Zmuda A

The generation of prostacyclin by arteries and by the coronary vascular bed is reduced in experimental atherosclerosis in rabbits

Experimental atherosclerosis in rabbits was associated with a suppression of prostacyclin generation from exogenous arachidonic acid by the coronary vascular bed. The spontaneous formation of prostacyclin by incubated rings of mesenteric artery was also diminished. These results suggest that in atherosclerosis an impaired activity of the endothelial prostacyclin synthexizing system contributes to the intra-arterial formation of thrombi.

Aspirin-induced Asthma

Abstract Eighteen patients with asthma and aspirin hypersensitivity have been challenged with increasing doses of aspirin, fenoprofen, ibuprofen, and dextropropoxyphene. Low doses of the first three drugs induced bronchoconstriction in all the patients as evidenced by fall in peak expiratory flow and appearance of clinical symptoms. There were no reactions to therapeutic doses of dextropropoxyphene. Aspirin, fenoprofen, and ibuprofen, but not dextropropoxyphene, inhibited prostaglandin synthetase activity in three different microsomal preparations, i.e., in bovine seminal vesicles, in rabbit brain and, in rabbit kidney medulla. Expected in vivo antienzymic potency of a drug, calculated from experiments using rabbit brain microsomes, corresponded roughly with its potency to induce bronchoconstriction in the challenge tests. An individual pattern of sensitivity to threshold doses of prostaglandin, synthetase inhibitors was demonstrated for each patient. The results obtained suggest that precipitation of asthmatic attacks by nonsteroidal anti-inflammatory drugs is mediated through inhibition of prostaglandin biosynthesis. The degree of enzymic inhibition, which is sufficient to precipitate bronchoconstriction, is an individual hallmark. Knowing the threshold dose for any of prostaglandin synthetase inhibitors in a patient, one can predict the threshold doses for the rest of aspirin-like drugs in this particular patient.

Experimental atherosclerosis in rabbits: Platelet aggregation, thromboxane A2 generation and anti-aggregatory potency of prostacyclin

Experimental atherosclerosis in rabbits was associated with increased aggregation of their platelets to arachidonic acid, and with increased generation of thromboxane A2 by their platelet-rich plasma. A heightened susceptibility of platelets to the anti-aggregatory action of prostacyclin against the ADP-induced aggregation was also observed. It is concluded that in advance atherosclerosis the platelet system is hypersensitive to biologically active metabolites of arachidonic acid.

Role of mucosal prostaglandins and DNA synthesis in gastric cytoprotection by luminal epidermal growth factor.

This study compares the effect of epidermal growth factor and prostaglandins (PGE2 or PGI2), applied topically to gastric mucosa, on gastric secretion and formation of ASA-induced gastric ulcerations in rats. Epidermal growth factor given topically in non-antisecretory doses prevented dose-dependently the formation of ASA-induced ulcers without affecting prostaglandin generation but with a significant rise in DNA synthesis in the oxyntic mucosa. The anti-ulcer effect of topical prostaglandins was also accompanied by an increase in DNA synthesis. This study indicates that topical epidermal growth factor, like PGE2 or PGI2, is cytoprotective and that this cytoprotection is not mediated by the inhibition of gastric secretion or prostaglandin formation but related to the increase in DNA synthesis in oxyntic mucosa.

Aspirin-induced asthma: Hypersensitivity to fenoprofen and ibuprofen in relation to their inhibitory action on prostaglandin generation by different microsomal enzymic preparations

Abstract Eighteen patients with asthma and aspirin hypersensitivity have been challenged with increasing doses of aspirin, fenoprofen, ibuprofen, and dextropropoxyphene. Low doses of the first three drugs induced bronchoconstriction in all the patients as evidenced by fall in peak expiratory flow and appearance of clinical symptoms. There were no reactions to therapeutic doses of dextropropoxyphene. Aspirin, fenoprofen, and ibuprofen, but not dextropropoxyphene, inhibited prostaglandin synthetase activity in three different microsomal preparations, i.e., in bovine seminal vesicles, in rabbit brain and, in rabbit kidney medulla. Expected in vivo antienzymic potency of a drug, calculated from experiments using rabbit brain microsomes, corresponded roughly with its potency to induce bronchoconstriction in the challenge tests. An individual pattern of sensitivity to threshold doses of prostaglandin, synthetase inhibitors was demonstrated for each patient. The results obtained suggest that precipitation of asthmatic attacks by nonsteroidal anti-inflammatory drugs is mediated through inhibition of prostaglandin biosynthesis. The degree of enzymic inhibition, which is sufficient to precipitate bronchoconstriction, is an individual hallmark. Knowing the threshold dose for any of prostaglandin synthetase inhibitors in a patient, one can predict the threshold doses for the rest of aspirin-like drugs in this particular patient.

