Pilot study on the effects of nitrendipine on cerebral blood flow in hypertensive patients with a history of cerebral infarction

CURRENT THERAPElUTIC FtlmARcH@ VOL. 66, NO. 7, JULY 1996

PILOT STUDY ON THE EFFECTS OF NITRENDIPINE ON CEREBRAL BLOOD FLOW IN HYPERTENSIVE PATIENTS WITHA HISTORY OF CEREBRAL INFARCTION HIROAKI NARITOMI,

TAKAO

SBIMIEU,KOTAKOMNASIIITA, HIEOSHIOE, AND TOI-IEUSAWADA

Cerebrovaecuku Division, Department of Medicine, National Caniiovaecuiw Osaka, Japan

Center,

ABSTRACT

Single daily administration of nitrendipine, a long-acting calcium channel blocker, reducesblood pressure during the day with minimal nocturnal hypotensive effects. Because ischemic stroke often occurs at night and is probably related to nocturnal hypotension, nitrendipine is considered suitable for antihypertensive therapy in stroke patients. In 10 hypertensive patients with a history of cerebral infarction (7 men and 3 women, ages 55 to 73 year&, 16mg nitrendipine once daily after breakfast was administered for 8 weeks, and cerebral blood flow (CBF) was measured before and after treatment. After 8 weeks of treatment, blood pressure decreased from 169 f 12/95 f 6 mm Hg to 142 & 12/78 f 4 mm Hg. The CBF increased by 8.8 f 11.2% in the infarcted hemisphere and by 7.3 f 10.2% in the healthy hemisphere. The CBF increase in the infarcted hemisphere was significant (P < 0.05). None of the patients exhibited symptoms suggestive of cerebral &hernia after therapy. Single daily administration of lo-mg nitrendipine appears to be useful for management of blood pressure in stroke patients with hypertension. INTKODUCTION

Hypertension is an important risk factor of stroke, and its management significantly influences the long-term prognosis of stroke.’ Administration of inappropriate antihypertensive drugs may reduce cerebral blood flow (CBF), exposing patients to the danger of cerebral ischemia.‘s2 Calcium channel blockers, such as nifedipine, nicardipine, verapamil, nilvadipine, and nitrendipine, have potent cerebral vasodilatory actions. Their single administration has been shown to increase CBF in animals3*4and hypertensive patients. ‘-’ Thus these calcium channel blockers are commonly used to treat stroke patients with hypertension. However, the chronic effects of these agents on CBF in stroke patients have not yet been fully elucidated. Addrem correspondence to: h. Hiroaki Naritomi, Cerebrovmcular Division, Department of Medicine, National Cardiovascdar center, 5-7-l Fujiehirudai, Suita, Osaka 566, Japan. Received fir publication on April 21,1996. Printed in the U.S.A. Repmduction in whole or part ia not permitted. 649

0011-39sx/96/(s.60

NITRENDIPINE

IN HYPERTENSIVE

STROKE

PATIENTS

Nitrendipine is a long-acting calcium channel blocker. Single daily administration of nitrendipine exerts a sufficient blood pressure-lowering effect during the day without a nocturnal hypotensive effect.g The absence of this nocturnal hypotensive effect is advantageous for the treatment of stroke patients, as ischemic stroke often occurs at night and is probably related to excessive hypotension.lO’ll In the present study, CBF was measured before and 8 weeks after nitrendipine therapy in 10 hypertensive patients with a history of cerebral infarction. The purpose of this pilot study was to clarify the cerebral hemodynamic effects of nitrendipine therapy in hypertensive stroke patients. Results of the unblinded and uncontrolled study may provide information on the cerebral circulatory changes caused by nitrendipine-induced hypotension in stroke patients. PATIENTSANDMETHODS

