dinoprost and imidazole

This study describes the contractile action of bradykinin on rat isolated mesenteric arterial rings and a possible mechanism responsible for this action. Bradykinin induced dose-dependent contraction of relaxed mesenteric arterial rings from Holtzman rats, but not from Wistar rats. A second bradykinin challenge in the same ring induced a very small effect or no effect at all. Destruction of the endothelium did not modify the response to bradykinin. des-Arg9-[Leu8]bradykinin failed to antagonize bradykinin's action. HOE 140 (D-Arg- [Hyp3, Thi5,D-Tic7,Oic8]bradykinin) reduced bradykinin-induced contractions. Indomethacin abolished the contractile response to bradykinin; prostaglandin F2 alpha induced a long-lasting contraction, dissimilar from that induced by bradykinin; L-655,240 (3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]-2,2-dimethyl propanoic acid), an antagonist of the thromboxane receptor, inhibited bradykinin-induced contractions. These results suggest that bradykinin-induced contraction in mesenteric arterial rings is indirect, through activation of bradykinin B2 receptors, resulting in liberation of prostanoids from outside the endothelium. Thromboxane A2 is probably an intermediate in this response but we cannot exclude the participation of other prostanoids.

Topics: Animals; Arachidonic Acid; Bradykinin; Bradykinin Receptor Antagonists; Dinoprost; Endothelium, Vascular; Enzyme Inhibitors; Imidazoles; In Vitro Techniques; Indoles; Indomethacin; Mesenteric Artery, Superior; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Prostaglandin Antagonists; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Bradykinin

The effect of OKY-046 (ONO, Japan), a selective TX inhibitor, was studied for its effect on uterine and platelet activity. On day 21 of pregnancy, rats were injected with either 0, 1, or 5 mg/kg OKY-046 via the tail vein. One hour following injections, in vitro activity of uteri and platelets was assessed. A decrease (P less than .01) in uterine TXB2 production (measured by RIA) occurred with increasing OKY-046 dose (104 +/- 31 vs 44 +/- 6 vs 24 +/- 2 ng TXB2/g tissue/45 min). OKY-046 treatment had no effect on other prostanoids. Contractile activity was not affected by OKY-046. The amount of TXB2 produced in platelets from OKY-046 (5 mg/Kg) treated rats was 45.5% less than that from controls (P less than .001). Likewise, arachidonate-induced aggregation of platelets from OKY-046 treated rats was 46.1% less (P less than .05) than that of controls. In summary, in vivo administration of OKY-046 selectively reduced uterine TXB2 without altering other prostanoids, or affecting uterine contractions. In contrast, both platelet TXB2 production and platelet function (aggregation) was decreased.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Blood Platelets; Dinoprost; Dinoprostone; Female; Imidazoles; Methacrylates; Pregnancy; Pregnancy, Animal; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxanes; Uterus

Whereas numerous studies have investigated the role of prostacyclin and thromboxane A2 in the maintenance of coronary blood flow, most of these have focused on normal vessels. In the present investigation, we examined the prostaglandin- and thromboxane-synthesizing capacity of isolated coronary artery segments obtained from the site of a critical coronary artery stenosis. Cyclic flow variations were produced by placing a hard cylindrical constrictor on the proximal left anterior descending coronary artery in open-chest, anesthetized dogs. Cyclic flow variations are characterized by progressive declines in coronary blood flow, interrupted by sudden spontaneous restorations of flow. After cyclic flow variations had been induced, the hearts were removed, and the left anterior descending and circumflex coronary arteries were dissected. The vessels were cut into segments and incubated in the presence of increasing concentrations of arachidonic acid (10(-4)-10(-6) M). The synthesis of prostaglandin E2, thromboxane B2, and 6-keto prostaglandin F1 alpha by the coronary segments was measured by radioimmunoassay. When incubated in the presence of 10(-5) M arachidonic acid, coronary artery segments obtained from the left anterior descending coronary artery undergoing cyclic flow variations produced substantially more thromboxane B2 (142 +/- 27 vs. 29 +/- 3 pg/mg P less than 0.01) and less 6-keto prostaglandin F1alpha (125 +/- 12 vs. 350 +/- 30 pg/mg, P less than 0.01) than control circumflex coronary artery segments. Circumflex coronary vessels in which the endothelium was removed ex vivo produced 6-keto prostaglandin F1alpha levels comparable to those found in the left anterior descending coronary artery (147 +/- 17 pg/mg), but did not synthesize thromboxane B2 (23 +/- 2.6 pg/mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aortic Valve Stenosis; Arachidonic Acid; Arachidonic Acids; Chromatography, High Pressure Liquid; Coronary Circulation; Coronary Vessels; Dinoprost; Dinoprostone; Dogs; Epoprostenol; Imidazoles; Male; Platelet Aggregation; Prostaglandins E; Prostaglandins F; Regional Blood Flow; Thromboxane A2; Thromboxane B2; Thromboxanes

