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At least 217 records · Page 12Linked to original sources
PubMed1975

Quantitative in vitro vasoactivity of 5-hydroxytryptamine on the human basilar artery.

The importance of autacoidal substances in the genesis of cerebral vascular constriction and spasm is an unresolved issue. Comparative vasoactivity of 5-hydroxytryptamine (5HT) and norepinephrine (NE) on the human basilar artery was quantitatively assessed in vitro. 5HT was decidedly more vasoactive in this preparation. Three patterns of vasoactivity were noted with 5HT. Type I was an immediate sustained increase in tension lasting more than 30 minutes. Average increase in tension was 2988 mg (range 120-8600). Type II consisted of a sharp immediate increase in tension to average 1555 mg (range 240-4500) followed by gradual dissipation to base-line levels within 15 minutes. Type III pattern was a lesser immediate increase (372 mg; range 100-850) and more rapid dissipation over ten minutes. NE-induced Type I and Type III activity was present in only six of 20 segments. This study demonstrates that 5HT is vasoactive in human cerebral arteries. Type I sustained contractions may possibly be implicated in spasm. It is hypothesized that such autacoid-induced contraction may contribute to vascular wall ischemia, necrosis, and irreversible constriction as seen in human vasospasm.

Adult↗
PubMed1992

Role of bradykinin in the cardiac effects of angiotensin-converting enzyme inhibitors.

Angiotensin-converting enzyme (ACE) inhibitors exert their beneficial effects not only via endocrine mechanisms, but most probably also via interference with autocrine-paracrine actions involving local renin-angiotensin and kallikrein-kinin systems with subsequent autacoid release. Inhibition of ACE (kininase II) results in the reduction of angiotensin II generation and kinin degradation, leading to beneficial cardiovascular effects. Bradykinin and prostacyclin release from isolated rat hearts was increased by local ACE inhibitions with ramiprilat. In different models the bradykinin-mediated effects of ACE inhibition were abolished with the specific B2 kinin-receptor antagonist Hoe 140: The cardioprotective effects of ramiprilat or ramipril such as reduction of postischemic reperfusion injuries in isolated rat hearts or the reduction in infarct size in dogs and rabbits were abolished by coadministration of Hoe 140. Furthermore, left ventricular hypertrophy in rats with aortic banding could be prevented or regression was induced when the ACE inhibitor was given in a non-blood pressure-lowering dose. These beneficial effects were also abolished by Hoe 140. In conclusion, in different experimental models, ACE inhibitors exert cardioprotective effects. An enhancement of endothelial autacoid formation (nitric oxide and prostacyclin) by inhibiting degradation of bradykinin may contribute to these effects.

Angiotensin II↗
PubMed1989

Influence of a stable prostacyclin analogue (iloprost) and cyclooxygenase inhibition on angiotensin-II in the perfused human placenta.

Studies were undertaken on perfused human placentas to examine the effect of a stable prostacyclin analogue (iloprost) on the angiotensin-II (A-II) response in the placental vessels, and to examine how this response is influenced by cyclooxygenase inhibition. Iloprost, in doses of 1, 5, and 10 micrograms significantly reduced the response of 50 micrograms of A-II. The vasoconstriction produced by the autacoid was attenuated by the three doses of iloprost by 43.9 +/- 5.2%, 56.5 +/- 6.1%, and 39.7 +/- 6.0%, respectively (MEAN +/- S.E.). The 1 microgram dose of the analogue did not differ significantly from either the 5 micrograms or 10 micrograms dose in this regard. A 5 mg dose of the cyclooxygenase inhibitor indomethacin, when combined with 1 microgram of iloprost, also significantly attenuated the A-II response, although the dilating effects of iloprost was significantly reduced by indomethacin. This response of the autacoid was significantly reduced when compared to the A-II response preceded by only iloprost. Because the effects of A-II were attenuated by indomethacin, it is suggested that part of the mechanism of A-II is due to prostaglandin release into the placental circulation, the majority of which appear to have a pressor effect on the placental vessels.

Angiotensin II↗
PubMed1989

Beta 2-adrenergic agonist regulation of immune aggregate- and platelet-activating factor-stimulated hepatic metabolism.

