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PubMed1988

Stimulation of release of prostaglandins and thromboxanes from isolated guinea pig lung cells by bradykinin, f-Met-Leu-Phe, phorbol myristate, ionophore A23187, and leukotrienes.

Guinea pig lungs were perfused for 15 min with a solution of protease type VII (0.05 mg/ml) and dispersed to yield a suspension of morphologically intact and metabolically active lung cells (over 250 X 10(6) cells per animal). The viability of these cells assessed with the Trypan blue exclusion technique was more than 80%. Treatment of these mixed cells (1 X 10(6) cells/ml) with chemicals such as phorbol myristate acetate (1 X 10(-9) to 1 X 10(-7) M), f-Met-Leu-Phe (5 X 10(-6) to 1 X 10(-4) M), and the calcium ionophore A23187 (3.1 X 10(-7) to 2.5 X 10(-6) M), and with autacoids such as bradykinin (1 X 10(-5) to 1 X 10(-4) M), leukotriene B4 (1 X 10(-13) to 1 X 10(-7) M), and leukotriene D4 (1 X 10(-10) to 1 X 10(-7) M) stimulated to a variable degree the release of prostaglandin E2 and thromboxane B2 (measured with a novel enzyme immunoassay). It is suggested that icosanoid release from the lungs is the result of direct chemical or hormonal stimulation of the cells and not a consequence of vascular changes. Studies are in progress to purify lung cell populations and characterize the cells responsible for the release of these icosanoids.

Animals↗

PubMed1986

Converting enzyme activity of free airway cells.

The pulmonary circulation was previously shown to inactivate and even activate a number of autacoids. Further studies showed that these enzymatic activities were localized in vascular endothelial cells. The present results shows that guinea pig free airway cells (FACs) convert angiotensin I to angiotensin II and inactivate bradykinin, whereas they do not inactivate serotonin, prostaglandin E2, histamine, and noradrenaline. In the presence of a converting enzyme inhibitor (SQ14225), the angiotensin I was not converted into angiotensin II, but bradykinin was still inactivated, although the speed of inactivation was decreased. Furthermore, when FACs were separated as adherent and nonadherent cells, the cleavage of angiotensin I by adherent cells was similar to that of the total cell suspension. The inactivation of bradykinin was more pronounced in incubation with nonadherent than with the adherent cells. Using selected enzyme inhibitors, we also showed that the conversion of angiotensin by FAC is the result of specific kinase II activity most likely located in macrophages, whereas the bradykinin inactivation is the result of the cooperation of many enzymes including kinase I and II produced by various cell types.

Angiotensin I↗

PubMedDate not supplied

Oxygen-radical/nitric oxide mediate calcium-dependent hormone action on cyclic GMP system: a novel concept in signal transduction mechanisms.

The broad objective of these studies was to understand the nature of cyclic GMP system and the mechanism(s) whereby hormone, autacoids and drugs alter this signal in various physiological systems. Studies were undertaken on the modulation of guanylate cyclase activity by oxygen-radicals/nitric oxide and the mechanism(s) of generation of nitric oxide by receptor-selective hormones. We observed that cytosolic guanylate cyclase undergoes significant stimulation in the presence of oxygen-radicals/nitric oxide. This activation by nitric oxide can be reversed by hemeproteins, thus, enabling guanylate cyclase system to cycle between activated and deactivated state. The evidence is presented that oxygen-radicals are required for the synthesis of nitric oxide by NO synthase as demonstrated by inhibition of NO formation by oxygen-radical scavengers. And finally, the data is presented that acetylcholine-induced elevations of intracellular levels of cyclic GMP can be attenuated by muscarinic antagonist, atropine and superoxide anion scavenger, nitroblue tetrazolium. These observations establish a novel concept that activation of hormone receptors on the cell surface, triggers generation of oxygen radicals and hydrogen peroxide which participates in the catalytic conversion of L-arginine to nitric oxide by nitric oxide synthase in the presence of calcium ion. The oxygen-radicals/NO, thus formed, oxidatively activate guanylate cyclase and transduce the message of calcium-dependent hormones.

