteronesystem in patients with essential hypertension. Am Heart J 104:1346-1350 13. Kiowski W, Hulthen UL, Erne B, Bolli R Biihler FR (1983) Antihypertensive Wirkung und Wirkmechanismus von Kalziumantagonisten bei essentieller Hypertonie. Therapiewoche 33: 1869-1878 14. Klein W, Brandt D, Vrecko K, Hfirringer M (1983) Role of calcium antagonists in the treatment of essential hypertension. Circ Res 52 [Suppl 1]: 174-18l 15. Konsunen KJ (1977) Plasma renin activity, angiotensin II and aldosterone after mental arithmetic. Scand J Clin Lab Invest 37: 425-429 16. Konsunen KJ, Pakarinen AJ (1976) Plasma renin, angiotensin II and plasma and urinary aldosterone in running exercise. J Appl Physio141:26-29 17. Lederballe Pedersen O, Mikkelsen E, Christensen N J, Kornerup H J, Pedersen EB (1979) Effect of nifedipine on plasma renin, aldosterone and catecholamines in arterial hypertension. Eur J Clin Pharmaco115: 235-240 18. Lejeune PH, Gunselmann W, Hennies L (1985) Effects of BAY J 5240, a fixed combination of low-dose nifedipine and acebutolol on essential hypertension: Comparison with standard dose nifedipine. Eur J Clin Pharmaco127:17-21 19. Leren R Foss OR Helgeland A, Hjermann I, Holme I, Lund-Larsen PG (1980) Effect of propranolol and prazosin on blood lipids, The Oslo Study. Lancet II: 4~5 20. Muiesan G, Agabiti-Rosei E, Castellano M, Alicandri CL, Corea L, Fariello R, Beschi M, Romanelli G (1982) Antihypertensive and humoral effects of verapamil and nifedipine in essential hypertension. J Cardiovasc Pharmacol 4 [Suppl3]: 325 329

439 21. Os I, Kjeldsen SE, Westheim A, Normann N, Aakesson I, Hjermann I, Eide I (1987) Central Dopaminergic Control of Prolactin in Essential Hypertension Acta Med Scand 221 [Suppl 714]: 113-117 22. Petersen K-G, Ortgiese G, Schuler G, Khalaf N, Schliebs B, Kerp L (1989) Glukosetoleranz und Elektrolytstoffwechsel unter Nifedipin and Nifedipin-Dihydroergotoxin bei Gesunden. Arzneim-Forsch/Drug Res 39:612~514 23. Rfimsch K-D (1983) Pharmakokinetic verschiedener Darreichungsformen von Adalat. In: Just HJ (ed) Erfahrungen mit Adalat in Klinik und Praxis: Prtifergespr~ich am 23.10. 1982 in Miinchen. Perimed, Erlangen, pp 19-26 24. Schoenberger JA (1988) Calcium-antagonists: Use in hypertension: Evaluation of calcium-antagonists in combination with diuretics. Augiology 39:87-93 25. Sluiter HE, Huysmans FThM, Thien ThA, Koene RAP (1985) The influence of alphal-adrenergic blockade on the acute antihypertensive effect of nifedipine. Eur J Clin Pharmacol 29: 263-267 26. Stella A, Zanchetti A (1984) Neural control of renin secretion. J Hypertension 2 [Suppl 1]: 83-87 27. Stumpe KO, Kolloch R, Higuchi M, Kruck F, Vetter H (1977) Hyperprolactinemia and antxhypertensive altered central dopaminergic activity of prolactin in essential hypertension: Effect of bromocriptine in essential hypertension. Lancet II: 211 214 28. Thames MD (1984) Renin Release: Reflex control and adrenergic mechanisms. J Hypert 2 [Suppl 1]: 57-66 29. Weidmann PA, Gerber A, Mordasini R (1983) Effects of antihypertensive therapy on serum lipoproteins. Hypertension 5 [Suppl 3]: 120-131 Prof. Dr. med. R. Kirsten Abteilung Klinische Pharmakologie -Haus 74 Johann Wolfgang von Goethe Universitfit Theodor-Stern-Kai 7 W-6000 Frankfurt am Main 70, FRG