Inhibitory effects of amitriptyline, sertraline and chlorpromazine on the thrombin-induced aggregation of platelets

Sang-Hyun Choi, Y. J. Le, Kyung-Ho Shin, Y. S. Chun, B. G. Chun

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Platelets resemble monoaminergic neurons in several respects, i.e the uptake of 5-HT and its inhibition, the subcellular storage and release of 5-HT, and the metabolism of aromatic amines brought about by monoamine oxidase. And the 5-HT content of rabbit platelets is well known to be about 40 times higher than that of human platelets. Therefore, this study was carried out to investigate the influences of amitriptyline (AMT) and sertraline (SRT) on the aggregation, contents of signaling second messengers, and protein phosphorylation of rabbit platelets in response to thrombin, 0.25 unit/ml, comparing with those of chlorpromazine (CPZ). Thrombin-induced aggregation was inhibited by SRT (IC50: 4.37 x 10-5 M), CPZ (IC50: 5.76 x 10-5 M), and AMT (IC50: 1.15 x 10-4 M), respectively, and the aggregation by A23187 (1.0 μM) or PMA (320 nM) was also inhibited by SRT, CPZ, and AMT. AMT, SRT, and CPZ had little affects on basal contents of platelet TXB2 and PGE2, but all of them inhibited the thrombin-induced increase of TXB2. Thrombin did not change the platelet contents of cAMP and cGMP. CPZ, AMT, and SRT produced the slight decrease of basal cAMP content, and their effects were not affected by thrombin-treatment. But SRT and AMT moderately increased the basal cGMP content, and the cGMP content of thrombin-stimulated platelets was gradually increased by the pretreatment with SRT, AMT, and CPZ. Particularly, the SRT-dependent increase of the cGMP content was notable. Platelet Ins(1,4,5)P3 content was rapidly increased up to a plateau within 10 sec after thrombin-stimulation. AMT, SRT, and CPZ increased the basal Ins(1,4,5)P3 content, and the thrombin-dependent increase was enhanced by pretreatment with CPZ and AMT, but was blunted by SRT. Platelet [Ca2+](i) was rapidly increased up to a peak level within 20 sec after thrombin-stimulation. The increase of [Ca2+]i was significantly inhibited by AMT, SRT, and CPZ. Thrombin- or PMA-induced phosphorylations of platelet 41 ~ 43 kDa and 20 kDa proteins were significantly inhibited by AMT, SRT, and CPZ. These results suggest that the antiplatelet activities of AMT and CPZ may be considerably attributed to the inhibition of protein kinase C activity, and the activity of SRT may be associated with the inhibitory effect on the thrombin-induced increase of Ins(1,4,5)P3 and the increasing effect on the cGMP content of platelets. Therefore, it seems to be evident that AMT and SRT may produce their antidepressant activity, at least, partly through the inhibition of protein kinase C activity or the increase of resting Ins(1,4,5)P3 content and in case of SRT, to a lesser extent, via the increase of cGMP in the brain.

Original languageEnglish
Pages (from-to)299-311
Number of pages13
JournalKorean Journal of Pharmacology
Volume31
Issue number3
Publication statusPublished - 1995 Dec 1

Fingerprint

Sertraline
Amitriptyline
Chlorpromazine
Platelet Aggregation
Thrombin
Blood Platelets
Inhibitory Concentration 50
Serotonin
Protein Kinase C
Phosphorylation
Rabbits
Monoamine Oxidase
Calcimycin
Second Messenger Systems
Dinoprostone

Keywords

  • [Ca](i)
  • amitriptyline
  • cAMP
  • cGMP
  • chlorpromazine
  • Ins(1,4,5)P
  • platelet aggregation
  • protein phosphorylation
  • sertraline
  • thromboxane

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibitory effects of amitriptyline, sertraline and chlorpromazine on the thrombin-induced aggregation of platelets. / Choi, Sang-Hyun; Le, Y. J.; Shin, Kyung-Ho; Chun, Y. S.; Chun, B. G.

In: Korean Journal of Pharmacology, Vol. 31, No. 3, 01.12.1995, p. 299-311.