Animals↗

PubMed1992

Neurochemical evidence for a neuronal GABAergic system in the rat sympathetic superior cervical ganglion.

Some characteristics of gamma aminobutyric acid (GABA) uptake and release in rat superior cervical ganglion (SCG) were investigated. Kinetic analysis of GABA uptake indicated the existence of both high affinity (Km = 18.6 microM) and low affinity (Km = 485 microM) uptake systems. 3H-GABA influx was decreased by inhibitors of glial (beta-alanine), neuronal (2,4-diaminobutyric acid, DABA), or glial and neuronal GABA uptake (nipecotic acid). 3H-GABA efflux was elicited by K+ depolarization in a dose-dependent manner, an effect unaltered by severing the preganglionic nerve fibers. Superfusion of SCG explants with DABA or beta-alanine resulted in increased 3H-GABA efflux from tissue, an effect amplified by the absence of calcium in the superfusion medium. 3H-GABA loading in the presence of DABA, but not in the presence of beta-alanine, resulted in abolition of K(+)-elicited 3H release. At 20 mM, but not at 50 mM K+, the release of 3H-GABA was inhibited by replacing Ca2+ by Mg2+ and by adding EGTA, or by incubating SCG in the presence of the Ca(2+)-channel blocker verapamil. Veratrine evoked GABA release in Ca(2+)-independent manner. None of several putative SCG autacoids or agonists (nicotine, muscarine, norepinephrine, dopamine, serotonin, baclofen, muscimol) significantly modified GABA release.

Acetanilides↗

PubMed1979

[Prostaglandins in cardiovascular and renal function. Biochemical, physiological and clinical findings (author's transl)].

Prostaglandins (PG) are highly unsaturated, cyclic fatty acids with 20 carbon atoms which are biosynthesized from dihomo-gamma-linolenic, arachidonic and eicosapentaenoic acids. These fatty acids are either ingested or are biosynthesized from linoleic and linolenic acids, respectively. The PG-precursor fatty acids are liberated from membrane phospholipids by phospholipase A and are converted to prostaglandins by the multienzyme complex PG-synthetase. The activity of the PG-system is influenced by extracellular hormonal, neural and mechanical stimuli and by intracellular factors such as ion-concentration and activity of the enzymes adenyl- and guanylcyclase. Prostaglandins are tissue hormones or autacoids which act on their receptors near their site of synthesis and degradation. The prostaglandin family constitutes a group of more than 10 natural occurring compounds showing a variety of biological actions. In arteries and veins the different PG:s have vasodilating as well as vasoconstricting effects. In addition, they are involved in the regulation of vascular smooth muscle proliferation. Within the kidney PG:s have vascular and tubular actions. They antagonize the effect of ADH, mediate renin secretion and are involved in the control of electrolyte balance. In the regulation of platelet aggregation and platelet adhesion PG:s have opposite functions: Prostacyclin which is synthesized in the vascular wall antagonizes the aggregating action of Thromboxane A2 which is formed in the platelets. A defect or an imbalance in the production of PG:s in the vascular wall, in platelets or in the kidney is assumed to play a pathogenetic role in a variety of cardiovascular and renal diseases such as in hypertension, atherosclerosis, persistent ductus arteriosus and Bartter's syndrome.

Arteriosclerosis↗

PubMed1979

[The sympathetic neuron: regulation mechanisms for transmitter synthesis, transmitter release, and stimulus response (author's transl)].

A great multitude of factors acting at different sites of the afferent sympathetic nerve are capable to modify the magnitude of its stimulus-induced effects. 1) Specific receptors, located at the ganglionic synapse display inhibitory of facilitatory effects on the ganglionic transmission of the nerve impulse. 2) The rate of synthesis of the neurotransmitter noradrenalin is regulated at the level of the tyrosine hydroxylase. Transsynaptic mechanisms adapt the rate of synthesis of noradrenalin to nerve activity and transmitter release. 3) The amount of transmitter released per nerve impulse is controlled by a variety of receptors located presumably presynaptically at neuronal sites. Inhibitory and facilitatory "auto"-receptors stimulated by the released transmitter itself represent a local feed-back control. Similarly receptors for transmitters of cholinergic or serotoninergic neurons as well as autacoid hormones are involved in the local control of noradrenalin release. In addition, kinines, prostaglandins, or compounds like adenosine, some of them released from the target cells by the sympathetic stimuli or delivered by the blood stream are involved in the modulation of stimulus-evoked noradrenalin release. 4) Stimulus responses of the target cells can be modulated by similar mechanisms.