Study participants included 10 hypertensive patients (7 men and 3 women, ages 55 to 73 years) with a history of cerebral infarction. Informed consent was obtained from all patients prior to the study. All patients had had a cerebral infarction more than 2 months before the study and required antihypertensive therapy. The diagnosis of cerebral infarction was established on the basis of computed tomography scans. All patients had minor neurologic deficits due to cerebral infarction; all were capable of independent ambulation. Each patient received 10 mg of oral nitrendipine once daily after breakfast for 8 weeks. CBF was measured before and after treatment. CBF was measured with the xenon 133 (133Xe) inhalation methods described by Obrist et a1,12and used by us in previous clinical pharmacologic studies.13p’* CBF measurements were all performed at 9 to 11 AM. Briefly, measurements were taken with the patients in the resting, relaxed state (in a dark and quiet room with the patients lying on a bed with their eyes closed). Nine probes were mounted over each cerebral hemisphere. Patients inhaled 133Xe, mixed with room air (111 MBq/L), for 1 minute through a close-fitting face mask and nonrebreathing system. The clearance of 133Xefrom the brain was recorded for 10 minutes using nine pairs of sodium iodide collimated scintillation detectors incorporated into an online computerized system, and applied externally over homologous regions of both the infarcted and the healthy cerebral hemispheres in a standard position. The CBF was computed for each data curve as the initial slope index derived from the initial slope of the clearance curve.” The blood-brain partition coefficient of 133Xewas chosen arbitrarily as 1.0, and CBF data were expressed in mL/lOO g per minute. Mean values of CBF data obtained from the nine detectors in each cerebral hemisphere were 650

H.

NARITOMI ET AL.

used for the analysis. During CBF measurements, blood pressure was measured from the left upper arm with use of a tourniquet. Arterial blood was sampled from the right brachial artery 2 minutes after inhalation of 133Xe to measure arterial oxygen partial pressure and arterial carbon dioxide partial pressure; pH levels were also determined. The results obtained are given as mean + SD. The statistical significance of the data was evaluated by using the paired t test. CBF changes in individual patients were considered meaningful if values after 8 weeks of nitrendipine treatment increased or decreased by >12.5%13 compared with baseline values. RESULTS

The age, sex, and clinical diagnosis for each patient are shown in Table I. None of the patients showed symptoms, such as dizziness or vertigo, suggestive of cerebral ischemia during the study. No other adverse effects were noted and the measurements were completed successfully in all patients. Table II shows the results of blood pressure measurements taken during the CBF measurements before and after nitrendipine treatment. Before treatment, systolic blood pressure was 3160 mm Hg in all patients except for patient No. 3, whose baseline systolic pressure was 147 mm Hg. In this particular patient, however, systolic blood pressure measured 1 day before baseline CBF measurement exceeded 160 mm Hg and because she had a history of high blood pressure, she was included in the study. After treatment, mean blood pressure values decreased in all patients, from 169 + 12 mm Hg to 142 * 12 mm Hg for systolic blood pressure, from 95 + 6 mm Hg to 78 + 4 mm Hg for diastolic blood pressure, and from 120 ? 7 mm Hg to 99 * 4 mm Hg for mean blood pressure. All these changes were significant (P < 0.01). After treatment, systolic blood pressure was ~150 mm Hg in eight patients. Table I. Baseline characteristics of study patients.

m

60X

(Y)

Clinlcrl Diapnosir Left cerebral infarction Left cerebral infarction Left cerebral infarction Left cerebral infarction Left cerebral infarction Left cerebral infarction Ri ht cerebral infarction Le\ cerebral infarction Left cerebral infarction Left cerebral infarction

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NITRRNDIPINE

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Table II. Blood pressure levels (mm Hg) in hypertensive patients with a history of cerebral infarction before and after 10 mg oral nitrendipine once daily for 8 weeks. Baseline Patient No.

Met Treatment’

SBP

DBP

MBP

SBP

DBP

:

1::

1::

128 120

1::

7:

‘F

: :

147 1::

z ::

1:: 115

:‘:

;;i

H

1:; 171 187

101 :;

% 124 127

131 147 156 138 137 165 125

Y!. ;;

103 ::

MeanlOt SD

169160 2 12

959+86

120119+ 7

142136 k 12

76 ;;5 4

991::-t 4

MBP

FBP = s stolic blood pressure; DBP = diastolic blood pressure; MBP = mean blood pressure. P < 0.d versus baseline for all SBP, DBP, and MBP values.

