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Biomedical subjects

A Raz

Publications and source records attributed to A Raz.

At least 235 records · Page 13Linked to original sources
PubMed1977

Characterization of a novel metabolic pathway of arachidonate in coronary arteries which generates a potent endogenous coronary vasodilator.

Bovine coronary artery strips were incubated with [1-14C]arachidonic acid and the chemical properties of the various prostaglandins (PG) formed were studied. Arachidonate was converted to two major prostaglandin products, PGE2 and a novel prostaglandin having chemical (i.e. base hydrolysis and borohydride reduction) and chromatographic properties identical with 6-keto-PGF1alpha. This final compound was inactive on coronary artery strips. The endoperoxide intermediates, PGG2 or PGH2, previously shown to induce coronary relaxation, were not released into the medium from isolated bovine coronaries. The arachidonic acid-induced dilation may have been due to an intracellular action of PGH2 (or PGG2) or to the action of another, yet unidentified, labile intermediate formed in the enzymatic conversion of endoperoxides to 6-keto PGF1alpha. When PGH2 was incubated with bovine coronary microsomes, the PGH2 was completely metabolized (i.e. loss of rabbit aorta contraction) but a compound was generated which was a much more potent coronary relaxant. We suggest that this major novel metabolic pathway of arachidonate generates a substance, intermediate between PGH2 and the final 6-keto PGF1alpha-like product, which is a potent coronary vasodilator.

Animals↗
PubMed1977

Coronary tone modulation: formation and actions of prostaglandins, endoperoxides, and thromboxanes.

Exogenous prostaglandin (PGE2) contracts bovine and human coronary arteries but its precursor, arachidonic acid, relaxes them. The endoperoxides PGH2 and PGH3 relax bovine coronary strips, but PGH1 produces contraction. The primary prostaglandins exert opposite effects to their own endoperoxide precursors, thus, PGE2 and PGE3 contract, and PGE1 relaxes the bovine coronary arteries. The paradoxical coronary dilation produced by the arachidonate or the PGH2 suggest that little if any coronary isomerase which converts endoperoxide into PGE2 exists, or that a novel, potent, PG-like substance is produced by the isolated coronary arteries. Although the coronaries do not possess thromboxane A2 synthetase activity, the vessels are profoundly contracted by exogenous thromboxane A2. Thromboxane A2 can be synthesized and released by circulating platelets when they are aggregated by endothelial injury or thrombin. Thus, coronary tone, and possible spasm, in ischemic myocardial zones may be influenced markedly by interplay between prostaglandins, endoperoxides, and thromboxane formed by platelets on the one hand, and endoperoxide products synthesized endogenously in the coronary arteries on the other.

Animals↗
PubMed1977

Imidazole: a selective inhibitor of thromboxane synthetase.

Imidazole inhibits the enzymic conversion of the endoperoxides (PGG2 and PGH2) to thromboxane A2 by platelet microsomes (IC50: 22 MICRONG/ML; DETERMINED BY BIOASSAY). The inhibitor is selective, for prostaglandin cyclo-oxygenase is only affected at high doses. Radiochemical data confirms that imidazole blocks the formation of 14C-thromboxane B2 from 14C-PGH2. Several imidazole analogues and other substances were tested but only 1-methyl-imidazole was more potent than imidazole itself. The use of imidazole to inhibit thromboxane formation could help to elucidate the role of thromboxanes in physiology or pathophysiology.

Animals↗
PubMed1977

Hormonal stimulation of arachidonate release from isolated perfused organs. Relationship to prostaglandin biosynthesis.

The lipids of isolated Krebs perfused rabbit kidneys and hearts were labelled with [14C]arachidonic acid. Subsequent hormonal stimulation (e.g. bradykinin, ATP) of the pre-labelled tissue resulted in dose-dependent release of [14C]prostaglandins; little or no release of the precursor [14C]arachidonic acid was observed. When fatty acid-free bovine serum albumin was added to the perfusion medium as a trap for fatty acids substantial release of [14C]arachidonic acid was detected following hormonal stimulation. The release of [14C]arachidonic acid was dose-dependent and greater than 3 fold that of [14C]prostaglandin release. Indomethacin by inhibiting the cyclo-oxygenase, completely inhibited release of [14C]prostaglandins and only slightly inhibited release of [14C]arachidonic acid. These results demonstrate that in both rabbit kidney and heart much more substrate is released by hormonal stimulation than is converted to prostaglandins. This suggests that either the deacylation reaction is not tightly coupled to the prostaglandin synthetase system or that there are two deacylation mechanisms, one which is coupled to prostaglandin synthesis while the other is non-specific. It has previously been shown that prostaglandin release due to hormones such as bradykinin is transient despite continued presence of the hormone (tachyphylaxis). By utilizing albumin to trap released fatty acid, it was found that hormone-stimulated release of arachidonic acid is also transient. This directly demonstrates that tachyphylaxis occurs at a step prior to the cyclo-oxygenase.

