Angiotensin II stimulation of renal prostaglandin synthesis elevates circulating prostacyclin in the dog

The ability of the kidney to release prostacyclin (PGI2) under direct stimulation with exogenous angiotensin II was studied in the pentobarbital-anesthetized dog. We assayed for prostacyclin-like activity in systemic arterial blood by continuously monitoring platelet aggregation in vivo and with the blood-bathed bovine coronary artery, which relaxes to prostacyclin. This parallel bioassay allows detection of small amounts of prostacyclin-like activity released into the systemic circulation. Angiotensin II, infused at a rate of 10 or 20 ng/kg/min into the renal artery inhibited latelet aggregation in 8 out of 18 dogs, relaxed the bovine coronary artery in 13 of 16 dogs, and lowered systemic arterial blood pressure 5-10 mm Hg in all but 3 animals. These effects of antiotensin II could be blocked by treating the animal with indomethacin (2 mg/kg, i.v.) and mimicked by administration of exogenous prostacyclin. Infusion of the same dose of angiotensin II (10 or 20 ng/kg/min) intravenously did not release prostacyclin; blood pressure increased during intravenous infusion, and platelet aggregation remained unchaged. These data are consistent with the hypothesis that prostacyclin, of renal origin in these experiments, can act as a circulating hormone. Prostacyclin should not be regarded only as an antiaggregatory substance, but also as a potentially important modulator of blood pressure.     

Attenuation by bradykinin of adrenergically-induced vasoconstriction in the isolated perfused kidney of the rabbit: relationship to prostaglandin synthesis.

1 In the isolated kidney of the rabbit perfused with oxygenated Tyrode solution, we studied the effect of bradykinin on the vasoconstriction evoked by sympathetic nerve stimulation (3Hz, 1 ms) and by injections of noradrenaline (50 to 75 ng) in the presence and in the absence of indomethacin (1 microgram/ml), an inhibitor of prostaglandin biosynthesis. Prostaglandin E(PGE)-like material in the renal effluent was measured by bioassay after extraction with organic solvents and separation by thin layer chromatography. 2 Bradykinin in concentrations of 10 to 100 ng/ml reduced the vasoconstrictor response to sympathetic nerve stimulation and to injected noradrenaline. Also, the peptide (1 to 10 ng/ml) increased the basal release of PGE-like material and the release induced by sympathetic nerve stimulation. 3 Indomethacin, 1 microgram/ml, diminished the inhibitory effect of bradykinin on the vasoconstrictor response to nerve stimulation, minimized the reduction of the noradrenaline-induced vasoconstriction caused by bradykinin (100 ng/ml), and abolished the release of PGE-like material. 4 This study indicates that bradykinin reduces the renal vascular reactivity to adrenergic stimuli and suggests that part of the action of the kinin at the vascular adrenergic neuroeffector junction in the rabbit kidney depends upon the biosynthesis of renal prostaglandins.     

前列腺素介导缓激肽诱导预适应对缺血再灌心肌的保护作用(英文)

在大鼠离体心脏观察了前列腺素介导缓激肽诱导的预适应对缺血再灌心肌的保护作用．３０ｍｉｎ缺血和３０ｍｉｎ再灌引起心功能降低（左室内压和左室内压最大上升速率下降）,冠脉流量和心率降低以及肌酸激酶（ＣＰＫ）释放增加．缺血预适应（５ｍｉｎ缺血,５ｍｉｎ再灌,重复３次）能显著改善心功能,促进心率和冠脉流量的恢复,减少ＣＰＫ释放．其作用不受吲哚美辛（１０μｍｏｌ·Ｌ－１预先灌流３０ｍｉｎ）影响．预先用缓激肽（０．５μｍｏｌ·Ｌ－１）处理５ｍｉｎ产生缺血预适应样心肌保护作用,表现为促进心功能恢复,减少ＣＰＫ释放．该作用被预先灌流吲哚美辛取消．对照组,缺血再灌组,缓激肽组,吲哚美辛加缓激肽组的ＣＰＫ分别为（０．２８±０．０３）,（２．２３±０．０６）,（０．３９±０．０９）,（１．８７±０．０５）μｍｏｌ·ｍｉｎ－１·ｇ－１湿组织．结果提示：缓激肽诱导预适应对缺血再灌心肌的保护作用与促前列腺素生成有关     

Interaction of prostaglandin E2 and bradykinin in the induction of afferent splanchnic nerve discharges in cats

