Journal of Internal Medicine 1990; 228: 503-509

Nisoldipine-effec t s on the renin-angiotensin-aldosterone system and catecholamines. Studies in normotensive and hypertensive subjects A.-M. OTTOSSON 81B. E. KARLBERG* From the Endocrine-Hgpertension Unit. Departments o/ lnternal Medicine, Norrkiiping and Linkiiping. and the *Clinical Research Centre. University Hospital, Linkiiping, Sweden

Abstract. Ottosson A-M, Karlberg BE (Endocrine-Hypertension Unit, Departments of Internal Medicine, Norrkoping and Linkoping, and the Clinical Research Centre, University Hospital, Linkoping, Sweden). Nisoldipine-effects on the renin-angiotensinaldosterone system and catecholamines. Studies in normotensive and hypertensive subjects. Journal of Internal Medicine 1990: 228: 503-509. We have studied the effects of nisoldipine, a new calcium channel antagonist, on the renin-angiotensin-aldosteronesystem and on plasma catecholamines in 10 healthy volunteers and in 29 patients with primary essential hypertension. Of these 29 patients, thirteen had normal renin hypertension (NRH).and sixteen had low renin hypertension (LRH). Fight healthy volunteers received placebo. Short-term (24 h) effects were measured in all subjects and long-term (up to 6 months) effects of 10-40 mg nisoldipine daily were monitored in the 29 hypertensive patients. Plasma renin activity (PRA) increased slightly, although this rise was not statistically significant, 1h after the first dose of nisoldipine in both normotensive subjects and hypertensive patients. After 2 h PRA had returned to the pre-treatment level. No change in PRA was observed after administration of placebo. Plasma angiotensin n (An) levels showed considerable variation after nisoldipine administration. Plasma aldosterone levels decreased despite the increase in PRA and A11 concentrations. However, no concomitant reduction in urinary aldosterone excretion was observed. Plasma noradrenaline levels increased slightly 2 4 h after administration of nisoldipine. and decreased again thereafter, but no changes in plasma adrenaline levels were seen. Nisoldipine had no long-term effects on the reninangiotensin-aldosterone system or on serum catecholamine levels.

Keywords :aldosterone. calcium channel antagonists, catecholamines, nisoldipine. reninangiotensin-aldosterone system.

Introduction Calcium channel blockers are widely used in the treatment of both ischaemic heart disease and hypertension. Calcium ions play an important role in the release of a number of hormones [l-61, including catecholamines both from the adrenal medulla [7] and from terminal nerve endings [8, 91, and drugs such as the calcium channel antagonists, that interfere with these calcium-dependent mechanisms, may thus have important endocrine effects. Nisoldipine is a new calcium channel blocker of the dihydropyridine type [lo]. We here report a study of the acute effects of nisoldipine treatment on the

renin-angiotensin-aldosterone system (RAAS) and plasma catecholamine concentrations in normotensive subjects, and the acute and long-term effects on RAAS and plasma catecholamine levels in patients with various subtypes of hypertension.

Methods Control subjects and patients Ten healthy normotensive subjects of mean age 47 years (range 24-65 years) received nisoldipine, and eight subjects of mean age 46 years (range 25-69 years) received placebo. Five of these individuals took 503

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Table 1. Clinical and biochemical characteristicsof the various groups of normotensive subjects and hypertensive patients investigated Normotensive nisoldipinetreated subjects (n = 10)

Normotensive placebo-treated subjects. (n = 8) Hypertension class WHO I WHO I1 WHO III Sex (M/F) Mean age (years) Range (years) Blood pressure (mmHg) Supine Erect Heart rate (beats min-') Serum creatinine (pmol I-') Body mass index (kg m-*) Previous anti-hypertensive treatment Yes/No

-

414 46 25-69

515 47 24-65

123/76+ 1316 122/77+8/5 66+8 82 +4 23.2f 3.0 -

127/79+ 11/11 112/76* 1216 69+11 86*4 24.2 f 2.8 -

Normal-renin hypertensive patients (n = 13)

Low-renin hypertensive patients (n = 16)

10 3 -

13 3 6/10 58 40-74

518

49 32-70 166/107+ 1918 1 SS/lOS* 1318 75*9 74k2.9 24.7+ 2.6 815

164/102f 1316 158/103&17/9 76k12 83k3 24.8k3.5 1016

Five of the normotensive placebo-treated subjects were also examined as part of the normotensive nisoldipine-treated group. Mean valuesf SD are shown.

sive and hypertensive subjects are summarized in Table 1.