Table III summarizes the arterial blood gas values and pH levels before and after treatment with nitrendipine. There were no significant changes in any values after treatment. Table IV shows CBF values in the infarcted and healthy hemispheres before and after treatment. Before treatment, mean CBF values were 43.3 + 5.8 mL/lOO g per minute in the infarcted hemisphere and 44.3 + 6.2 mL/lOO g per minute in the healthy hemisphere. After treatment, mean CBF values in the infarcted hemisphere increased significantly by 8.8 + 11.2% to 46.9 2 5.5 mWlO0 g per minute (P < 0.05). The mean CBF values in the healthy hemisphere increased by 7.3 + 10.2% to 47.3 + 5.8 mL/lOO g per minute, although this increase was not significant (P < 0.1). No patient displayed a CBF reduction of ~12.5% in the healthy or infarcted hemisphere, whereas four patients showed a CBF increase of ~12.5% in the infarcted or healthy hemisphere. There was no significant correlation between the age of the patients and the level of CBF changes. Likewise, no significant correlation was observed between the extent of blood pressure reduction and the level of CBF changes. Table III. Arterial blood gases and pH levels in hypertensive patients with a history of cerebral infarction before and after 10 mg oral nitrendipine once daily for 8 weeks.

PO,(mmNJ) ;p (mmHg)

Baseline

After Treatment’

97.4 k 6.1 36.3 2 3.7 7.407 -t 0.02

93.1 2 5.9 30.3 2 3.4 7.401 t 0.02

PO, = arterial oxygen partial pressure; Pco, = arterial carbon dioxide partial pressure * There were no significant changes in any values after treatment. 652

Table IV. Cerebral blood flow* in the infarcted and healthy hemispheres of hypertensive etroke patients before and after 10 mg oral nitrendipine once daily for 8 weeks. AfterTnrtmenl

(% change)

Baseline Patient No.

Heelthy (mUl66 g per minute)

:

it:

t:*i

E

so:3 45g.i

53:1

E:i

E $;

:

SD

Iefereted Heelthy (ml/l MI g per minute)

:I:!

45:L-l

B f&an’:

Infarcted

43.33719 2 5.0

44.33714 + 6.2

46.9 2 5.5t (6.8 f 11.2%)

(7.3 ” 10.2%)

* Measuredby xenon133 inhalation method. t P < 0.05 compared with baseline. DISCUSSION AND CONCLUSION

Single administration of nifedipine or verapamil is known to increase CBF in animals314and in patients with a hypertensive emergency.5 Single administration of nicardipine6 or nilvadipine’ has been reported to increase CBF in stroke patients with hypertension. Despite such information, little is known about the effect of chronic administration of calcium channel blockers on CBF in stroke patients. Nobile-Orazio and St.erzi2reported the occurrence of cerebral ischemia after chronic nifedipine therapy, suggesting that CBF may be reduced by chronic nifedipine administration. Thus CBF data obtained by single administration may not thoroughly affirm the safety of antihypertensive drugs in chronic treatment of stroke patients. Long-term CBF studies are needed to clarify the safety of antihypertensive therapy in stroke patients. Nitrendipine has advantages over other calcium channel blockers, such as nifedipine or nicardipine, because of its long-lasting antihypertensive effects. Its single daily administration provides satisfactory blood pressure control during the day with minimal nocturnal hypotensive effects.’ Ischemic stroke most commonly occurs at night between 12 PM and 6 AM” or 1 AM and 5 AM,~~ during which time the blood pressure is usually lowest. Because of its absence of nocturnal hypotensive effects, nitrendipine may be more effective for treatment of stroke patients than nifedipine or nicardipine. In the present study, single daily administration of 10 mg nitrendipine over 8 weeks in stroke patients brought about satisfactory blood pressure 653