Humans↗

PubMed1991

Renal blood flow control by tubuloglomerular feedback (TGF) in normal and spontaneously hypertensive rats--a role for dopamine and adenosine.

Following the elementary laws of hemodynamics and the functional characteristics of the renal myogenic and macula densa-mediated (TGF) vascular resistance control mechanisms, TGF-mediated changes of renal vascular resistance are amplified by cooperative changes of the myogenic mechanism. Myogenically induced changes, on the other hand, would be antagonized by TGF. Resetting of renal vascular flow resistance by alterations to the TGF mechanisms might thus be more effective than alterations to the myogenic mechanism. Dopamine and adenosine, two autacoids occurring normally in the tubular fluid, may play a key role in operating such a resetting mechanism. Dopamine and adenosine were found in proximal tubular fluid at concentrations of 10(-8) and 0.5 10(-6) M respectively. Dopamine inhibits the tubuloglomerular feedback mechanism, this inhibition is antagonized concentration-dependently by adenosine. These effects most likely occur via D1 and A1 receptors and hence by regulation of the adenyl cyclase activity in the macula densa cells. The balance between adenosine and dopamine in tubular fluid appears to be under the control of extrarenal parameters. In normal rats, high dietary salt intake, by influencing the secretion of an unknown adrenal hormone, and inhibition of Na-K-ATPase might be of importance. In spontaneously hypertensive rats unknown genetic parameters may also play a role.

Adenosine↗

PubMed1991

The endothelial L-arginine/nitric oxide pathway and the renal circulation.

Endothelial cells contain an enzyme(s) which produces nitric oxide from L-arginine in response to a variety of mechanical stimuli as well as to autacoids and local and circulating hormones. Nitric oxide is a potent vasodilator and inhibitor of platelet function; it exerts its effects via activation of soluble guanylate cyclase and subsequent formation of cyclic 3'-5'-guanosine monophosphate. In the kidney, activation of the endothelial L-arginine pathway is associated with increases in renal blood flow, diuresis and natriuresis, while the glomerular filtration rate remains constant. The activity of the endothelial L-arginine pathway is impaired in hypertension and during chronic therapy with cyclosporine A. In addition, diabetes and atherosclerosis impair this pathway. Thus, the endothelial L-arginine pathway plays an important role in the local regulation of blood flow. Alterations in the activity of this pathway may play an important role in the pathophysiology of hypertension and renal disease.

Animals↗

PubMed1985

Quantitative cytophotometric analyses of mesenteric mast cell granulation in acute soman intoxicated rats.

Effects of the organophosphate neurotoxin soman on rat mesenteric mast cell granule content were determined using scanning-integrating microdensitometric analysis of individual cell metachromasia. Mast cell degranulation was evidenced both with sublethal (0.5 LD50) and lethal (1.5 LD50) dosages and as early as 3-10 min post-injection. These data indicate a possible contribution of mast cell autacoids in the genesis of organophosphate-induced respiratory and circulatory collapse.

Animals↗

PubMed1981

The influence of a new corticosteroid, budesonide, on anaphylactic bronchoconstriction and SRS-A release in the guinea pig.