Adenosine Triphosphate↗
PubMed1977

A novel prostaglandin is the major product of arachidonic acid metabolism in rabbit heart.

The prostaglandins (PGs) released from the heart have generally been characterized as resembling PGE by bioassay techniques. The major PG formed from [14C]arachidonate (C20:4) by the isolated perfused rabbit heart has chromatographic mobility similar to that of PGE2 in most solvent systems. However, additional analysis of this radioactive "PGE" peak suggests that two substances are formed by the heart and migrate like PGE2: one has chemical properties similar to those of authentic PGE2 and the other is a novel PG. The unknown compound is the major PG formed by the heart from either exogenous arachidonate or hormonal stimulation of PG biosynthesis. The novel PG produced by the heart may be identical with either 6(9)-oxy-PGF or 6-keto-PGF1 alpha.

8,11,14-Eicosatrienoic Acid↗
PubMed1977

Application of imidazole as a selective inhibitor thromboxane synthetase in human platelets.

Human platelet suspensions release a rabbit-aorta-contracting substance (previously identified as thromboxane A2) during aggregation produced by arachidonic acid, prostaglandin endoperoxide, thrombin, and collagen. Incubation of platelets with imidazole did not interfere with the aggregation produced by these agonists but markedly reduced the generation of the rabbit-aorta-contracting substance. We find that imidazole inhibited the conversion of exogenous or endogenous prostaglandin endoperoxide into thromboxane A2-Imidazole selectively inhibits thromboxane synthetase in intact human platelets, because this agent blocks the conversion of [14C]arachidonate into [14C]thromboxane B2 but does not inhibit the conversion of [14C]arachidonate into [14C]prostaglandin E2. The inhibition of thromboxane synthetase by imidazole is not the result of an alteration in platelet 3':5'-cyclic AMP levels. These results illustrate the utility of imidazole as a pharmacological tool and demonstrate the two unique and dissociable properties of the endoperoxides themselves--their ability to aggregate platelets and their enzymatic conversion to the potent vasoconstrictor thromboxane.

Blood Platelets↗
PubMed1977

Cyclic adenosine 3',5'-monophosphate inhibits the availability of arachidonate to prostaglandin synthetase in human platelet suspensions.

When thrombin is added to washed human platelets, one of its actions results in activation of a phospholipase that hydrolyzes arachidonic acid from phospholipids. The arachidonate is converted to the cyclic endoperoxides (prostaglandin G2 and prostaglandin H2) by fatty acid cyclo-oxygenase. These compounds are then converted to thromboxane A2, also called rabbit aorta-contracting substance, by thromboxane synthetase. These labile, pharmacologically active compounds then break down to inactive products including thromboxane B2 and malonaldehyde. Incubation of platelets with either dibutyryl cyclic adenosine 3',5'-monophosphate (dBcAMP) or prostaglandin E1 (PGE1) before thrombin addition blocks the subsequent formation of oxygenated products of arachidonic acid including thromboxane A2, thromboxane B2, and malonaldehyde. In contrast, when arachidonic acid is added directly to platelets, prior incubation with dBcAMP or PGE1 does not inhibit production of the prostaglandins or their metabolites. Thrombin treatment of platelets also blocks the acetylation of cyclo-oxygenase by aspirin since the hydrolyzed arachidonic acid competes with aspirin for the active site on cyclo-oxygenase. Prior treatment of platelets with dBcAMP or PGE1 reverses the thrombin inhibition of the acetylation of cyclo-oxygenase. We conclude that agents which elevate platelet cAMP levels inhibit the hydrolysis of arachidonic acid from platelet phospholipids. We also find that prostaglandin synthesis can be dissociated, in part, from platelet aggregation and release, and that cAMP has separate actions on these processes. Higher thrombin concentrations are required to stimulate prostaglandin synthesis (0.05-2 U/ml) than are required to induce [14C]serotonin release (0.02-0.1 U/ml). Furthermore, dBcAMP and PGE1 both inhibit platelet aggregation induced by either arachidonic acid or prostaglandin H2 without affecting the production of prostaglandin metabolites from these compounds.