Vasoconstriction and subsequent glycogenolysis stimulated by immune complex infusion into perfused rat livers was inhibited by prior infusion of isoproterenol. Similarly, isoproterenol inhibited the biosynthesis of bioactive lipid autacoids such as platelet-activating factor, prostaglandin E2, and thromboxane B2 which was stimulated by immune aggregates. The adrenergic receptor specificity of these effects was determined through the use of specific adrenergic subtype-specific agonists and antagonists to be mediated by beta 2-adrenergic receptors. Indirect evidence for the differential expression of hepatic sinusoidal and parenchymal beta-adrenergic receptors in the male rat during ontogeny suggested that inhibition of immune aggregate-stimulated autacoid biosynthesis, vasoconstriction, and glycogenolysis by isoproterenol occurs at a sinusoidal locus, most likely Kupffer cells. In contrast with the ability of beta 2-adrenergic agonists to inhibit immune aggregate- and platelet-activating factor-stimulated hepatic metabolism, dibutyryl cyclic AMP did not mimic these sinusoidal beta 2-adrenergic effects, despite stimulating hepatic parenchymal cell glycogenolysis as effectively as isoproterenol. These observations suggest a role for cyclic AMP-independent mechanisms in the regulation of heterologous stimulus-response coupling by hepatic sinusoidal beta 2-adrenergic receptors.

Animals↗
PubMed1989

Bradykinin augments the in vitro migration of nonsensitized lymphocytes.

Bradykinin and related peptides have been considered important as mediators of acute inflammation, but their role in the cell-mediated immune response has not been extensively investigated. We have examined the effect of physiological concentrations of these autacoids on the migration of nonsensitized lymphocytes employing an in vitro micropore filter assay system. Bradykinin at a concentration of 0.01-1 nM significantly stimulated the migration of both human peripheral blood and rat splenic lymphocytes. Related naturally-occurring kinins (kallidin, MetLys-bradykinin, desArg9-bradykinin) had a similar effect but other autacoids (angiotensins I and II, histamine, serotonin) were inactive. Bradykinin was more active on freshly harvested lymphocytes than on cells incubated for up to 48 h with or without mitogen. Bradykinin appeared to act predominantly as a chemokinetic agent (augmenting random nondirectional motility), as determined by checkerboard analysis. Bradykinin appeared to exert its effect on lymphocytes predominantly through the B1 class of bradykinin receptors. The migratory response to bradykinin could not be attributed to the release of arachidonic acid metabolites, but stimulated migration could be significantly inhibited by the histamine type 2 receptor antagonist cimetidine. These studies provide a novel mechanism whereby nonsensitized lymphocytes may be recruited to sites of delayed-type hypersensitivity reactions.

Angiotensin II↗
PubMed1986

Prostaglandins and other eicosanoids: their ocular transport, pharmacokinetics, and therapeutic effects.

Since prostaglandins (PGs) were originally discovered in the eye in a search for the mediators of the ocular irritative responses, it is not surprising that the first decade of research on the ocular effects of these autacoids concentrated on their potential role in inflammation and other pathological processes. It is clear that PGs, like most other biologically active compounds, can have pathological effects when introduced into the eye in sufficiently high doses. More recent studies indicate, however, that PGs are also involved in the normal physiological processes of the eye, and that some PGs effectively reduce intraocular pressure and may actually moderate rather than mediate ocular inflammation. We must therefore consider the eicosanoids as a new class of potential ocular therapeutic agents. This paper reviews the evidence that these autacoids are actively transported by some tissues, including the ciliary epithelium, and considers the role of such transport processes in the ocular and systemic pharmacokinetics of endogenous eicosanoids and their therapeutically applied prodrugs.

Animals↗
PubMed1984

Pathophysiologic modulation of arachidonate metabolism.

Low concentrations of lipid hydroperoxides are necessary to activate the biosynthesis of prostaglandins and other autacoids from arachidonate. When the concentration is too low (less than 10(-9) M) that biosynthesis is suppressed. However, lipid peroxides at concentrations higher than micromolar can inactivate prostacyclin synthase and, at higher levels, even prostaglandin H synthase. Thus, lipid hydroperoxides may be important regulators of biological processes, and their reliable quantitation is important in interpreting the physiologic status of a tissue. The plasma levels of lipid hydroperoxide that are indicated by the thiobarbituric acid (TBA) assay of normal human plasma (26-63 microM) would be high enough to totally inactivate prostacyclin synthase and thus they seem incompatible with a healthy vascular system. To resolve this paradox, we have developed a new assay which directly measures the level of lipid hydroperoxide. Controlled studies showed that the TBA-positive response of normal human plasma gave values for hydroperoxide that had no clear relationship to the actual level of hydroperoxide that was present and were 50-100 times greater than the directly observed values. The new direct assay indicates that the normal level of plasma lipid hydroperoxide may be approximately 0.5 microM. Such a level may provide chronic stress on the ability of vascular endothelial cells to provide sufficient amounts of the antithrombotic autacoid, prostacyclin. Our results indicate that relatively slight elevations from the normal circulating hydroperoxide levels might be expected to have undesirable effects, and that a reliable monitoring of plasma hydroperoxide levels may be useful.

