No abstract

1 We investigated the contracting actions of the isoprostanes (isoPs), 8-iso-prostaglandin (PG) F 2a and 8-iso-PGE 2 , in comparison to the eects of the thromboxane (TX) A 2 -mimetic U 46619 and the traditional prostaglandin PGE 2 in the isolated rat aorta, isolated rat gastric fundus and the isolated guinea-pig ileum. 2 U 46619 and 8-iso-PGF 2a caused contractions in the rat aorta and rat gastric fundus in a concentration-dependent manner, whereas these agonists showed no eects in the guinea-pig ileum. However, 8-iso-PGE 2 and PGE 2 caused contractions in all isolated organs used. 3 The prostanoid TP-receptor antagonist SQ 29,548 (10 nM) signi®cantly antagonized vasoconstrictions induced by the agonists used in the rat aorta. SQ 29,548 at a ®nal concentration of 3 mM, but not at lower concentrations, signi®cantly inhibited contractions induced by U 46619, 8-iso-PGF 2a and 8-iso-PGE 2 in the rat fundus. Responses to PGE 2 were unchanged. The prostanoid EP 1 -receptor antagonist SC 51089 (3 mM) signi®cantly inhibited contractions induced by 8-iso-PGE 2 and PGE 2 in the rat fundus and in the guinea-pig ileum. SC 51089 had no eect on responses to any of the agonists tested. 4 Our results show that 8-iso-PGE 2 , in contrast to 8-iso-PGF 2a , can also cause contractions by activation of the EP 1 -receptors in the rat gastric fundus and the guinea-pig ileum. The ®ndings of the present study do not support the existence of a unique isoP-receptor in the tissues used.

This study demonstrates that increased post-operative release of fNA and fA as well as of cNA and cA correlates with high post-operative serum levels of troponins in cardiac risk patients undergoing non-cardiac surgery.

1 The non-peptide bradykinin (BK) antagonist (E)-3-(6-acetamido-3-pyridyl)-N-[N- [2,4-dichloro-3-[(2-methyl-8-quinolinyl)oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide (FR173657) was tested in intestinal, uterine, tracheal and vascular in vitro preparations. The investigation aimed at determining the antagonistic potency, duration of action, speci®city for BK receptors and apparent mode of antagonistic action of FR173657. 2 Contractions of the isolated ileum of the guinea-pig in response to BK were inhibited by FR173657 (10 ± 300 nM) in a concentration-dependent manner. The inhibition lasted for up to 90 min after washout of FR173657. Cumulative concentration-response curves to BK were shifted to the right with a concomitant decrease in the maximum eect. A pK B value of 8.7 was determined. FR173657 had no eect on contractions induced by acetylcholine, histamine, 5-hydroxytryptamine, substance P, angiotensin II or caerulein. 3 The concentration-response curves for B 2 receptor-mediated relaxations of the rat isolated duodenum induced by BK were shifted to the right together with a concomitant reduction of the maximum BK eect in the presence of FR173657 (10 ± 300 nM). A pK B of 9.0+0.2 was calculated. FR173657 had no eect on B 1 receptor-mediated relaxations in response to des-Arg 9 -BK. 4 The concentration-response curves for BK-induced contractions of the rat isolated uterus were shifted to the right by FR173657 (3 ± 300 nM) in a concentration-dependent and parallel manner. The Schild plot for the inhibition caused by FR173657 had a slope of 70.98 indicating a competitive mode of antagonism. A pA 2 value of 9.1 was determined. 5 Contractions of the circular smooth muscles of the guinea-pig isolated trachea in response to BK were concentration-dependently inhibited by FR173657 (10 ± 100 nM). An anity estimate of 9.3 was calculated for FR173657. Contractions induced by acetylcholine and relaxations in response to isoprenaline remained completely unaected by FR173657. 6 In the rabbit isolated perfused ear, BK (0.01 ± 10 nmol) produced a dose-dependent vasoconstriction. In the presence of 30 nM FR173657, the eects of BK were reduced by at least 60%, while FR173657 completely abolished the eects of all BK doses at 300 nM. FR173657 did not aect vasoconstriction induced by noradrenaline or angiotensin II. 7 The arterial injection of BK (10 nmol) into the rabbit isolated perfused ear caused an approximately three fold increase in the release of the prostaglandins E 2 and I 2 into the venous euent. The BKstimulated prostaglandin release was completely abolished in the presence of FR173657 (300 nM) while the basal prostaglandin release was unchanged. 8 In summary, FR173657 was shown to be a highly potent and selective BK antagonist which was active on B 2 , but not B 1 , receptors. FR173657 was a competitive antagonist in the rat uterus but showed a deviation from competitive inhibition in the other preparations studied similar to other second generation peptide antagonists. The inhibitory action in vitro was lo...

1. Injection or infusion of histamine intraarterially into the isolated perfused rabbit ear dose-dependently stimulated the release of prostaglandins (PGs) as measured by radioimmunoassay (PGE), bovine coronary artery strips (PGI2) and by the prelabeling technic with [1-14C]-arachidonic acid (PGI2, PGE2, PGF2 alpha, PGD2). 2. PG release was abolished by indometacin (1-3 microgram/ml) and reduced by the phospholipase A2 inhibitor quinacrine (10 microgram/ml) as well as by perfusing with calcium-free, 1 mM EGTA containing solution. 3. The histamine H2-receptor antagonists burimamide (5 microgram/ml) and cimetidine (2 microgram/ml) did not influence histamine-induced PG release. The H1-receptor antagonist mepyramine (0.1-1 microgram/ml) abolished histamine-induced mepyramine (0.1-1 microgram/ml) abolished histamine-induced PG release. 4. In the presence, but not in the absence, of bovine serum albumin there was a basal release of high amounts of arachidonic acid. Histamine tended to increase the released amount of radioactive arachidonic acid. In contrast to indometacin which only blocked PG release, mepyramine significantly reduced the histamine-stimulated release of arachidonic acid, too. 5. The results show that in the peripheral vascular bed, histamine, via H1-receptors, activates a phospholipase A2 mainly by increasing a transfer of extracellular calcium into the cell. Activation of a phospholipase A2 results in the release of arachidonic acid possibly from a rather small endogenous pool which specifically provides substrate for the PG synthetase system.