Comparison of anti-aggregatory effects of PGI2, PGI3 and iloprost on human and rabbit platelets.

In human, prostaglandin I3 (PGI3) is as potent inhibitor of platelet aggregation as prostacyclin (PGI2). However the data on the anti-aggregatiory effect of this prostaglandin is scanty on human and is absent on platelets of other species. The potency of PGI3 on other species may be different if there are differences in the structure of receptors. Comparison of the rank orders of the potency of the selective agonists in different species may provide evidence for the existence of such differences. The aim of this work was to study the anti-aggregatory effect of PGI3 on the platelets of human and rabbit and compare the rank orders of the potency of PGI2, PGI3, and iloprost, a synthetic analogue of PGI2, on the platelets of the two species. Experiments were performed in the suspensions of washed platelets prepared from the blood anticoagulated with trisodium citrate solution. A prostaglandin concentration causing 50% inhibition of ADP-induced platelet aggregation (IC50) was obtained from concentration-effect curves. On human platelets, PGI3 was as effective as PGI2, while on rabbit platelets, the value of IC50 for PGI3 (10.2 +/- 1.6 nM) was twofold higher than that of PGI2. The rank orders of agonist potency are different in rabbit compared to those of human. This indicates that the prostacyclin receptors of rabbit platelets are pharmacologically different from those of human.

Blood plasma influences anti-aggregatory potency of prostaglandins: effect of albumin.

The anti-aggregatory effects of prostaglandins (PGs) were compared in platelet-rich plasma (PRP) with that in washed platelets (WP). PGE(1), 13,14-dihydro-PGE(1), 5,6-dihydro-PGE(3) and ethyl ester of PGE(1) had the same potency in both platelet preparations. Iloprost was significantly more potent in WP compared to PRP, while 5,6-trans-PGE(2) and PGE(3) had higher potency in PRP than in WP. Albumin (35 mg/ml) in WP decreased the potency of iloprost but did not change the IC(50) value for PGE(3). In PRP, PGs were 1.5-2.8 times more potent when incubated 3 min as compared to 30 s, while in WP, the incubation time did not affect the IC(50) values for PGs. In WP with albumin, the potency of iloprost was significantly lower when it was incubated 30 s as compared to 3 min. Thus, plasma albumin is responsible for time-dependent effect of PGs and for the lower potency of iloprost but not for the higher potency of PGs in PRP.

Modulatory effect of 8-iso-PGE2 on platelets.

1. 8-Iso-PGE2 induced either reversible or irreversible aggregation of platelets in human platelet-rich plasma (PRP) or in the suspension of washed platelets (WP). The values of EC50 for irreversible aggregation in PRP and WP were 4 and 2 microM, respectively. 2. In rabbit PRP, 8-iso-PGE2 (0.1-100 microM) itself did not induce or induced only reversible aggregation. 3. 8-Iso-PGE2 (0.1-20 microM) potentiated adenosine diphosphate-(ADP) induced platelet aggregation in both human and rabbit. The same effect also was found for adrenaline-induced platelet aggregation in rabbit. 4. The lower concentrations (0.2-0.5 microM) of 8-iso-PGE2 decreased, and higher concentrations (1-2 microM) increased platelet aggregating factor- (PAF) induced aggregation in human PRP. In rabbit PRP, 8-iso-PGE2 (0.02-200 microM) had only a decreasing effect on PAF-induced aggregation. 5. The results suggest that low concentrations of 8-iso-PGE2 can amplify or weaken platelet aggregation induced by various aggregatory agents.

A 15-nonstereogenic carbocyclic analogue of prostacyclin: effects on human platelets and uterine artery.

Platelet-suppressant and vasodilator effects of the (+) enantiomer of 13,14-dihydro-15,16,17,18,19,20-hexanor-14-(1-hydroxycyclohexyl)++ +carbocyclin (MM706), a carbocyclic analogue of prostacyclin with the 15-hydroxyl group located at a symmetrically substituted carbon atom were studied on human platelets and isolated uterine artery. In washed platelets it inhibits platelet aggregation with an IC50 value of 77 nM as compared to IC50 = 1.3 nM for PGI2. In the presence of indomethacin its potency like that of PGI2 decreases about 2-fold. Also, MM706 like PGI2 fails to inhibit the norepinephrine (NE)-stimulated contractions of isolated human uterine artery in the absence of indomethacin. Pretreatment of the artery with indomethacin (3 microM) makes it sensitive to both MM706 and PGI2, the EC50 values being 99 and 3.1 nM, respectively. The results show that MM706 is an effective inhibitor of platelet aggregation and NE-stimulated contractions of the indomethacin-treated uterine artery.

Comparison of the inhibitory effect of E-prostaglandins in human and rabbit platelet-rich plasma and washed platelets.

1. The anti-aggregatory potency of a number of E-type PGs was compared in human and rabbit platelet-rich plasma (PRP) and washed platelets. The potency of 13,14-dihydro-PGE1 and 5,6-dihydro-PGE3 is significantly higher in human than in rabbit washed platelets, while the potency of 15-keto-13,14-dihydro-PGE1 is higher in rabbit. 2. The potency of PGEs in rabbit PRP is very similar to that of washed platelets, with the exception of 1a,1b-dihomo-PGE2, which is of a significantly lower potency in PRR. 3. In human, 5,6-trans-PGE2, PGE3, and 15-keto-13,14-dihydro-PGE1 are more potent in PRP than in washed platelets. 4. The results indicate that the potency of E-type PGs in human and rabbit platelets is different and plasma can essentially influence the anti-aggregatory effect of PGEs; plasma can either decrease or increase potency.