Arachidonic Acid↗
PubMed1993

Endothelium-derived bradykinin: implications for angiotensin-converting enzyme-inhibitor therapy.

The effects of angiotensin-converting enzyme (ACE) inhibitors on endothelial autacoid formation were determined in human cultured endothelial cells and in endothelium-intact bovine coronary arteries under resting conditions and after stimulation with bradykinin. Incubation of cultured human endothelial cells with moexiprilat or ramiprilat (0.3 microM) caused a maintained increase in resting intracellular calcium [Ca2+]i, which was prevented by the selective B2-receptor antagonist Hoe 140 (0.1 microM). Both ACE inhibitors also significantly enhanced the increase in [Ca2+]i elicited by bradykinin (3 nM). In parallel with their effect on resting [Ca2+]i, moexiprilat and ramiprilat both induced an increase in intracellular cyclic GMP (cGMP). This increase was prevented by Hoe 140 (0.1 microM) and was abolished by NG-nitro-L-arginine (30 microM), indicating a kinin-induced nitric oxide (NO) formation in this response. The elevation in [Ca2+]i also led to an enhanced production of prostacyclin (PGI2), as indicated by an increase in the concentration of 6-keto prostaglandin F1 alpha (PGF1 alpha) in the cell supernatant. Similar effects of the ACE inhibitors on endothelial autacoid production were observed in endothelium-intact bovine coronary arteries. Like bradykinin (30 nM), moexiprilat (0.3 microM) elicited a nearly twofold increase in the cGMP content of these arteries, which was abolished by both NG-nitro-L-arginine and removal of the endothelium. The functional consequences of this ACE inhibitor-induced increase in vascular cGMP were reflected by a distinct relaxation of arteries preconstricted with PGF2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Furosemide enhances the release of endothelial kinins, nitric oxide and prostacyclin.

Despite a wealth of data, the mechanism of the direct dilator effect of furosemide on the systemic arterial and venous systems is far from being satisfactorily understood. Therefore, we investigated whether furosemide is capable of stimulating the production of the endogenous vasodilators nitric oxide and prostacyclin in primary cultured bovine aortic endothelial cells by an enhanced synthesis and release of endothelium-derived kinins. Nitric oxide production was assessed in terms of intracellular guanosine cyclic-3',5' monophosphate accumulation; kinin and prostacyclin release were determined by specific radioimmunoassays. Furosemide concentration- and time-dependently increased the formation of nitric oxide and prostacyclin. Maximal increases of both autacoids were already obtained after a 5-min incubation with 3 x 10(-7) to 10(-6) mol/l of furosemide. In the same concentration range, furosemide led to an enhanced release of kinins into the supernatant of the cells. This observation was supported by the inhibitory effect of the specific B2 kinin receptor antagonist icatibant (Hoe 140) on the furosemide-induced increase of nitric oxide and prostacyclin. Thus the hemodynamic effects, and in particular the direct early dilator effect, of furosemide may be explained in part by an enhanced endothelial synthesis and release of bradykinin and related kinins, which in turn stimulates endothelial autacoid formation via B2 kinin receptor activation.

Animals↗
PubMed1994

Interactions of hormones with the vascular endothelium. Effects on the control of vascular tone.

Due to their anatomical location vascular endothelial cells are an obvious target for hormones which are transported by the bloodstream. Studies on cultured endothelial cells, isolated vessels and the intact organism revealed the existence of multiple interactions between endothelial cells and circulating hormones. Not only are endothelial cells involved in the clearance of some specific circulating hormones, but they also form a tight barrier for other hormones thus preventing or attenuating their direct effects on vascular smooth muscle. Endothelial cells are also involved in the production of circulating angiotensin II by the angiotensin converting enzyme. Probably the most significant effect of hormones in vascular control is the ability of many of them to modulate the release of vasoactive autacoids such as nitric oxide, prostaglandins and endothelin-1. Aside from acute stimulating effects on autacoid production, some hormones, particularly steroids, exert chronic effects on vasoactive-factor gene expression. Apparently, in the control of vascular tone, interactions between circulating hormones and the endothelium play a major role. However, the functional significance of these interactions, especially in pathophysiologic conditions remains to be determined.