Arachidonic Acids↗
PubMed1977

Prostaglandins and the renin-angiotensin system in canine endotoxemia.

Adminstration of endotoxin to dogs caused a rapid initial decline in blood pressure followed by a transient recovery preceding death. Plasma renin activity was elevated 5 minutes after endotoxin administration and continued to rise throughout the course of shock. Indomethacin given 60 minutes after endotoxin caused an elevation of blood pressure and a 50% decrease in plasma renin activity. Pretreatment with indomethacin markedly attenuated both the hemodynamic changes and the rise in plasma renin activity caused by endotoxin administration. Prostaglandin (PG) E-like material was observed in renal venous blood 30 minutes after endotoxin administration and was abolished by indomethacin. In addtion, a non-PG substance was found in dialysate from both arterial and renal venous blood within 5 minutes of endotoxin administration, Renal and mesenteric angiograms were taken at various stages of shock. Endotoxin administration caused a substantial increase in the diameter of intrarenal arterial branches which was temporally associated with the appearance of PGE-like material in the renal venous effluent. The mesenteric arteries were initially and transiently constricted by endotoxin and then were markedly and chronically dilated. Indomethacin simultaneously abolished renal PG and decreased renal and mesenteric arterial diameter.

Angiotensin II↗
PubMed1976

Effects of local anaesthetics on intracellular fusion processes. Enhancement of concanavalin A-induced macrophage vacuolation.

The extensive vacuolation elecited in mouse peritoneal macrophages in response to interaction with concanavalin A is markedly enhanced by a simultaneous exposure to anaesthetics. The potency of enchancing vacuolation increases within the series of normal alcohols with chain length C10 greater than C8 greater than C7 greater than C6. From the four tertiary amine local anaesthetics tested lidocaine and procaine are by far more effective than tetracaine and dibucaine. The latter two induce extensive cell shrinkage at concentrations at which the first two exhibit optimum enhancing capacity. Of the tested compounds chlorpromazine has the highest membrane/buffer partition coefficient and it exhibits its optimum enhancing effect on concanavalin A-induced macrophage vacuolation at the lowest drug concentration. The binding of [3H] concanavalin A as well as its internalization by macrophages incubated with the lectin for 15, 45 and 90 min are not affected significantly in the presence of decanol, procaine or chlorpromazine at concentrations of maximum enhancing effect on vacuolation. Thus enhancement of vacuolation does not stem from an increase in the rate or extent of concanavalin A interiorization. The rate at which vacuoles are generated is however markedly increased in the presence of chlorpromazine and the resulting vacuoles are of a larger diameter. At 2-5 fold the concentration required for inhibition of maximum enhancing effect, the drugs lead to extensive macrophage shrinkage and to depletion of intracellular ATP. Phagocytosis of heat-killed yeast cells is reduced by tertiary amine anaesthetics at concentrations optimal for enhancement of concanavalin A-induced vacuolation. Enhanced intracellular fusion of concanavalin A-bearing pinosomes to form vacuoles is discussed in terms of current ideas on factors vacuoles is discussed in terms of current ideas on factors vacuoles is discussed in terms of current ideas on factors affecting membrane fusion and the effects of anaesthetics on membrane organization of lipids, intramembraneous particles, glycoprotein receptors and the possible control by cytoskeletal elements. The results best fit the hypothesis that enhanced fusion correlates with membrane aggregation of both intramembraneous particles and concanavalin A receptor and the formation of areas relatively deplete of these structures and enriched in phospholipids.

Adenosine Triphosphate↗
PubMed1976

Chemical and enzymatic transformations of prostaglandin endoperoxides: evidence for the predominance of the 15-hydroperoxy pathway.