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PATIENTS

reduction and a significant mean increase in CBF in the infarcted hemisphere. No adverse effects, including cerebral ischemic episodes, headache, and nausea were noted in any of the patients. Ruttimann et al8 reported that chronic nitrendipine administration for 2 to 4 weeks caused no CBF changes in patients with uncomplicated hypertension. In this respect, the results of the present study and those of Ruttimann et al do not agree. Effects of calcium channel blockers are, however, often exerted more extensively in the ischemic brain than in the nonischemic brain. Single administration of nimodipine was also reported to increase CBF in the infarcted hemisphere while having no effect on CBF in the healthy hemisphere. l6 Presumably, CBF increases in the infarcted hemisphere caused by nimoclipine and nitrendipine are, in part, attributable to their cerebral protective effects.16~f7 In previous studies,13*14we estimated cerebral hemodynamic effects of other antihypertensives, such as the alpha/beta-blocker arotinolol and the angiotensin-converting enzyme inhibitor alacepril, in stroke patients by using the same methods. We found that therapy with 15 mg daily of arotinolo1 for 2 to 3 weeks reduced mean blood pressure by 18 mm Hg and caused no significant changes in CBF in either hemisphere.13 In contrast, therapy with 50 mg daily of alacepril for 4 weeks reduced mean blood pressure by 12 mm Hg and caused a 10.6% increase in CBF in the ischemic hemisphere and a 12.5% increase in CBF in the healthy hemisphere.14 In the present study, therapy with 10 mg daily of nitrendipine for 8 weeks caused a reduction of 21 mm Hg in mean blood pressure, which is greater than the reduction caused by arotinolol or alacepril. Considering the differences in blood pressure reduction, the circulatory ameliorating effect of nitrendipine is considered superior to that of arotinolol and similar to that of alacepril. In conclusion, single daily administration of lo-mg nitrendipine exerts satisfactory blood pressure-lowering effects in association with an increase in CBF in the infarcted hemisphere in hypertensive stroke patients. The lack of nocturnal hypotensive effects and the favorable effects on cerebral circulation make nitrendipine potentially useful for antihypertensive treatment of stroke patients. Acknowledgment This study was supported in part by Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan. References: 1. Irie K, Yamaguchi T, Minematau K, Omae T. The J-curve phenomenon in stroke recurrence. Stroke. 1993;24:1644-1649. 654

2. Nobile-Grazio E, Sterzi R. Cerebral iechemia after nifedipine treatment. BMJ. 1981;283: 948. Abstract. 3. Grabowski M, Johansson BB. Nifedipine and nimodipine: Effect on blood pressure and regional cerebral blood flow in conscious normoteneive and hypertensive rats. J Cardiovase Phurmacol. 1985,7:1127-1133. 4. Metzger HP, Savae Y. The influence of the calcium antagonists flunanz ine and verapamil on cerebral blood flow and oxygen tension of aneethetized WFS-rata. Adu Exp Med Biol. 1988;222:411-418. 5. Bertel D, Conen D, Randu FW, et al. Nifedipine in hypertensive emergencies Br Med J Clin Res Ed. 1983,286:19-21. 6. Kuriyama Y, Hashimoto H, Nagatsuka K, et al. Effecta of dihydropyridines on cerebral vessels. J Hypertens. lSS3;11(Suppl6):SS-512. 7. Kobayaehi S, Yamaguchi S, Okada K, et al. Effect of single oral administration of nilvadipine on cerebral blood flow in chronic cerebral infarction. Angiobgy. 1992;43:801809. 8. Ruttimann S, No11G, Dreifuse M, Muller-Brand J. Cerebral blood flow is not altered by treatment with nitrendipine in patients with mild to moderate hypertension. J Cardb~08~Phtumucol. lSS1;18(Suppl l):SlOS-5111. 9. Honorato J, Azanza J, Guindo N, Suarez JR. Double-blind placebo-controlled study of the antihypertensive efficacy of nitrendipine in patienta submitted to ambulatory blood preesure monitoring. Curr Ther Res. 1989;46932-939. 10. Hoeemann V. Circadian changes of blood preesure and stroke. In: Zulch KJ, ed. CerebraI Cimtin and Stroke. Berlin/Heidelberg/New York Springer, 1971:203-208. 11. Marshall J. Diurnal variation in occurrence of strokes. Stroke. 1977;8:230-231. 12. Obrist WD, Thompeon HK, Kin CH, Wang HS. Regional cerebral blood flow estimated by ‘=Xe inhalation. Stroke. lS75;6:245-256. 13. Naritomi H, Murata T, Shimizu T, et al. F&&e of arotinolol on regional cerebral blood flow in hypertensive patients with a history of stroke. Drug Deu Res. 1990,21:143-149. 14. Naritomi H, Shimizu T, Watanabe Y, et al. Effects of angiotenein-converting enzyme inhibitor alacepril on cerebral blood flow in hypertensive stroke patients A pilot study. Curr Ther Res. 19&1,55:1446-1454. 15. Risberg J, Ali Z, Wilson EM, et al. Regional cerebral blood flow by lSSXenon inhalation. Stroke. 1975;6:142-148. 16. Auer LM, Pfurtacheller G, Abobaker S, et al. Penumbra around chronic cerebral infarction? Neural Res. 1988,10:246-251. 17. Aihara K, Inui J. Nitrendipine facilitates recovery of cerebral blood flow, EEG and metabolitee following cerebral ischemia in anesthetized rabbits. Tohoku J Exp Med. lSS1;165:13-24.

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