Research output: Contribution to journalArticle

@article{3c849242429944f2a3a98478e27bfdd4,
title = "Inhibitory effects of amitriptyline, sertraline and chlorpromazine on the thrombin-induced aggregation of platelets",
abstract = "Platelets resemble monoaminergic neurons in several respects, i.e the uptake of 5-HT and its inhibition, the subcellular storage and release of 5-HT, and the metabolism of aromatic amines brought about by monoamine oxidase. And the 5-HT content of rabbit platelets is well known to be about 40 times higher than that of human platelets. Therefore, this study was carried out to investigate the influences of amitriptyline (AMT) and sertraline (SRT) on the aggregation, contents of signaling second messengers, and protein phosphorylation of rabbit platelets in response to thrombin, 0.25 unit/ml, comparing with those of chlorpromazine (CPZ). Thrombin-induced aggregation was inhibited by SRT (IC50: 4.37 x 10-5 M), CPZ (IC50: 5.76 x 10-5 M), and AMT (IC50: 1.15 x 10-4 M), respectively, and the aggregation by A23187 (1.0 μM) or PMA (320 nM) was also inhibited by SRT, CPZ, and AMT. AMT, SRT, and CPZ had little affects on basal contents of platelet TXB2 and PGE2, but all of them inhibited the thrombin-induced increase of TXB2. Thrombin did not change the platelet contents of cAMP and cGMP. CPZ, AMT, and SRT produced the slight decrease of basal cAMP content, and their effects were not affected by thrombin-treatment. But SRT and AMT moderately increased the basal cGMP content, and the cGMP content of thrombin-stimulated platelets was gradually increased by the pretreatment with SRT, AMT, and CPZ. Particularly, the SRT-dependent increase of the cGMP content was notable. Platelet Ins(1,4,5)P3 content was rapidly increased up to a plateau within 10 sec after thrombin-stimulation. AMT, SRT, and CPZ increased the basal Ins(1,4,5)P3 content, and the thrombin-dependent increase was enhanced by pretreatment with CPZ and AMT, but was blunted by SRT. Platelet [Ca2+](i) was rapidly increased up to a peak level within 20 sec after thrombin-stimulation. The increase of [Ca2+]i was significantly inhibited by AMT, SRT, and CPZ. Thrombin- or PMA-induced phosphorylations of platelet 41 ~ 43 kDa and 20 kDa proteins were significantly inhibited by AMT, SRT, and CPZ. These results suggest that the antiplatelet activities of AMT and CPZ may be considerably attributed to the inhibition of protein kinase C activity, and the activity of SRT may be associated with the inhibitory effect on the thrombin-induced increase of Ins(1,4,5)P3 and the increasing effect on the cGMP content of platelets. Therefore, it seems to be evident that AMT and SRT may produce their antidepressant activity, at least, partly through the inhibition of protein kinase C activity or the increase of resting Ins(1,4,5)P3 content and in case of SRT, to a lesser extent, via the increase of cGMP in the brain.",
keywords = "[Ca](i), amitriptyline, cAMP, cGMP, chlorpromazine, Ins(1,4,5)P, platelet aggregation, protein phosphorylation, sertraline, thromboxane",
author = "Sang-Hyun Choi and Le, {Y. J.} and Kyung-Ho Shin and Chun, {Y. S.} and Chun, {B. G.}",
year = "1995",
month = "12",
day = "1",
language = "English",
volume = "31",
pages = "299--311",
journal = "Korean Journal of Physiology and Pharmacology",
issn = "1226-4512",
publisher = "Korean Physiological Soc. and Korean Soc. of Pharmacology",
number = "3",

}

TY - JOUR

T1 - Inhibitory effects of amitriptyline, sertraline and chlorpromazine on the thrombin-induced aggregation of platelets

AU - Choi, Sang-Hyun

AU - Le, Y. J.

AU - Shin, Kyung-Ho

AU - Chun, Y. S.

AU - Chun, B. G.