part in both the placebo and active treatment studies. Twenty-nine patients with hypertension were also included in the study, all of whom underwent a renin-stimulation test (80 mg frusemide administered orally [ l l ] ) which showed 1 3 individuals (8 men and five women) to have normal renin hypertension (NRH) (post-frusemide plasma renin activity (PRA) 2 0.38 pkat 1-l); their mean age was 48.5 years (range 32-70 years). A further 1 6 hypertensive subjects (six men and ten women) were found to have low renin primary hypertension (LRH) (stimulated PRA < 0.38 pkat 1-l); their mean age was 58 years (range 40-74 years). Of the 29 hypertensive patients, 1 8 individuals had received antihypertensive treatment prior to entering the study, while the remaining 11 patients had newlydiagnosed untreated primary hypertension. The patients and subjects have been described in more detail in a previous report [12]. Clinical and biochemical data for the normotenBP/ HR Toblet intoke Blood sompling Urine collection

c 4 c c 1 1 1 1 1 ...............................

c

4 4

Patients who had received antihypertensive treatment before entering the study switched to placebo tablets 3 weeks before participating in the study. Previously untreated patients received placebo for 1 week before taking part in the study. The patients were admitted to our research unit for 2 4 h immediately after the first dose of nisoldipine. Subjects and patients were required to fast from midnight prior to receiving nisoldipine at 08.00 hours. They remained supine from the time they took nisoldipine until 12.00 hours. The study protocol is illustrated in Fig. 1. The two groups of healthy volunteers only participated during the initial 2 4 h of the study. The hypertensive patients then continued nisoldipine, 10

c

c c

c

Study protocol

...............

4

I

0

1.0

2.0

4.0 Time ( h )

8.0

24

Fig. 1. Design of the first-dose and steady-state studies.

EFFECTS OF NISOLDIPINE

mg once daily, and the dose was increased stepwise to 20 mg twice daily if necessary to achieve a diastolic blood pressure < 90 mmHg in patients aged < 60 years or < 95 mmHg in those aged > 60 years. After 6 months of continuous treatment with nisoldipine, patients received placebo tablets identical in appearance to nisoldipine during a 1-week wash-out period. All patients were again admitted to the research unit, after an overnight fast, at 07.30 hours on the first morning of the wash-out period. Half an hour later each patient took 10 mg nisoldipine orally, and blood samples were collected as during the acute study (see Fig. 1).Urine was collected in fractionated samples and then as 24-h collections throughout the remainder of the wash-out period, for aldosterone and creatinine analyses.

505

method modified from that of Kappelgaard et al. [161. Aldosterone in plasma and urine was estimated by RIA after extraction in dichloromethane [17, 181. Statistical methods

Data are expressed as mean values SEM. Differences between the means were calculated by Student's paired and, where appropriate, unpaired t-test. A Pvalue < 0.05 was considered to be statistically significant.

Results The effects of nisoldipine on blood pressure and heart rate in the various study groups have been reported previously [121.

Analytical methods

Analysis of plasma catecholamines [noradrenaline (NA) and adrenaline (A)] was performed according to a highly specific high-performance liquid chromatographic (HPLC) method with amperometric detection [13, 141. Plasma renin activity was measured by specific radioimmunoassay (RIA) [15]. Plasma angiotensin I1 levels were measured by a RIA

Hormonal changes Plasma renin activity. There was a slight (not statistically significant) increase in PRA in hypertensive patients (both with NRH and LRH) and in normotensive subjects 1 h after the first dose of nisoldipine (Tables 2 and 3). No change in PRA was observed after placebo administration in normotensive subjects

Table 2. Plasma renin activity (PRA). plasma angiotensin II (An) and serum aldosterone concentrations at various times after the administration of 10 mg nisoldipine to 29 hypertensive patients Normal-renin hypertensive patients

Low-renin hypertensive patients

Time (h)

PRA (pkat 1-l)

A11 (pmol I-')

Aldosterone (pmol I-')

PRA (pkat 1-l)

A11 (pmol 1-l)

Aldosterone (pmol I-')

0 1 2 4 8

0.62f0.17 0.82f0.22 0.55+0.13 0.53f0.09 -

4.4k1.0 4.0k1.1 5.1k1.3 4.8f0.7 6.5k1.5

183f37 118f22 105k23 170f42 313k80

0.18 f 0.03 0.24 f 0.04 0.16 k0.02 0.19f0.02 -

2.5 k 0 . 3 2.0 k0.3 2.5 f 0 . 3 3.3k0.9 4.0k1.0

142 f 25 98 f 19 94+16 11 7 k 2 0 . 231 2 4 9

* Mean values k SEM are shown. Table 3. Plasma renin activity (PRA). plasma angiotensin II (An) and serum aldosterone concentrations in normotensive subjects at various times after the administration of 10 mg nisoldipine (n = 10) or placebo (n = 8) After nisoldipine treatment