In anesthetized cats, the administration of either bradykinin (BK) (0.3-3 micrograms/kg) or prostaglandin E2 (PGE2) (1-30 micrograms/kg) into the cranial mesenteric artery dose-dependently evoked the firing discharge in the proximal end of the afferent greater splanchnic nerves with a latency of about 10 sec, the pronounced contraction of the longitudinal muscle of the jejunum, and changes in blood pressure. PGE2 at the doses of 1-10 micrograms-kg i.a. potentiated the BK (1 microgram/kg i.a.)-induced firing discharge of the afferent splanchnic nerves of which latency was also shortened, but did not alter the BK-induced jejunal contraction and blood pressure change. However, trimoprostil (30 micrograms/kg i.a.), a trimethyl PGE2 derivative, did not change all of these responses to BK. Aspirin at 50 mg/kg i.v. markedly prevented the BK-induced nerve discharges, but not the BK-induced jejunal contraction. These results taken together indicate that PGE2 may be involved in the facilitatory response of afferent splanchnic nerve discharges to BK, but not involved in the BK-induced jejunal contraction and blood pressure change. The findings on trimoprostil present the possibility that derivatization of PGE2 could modify its inherent ability to produce adverse side-effects.     

Difference in prostaglandin modulation of arterial and venous smooth muscle responses to bradykinin and norepinephrine

The role of endogenously synthesized prostaglandins as modulators of canine vascular smooth muscle responses to bradykinin (BK) and norepinephrine (NE) was evaluated in vitro with the use of helical strips of canine arteries and veins and measurement of prostaglandins with bioassay and thin layer chromatography. Inhibition of prostaglandin synthetase with indomethacin (INDO) resulted in a small, but significant, enhancement of the contractile responses of mesenteric and splenic arteries and portal veins to NE. Eicosatetraynoic acid (ETYA), another inhibitor of prostaglandin synthetase, did not affect the contractile responses of canine splenic and mesenteric arteries and portal veins to NE. ETYA (1 x 10(-5) M), inhibited prostaglandin biosynthesis. Addition of INDO to arterial smooth muscle strips, in which prostaglandin synthesis was inhibited with ETYA, also resulted in consistent enhancement of the responses to NE. INDO did not effect the contractile responses of canine mesenteric and splenic veins to NE. BK-induced relaxation of canine mesenteric, but not splenic, arteries was inhibited by INDO, INDO did not effect BK-induced contraction of splenic, mesenteric or portal veins. ETYA was without effect on the responses of either arteries or veins to BK. After inhibition of prostaglandin synthetase with ETYA, INDO was still an effective inhibitor of BK-induced relaxation of arterial smooth muscle. Tranylcypromine (1 x 10(-5) M) inhibited prostacyclin (PGI2) synthesis but did not affect the responses of the vascular smooth muscle to BK or NE. These findings are consistent with the conclusion that in canine vascular smooth muscle in vitro, endogenously synthesized prostaglandins do not modulate the contractile responses to NE or BK. The data also confirm the presence of a direct vascular smooth muscle action for INDO.     

Effect of bradykinin antagonists on bradykinin-induced plasma extravasation, venoconstriction, prostaglandin E2 release, nociceptor stimulation and contraction of the iris sphincter muscle in the rabbit.

1 The inhibition of the bradykinin-induced plasma extravasation by six bradykinin (Bk) antagonists was tested on rabbit skin. All of them showed inhibitory effects without an agonistic action in the does used. B4310 (Lys-Lys-3-Hyp-5,8-Thi-7-DPhe-Bk) was the most active antagonist and was therefore used in the subsequent experiments. 2 B4310 (5-500 nM) antagonized the bradykinin-induced reduction of the venous outflow from the rabbit isolated ear in dose-dependent manner without affecting the arterial vasoconstriction induced by angiotensin II. 3 The bradykinin-induced release of prostaglandin E2 (PGE2) from the perfused rabbit ear was reduced by 63% when B4310 (800 nM) was infused before, during and after the bradykinin injection. 4 Bradykinin was injected into the ear artery of anaesthetized rabbits and the reflex hypotensive response was used as indicator of the nociception. The response was antagonized by a local infusion of B4310 (50 and 500 nM). The antagonism was dose-dependent and reversible. The parallel shift of the dose-response curve to bradykinin suggests a competitive inhibition. However, B4310 did not antagonize acetylcholine-induced nociceptor stimulation. 5 B4310 inhibited bradykinin-induced stimulation of the trigeminal nerve which results in a substance P-mediated contraction of the iris sphincter muscle. A pA2 of 7.59 was calculated. B4310 did not inhibit capsaicin-induced contractions. 6 It is concluded that B4310 inhibits specifically five different actions of bradykinin which are related to its possible pathophysiological role.     

