Comparison in anesthetized dogs of the anti-aggregatory and hemodynamic effects of prostacyclin and a chemically stable prostacyclin analog, 6a-carba-PGI2 (carbacyclin)

Aiken, James W.; Shebuski, Ronald J.

doi:10.1016/s0090-6980(80)80011-6

Cited by 72 publications

(19 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The data on three of these animals given the control antibody before 7E3-F(abm)2 are shown in Figure 2. One monkey given 0.4 mg/kg of the control antibody at a time when thrombus formation had just begun, stopped forming thrombi approximately [15][16][17][18][19][20] …”

Section: Control Antibodymentioning

confidence: 99%

Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors.

et al. 1989

View full text Add to dashboard Cite

We studied the dose-response effects of the F(ab')2 fragments of murine monoclonal antibodies to the platelet GPIIb/IIIa receptor (7E3 and 10E5) on in vivo platelet thrombus formation in a well-characterized monkey model in which the carotid artery is stenosed and thrombus formation is provoked and augmented by intimal We previously showed that a dose of 0.8 mg/kg of the F(ab')2 fragment of a murine monoclonal antibody (7E3) directed against the platelet GPIIb/IIIa

show abstract

Section: Control Antibodymentioning

confidence: 99%

Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors.

et al. 1989

View full text Add to dashboard Cite

show abstract

“…However, the synthesis and biological actions of stable carbocyclic analogues of prostacyclin, in which the enol-ether oxygen atom is replaced by a methylene group, has attracted much attention and has been described by several groups.9 '6 Carbacyclin analogues. Carbacyclin, or (5E)-6a carbaprostaglandin '2 (figure 1, A), inhibits human platelet aggregation induced by a variety of agents including ADP, collagen, and arachidonic acid, while also inhibiting aggregation in platelet-rich plasma (PRP) obtained from several species, including the rabbit, rat, and dog.12 16 In our studies with carbacyclin,'3 this stable analogue was 0.03 times as potent as prostacyclin as an inhibitor of aggregation induced by ADP (table 1), collagen, and arachidonic acid. As with prostacyclin, the antiaggregating activity of carbacyclin was enhanced by preincubation of platelets with theophylline, the phosphodiesterase inhibitor,'3' 1 ' indicating stimulation of cyclic AMP as its mechanism of inhibitory action.…”

mentioning

confidence: 99%

Platelet actions of stable carbocyclic analogues of prostacyclin.

Whittle¹,

Moncada²

1985

Circulation

View full text Add to dashboard Cite

SINCE THE TIME of the discovery of prostacyclin' and the elucidation of its chemical structure as prostaglandin (PG) (5Z)-9 deoxy-6, 9 a-epoxy-&APGF,,2 many synthetic prostacyclin analogues have been pre- Many structural variants of prostacyclin have been synthesized, including 5,6-dihydro analogues, exemplified by 6f3-PGI,,3-5 thia prostacyclins such as (5Z)-6,9-thia prostacyclin,6 nitrogen-containing analogues such as 9-deoxy-9a-6-nitrilo-PGF ,7 ring-expanded 5,9-epoxy derivatives such as 9-deoxy-5, 9a-epoxy-PGFI,7 and interphenylene analogues.' However, the synthesis and biological actions of stable carbocyclic analogues of prostacyclin, in which the enol-ether oxygen atom is replaced by a methylene group, has attracted much attention and has been described by several groups.9'6 Carbacyclin analogues. Carbacyclin, or (5E)-6a carbaprostaglandin '2 (figure 1, A), inhibits human platelet aggregation induced by a variety of agents including ADP, collagen, and arachidonic acid, while also inhibiting aggregation in platelet-rich plasma (PRP) obtained from several species, including the rabbit, rat, and dog.12 16 In our studies with carbacyclin,'3 this stable analogue was 0.03 times as potent as prostacyclin as an inhibitor of aggregation induced by ADP (table 1), collagen, and arachidonic acid. As with prostacyclin, the antiaggregating activity of carbacyclin was enhanced by preincubation of platelets with theophylline, the phosphodiesterase inhibitor,'3' 1 ' indicating stimulation of cyclic AMP as its mechanism of inhibitory action. Indeed, other studies have shown an elevation of platelet cyclic AMP after incubation with the analogue. 14 Carbacyclin has been shown to be a potent inhibitor of platelet aggregation ex vivo when infused intravenously in the dog and rabbit, being 0.1 times as active as the parent, prostacyclin.'3 Likewise, this analogue was effective in vivo in reducing formation of thrombi in canine coronary arteries'6 when infused intravenously. Studies with carbacyclin in anesthetized baboons have likewise shown inhibition of platelet aggregation determined ex vivo after intravenous or intragastric administration. 17In our studies in human PRP with analogues synthesized and supplied by the Upjohn Company, (5Z)-carbacyclin was less active than the (5E)-analogue, the latter being isosteric'2 with naturally occurring prostacyclin (5Z-PGI2). As expected, the (15R)-epimer had mimimal activity, as did the 2-nor derivative (table 1). Substitution in the 9 position'5 can also alter antiaggregating potency, with (5Z)-9,8-ethynyl and 9-cyano groupings enhancing activity and 9,3-methyl, 9-pentyl-1-ynyl, and 9-ethyl groupings decreasing activity compared with that induced by carbacyclin itself (table 1).Studies in human PRP with 9,f-methyl-carbacyclin (ciprostene; figure 2, B) have shown it to have comparable potency as an antiaggregating agent against several aggregating agents (table 2). This compound is equiactive in vitro in human PRP and whole blood, and elevates platelet cyclic AMP levels.'9Studies using...