Groups of guinea pigs sensitized with ovalbumin were treated with budesonide and beclomethasone dipropionate, respectively, in an intraperitoneal dose of 50 mg/kg. 20 h later, the anaphylactic release of histamine and slow reacting substance of anaphylaxis (SRS-A) from chopped lung tissue was studied. Whereas the corticosteroids studied had no effect on the tissue content of histamine or on the amount of antigen-induced release of this autacoid, budesonide and beclomethasone dipropionate to a great extent inhibited the release of SRS-A. The anti-anaphylactic effect of budesonide and beclomethasone was also shown in sensitized guinea pigs pretreated with mepyramine, 2.5 mg/kg intraperitoneally, and challenged with nebulized ovalbumin. We suggest that the partial protection given by the corticosteroids budesonide and beclomethasone dipropionate is due to the inhibiton of SRS-A release.

Anaphylaxis↗

PubMed1993

A comparison of serotonin (5-HT) blood levels and activity of 5-HT2 antagonists in adjuvant arthritic Lewis and Wistar rats.

The total plasma 5-HT levels of adjuvant arthritic rats were increased in animals of both strains in comparison to healthy controls. The exception was day 1, when the 5-HT plasma level in arthritic Lewis rats was decreased by 77%, but only by 17% in Wistar rats. Treatment with the 5-HT2 receptor antagonist ritanserin caused a significant inhibition of macroscopic arthritis at day 14 in Lewis but not in Wistar rats. The total plasma 5-HT level was significantly decreased by the 5-HT2 antagonists in both strains at various times. 5-HT as an autacoid with effects on the T-lymphocytes and on delayed hypersensitivity reactions might be responsible, at least in part, for strain differences regarding the incidence of secondary lesions in rat adjuvant arthritis.

Animals↗

PubMed1998

Thromboxanes: synthase and receptors.

Thromboxane A2 is a biologically potent arachidonate metabolite through the cyclooxygenase pathway. It induces platelet aggregation and smooth muscle contraction and may promote mitogenesis and apoptosis of other cells. Its roles in physiological and pathological conditions have been widely documented. The enzyme that catalyzes its synthesis, thromboxane A2 synthase, and the receptors that mediate its actions, thromboxane A2 receptors, are the two key components critical for the functioning of this potent autacoid. Recent molecular biological studies have revealed the structure-function relationship and gene organizations of these proteins as well as genetic and epigenetic factors modulating their gene expression. Future investigation should shed light on detailed molecular signaling events specifying thromboxane A2 actions, and the genetic underpinning of the enzyme and the receptors in health and disease.

Alternative Splicing↗

PubMed1991

The role of platelet-activating factor (PAF) in experimental glomerular injury.

Platelet-activating factor (PAF) is a potent autacoid that participates in inflammation and other pathophysiological processes. In this review we deal with recent evidence suggesting that PAF is a mediator that is released early during glomerular injury. PAF can be synthesized in the glomerulus by infiltrating intrinsic glomerular cells. Normal glomeruli produce PAF upon stimulation, and glomerular PAF synthesis is increased in a variety of experimental glomerulopathies. The local infusion of PAF into the renal artery of isolated blood-free kidneys induces proteinuria. PAF attracts and activates inflammatory cells. Glomerular mesangial, endothelial and epithelial cells are also targets for PAF. Therapy with specific PAF receptor antagonists has prevented or reduced proteinuria and improved glomerular inflammation in several experimental models of proliferative glomerulonephritis and minimal change nephrosis. However, the beneficial effect of administration of PAF antagonists once proteinuria is fully developed has been minimal. PAF may also play a role in the recruitment of inflammatory interstitial cells.

Animals↗

PubMed1999

Stabilization of rat serum proteins following oral administration of fish oil.

