Effects of Prostaglandins and Thromboxane Analogues on Bullock and Dog Iris Sphincter Preparations

It is well known that the anticonvulsant effect of antiepileptic drugs is reduced by repeated administration in both experimental animals and man (Frey and Kampmann, 1965; Masuda et al., 1979; Rawling et al., 1975). The purpose of this investigation was to verify if denzimol, an arylalkylimidazole anticonvulsant agent (Nardi et al., 1981; Graziani et al., 1983) induces tolerance after repeated treatment in mice. Phenobarbitone (PB) and carbamazepine (CB) were used as reference drugs.We have investigated the antielectroshock activity (MES) and the brain levels of denzimol, after acute and repeated treatment, to verify whether the development of denzimol tolerance involves mechanisms of adaptation of the central nervous system or an induction of hepatic microsomial enzymes.Three groups of 20 mice each were treated p.o. for 14 days with denzimol (30 mg/kg), PB (25 mg/kg) or CB (30 mg/kg). Three control groups of mice received the vehicle (0.5% methocel). 24 hours after the end of the prolonged treatment, the respective drugs and vehicle, at the same dose as above, were given to the treated and control groups of animals. The anticonvulsant effect of each drug against MES was examined at 1,2,4,6,8 hrs after the last administration. The protection against the tonic extension of forelimb (TFP) and hindlimb (THP) induced by MES was the criterium used for the assessment of positive response.After MES, animals treated with denzimol were sacrificed and brains were removed for tissue drug levels evaluation (Abbiati et al. 1985).The present study shows that repeated administrations of PB, CB and denzimol resulted in a development of tolerance to their anticonvulsant action. Tolerance induced by denzimol against TFP and THP extension, resulted lower than that of PB and probably of CB. When denzimol was administered in a single dose to denzimol tolerant mice, its brain concentrations was markedly reduced if compared to non-tolerant mice. Moreover the disappearance of brain denzimol concentrations, after a single dose of drug, was alterated by repeated treatment of mice with denzimol. These findings seem to suggest that decreased anticonvulsant activity of denzimol, following repeated administrations, might be due to a development of pharmacokinetic tolerance.Abbiati G.A., Restelli G.V., Graziani G., Testa R. (1985) In previous experim-ents we have shown that prolactin (PRL) secretion in avian species is under a tonic inhibitory control of dopa;-iine (disticb et al.,1979). The present study was carried out in order to assess the role played b, cholinergic mechanisms in the control of PRL secretion in pigeons (Columba livia). In particular, we have assessed the effects of drugs enhancing by different mechanisms cholinergic transmiission, i.e. carbachol, muscarine and physostigmine, on morphology (studied by SEM5 and TEll) of crop-sac mlucosa and pituitary lactoWrophs.Carbachol, microinfused into the III cerebral ventricle (6 nrmiol) for 3 consecutive days, produced intense crop-sac stimulation with rmiilk-like secretion and...

Section: Treatmentsupporting

confidence: 72%

Poster Communications

1985

“…The first is activated by thromboxane-like agents to produce contraction and is readily blocked by EP 045; the second mediates a relaxant effect and is sensitive to PGE2 and its 15-methyl analogue; the third gives rise to a contractile effect and PGE2 analogues are potent agonists, but it is not blocked by EP 045. This latter system may be similar to that identified recently by us in the bullock iris sphincter muscle (Dong & Jones, 1982) (Jones et al, 1979;Jones & Wilson, 1980) should be disregarded because in many cases, in an attempt to construct a complete log concentration-response curve on a single preparation, insufficient time was allowed for achievement of a stable increase in tension by each dose.…”

Section: Effectofep045on the Action Ofotherprostaglandin Analoguesmentioning

confidence: 89%

Antagonism of the Thromboxane‐sensitive Contractile Systems of the Rabbit Aorta, Dog Saphenous Vein and Guinea‐pig Trachea