Central and peripheral effects of bradykinin and prostaglandin E2 on blood pressure in conscious rats

Summary Bradykinin or prostaglandin E2 (PGE2), when injected intravenously, decreased blood pressure of conscious rats in a dose-dependent manner, while intracerebroventricular injections of bradykinin or PGE2 caused a dose-dependent increase in blood pressure. SQ 14,225, an inhibitor of angiotensin converting enzyme, potentiated the central pressor or peripheral depressor effect of bradykinin. Indomethacin, an inhibitor of prostaglandin synthesis, almost completely inhibited the central pressor effect of bradykinin when injected intraventricularly. Indomenthacin, when injected intravenously, failed to inhibit the peripheral depressor effect of bradykinin, whereas it significantly attenuated the peripheral depressor effect of bradykinin when the angiotensin converting enzyme was inhibited with SQ14,225. These results suggest that the central pressor effect of bradykinin is mainly mediated by the synthesis of prostaglandins in the central nervous system, while only a small fraction of peripheral depressor effect of bradykinin is, at least in conscious rats, mediated by the synthesis of prostaglandins in the systemic circulation.     

Effect of des arginine9-bradykinin and other bradykinin fragments on the synthesis of prostacyclin and the binding of bradykinin by vascular cells in culture

Bradykinin (BK) fragments, des arg1-BK, des arg1,pro2-BK, des phe8,arg9-BK and des pro7,phe8,arg9-BK were synthesized and along with des arginine9-BK (daBK), tested for their ability to induce prostacyclin synthesis in homogeneous cultures of cells from the calf pulmonary artery. Of the fragments daBK was the only peptide, in addition to bradykinin (BK), to activate the synthesis of prostacyclin (PGI2) and platelet activating factor (PAF) in endothelial cells and PGI2 in fibroblasts and smooth muscle cells. Half-maximal activation of PGI2 synthesis differed with the cell type. The other fragments tested did not directly affect PGI2 synthesis. These fragments also did not inhibit daBK or BK activation of PG synthesis. BK bound to endothelial cells with a dissociation constant (Kd) of 2.1 nM and a Bmax of 47.9 fmoles/10(6) cells. The Kd for the binding of BK to smooth muscle cells and fibroblasts was somewhat higher, 4.9 nM and 7.9 nM, respectively. None of the fragments tested, including daBK, altered the binding of BK. Des arg9[leu8]-BK, reported to be a competitive antagonist of the bradykinin B1 receptor, inhibited daBK induced PG of PAF synthesis in endothelial cells but had little effect of BK binding or BK induced PG synthesis. Finally, the BK antagonist [thi5,8, d-phe7]-BK blocked both BK binding and the ability of either BK or daBK to induce PG synthesis, thus substantiating that the binding of these kinins is a step in the activation of PG synthesis.     

Converting enzyme activity in sow oviducts at different stages of the sex cycle. Influence of inhibitors of prostaglandin synthesis and its possible role in the inotropic effects of bradykinin

The existence of angiotensin I converting enzyme (CE) activity in isolated sow Fallopian tubes and the "in vitro" influences of exogenous bradykinin (BK) on the spontaneous motility of sow oviducts, were explored. Independently of the stage of the sex cycle, the ampullary region of sow Fallopian tubes presented a higher basal CE activity than the isthmic one. On the other hand a greater CE activity was found in the isthmus at estrus and metestrus than at proestrus. Acetylsalicylic acid and mefenamic acid, two inhibitors of prostaglandin synthesis, reduced the CE activity only in ampullary segments obtained at metestrus. BK (0.06 microgram.ml-1) stimulates the spontaneous contractions of isthmic and ampullary tubal segments, triggering tonic responses. The positive inotropism had a longer duration in the isthmus than in the ampulla; presented at estrus a higher magnitude than at proestrus and was enhanced by captopril (50 microgram.ml-1). The data suggest that the low CE activity found in the isthmic tubal region could be subserving the positive inotropic action of BK in the isthmus, long lasting in comparison to that evoked in the ampulla. Moreover, at metestrus some tissue eicosanoid might be modulating the CE activity of ampullary tubal segments. Alternatively the foregoing results could be explained assuming the presence of a carboxy-peptidase different than CE in one region of the oviducts and not in the other, i.e., either one with different sensitivity towards sex hormones and prostaglandin synthesis blockers.     