Serum lipoproteins, lipid peroxides and prostacyclin biosynthesis in patients with coronary hear diseases

Serum low-density lipoproteins (LDL) and high-density lipoproteins (HDL) were prepared by gradient ultracentrifugation and dialysis from 12 healthy subjects and 15 patients with coronary heart disease and hyperlipoproteinemia. In both lipoprotein fractions cholesterol and lipid peroxides were determined. The effect of these lipoproteins on spontaneous prostacyclin biosynthesis in rat aortic slices was studied. Serum lipoproteins were susceptible to peroxidation during the preparation procedure. LDL were more prone to peroxidation than HDL. Little lipid peroxides were formed in lipoproteins when calcium ions had been removed by EDTA, and when butylated hydroxytoluene (BHT) was present at all stages of their preparation. LDL when prepared without these precautions either from healthy subjects or from patients with coronary heart disease markedly suppressed prostacyclin generation by rat aortic slices. This inhibition was unrelated to LDL-cholesterol, but was due to LDL-lipid peroxides. Peroxide-low LDL prepared from most of the healthy subjects and patients with coronary heart disease and concomitant hyperlipoproteinemia, did not inhibit prostacyclin biosynthesis. However, in one quarter of the patients, LDL was inhibitory. Consequently, in some patients with coronary heart disease, there operate unknown mechanisms which are responsible for the inhibitory activity of LDL on prostacyclin generation.

Prostacyclin formation by myometrial & decidual fractions of the pregnant rat uterus

Chopped samples of myometrium, decidua and extrinsic blood vessels from the pregnant rat uterus when incubated at room temperature generated a prostacyclin-like substance. Activity in the incubation mixtures was compared against authentic prostacyclin in two assay systems: relaxation of strips of bovine coronary artery and inhibition of ADP-induced aggregation of rabbit platelet-rich plasma. Results estimated from inhibition of platelet aggregation showed that activity generated by all samples was low on day 12 of pregnancy (less than 0.25 ng/mg). However at the time of delivery (day 22) myometrial synthesis had increased 18.5 fold to over 3 ng/mg of prostacyclin whereas decidual production had only increased 5 times. As there was no increase in synthesis by the extrinsic uterine blood vessels over this period it is proposed that the myometrial muscle cells are the probable source of the prostacyclin-like material.

A potent inhibitor of thromboxane A2 biosynthesis in aggregating human blood platelets

Summary 1′(Isopropyl-2-indolyl)-3-pyridyl-3-ketone (L 8027) inhibited biosynthesis of thromboxane A 2 from arachidonic acid in human platelet rich plasma and inhibited platelet aggregation. The anti-enzymic and anti-aggregating potencies of L 8027 were closely linked to each other and both of them were inversely proportional to concentrations of arachidonic acid which platelets were exposed to. Very low concentrations of L 8027 (0.1 fM – 40 nM) were needed to inhibit generation of thromboxane A 2 and aggregation of platelets by the threshold pro-aggregatory concentrations of arachidonic acid. A concentration of 4 uM of L 8027 was sufficient to inhibit platelet aggregation induced by any concentration of arachidonic acid. L 8027 inhibits the activity of the arachidonate cyclo-oxygenase in many biological systems including platelets. However, unlike indomethacin L 8027 is a more potent thromboxane A 2 synthetase inhibitor than a prostaglandin synthetase inhibitor.

Influence of no-donor (SIN-1) on functions of inflammatory cells

SummaryNO-donor SIN-1 (0.01–1.0 mM) dose-dependently inhibited the basal and FMLP (30.0 mM)-stimulated release of beta-glucuronidase from rat peritoneal leukocytes and antigen-specific stimulation of Inter-leukin-2 production by T-hybridomas. I-123 LDL binding to human lymphocytes was inhibited by Iloprost (1 mM) but activated by SIN-1 (0.3 mM). We conclude that beside the smooth muscle cells and platelets the blood inflammatory/immune cells are under the PGI2/NO control, however, the precise regulation as well as physiologcial importance need further investigation.