The mechanism of action of fish oil (FO), currently used in different chronic inflammatory conditions such as rheumatoid arthritis (RA), is not completely understood, although it is thought that it could alter the metabolism of endogenous autacoids. In addition, we hypothesized that the known capability of fatty acids (FA) of stabilizing serum albumin and perhaps other proteins, may be of pharmacological relevance considering that it is shared by other anti-rheumatic agents (e.g. nonsteroidal antiinflammatory drugs). Thus, we studied the effect of oral administration of FO and corn oil (CO), a vegetable oil with a different composition, on the stability of rat serum proteins, evaluated by a classical in vitro method based on heat-induced protein denaturation. FO, and, to a lower extent, CO inhibited heat-induced denaturation of rat serum (RS): based on the inhibitory activity (EC50) of the major fatty acids against heat-induced denaturation of RS in vitro, it was possible to speculate that in vivo effects of palmitic acid (C16:0) and eicosapentaenoic acid (EPA, C20:5, n-3) may be more relevant than that of linolenic acid (C18:2). To better investigate this phenomenon, we extracted albumin from the serum of animals treated or not with FO with a one-step affinity chromatography technique, obtaining high purity rat serum albumin preparations (RSA-CTRL and RSA-FO), as judged by SDS-PAGE with Coomassie blue staining. When these RSA preparations were heated at 70 degrees C for 30 min, it was noted that RSA-FO was much more stable than RSA-CTRL, presumably due to higher number of long chain fatty acids (FA) such as palmitic acid or EPA. In conclusion, we provided evidences that oral administration of FO in the rat stabilizes serum albumin, due to an increase in the number of protein bound long chain fatty acids (e.g. palmitic acid and EPA). We speculate that the stabilization of serum albumin and perhaps other proteins could prevent changes of antigenicity due to protein denaturation and glycosylation, which may trigger pathological autoimmune responses, suggesting that this action may be involved in the mode of action of FO in RA and other chronic inflammatory diseases.

Administration, Oral↗

PubMed1998

ATP release caused by bradykinin, substance P and histamine from intact and cultured smooth muscles of guinea-pig vas deferens.

Histamine (60 microM) produced ATP release from segments of guinea-pig vas deferens which was blocked by pyrilamine and triprolidine, H1-blockers, but not by ranitidine, an H2-blocker. The evoked-release was inhibited by the mitochondrial inhibitors, carbonyl cyanide-m-chlorophenylhydrazone (CCCP) and oligomycin. Bradykinin (BK) and substance P (SP) also caused substantial and moderate release of ATP, respectively. The BK-evoked release of ATP was inhibited by HOE140, a B2-antagonist, but not by [Des-Arg10] HOE140, a B1-antagonist. On the other hand, VIP, angiotensin II (AII) and cholecystokinin-octapeptide (CCK-8) failed to elicit a measurable release of ATP. Histamine and BK also enhanced the release of ATP from superfused cultured smooth muscle cells. These results suggest that ATP may be released as an autacoid from the smooth muscles in the presence of these chemical mediators.

Adenosine Triphosphate↗

PubMed2006

Effect of endothelin-1 on erythropoietin production in a rat model under normoxia and functional carbon monoxide-induced hypoxia.

It has been hypothesized that autacoids, such as endothelin-1 (ET), may modulate erythropoietin (Epo) secretion. Therefore, we studied the effect of ET-1 infusion and of a nonselective ET(A/B) receptor antagonist on Epo secretion under carbon monoxide (CO) exposure. Anesthetized rats were supplied with room temperature air containing increasing concentrations of CO by an aerating cap. A CO-Epo dose-response curve over the range of 0.02-0.14 vol% CO was conducted. Subpressor doses of ET-1 (3 pmol/min/kg BW) and the ET(A/B) receptor antagonist LU302872 (LU; 30 mg/kg) were applied to anaesthetized rats under normoxia (controls CON, ET, LU) and following hypoxia (CO exposure; H-CON, H-ET, H-LU). Mean arterial blood pressure (MAP), glomerular filtration rate (GFR, inulin clearance), Epo and ET-1 serum concentrations (ELISA) and renal Epo mRNA (Light Cycler) were determined. The EC50 value for CO was 0.1 vol% with a 70-fold increase in Epo serum concentrations. CO exposure increased Epo serum and Epo mRNA concentrations in the expected range in all groups. None of the treatments with ET or LU influenced the effect of hypoxia on Epo serum concentrations and renal Epo mRNA content. Under hypoxia, administration of ET-1 as well as LU prevented the hypoxia-induced decrease in MAP (p<0.05). Under hypoxia, GFR was reduced by 50% except for H-LU with values comparable to normoxia. Taken together, the influence of hypoxia exceeds by far the effect of ET-1 on Epo production, irrespective of the presence or absence of exogenous ET-1. Thus, ET-1 does not appear to be a major modulator of Epo production.