Correlation of leukocyte interleukin-1 production with the stimulation of prostaglandin and tissue factor synthesis by human umbilical vein endothelial cells

Human leukocyte suspensions (neutrophils 80-85%, monocyte 15-20%) were incubated alone or with cultured human umbilical vein endothelial cells. Leukocytes were either directly added to the endothelial cell cultures or separated from them by a 0.4 micron insert filter. Supernatants or cell lysates were obtained at 0.5, 1, 2, and 4 hours of incubation. Supernatants were assayed for the prostacyclin (PGI2) metabolite 6-keto prostaglandin F1 alpha and prostaglandin E2 (PGE2) by radioimmunoassay and for interleukin-1 (IL-1) by the thymocyte co-mitogen assay. Cell lysates were analyzed for cell-associated procoagulant activity (PCA). Co-incubation of endothelial cells with leukocytes stimulated the synthesis of PGI2, PGE2, and PCA. These biochemical changes correlated partially with the release of IL-1 beta. The results suggest that IL-1 released in monocyte neutrophil co-cultures can produce prothrombotic (increased PCA expression) and inflammatory changes (increased synthesis of vasodilatory and permeability enhancing PGI2 and PGE2) in endothelial cells. Neutrophils may represent a source of the released IL-1 and/or may act to stimulate monocyte release of this cytokine and thus play an important role in vascular pathology by a mechanism unrelated to their more direct cytotoxic activity.     

Involvement of nitric oxide and prostaglandin pathways in the cardioprotective actions of bradykinin in rats with experimental myocardial infarction.

Bradykinin is a potent endothelium-dependent vasodilator in the coronary vascular bed. Endothelial mediators released by bradykinin include nitric oxide, prostacyclin and as yet unidentified endothelium-derived hyperpolarising factors. We wished to determine the involvement of nitric oxide and prostaglandin pathways in the cardioprotective actions mediated by bradykinin via the combined inhibition of ACE and aminopeptidase P (APP) in an in vivo rat model of acute ischemia (30 min) and reperfusion (4h). Myocardial infarct size was measured by using the staining agent 2,3,5-triphenyl tetrazolium chloride (TTC). Lipid peroxide levels in serum and in heart tissue were estimated spectrophotometrically. A lead II electrocardiogram was monitored at various intervals throughout the experiment. Infarct size reduction obtained with the combined inhibition of enalapril and apstatin, lisinopril and apstatin was blocked partially but significantly with the prior administration of L-NAME (Nomega-nitro-L-arginine methyl ester) or aspirin, suggesting the involvement of both nitric oxide and prostaglandin pathways in the cardioprotective actions mediated by bradykinin.     

The effects of bradykinin and prostaglandin E1 on rat cutaneous afferent nerve activity.

1 The activity produced by intra-arterial bradykinin and prostaglandin E1 was investigated in multifibre strands dissected from the saphenous nerves of anaesthetized rats. 2 Bradykinin (0.5-10mug) alone produced little activity in nerve strands but produced considerable activity following a 10 min infusion, but not a single injection, of prostaglandin E1 (5-100 ng). 3 Prostaglandin E, alone produced a few large height spikes but following several injections of bradykinin smaller height spikes were also produced by prostaglandin E1. 4 It was concluded that the presence of a low concentration of prostaglandin E, is required for bradykinin to manifest its actions and that bradykinin and prostaglandin E1 are mutually potentiating in their effects on afferent nerve terminals.     

Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most highly utilized classes of pharmaceutical agents in medicine. All NSAIDs act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective drugs. These pharmaceutical agents have quickly become established as important therapeutic medications with potentially fewer side effects than traditional NSAIDs. Additionally, characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever. Of particular importance has been the investigation of COX-1 and -2 isozymic functions in cancer, dysregulation of inflammation, and Alzheimer's disease. More recently, additional heterogeneity in COX-related proteins has been described, with the finding of variants of COX-1 and COX-2 enzymes. These variants may function in tissue-specific physiological and pathophysiological processes and may represent important new targets for drug therapy.     

Ethanol-inhibited platelet prostaglandin synthesis in vitro.

Inhibition of human platelet malonyldialdehyde (an indicator of platelet prostaglandin synthesis) in platelet-rich plasma, not found after 100 mg of ethanol per 100 ml in vitro, was dose-related at 200, 400 and 750 mg per 100 ml.     

Paracetamol potentiates acetylsalicylate in inhibiting prostaglandin synthesis

Lower concentrations of paracetamol stimulated, but a higher concentration inhibited prostaglandin synthesis by bull seminal vesicle homogenate in the absence of added co-factors. Admixed with acetylsalicylate or indomethacin, paracetamol strongly potentiated the inhibition of prostaglandin synthesis in vesicle homogenate, and weakly potentiated inhibition in rat gastric fundus strip. We propose that, by acting as a phenolic co-factor, paracetamol stimulates prostaglandin synthesis and thus renders the cyclo-oxygenase more vulnerable to acetylsalicylate or indomethacin.