Comparison of the vasodepressor action of ZK 36 374, a stable prostacyclin derivative, PGI2 and PGE1 with their effect on platelet aggregation and bleeding time in rats

Casals-Stenzel, J.; Buse, M; Losert, Wolfgang

doi:10.1016/s0262-1746(83)80010-9

Cited by 39 publications

(8 citation statements)

References 18 publications

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“…26,27 Furthermore, human SMCs are known to express IP-receptors and a variety of EP receptors. 28 Accordingly, mRNA transcripts of the IP, EP 1 , EP 2 , EP 3 , and EP 4 receptors were detected by RT-PCR in SMCs from the mammary artery that were used in the present study (not shown).…”

Section: Iloprost Induces Has2 Via Stimulation Of Ip Receptorsmentioning

confidence: 99%

Induction of Hyaluronic Acid Synthase 2 (HAS2) in Human Vascular Smooth Muscle Cells by Vasodilatory Prostaglandins

Sussmann

Sarbia

Meyer-Kirchrath

et al. 2004

Circulation Research

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Abstract-Hyaluronic acid (HA) is a prominent constituent of the extracellular matrix of atherosclerotic vascular lesions in humans known to modulate vascular smooth muscle phenotype. The regulation of HA synthesis by vasodilatory prostaglandins was analyzed in human arterial smooth muscle cells (SMCs). The prostacyclin analogue, iloprost (100 nmol/L), markedly increased pericellular formation of HA coats and HA secretion into the cell culture medium in human arterial SMCs (8.7Ϯ1.6-fold). Expression of HA synthase 2 (HAS2) was determined by semiquantitative RT-PCR and found to be strongly upregulated at concentrations of iloprost between 1 and 100 nmol/L after 3 hours. Furthermore, endogenous cyclooxygenase-2 (COX2) activity was required for basal expression of HAS2 mRNA in SMCs in vitro. Total HA secretion in response to iloprost was markedly decreased by RNA interference (RNAi), specific for HAS2. In addition, siRNA targeting HAS2 strongly increased the spreading of human SMCs compared with mock-transfected cells. HAS2 mRNA levels were also stimulated by a selective prostacyclin receptor (IP) agonist, cicaprost (10 nmol/L), prostaglandin E 2 (10 nmol/L), and the EP 2 receptor agonist, butaprost (1 mol/L). Induction of HAS2 mRNA and HA synthesis by prostaglandins was mimicked by stable cAMP analogues and forskolin. In human atherectomy specimens from the internal carotid artery, HA deposits and COX2 expression colocalized frequently. In addition, strong EP 2 receptor expression was detected in SMCs in HA-rich areas. Therefore, upregulation of HAS2 expression via EP 2 and IP receptors might contribute to the accumulation of HA during human atherosclerosis, thereby mediating proatherosclerotic functions of COX2.

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Section: Iloprost Induces Has2 Via Stimulation Of Ip Receptorsmentioning

confidence: 99%

Induction of Hyaluronic Acid Synthase 2 (HAS2) in Human Vascular Smooth Muscle Cells by Vasodilatory Prostaglandins

Sussmann

Sarbia

Meyer-Kirchrath

et al. 2004

Circulation Research

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“…The bullock iris sphincter preparation contains a PGE-sensitive contractile system which is blocked by SC 19220 (Posner, 1973). Our recent studies (Dong & Jones, 1982) have revealed that iloprost, a stable and potent mimetic of PGI2 (Casals-Stenzel et al, 1983) (Figure 1), possesses remarkably high agonist activity on the iris preparation and appears to behave as a partial agonist at the PGE receptor. We have investigated the action of iloprost on several other PGE sensitive preparations and also examined two other potent PGI2 mimetics, 6a-carba-A6'1PGI1 (Shibasaki et al, 1983) and ZK 96480 (Mueller et al, 1984) ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E receptor subtypes in smooth muscle: agonist activities of stable prostacyclin analogues