Cyclic prostaglandin endoperoxides prostaglandin G2 and H2 are intermediates formed in the biosynthesis of prostaglandins from arachidonic acid. These endoperoxides can be converted chemically or enzymatically to prostaglandins E2, D2 and F2alpha. The effects of several reducing compounds on the chemical and enzymatic transformations of prostaglandins G2 and H2 were studied in order to determine the possible existence of two alternative enzymatic pathways for the conversion of prostaglandin G2 to prostaglandins. The chemical transformation of prostaglandin H2 to prostaglandins by cleavage of the 9,11-cycloendoperoxide ring was unaffected by the presence of reduced glutathione, heme or tryptophan while hydroquinone and mercaptoethanol promoted the chemical reduction to prostaglandin F2alpha. In contrast the enzymatic transformation of prostaglandin H2 to prostaglandins by a solubilized prostaglandin synthetase from sheep vesicular gland was unaffected by hydroquinone or mercaptoethanol, but was markedly stimulated by reduced glutathione to yield mainly prostaglandin E2. Prostaglandin G2 transformation to prostaglandins involves cleavage of the 9,11-endoperoxide ring and a reduction of the 15-hydroperoxy group. The chemical reduction in buffer in the 15-hydroperoxy group is not affected by the presence of reduced glutathione, hydroquinone, heme or tryptophan. In contrast, the enzymatic reduction of the 15-hydroperoxy group is catalyzed by the solubilized prostaglandin synthetase and is further stimulated by reduced glutathione and hydroquinone. Results are presented which indicate that the enzymatic conversion of prostaglandin G2 to prostaglandins can proceed via two alternative pathways, one involving the intermediate formation of prostaglandin H2 and the other the formation of 15-hydroperoxy prostaglandins. The latter pathway appears to be the major pathway for the enzymatic conversion of prostaglandin G2 to prostaglandins.

Animals↗
PubMed1976

The effect of hashish compounds on pphospholipid phase transition.

The interaction of hashish compounds, delta 1-tetrahydrocannabinol and cannabidiol, with dipalmitoyl phosphatidylcholine was investigated using differential scanning calorimetry. Both drugs affect the transition of dipalmitoyl phosphatidylcholine from the gel to liquid crystalline state, decreasing both the melting temperature and the enthalpy of melting. At a drug to dipalmitoyl phosphatidylcholine ratio of approx. 1:5, two peaks appear in the transition profile, suggesting a phase separation in the drug dipalmitoyl phosphatidylcholine mixture.

Binding Sites↗
PubMed1976

Thromboxanes: selective biosynthesis and distinct biological properties.

The prostaglandin endoperoxide ring structure alone does not establish suitability as a substrate for thromboxane synthetase, but the degree of unsaturation and carbon chain length are also essential features. Thus, human platelet microsomes can synthesize thromboxane A2, thromboxane A3, but not thromboxane A1 from their respective endoperoxides. The potent vasoconstrictor property of thromboxanes can be dissociated from its capacity to produce platelet aggregation. Furthermore, thromboxane formation is not an essential process in platelet aggregation. The observations indicate the remarkable structural specificity of both the synthetic enzymes, cyclooxygenase and thromboxane synthetase, as well as the vascular and platelet receptor sites.

Aorta↗
PubMed1976

Properties of prostaglandin synthetase of rabbit kidney medulla.

The formation in vitro of prostaglandins E2, D2, and F2alpha from arachidonic acid by rabbit kidney medulla homogenate or microsomal fraction is markedly affected by the composition of the incubation medium employed. Optimal biosynthesis is obtained in 0.1 M potassium phosphate buffer, with the optimum pH being 8.0--8.8. Under these conditions prostaglandin formation is linear up to arachidonic acid concentration of 30 muM. The initial rate of formation of prostaglandin E2 + prostaglandin D2 is 3--4 times higher than that of prostaglandin F2alpha. Reduced glutathione (1 mM) did not affect the biosynthesis by medulla homogenate and produced only small stimulation of the biosynthesis by microsomal powder. Hydroquinone produced a small stimulation at a low concentration of 0.005 mM, and a strong inhibition at concentrations of 0.1 mM or higher. Addition of bovine serum albumin (0.1%) reduced the microsomal biosynthesis of prostaglandins by approximately 80%. Addition of boiled homogenate or boiled 140 000 X g supernatant produced small stimulation of microsomal biosynthesis while 140 000 X g supernatant (not boiled) caused small inhibition which was not dose-related. It appears that rabbit kidney prostaglandin-synthetase converts arachidonic acid to prostaglandins E2 and F2alpha in comparable amounts, without apparent need for a cytoplasmic soluble cofactor or specific reducing agents.

Animals↗