Animals↗

PubMed1996

Blockade of nitric oxide formation inhibits the stimulation of the renin system by a low salt intake.

This study aimed to investigate the possible involvement of endothelial autacoids such as nitric oxide or prostaglandins in the well-known stimulatory effect of a low salt intake on renin secretion and renin gene expression in the kidney. To this end, plasma renin activity (PRA) and kidney renin mRNA levels were determined in male Sprague-Dawley rats fed either a normal (0.6% w/w) or a low (0.03%) NaCl diet for 10 days. To inhibit nitric oxide formation, the animals received L-nitro-argininemethylester (L-NAME, 40 mg/ kg twice a day), to inhibit prostaglandin formation the animals received meclofenamate (8 mg/kg twice a day) during the last 2 days. In animals fed a normal salt diet, L-NAME decreased PRA from 6.5 to 4.9 ng angiotensin I x h(-1) x ml(-1) and decreased renin mRNA levels by about 15%. Meclofenamate did not change PRA or renin mRNA in animals fed on normal salt diet. In vehicle-treated animals fed a low salt diet, PRA increased from 6.5 to 20.2 ng ANGI x h(-1) x ml(-1) and renin mRNA levels increased by 100%. Meclofenamate treatment did not alter these changes of PRA and renin mRNA during the intake of a low salt diet. In animals treated with L-NAME, PRA increased to only 7.2 ng ANGI x h(-1) x ml(-1) and renin mRNA increased by 20%. These findings indicate that inhibition of nitric oxide formation but not of prostaglandin formation substantially attenuates the stimulatory effect of a low salt intake on the renin system, suggesting that nitric oxide is required for this process.

Animals↗

PubMed1997

Elevation of plasma viscosity induces sustained NO-mediated dilation in the hamster cremaster microcirculation in vivo.

We studied whether a flow-independent increase of luminal wall shear stress (WSS) could dilate hamster arterioles in vivo and which endothelial mediators are potentially involved. To this end the plasma viscosity was elevated by exchanging blood for dextran-erythrocyte solution thereby augmenting WSS. Diameters of small and large arterioles as well as red blood cell velocities were measured before and after exchange of blood for solutions of identical haematocrit containing either high- (HMWD) or low-molecular weight dextran (LMWD). The potential role of endothelial autacoids was investigated by local application of the NO-synthase inhibitor NG-nitro-L-arginine (L-NNA), the inhibitor of cyclooxygenase, indomethacin (3 microM), or the K+-channel blocker, tetrabutylammonium (TBA, 0.1 mM) to assess the potential effects of EDHF. HMWD (n = 11 animals) increased plasma viscosity by 64 +/- 3% and dilated arterioles of all branching orders (A1-A4) significantly [by 24 +/- 3% (A1-A2) and 32 +/- 3% (A3-A4)]. This dilation compensated fully for the calculated initial increase of WSS. LMWD (n = 6) did not affect plasma viscosity or arteriolar diameters. Tissue treatment with L-NNA (30-300 microM, n = 12) substantially diminished the HMWD-induced dilation in small arterioles (A3-A4; to 13 +/- 3%; P<<0.05) and virtually abolished it in large ones (A1-A2). Consequently, the calculated WSS increased significantly in these arterioles (by 31 +/- 5%). TBA combined with L-NNA (n = 4) did not reduce further the remaining dilation. Indomethacin (n = 6) had no effect on HMWD-induced dilation. We conclude that an increase of WSS induces a mainly NO-mediated arteriolar dilation. This dilation occurs in all arteriolar branching orders and is of sufficient magnitude to compensate for the initial WSS-increase. Thus, any elevations of WSS fulfil the requirement for a signal to change diameter along the arteriolar tree in a coordinated manner. The fully compensating dilation which we observed indicates that WSS is a controlled variable. It does, however, raise questions as to its role as a continuous endothelial stimulus.

Animals↗