Eur J Clin Pharmacol (1990) 39:403-404

Short communications

European ,Iouma, of 1 ~ ( ~ : ~

@%QssaQ erle®9 @ Springer-Verlag 1990

Effect of nifedipine monotherapy on platelet aggregation in patients with untreated essential hypertension* Z. Ogmia~owska 1, M. N a r t o w i c z - S t o n i e w s k a 3, J. M. S~omi/lski ~, and B. K r u p a - W o j c i e c h o w s k a 2

Department of Diagnostic Laboratory, 2 Second Clinic of Internal Diseases, Institute of Internal Medicine and 3 Department of Pathophysiology, Institute of Pathophysiology, Medical Academy, Gdafisk, Poland

Received: April 19, 1989/Accepted in revised form: March 15, 1990

Summary. The effect of 6 weeks of nifedipine 30-60 mg/d on platelet aggregat ion and lipid parameters has been studied.

A diminut ion in ADP- , adrenal ine- and collagen-in- duced aggregat ion was observed. In the case of adren- aline- and col lagen-st imulated aggregat ion the decrease was statistically significant. It was found that platelets which aggregated marked ly during the p lacebo t rea tment were most strongly inhibited by nifedipine. The changes in lipid parameters were no t significantly correla ted with changes in aggregation.

Key words: nifedipine, hypertension; lipids, platelet ag- gregat ion

Calcium channel antagonists are amongst the mos t com- monly used drugs in rout ine ant ihypertensive therapy. In spite of their wide applicability, the side-effects of these drugs are not fully known. There are few reports of the ef- fects of nifedipine and b lood platelet funct ion [Dale et al. 1983, Nyrop and Zweifler 1988, Walley et al. 1989]. The aim of the present s tudy was to examine whether and how pro longed nifedipine t rea tment would affect platelet ag- gregat ion and lipid parameters , and what were the corre- lations be tween any parameters affected.

Subjects

Fifteen male patients aged 40-60 y (mean age 49.8 y) with mild to moderate untreated essential hypertension (WHO Group I -7, and Group II - 8 persons) were selected from outpatients attending the Department of Hypertension, Medical Academy of Gdafisk.

The patients had no history or clinical evidence of vascular dis- ease, diabetes mellitus, hepatic or haematological disorders. All sub- jects had normal urinalysis and renal function, as estimated by cre- atinine clearance. They were examined as outpatients and were at work. The patients were on a free diet with no restriction of sodium intake. None was addicted to alcohol or was taking any drugs. Smok- ing and food intake were not allowed for 12 h before sampling. The examinations were carried out between 08.30 and 09.00 h after

* This rePort is a part of a project realized within the frames of the government programme of studies of the side-effects of hypotensive drugs given for i year.

30 min of supine rest. Every subject was examined by the same physician. Patients gave their informed consent to participation in the study. Nifedipine 30-60 mg/d was administered for 6 weeks after 2 weeks on placebo. The characteristics of the 15 hypertensive men under study are listed in Table 1.

Methods

Blood was taken from the right antecubital vein by careful vene- puncture without stasis and was collected in plastic tubes containing 1/10 volume sodium citrate (3.8%) for measurement of platelet ag- gregation. At the same time blood was collected for lipid tests ac- cording to the specific requirements.

Platelet aggregation studies were performed using the turbi- dimetric method of Born [Born 1962]. Platelet rich plasma (PRP) was obtained by immediate centrifugation of the blood samples at 160 g for 10 rain at room temperature. The remaining blood was cen- trifuged at 3000 g for 20 min to obtain platelet poor plasma (PPP). The platelet count of the PRP was adjusted to 250-300 x 109.1- ~. An aggregometer Elvi 840 (ELVI S p.A. Milano, Italy) and Omni- scribe ® recorder Logos 176 were used for this procedure. The PPP and PRP were used as 100% and 0% light transmission standards, respectively.

Table 1. Characteristics of the hypertensive patients (n = 15)

After placebo After nifedipine

Body weight (kg)

Body mass index (kg.m-2)

Supine blood pressure (mmUg)

Systolic Diastolic Mean

Cholesterol (mmol.l-1)

LDL-Choles- terol (mmol.1 1)

HDL-Choles- terol (mmol. 1-1)

Triglycerides (mmol.l-1)*

82.3 (2.7) 81.8 (3.1) NS

27.8 (0.8) 26.9 (0.5) NS

138 (4) 120 (3) P < 0.001 104 (2) 88 (3) P < 0.001 115 (3) 101 (2) P < 0.001

6.28 (0.24) 6.35 (0.26) NS

4.21 (0.18) 4.38 (0.26) NS

1.18 (0.12) 1.21 (0.14) NS

1.98 (0.84-4.22) 1.71 (0.85-2.69) NS

Mean (SEM), * median and range. NS =not significant, P=significance of placebo-nifedipine dif- ference

404

Table 2. Aggregatory response after 2 6 weeks of nifedipine treatment

weeks on placebo and

Parameter After After placebo nifedipine

%LTforADP10 49.3 (3.2) 38.6 (2.5) P<0.01 (gmol.1 1) (n : 15) (n : 15)

% LT for ADP 2.5 37.4 (3.6) 31.7 (2.8) NS (Ixmol-1-1) (n = 15) (n = 15)

% LT for Adrenaline 45.8 (2.9) 28.2 (2.4) P < 0.01 10.0 (gmol-1-1) (n = 12) (n = 12)

%LTforAdrenaline 34.6 (3.5) 19.9 (2.5) P<0.001 1.0 (gmol-1-1) (n = 15) (n = 15)