A reproducible electrical injury to the hind limb was produced in rats, an injury characterized by progressive tissue necrosis. Serial histochemical examinations of cross sections with a peroxidase-antiperoxidase method revealed increased production of arachidonic acid metabolites, especially thromboxane, at distal sites near the entrance wound and in periosseous tissues more proximally. Levels of these vasoactive substances remained elevated during the time of progressive necrosis and demarcation of seemingly normal, uninjured tissue. Treatment with agents capable of blocking thromboxane production allowed tissue salvage, as evidenced by a decreased autoamputation rate and an increased total surviving length. From this study it appears that an electrical injury is thermal trauma, producing elevated levels of arachidonic acid metabolites in areas of greatest heat production. Prolonged thromboxane excess, with resultant vasoconstriction and thrombosis in the microcirculation, is seen to play a key role in the progressive tissue loss characteristic of the injury. The use of antithromboxane agents may be of benefit in halting this progression and salvaging tissue in these devastating injuries.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Burns, Electric; Dinoprost; Dinoprostone; Imidazoles; Male; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Thromboxane B2

The anti-hypoxic effect of drugs that inhibit different steps of arachidonic acid metabolism was studied using an experimental model of acute hypobaric hypoxia in mice. The drugs investigated were chloroquine, betamethasone, chlorpromazine (phospholipase A2 inhibitors), ketoprofen (cyclo-oxygenase inhibitor) and imidazole (TxA2 synthetase inhibitor). Prostacyclin (PGI2) and PGF2 alpha were also studied. The results show that all the inhibitors of arachidonic acid metabolism manifest an anti-hypoxic effect of a various degree. PGF2 alpha had a deleterious effect, and PGI2 showed a marked anti-hypoxic effect. The results suggest that it is advantageous to search for anti-hypoxic drugs among the blockers of arachidonic acid cascade.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Betamethasone; Chloroquine; Chlorpromazine; Cyclooxygenase Inhibitors; Dinoprost; Epoprostenol; Female; Hypoxia; Imidazoles; Ketoprofen; Mice; Phospholipases A; Phospholipases A2; Prostaglandins F; Thromboxane-A Synthase

Prostaglandin E1 and thromboxane A2 (PGE1 and TXA2) have been proposed to bind to DNA, regulate gene action and prevent mutagenesis. Benzo (a) pyrene (BP) is a known mutagen and tumor promotor. BP-induced damage to the bone marrow cells of mice was prevented and/or reversed by PGE1 and by colchicine, an agent which may enhance PGE1 synthesis and TXA2 synthesis or action. PGF2 alpha did not have any action. Imidazole, a selective TXA2 synthesis inhibitor, enhanced the mutagenic action of benzo (a) pyrene. These results lend support to the concept that an altered PG system may have a role in the pathogenesis of mutagenesis and carcinogenesis.

Topics: Alprostadil; Animals; Benzo(a)pyrene; Bone Marrow; Colchicine; Dinoprost; Imidazoles; Male; Mice; Mutation; Prostaglandins E; Prostaglandins F; Thromboxane A2