PY - 1995/12/1

Y1 - 1995/12/1

N2 - Platelets resemble monoaminergic neurons in several respects, i.e the uptake of 5-HT and its inhibition, the subcellular storage and release of 5-HT, and the metabolism of aromatic amines brought about by monoamine oxidase. And the 5-HT content of rabbit platelets is well known to be about 40 times higher than that of human platelets. Therefore, this study was carried out to investigate the influences of amitriptyline (AMT) and sertraline (SRT) on the aggregation, contents of signaling second messengers, and protein phosphorylation of rabbit platelets in response to thrombin, 0.25 unit/ml, comparing with those of chlorpromazine (CPZ). Thrombin-induced aggregation was inhibited by SRT (IC50: 4.37 x 10-5 M), CPZ (IC50: 5.76 x 10-5 M), and AMT (IC50: 1.15 x 10-4 M), respectively, and the aggregation by A23187 (1.0 μM) or PMA (320 nM) was also inhibited by SRT, CPZ, and AMT. AMT, SRT, and CPZ had little affects on basal contents of platelet TXB2 and PGE2, but all of them inhibited the thrombin-induced increase of TXB2. Thrombin did not change the platelet contents of cAMP and cGMP. CPZ, AMT, and SRT produced the slight decrease of basal cAMP content, and their effects were not affected by thrombin-treatment. But SRT and AMT moderately increased the basal cGMP content, and the cGMP content of thrombin-stimulated platelets was gradually increased by the pretreatment with SRT, AMT, and CPZ. Particularly, the SRT-dependent increase of the cGMP content was notable. Platelet Ins(1,4,5)P3 content was rapidly increased up to a plateau within 10 sec after thrombin-stimulation. AMT, SRT, and CPZ increased the basal Ins(1,4,5)P3 content, and the thrombin-dependent increase was enhanced by pretreatment with CPZ and AMT, but was blunted by SRT. Platelet [Ca2+](i) was rapidly increased up to a peak level within 20 sec after thrombin-stimulation. The increase of [Ca2+]i was significantly inhibited by AMT, SRT, and CPZ. Thrombin- or PMA-induced phosphorylations of platelet 41 ~ 43 kDa and 20 kDa proteins were significantly inhibited by AMT, SRT, and CPZ. These results suggest that the antiplatelet activities of AMT and CPZ may be considerably attributed to the inhibition of protein kinase C activity, and the activity of SRT may be associated with the inhibitory effect on the thrombin-induced increase of Ins(1,4,5)P3 and the increasing effect on the cGMP content of platelets. Therefore, it seems to be evident that AMT and SRT may produce their antidepressant activity, at least, partly through the inhibition of protein kinase C activity or the increase of resting Ins(1,4,5)P3 content and in case of SRT, to a lesser extent, via the increase of cGMP in the brain.

AB - Platelets resemble monoaminergic neurons in several respects, i.e the uptake of 5-HT and its inhibition, the subcellular storage and release of 5-HT, and the metabolism of aromatic amines brought about by monoamine oxidase. And the 5-HT content of rabbit platelets is well known to be about 40 times higher than that of human platelets. Therefore, this study was carried out to investigate the influences of amitriptyline (AMT) and sertraline (SRT) on the aggregation, contents of signaling second messengers, and protein phosphorylation of rabbit platelets in response to thrombin, 0.25 unit/ml, comparing with those of chlorpromazine (CPZ). Thrombin-induced aggregation was inhibited by SRT (IC50: 4.37 x 10-5 M), CPZ (IC50: 5.76 x 10-5 M), and AMT (IC50: 1.15 x 10-4 M), respectively, and the aggregation by A23187 (1.0 μM) or PMA (320 nM) was also inhibited by SRT, CPZ, and AMT. AMT, SRT, and CPZ had little affects on basal contents of platelet TXB2 and PGE2, but all of them inhibited the thrombin-induced increase of TXB2. Thrombin did not change the platelet contents of cAMP and cGMP. CPZ, AMT, and SRT produced the slight decrease of basal cAMP content, and their effects were not affected by thrombin-treatment. But SRT and AMT moderately increased the basal cGMP content, and the cGMP content of thrombin-stimulated platelets was gradually increased by the pretreatment with SRT, AMT, and CPZ. Particularly, the SRT-dependent increase of the cGMP content was notable. Platelet Ins(1,4,5)P3 content was rapidly increased up to a plateau within 10 sec after thrombin-stimulation. AMT, SRT, and CPZ increased the basal Ins(1,4,5)P3 content, and the thrombin-dependent increase was enhanced by pretreatment with CPZ and AMT, but was blunted by SRT. Platelet [Ca2+](i) was rapidly increased up to a peak level within 20 sec after thrombin-stimulation. The increase of [Ca2+]i was significantly inhibited by AMT, SRT, and CPZ. Thrombin- or PMA-induced phosphorylations of platelet 41 ~ 43 kDa and 20 kDa proteins were significantly inhibited by AMT, SRT, and CPZ. These results suggest that the antiplatelet activities of AMT and CPZ may be considerably attributed to the inhibition of protein kinase C activity, and the activity of SRT may be associated with the inhibitory effect on the thrombin-induced increase of Ins(1,4,5)P3 and the increasing effect on the cGMP content of platelets. Therefore, it seems to be evident that AMT and SRT may produce their antidepressant activity, at least, partly through the inhibition of protein kinase C activity or the increase of resting Ins(1,4,5)P3 content and in case of SRT, to a lesser extent, via the increase of cGMP in the brain.

KW - [Ca](i)

KW - amitriptyline

KW - cAMP

KW - cGMP

KW - chlorpromazine

KW - Ins(1,4,5)P

KW - platelet aggregation

KW - protein phosphorylation

KW - sertraline

KW - thromboxane

UR - http://www.scopus.com/inward/record.url?scp=0029555490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029555490&partnerID=8YFLogxK

M3 - Article

VL - 31

SP - 299

EP - 311

JO - Korean Journal of Physiology and Pharmacology

JF - Korean Journal of Physiology and Pharmacology

SN - 1226-4512

IS - 3

ER -