show abstract

“…The effect of prostanoids on intracellular cyclic AMP levels Both PGE2, the stable and specific PGI2 agonist carbaprostacyclin (Whittle et al, 1980;Aiken & Shebuski, 1980) and PGD2 induced significant increases in intracellular cyclic AMP levels in bovine chondrocytes in culture (Figure la) when compared to non-stimulated cells; this effect was concentration-dependent. Carbaprostacyclin was the most potent agonist tested, presenting an EC0= 1.49 + 0.8 nM (n = 3), followed by PGE2 with an EC50=55.11+8.91 nM (n=6), and by PGD2 (EC5 =1.65+1.12 pM, n=4).…”

Section: Resultsmentioning

confidence: 98%

Characterization of the PGE₂ receptor subtype in bovine chondrocytes in culture

Brum‐Fernandes

Morisset

Bkaily

et al. 1996

British J Pharmacology

View full text Add to dashboard Cite

1 Prostaglandin E2 (PGE2) is an autacoid that decreases proteoglycan synthesis, increases metalloprotease production by cultured chondrocytes, and can modulate some of the actions of interleukin-l on cartilage. The objective of the present study was to characterize the subtype of prostaglandin E2 receptor present in bovine chondrocytes in culture. 2 Primary cultures of articular chondrocytes were prepared from slices of bovine carpal cartilage by sequential digestion with type III hyaluronidase, trypsin, type II collagenase, followed by overnight incubation in Dulbecco's Modified Eagle's Medium (DMEM) with type II collagenase, washing, and seeding at a density of 2 x 105 cells cm-2 in DMEM with 10% foetal bovine serum.3 PGE2 and carbaprostacyclin induced dose-dependent increases in intracellular cyclic AMP in bovine chondrocytes in culture. The potencies of these compounds were different, and maximal doses of PGE2 and carbaprostacyclin had an additive effect. PGD2 induced a small increase in intracellular cyclic AMP only at a high concentration (10-' M).4 PGE2 was more potent that the EP2 agonist 11-deoxy-PGE, at inducing increases in intracellular cyclic AMP. The EP2 agonist butaprost, however, induced only a small increase at a concentration of l0-5 M. 17-Phenyl-PGE2 (EPI agonist), sulprostone and MB 28767 (15S-hydroxy-9-oxo-16-phenoxy-wotetranorprost-13E-enoic acid) (EP3 agonists) did not induce an increase in intracellular cyclic AMP at concentrations up to l0-' M. The EP4 antagonist AH 23848B ([1a(Z),2fl,5a]-(±)-7-[5-[[(l,1'-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-5-heptenoic acid) antagonized PGE2 but not carbaprostacyclin effects on intracellular cyclic AMP. The Schild plot slope was different from 1 but this could be due to an interaction of PGE2 with IP receptors in high doses. The exact nature of the antagonism by compound AH 23848B could not be definitely established in these experimental conditions. 6 Neither PGE2 nor any of its analogues inhibited the increase in intracellular cyclic AMP induced by forskolin, and pertussis toxin did not alter the response to PGE2, suggesting that no Gi-coupled PGE2 receptors are present in these cells. Stimulation with PGE2 did not induce significant increases in intracellular inositol-trisphosphate levels nor increases in intracellular free calcium as determined by confocal microscopy, suggesting the absence of phospholipase-C-coupled or of calcium channel-coupled PGE2 receptors in bovine chondrocytes in these experimental conditions. 7 These results show for the first time that bovine chondrocytes in culture present a functional PGE2 receptor that has some pharmacological characteristics of an EP4 subtype, as well as an IP receptor.

show abstract

Comparison in anesthetized dogs of the anti-aggregatory and hemodynamic effects of prostacyclin and a chemically stable prostacyclin analog, 6a-carba-PGI2 (carbacyclin)

Cited by 72 publications

References 4 publications

Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors.

Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors.

Platelet actions of stable carbocyclic analogues of prostacyclin.

Characterization of the PGE₂ receptor subtype in bovine chondrocytes in culture

Contact Info

Product

Resources

About

Comparison in anesthetized dogs of the anti-aggregatory and hemodynamic effects of prostacyclin and a chemically stable prostacyclin analog, 6a-carba-PGI2 (carbacyclin)

Cited by 72 publications

References 4 publications

Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors.

Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors.

Platelet actions of stable carbocyclic analogues of prostacyclin.

Characterization of the PGE2 receptor subtype in bovine chondrocytes in culture

Contact Info

Product

Resources

About

Characterization of the PGE₂ receptor subtype in bovine chondrocytes in culture