Duan

Jones

Wilson

1986

British J Pharmacology

155

101

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1 The agonist activities of a range of prostaglandin analogues on smooth muscle preparations sensitive to prostaglandin E2 (PGE2) have been investigated. When necessary thromboxane-like activity was eliminated using the thromboxane receptor antagonists EP 045 and EP 092. 2 On the bullock iris sphincter, rat stomach fundus and guinea-pig trachea, (±) w-tetranor-16-pchlorophenoxy PGE2 (ICI 80205) and 16,16-dimethyl PGE2 were more active contractile agents than PGE2, whereas for relaxant activity on the cat trachea, guinea-pig trachea and dog hind limb arterial vessels in vivo the order of potency was reversed. 1I -Deoxy PGEI exhibited greater relaxant than contractile activity when compared to PGE2.3 Iloprost and 6a-carba-A6,6aPGII (potent mimetics of PGI2) showed high contractile activity on the PGE-sensitive preparations. PG12 was less active and another potent PGI2 mimetic, ZK 96480, showed only very weak activity. When tested, the dibenzoxazepines SC 19220 and SC 25191 blocked the contractile actions of iloprost and 6a-carba-A6,'PGI, and those of PGE2 and 16,16-dimethyl PGE2 to similar extents. Each of the PG12 analogues showed weak activity on the relaxant systems.4 On the proximal portion of the ascending colon of the rat, PGI2, iloprost, 6a-carba-A6'IPGII and ZK 96480 always inhibited spontaneous activity at nanomolar concentrations. PGE2 and PGE, showed weak contractile activity. The distal portion of the ascending colon was more responsive to the contractile action of PGE analogues: both iloprost and 6a-carba-A6',PGI, showed evidence of contractile activity, whereas PGI2 and ZK 96480 always inhibited spontaneous activity. 5 Evidence was obtained that the rat stomach fundus also contains a PGF receptor; (± ) w-tetranor-16-m-trifluoromethylphenoxy PGF2A (ICI 81008) acted as a specific agonist. PGF2, and its w-tetranor-16-p-fluorophenoxy analogue produced a higher maximum response that ICI 81008 probably due to their additional agonist action at the PGE receptor. 6 The data support the hypothesis that there are two subtypes of the PGE receptor. ZK 96480 has minimal activity on both receptor subtypes and appears to be a highly specific PGI2 mimetic.

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“…In the experimental animal, Iloprost (ZK 36 374), a chemically stable carboprostacyclin derivative, was shown to be more potent than PGI2 with respect to antiplatelet properties, and it in duced less vasodilation [8,9]. Also, studies in which human platelets were incubated with ZK 36 374 de monstrated that the drug may be an even more power ful antiaggregating agent than PGI2 [8,10,11]. Fur ther, in human whole blood aggregation studies, ZK 36 374 caused disaggregation of preformed platelet aggregates [12].…”

Section: Discussionmentioning

confidence: 99%

Effect of Iloprost (ZK 36 374), a Novel Prostacyclin Analogue, on ADP-induced Platelet Aggregation

Wadenvik¹,

Kutti²

1985

Acta Haematol

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The effect of Iloprost (ZK 36 374), a chemically stable carboprostacyclin derivative, on ADP-induced platelet aggregation was investigated using platelet-rich plasma obtained from healthy male volunteers. It was shown that Iloprost in a dose-dependent fashion powerfully inhibits both the primary and secondary wave of ADP-induced platelet aggregation. Similarly, Iloprost immediately and most effectively disaggregates preformed platelet aggregates.

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Comparison of the vasodepressor action of ZK 36 374, a stable prostacyclin derivative, PGI2 and PGE1 with their effect on platelet aggregation and bleeding time in rats

Cited by 39 publications

References 18 publications

Induction of Hyaluronic Acid Synthase 2 (HAS2) in Human Vascular Smooth Muscle Cells by Vasodilatory Prostaglandins

Induction of Hyaluronic Acid Synthase 2 (HAS2) in Human Vascular Smooth Muscle Cells by Vasodilatory Prostaglandins

Prostaglandin E receptor subtypes in smooth muscle: agonist activities of stable prostacyclin analogues

Effect of Iloprost (ZK 36 374), a Novel Prostacyclin Analogue, on ADP-induced Platelet Aggregation

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