After placebo

Time (h)

PRA (pkat 1-l)

A11 (pmol I-')

Aldosterone (pmol I-')

PRA (pkat I-')

A11 (pmol I-')

Aldosterone (pmol I-')

0 1 2 4 8

0.29k0.04 0.43f0.13 0.35k0.13 0.24k0.05 -

4.1k1.0 4.2k1.3 3.8k1.2 5.5k2.0 7.0k2.8

201 f 39 94f21 75f57 186f58 253 f 80

0.1 7 f 0 . 0 4 0.20f0.04 0.17 f 0.04 0.22 aO.05

2.6k0.8 3.4f1.2 2.0 f 0.5 2.6f0.7 5.2f1.5

293k65 197k36 151 f 14 160f22 3 6 5 k 76

* Mean valuesf

SEM are shown.

-

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A.-M. OTTOSSON & B. E. KARLBERG

Table 4. Plasma renin activity (PRA). plasma angiotensin I1 (AII). aldosterone, adrenaline and noradrenaline levels during 6 months of treatment with nisoldipine Time (months)

PRA (pkat I-')

A11 (pmol I-')

Aldosterone (pmol I-')

Adrenaline (nmol I-')

Noradrenaline (nmol I-')

0

0.41k0.07 0.28k0.03

3.3k0.9 2.9k0.8

256k39 354k42

0.26k0.05 0.22k0.06

1.73k0.28 1.74k0.17

6

* Mean valueskSEM are shown.

(Table 3). Once patients and subjects were allowed to stand, PRA again increased. No increase in PRA from initial levels was observed in either LRH or NRH hypertensives after 10 mg nisoldipine following 6 months of drug treatment. There were no further changes in PRA in any of the hypertensive patients during long-term treatment (Table 4).

Angiotensin 11. Plasma concentrations of AII showed considerable variation after administration of nisoldipine in all groups (Table 2 and 3). No changes in plasma levels of MI were observed after placebo administration (Table 3) or during 6 months of treatment with nisoldipine. Aldosterone. Despite increases in PRA and occasionally in A11 after nisoldipine administration, plasma aldosterone levels decreased, reaching their

24 h after n isoldipine

After nisoldipine treatment for 6 rnont hs

lowest values 2 h after nisoldipine administration (P < 0.01 vs. time 0) (Tables 2 and 3 ) . Surprisingly, similar results were obtained after placebo administration. No differences were detected in hypertensive patients after their first dose or after a similar dose following 6 months of treatment. No further changes in plasma aldosterone levels were observed after long-term treatment (Table 4). Urinary aldosterone excretion did not decrease after nisoldipine administration, despite the fall in plasma levels. Urinary aldosterone excretion during the 4-h period after administration of 10 mg of nisoldipine was similar to that observed during the following 4 h (Fig. 2). No differences were found between any of the groups of hypertensive patients, and the pattern was similar in normotensive subjects. Long-term treatment with nisoldipine had no effect on urinary aldosterone excretion (Fig. 2).

After withdrawal of nisoldipine t reotmenl

Fig. 2. Urinary aldosterone excretion in 29 hypertensive patients before, during and after nisoldipine treatment. Bars a-e show excretion: a. 0-24 h before administration of 10 mg nisoldipine by mouth: b. 0 4 h after the nisoldipine dose: c, 4-8 h after nisoldipine: d, 8-24 h after nisoldipine: e, 0-24 h after nisoldipine. Bars f-j show excretion in the steady state after 6 months of treatment: f, 0-24 h before administration of a 10 mg dose of nisoldipine: g. 0 4 h after the dose: h. 4-8 h after the dose: i. 8-24 h after the dose: j. 0-24 h after the dose. Bars k and I show excretion after stopping nisoldipine treatment: k. 24-48 h after the final dose: 1. 144-168 h after the final dose.

EFFECTS OF NISOLDIPINE

507

5

4

0

a 0

2 4 6 8 10 12 14 16 18 202224

Time ( h ) Fig. 3. Plasma noradrenaline ( 0 )and adrenaline ( 0 )levels 0-24 h after oral administration of 10 mg nisoldipine in 1 5 hyertensive patients (left panel) and in six normotensive subjects (right panel). The asterisks indicate levels that were significantly different ( P < 0.05)from time 0.

Catecholamines. PA levels did not vary after either acute or long-term nisoldipine administration. PNA levels, on the other hand, increased slightly 2 4 h after nisoldipine administration, and subsequently slowly declined again, but failed to reach pretreatment levels 24 h after nisoldipine administration (Fig. 3). No changes in either PA or PNA levels were observed during long-term (> 6 months) treatment (Table 4).