Jones

Venkateswarlu

Wilson

1982

Self Cite

133

1 The thromboxane-sensitive contractile systems in spirally-cut preparations of the rabbit aorta, dog saphenous vein and guinea-pig trachea have been compared. The full or partial agonist activities of a range of bicyclic ring analogues were found to be remarkably similar on the three preparations. In addition, EP 045, a prostanoid with a phenylsemicarbazone w-chain, blocked the action of both thromboxane A2 (TXA2) and the bicyclic ring analogues. Using 11,9-epoxymethano prostaglandin H2 as the agonist, linear Schild plots with slopes close to unity were obtained on each preparation; this suggests a competitive type of antagonism. 2 Analogues of prostaglandin D2 (PGD2), PGE2 and PGF2a also contracted the three smooth muscle preparations; those analogues containing a 16-p-halophenoxy residue were highly active. On the rabbit aorta, EP 045 completely blocked the contractile actions of these agonists, perhaps indicating a single type of prostanoid receptor in this tissue. On the dog saphenous vein PGD2, PGE2 and 15-methyl PGE2 exhibited relaxant activity when the tissue was partially contracted with either a thromboxane agonist or noradrenaline. On the guinea-pig trachea 16,16-dimethyl PGE2 and the 16-p-chlorophenoxy analogue of PGE2 were potent contractile agents whose action was not blocked by EP045. PGE2 and 15-methylPGE2 showed similar properties but exhibited relaxant activity with increasing concentrations in the organ bath. Our results indicate the presence of three types of prostanoid receptors in the guinea-pig trachea: thromboxane-and PGE-sensitive systems mediating contraction and a PGE-sensitive system mediating relaxation. 3 The similarity of the thromboxane-sensitive systems in the three smooth muscle preparations is discussed with particular reference to the differences in the equilibrium dissociation constants for EP 045.

“…Further evidence for this mechanism of action derives from the observation (Gaion & Trento, 1984) that the contractile action of PGI2 is inhibited by noradrenaline, morphine and the purinergic receptor agonist N6-phenylisopropyl adenosine (PIA). Gaion & Gambaratto (1987) Figure 2) since we have shown it to be a highly specific agonist for IP-receptors (Dong et al, 1986), in contrast to iloprost which has unexpectedly high EP1-agonist potency (Dong & Jones, 1982;Dong et al, 1986;Sheldrick et al, 1988). We have also examined carbacyclin and 10,10-difluoro-13,14-didehydro PGI2; the latter has greater aqueous stability than PGI2 due to the electron-withdrawing effect of the fluoro substituents on the enol ether unit (Fried et al, 1980).…”

Section: Introductionmentioning

confidence: 86%

Characterization of receptors involved in the direct and indirect actions of prostaglandins E and I on the guinea‐pig ileum

Lawrence

Jones

Wilson

1992

Self Cite

144

1 A study of the effects of prostaglandin E2 (PGE2) and eleven synthetic analogues on the guinea-pig isolated ileum preparation has revealed three distinct contractile actions, each associated with a different prostaglandin E (EP-) receptor subtype. In addition, PGI2 (prostacyclin) and its stable analogues can activate prostaglandin I (IP-) receptors to elicit both contraction and relaxation of the ileum. The contractile action of 17-phenyl-co-trinor PGE2 on the ileum is unaffected by morphine. Since this analogue shows only weak agonist activity on the rabbit jugular vein (EP2 preparation) and guinea-pig vas deferens (EP3), it may be a more useful standard agonist than PGE2 in EPl1-receptor studies. 5In the presence of morphine and AH 6809, cicaprost inhibits histamine-induced contractions (IC25 = 22 nM). PGI2 and iloprost show mixed inhibitory/potentiating actions, whereas carbacyclin only potentiates histamine contractions. This IP-receptor-mediated inhibition may account for the bell-shaped log concentration-response curve of cicaprost (no inhibitors present) and the very marked block of iloprostinduced contractions by AH 6809. 6 We have found no evidence for either IP-receptors mediating direct contraction or EP-receptors mediating inhibition of the ileum longitudinal smooth muscle, as has been suggested in the literature. 7 In view of the complexity of prostanoid action on the guinea-pig ileum we feel that the preparation must be used with caution to ascertain the EPl agonist or antagonist potencies of novel compounds.