% LT for Collagen 55.6 (3.6) 46.4 (2.9) P < 0.01 0.1 (mg.m1-1) (n = 11) (n = 11)

% LT for Collagen 34.5 (3.8) 21.9 (2.8) P < 0.001 0.01 (mg-ml -I) (n = 15) (n = 15)

Lag phase for Collagen 30.0 (2.0) 43.0 (4.0) P < 0.05 0.1 mg.ml -I (second) (n : 11) (n = 11)

Lag phase for Collagen 40.0 (3.0) 62.0 (6.0) P < 0.001 0.01 mg. ml 1 (second) (n = 15) (n = 15)

Mean (SEM), P= significance of placebo-nifedipine difference, NS = not significant, LT = light transmission 5 min after addition of agonist

The aggregating agents (collagen, adrenaline, ADP - Sigma Chemical Co., St. Louis, USA) were added after 1 min of incubation of plasma, at 37 °C, with constant stirring, in plastic cuvettes in the aggregation module. All aggregation studies were done within i h of the venepuncture. The percentage light transmission was measured 5 min after adding the agonist.

Cholesterol and triglycerides in total plasma and cholesterol in various ultracentrifuged fractions were determined enzymatically by the CHOD-PAP and GPO-PAP methods, respectively (B oehringer, Mannheim, FRG).

Blood pressure was measured using a mercury sphygmo- manometer. Mean blood pressure was calculated as diastolic pres- sure + 1/3 pulse pressure. Body mass index was calculated as weight/height 2.

Z. Ogmiat:owska et al.: Nifedipine and platelet aggregation

The change in platelet aggregat ion was highly corre- lated with that in b lood pressure after nifedipine, espe- cially adrenaline- and col lagen-induced aggregat ion (r = 0.89). There was also an evident relationship be tween the diminut ion in aggregat ion after t rea tment and its initial level.

Discussion

The results do not provide evidence that nifedipine affects aggregat ion due to modif icat ion of lipid parameters , as has been found with beta adrenocep tor blockers [Burstein et al. 1979; N o r d o y and Svensson, 1979]. A decrease in lipid levels due to nifedipine has been repor ted [Trost and Weidmann, 1987], but in the present study the changes in lipids were not significantly correla ted with changes in ag- gregation. The inhibitory effect of nifedipine on aggrega- t ion may depend on the concent ra t ion of the aggregating agent. In the case of A D P as the aggregatory factor, the ef- fect of nifedipine became evident at a higher concentra- t ion of A D P (10 gM), confirming a previous repor t [Minuz et al. 1989, unpubl ished data]. For adrenal ine and collagen as the aggregat ing factors the more p r o n o u n c e d inhibition of aggregat ion by nifedipine was observed at lower concentra t ions of the agonists. Similar findings are repor ted by Walley et al. [Walley et al. 1989] f rom in vitro studies.

The inhibition of aggregat ion by nifedipine was found to depend on the aggregabili ty before t reatment . In par- ticular nifedipine suppressed abnormal platelet aggrega- tion. The mechan i sm of the p h e n o m e n o n and its possible clinical implications require fur ther study.

Acknowledgements. We thank Prof. R. Kaliszan for his suggestions and advice, and Dr. K. Ogmialowski for his help with statistical analysis.

Statistical analysis

Standard statistical methods were employed to calculate mean values, SEM, SD, median and linear regression. The values were tested by paired Student's t-test. A difference between means was considered significant if P < 0.05.

Results

The results of determinat ions are shown in Table 2. Pla- telet aggregat ion induced by lower concent ra t ion of A D P (2.5 gmol . 1-1) did not change after nifedipine t r ea tment as compared to the p lacebo phase. However , at the higher A D P concent ra t ion (10 gmol-1-1) a significant (P < 0.01) decrease in aggregat ion was observed. The adrenaline-in- duced aggregat ion was reduced after nifedipine t rea tment and the magni tude of the effect appeared to depend on the concent ra t ion of the agonist. A similar effect was seen with col lagen-induced aggregation. Af te r nifedipine, there was a diminution in transmission fol lowed by an ex- tension of the lag phase, especially at lower collagen con- centrations. No significant changes in the lipid parameters was found after nifedipine.

References

Born GVR (1962) Aggregation of blood platelets by adenosine di- phosphate and its reversal. Nature 194:927-930

Burnstein Y, Berns L, Heldenbug D, Kohn Y, Werbin BZ, Tamin J (1979) Increase in platelet aggregation following a rise in plasma free fatty acids. Am J Haematol 4:17-22

Dale J, Landmark KH, Myhre E (1983) The effects of nifedipine, a calcium antagonist on platelet function. Am Heart J 105:103-105

Hiroki T, Morishita Y, Inoue T, Yoshida T, Arakawa K (1986) Effect of nifedipine on platelet aggregation response to exercise in pa- tients with ischaemic heart disease. In: Lichtlen PR (ed) 6th Inter- national Adalat ® Symposium. Excepta Medica, Amsterdam

Nordoy A, Svensson B (1979) The effect of albuminebound fatty acids on platelets and endothelial cells. Thromb Res 15:215-226

Nyrop M, Zweifler A (1988) Platelet aggregation in hypertension and the effects of antihypertensive treatment. J Hypertens 6: 263- 269

Walley T J, Woods KL, Barnett DB (1989) Effects of calcium channel blockers on in vitro platelet function in whole blood using single platelet counting. Thromb Haemostas 61:137-139

Dr. Z. Ogmia{owska Arctowskiego 6/2 80-287 Gdafisk Poland