Discussion We studied the acute and long-term effects of the calcium antagonist nisoldipine on the reninangiotensin-aldosterone system and on plasma catecholamine levels. Our study appears to be the first to investigate the long-term effect of nisoldipine on AII, PRA levels or aldosterone secretion and excretion. In the present study PRA increased slightly 1 h after nisoldipine administration, but returned to pretreatment levels within 2 h of administration of the dose, and no changes in PRA were observed thereafter. A similar increase in PRA levels in different groups of hypertensive patients has been reported 3 h after administration of 10 mg oral nisoldipine [19]. We observed no long-term effect of nisoldipine on PRA. Acute administration of nifedipine has been shown to cause a transient increase in PRA, with maximum levels 1-2 h after administration [20-251, returning to baseline levels within 4 h [20, 23, 241. Some

authors have found a correlation between basal PRA and the increase in PRA after nifedipine treatment [20, 231, a finding which we have also noted after nisoldipine treatment. Few studies have reported long-term effects of nifedipine [20, 26, 271 although one described a sustained increase in PRA up to 5 months after starting treatment [28]. HulthCn et al. reported an increase in PRA after both acute and long-term administration of the potent calcium antagonist felodipine [29]. No acute or long-term effects on PRA have been reported after administration of other calcium channel antagonists, including nitrendipine or nicardipine [2 5, 301. Increases in AII levels have been described after shortterm nifedipine treatment [27]. In our study, AII levels varied considerably after nisoldipine treatment, and increased in many patients. Despite the increase in levels of both PRA and AII, the plasma aldosterone concentration decreased after nisoldipine. This was unexpected, as the acute administration of vasodilatory antihypertensive drugs, such as minoxidil and hydralazine, in experimental animals has been reported to cause a marked stimulation of RAAS, with increases in PRA and aldosterone levels [31]. One study reported that nifedipine reduces aldosterone secretion in patients with primary hyperaldosteronism [l], but others have failed to confirm this finding [30, 32, 331. A reduction in aldosterone production after infusion of both AII and potassium during treatment with verapamil [3, 331, nisoldipine [19, 33, 341 and nifedipine [2, 21, 311 has been reported. Since

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calcium is required for aldosterone secretion from the adrenal cortex [35]. blockade of the stimulatory effect of AII on aldosterone secretion by calcium channel antagonists may explain the discrepancy. The decline in plasma aldosterone levels in placebotreated subjects is probably a result of their being recumbent during the initial 4 h of the study. No concomitant increases in PRA or A11 were observed after placebo administration. However, the urinary excretion of aldosterone remained unchanged despite the reduction in plasma aldosterone levels during both acute and long-term nisoldipine treatment. We have already reported an acute diuretic and natriuretic effect, with a slight increase in urinary calcium and potassium excretion, during the initial 4 h after nisoldipine treatment [ 3 6 ] . Increased plasma NA levels have been reported during the early phase of calcium channel antagonist treatment. Increases in PNA levels have been reported 30 min [37] and 1h [22] after the sublingual administration of nifedipine and 30-120 min after tho intravenous injection of tiapamil, nifedipine and nisoldipine in hypertensive patients [38]. A slight increase in PNA after 30 min was also observed in normotensive subjects [ 3 71. Plasma adrenaline levels do not appear to be affected by calcium channel antagonists [20, 37, 381. The rise in plasma catecholamine levels following acute administration of calcium channel blockers is probably due to activation of the sympathetic nervous system caused by the reduction in blood pressure. The increase in PNA that we have noted in hypertensive patients 24 h after nisoldipine treatment may reflect the fact that these measurements were made during out-patient visits rather than in our metabolic ward. Increased plasma catecholamine levels have been reported up to 2 weeks after starting treatment with nifedipine [39] and nitrendipine [40]. Other groups, l i e us, have been unable to detect any long-term effects on plasma catecholamines [5.20, 37. 381. We conclude that nisoldipine causes a slight, but statistically insignificant, acute increase (1 h) in PRA, with a concomitant significant decrease in plasma aldosterone levels which was most pronounced after 4 h. There was also a slight increase in PNA levels after oral administration of nisoldipine. We found no long-term effects on the renin-angiotensinaldosterone system or on plasma catecholamine levels.

Acknowledgements Dr Jan Abelin, Bayer AG. Stockholm, Sweden, generously provided the nisoldipine and matching placebo used in this study. The study was supported by a grant from the County Of Ostergotland’s Research Fund. We thank Miss Leena Gustavsson, RN, for her help in caring for the patients and Mrs Britt-Marie Kvist for performing the biochemical analyses.

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Received 18 October 1989. accepted 12 February 1990. Correspondence: Dr Anna-Maria Ottosson, Medicinkliniken, Lasarettet. S-601 82 Norrkoping, Sweden.