[Action of carbacyclic 13,14-didehydro-analogs of prostacyclin on the contractile activity of the rat stomach muscles]. / Deistvie karbitsiklicheskikh 13,14-didegidro-ananlogov prostatsiklina na sokratitel'nuiu aktivnost' myshtsy zheludka krysy.

The pharmacological activity of bicyclooctane and bicycloheptane analogues of prostacyclin was studied on the rat stomach muscle strip. All the analogues are partial agonists. EC50 of the most active of them, 5E isomer of bicyclooctane analogue, is 2.8.10(-7) M-1.2.10(-7) M. 5E isomers of both bicyclooctane and bicycloheptane analogues with a normal length of alpha-chain are at least by an order of values more active than the corresponding 5Z isomers. At the increase of alpha-chain by one methylene group the activity of 5E and 5Z isomers of bicycloheptane analogue becomes similar.

Identification and biological activity of a novel natural prostaglandin, 5,6-dihydro-prostaglandin E3.

A novel natural E-prostaglandin was detected by HPLC among the endogenous prostaglandins extracted from ram seminal vesicles. The corresponding precursor - all-cis-eicosa-8, 11, 14, 17-tetraenoic acid was isolated from bovine liver lipids and the preparative biosynthesis with the microsomal fraction of ram seminal vesicles was performed. The isolated product was purified by HPLC and identified by GC-MS as 5,6-dihydro-PGE3. The results of in vitro tests demonstrate that 5,6-dihydro-PGE3 is 14 times less active uterine stimulant than PGE1, at the same time retaining 75% of the anti-aggregatory potency of PGE1. Thus, 5,6-dihydro-PGE3 meets the requirements of a selective antithrombotic agent more than PGE1.

Cholinoreceptors of the dentis retractor muscle of the sea urchin Strongylocentrotus intermedius.

Neostigmine increases and cholinergic blocking agents block contractions of Strongylocentrotus intermedius dentis retractor muscle caused by either acetylcholine or indirect stimulation. Both innervated and non-innervated parts of the muscle are sensitive to low acetylcholine concentration suggesting that there are both synaptic and extra-synaptic cholinoreceptors. Nicotinomimetics are more potent than muscarinomimetics. Both d-tubocurarine and atropine are weak blocking agents as compared to pentadecamethylene-bis-trimethylammonium or hexadecamethylene-bis-trimethylammonium, Kd being 1 X 10(-4) to 5 X 10(-5) and 5 X 10(-7) to 4 X 10(-7) M respectively. Disulphide bonds and carboxylic (or phosphate) groups were revealed in dentis retractor muscle cholinoreceptors using drugs modifying receptor structure. Cholinoreceptors of both nicotinic and muscarinic type were revealed in oesophagus longitudinal muscles of Strongylocentrotus intermedius.

The muscle chemoreceptors of the ascidian Halocynthia aurantium.

The body wall muscle of the ascidian, Halocynthia aurantium, is sensitive to both nicotinomimetics and muscarinomimetics. Atropine (4 X 10(-11 M) and benzilylcholine mustard (1 X 10(-5) M for 15 min) selectively block responses to muscarinomimetics. d-Tubocurarine (2 X 10(-6) M) and hexadecamethylene-bis-trimethylammonium (2 X 10(-7) M) prevent contractions induced by both nicotinomimetics and muscarinomimetics. In the cold season of the year the sensitivity of the muscle to muscarinomimetics disappears while responses to nicotinomimetics do not change throughout the year. The cooling of the water in the experimental bath results in an increase in the muscle contractions caused by muscarinomimetics while the responses to nicotinomimetic propionylcholine do not change. Catecholamines induce a decrease of the ascidian muscle responses to acetylcholine, cGMP and papaverine produce a similar effect.

[Pharmacologic analysis of the biphasic postsynaptic potentials of an identified neuron of the mollusk Planorbarius corneus]. / Farmakologicheskii analiz dvukhfaznykh postsinapticheskikh potentsialov identifitsirovannogo neirona molliuska Planorbarius corneus.

Identified neuron in the left pedal ganglion of the mollusc P. corneus responds by biphasic postsynaptic potential (BPSP) to nerve stimulation. The depolarizing phase of both the BPSP and the response to acetylcholine is abolished by tubocurarine, whereas the hypopolarizing phase is blocked by tetramethylammonium. The results obtained suggest that BPSP is due to activation of two kinds of cholinoreceptors in the neuronal membrane.

[Hyperpolarization response of an identified neuron of Planobarius corneus mollusks to several cholinomimetic substances]. / Giperpoliarizatsionnyi otvet identifitsirovannogo neirona molliuska Planorbarius corneus na nekotorye kholinomimeticheskie veshchestva

Two kinds of responses to cholinomimetics were found on the identified neuron (P-2) of Planorbarius corneus pedal ganglion using microelectrode technique. Nicotinomimetics caused depolization whereas some muscarinomimetics caused hyperpolarization of the neuron membrane. Acetylcholine usually depolarized the neuron membrane but after the blockade of nicotinic receptors with tubocurarine one can reveal a hyperpolarizing action of acetylcholine. These findings suggest that two kinds of receptors exist on the P-2 neuron membrane and these receptors differ both in pharmacological characteristics and in ionic permeability changes they control.