Animals↗
PubMed1997

[The effect of cyclooxygenase inhibitors on ion and water transport in the human kidney and frog skin and bladder].

In the frog urinary bladder and skin, block of cyclooxygenase with diclofenac (voltaren) resulted in an increase in the water permeability and a decrease in the potential difference and short-circuit current. Addition of 0.01 mumole of prostaglandine E2 decreased the osmotic water permeability to initial values and increased the transepithelial ion transport in the frog skin. In the kidney of children with nocturnal enuresis there was an increase in the night diuresis and in excretion of osmotically active substances. Voltaren by reducing the endogenous autacoid production, restored the kidney function and symptoms of enuresis disappeared. The results obtained indicate an important role of the rate of the endogenous autacoid production in regulation of the water and ion transport in the osmoregulating organs studied.

Adolescent↗
PubMed1995

Reduction in surgical ischemic-reperfusion injury with adenosine and nitric oxide therapy.

Ischemia and reperfusion impair the inherent capacity of the heart to protect itself from related pathophysiologic events by reducing endogenous oxygen radical scavengers and inhibitors. However, other endogenously produced agents, notably adenosine and nitric oxide, are produced during ischemia, reperfusion, or both. These autacoids have several cardioprotection actions in common, particularly antineutrophil effects and inhibition of endothelial-neutrophil interactions, which are key initial steps in ischemic-reperfusion injury. Studies have shown that nitric oxide exerts cardioprotection primarily during reperfusion. Adenosine, on the other hand, protects the myocardium to some extent during both ischemia and reperfusion, thereby covering both periods during which myocardial injury may be sustained during a cardiac operation. Native adenosine or active analogues, or donors of nitric oxide, may be given before or in conjunction with cardioplegia solutions. However, these endogenous agents can also be pharmacologically recruited to provide a new potent therapeutic approach against surgical ischemic-reperfusion injury. This article reviews the cardioprotective effects of primarily endogenous nitric oxide and adenosine in both nonsurgical and surgical models of ischemia-reperfusion injury. Both adenosine and nitric oxide provide potent cardioprotection in surgical and nonsurgical models of ischemia-reperfusion. An important mechanism in this cardioprotection is attenuation of neutrophil-mediated damage.

Adenosine↗
PubMed1998

Endothelial-dependent dynamic and antithrombotic properties of porcine aortic and pulmonary valves.

BACKGROUND: In the present study, the endothelium-dependent antithrombotic and dynamic properties of porcine aortic (AoV) and pulmonary valves (PuV) were investigated. METHODS: Fifteen fresh AoV and 15 fresh PuV were obtained from 25 9-month-old swines. The valves were examined for endothelial function by pharmacologic evaluation (with and without endothelium) of both the endothelial-releasing capacity of prostacyclin and the endothelial-dependent dynamic response to relaxing (acetylcholine from 10[-10] mol/L to 10[-4] mol/L in AoV and PuV segments precontracted with norepinephrine [3 x 10(-6) mol/L]) and contracting (endothelin-1, from 10[-11] mol/L to 10[-5] mol/L; and NG-monomethyl-L-arginine, 10[-4] mol/L) drugs. The ultrastructural integrity of the endothelial valve layer was also examined with transmission electron microscopy. RESULTS: Acetylcholine caused potent relaxation in both AoV and PuV specimens with, but not in those without, endothelium. Endothelin-1 produced a concentration-dependent tension increase in AoV and PuV with and without endothelium. However, the intrinsic activity of the peptide significantly increased in tissues without endothelium. NG-monomethyl-L-arginine evoked a progressive increase in resting tension of the preparations, but the AoV and PuV without endothelium were less sensitive to the inhibition of the nitric oxide generation. Aortic and pulmonary valves with an intact endothelium showed a spontaneous ability to release prostacyclin. The basal release of this lipidic autacoid significantly decreased in cardiac valves without endothelium. This phenomenon was observed in both basal conditions, and under stimulation with the aforementioned drugs. Transmission electron microscopy showed the perfect preservation of endothelial cells in all the preparations examined. CONCLUSIONS: Valvular endothelium of AoV and PuV seems to have similar antithrombotic and dynamic functions of vascular endothelium, actively participating in valvular homeostasis.

Acetylcholine↗
PubMed1997

Release of a stable cardiodepressant mediator after myocardial ischaemia during reperfusion.

OBJECTIVE: The aim of this study was to investigate whether cardiodepressant mediators are released after myocardial ischaemia during reperfusion. METHODS: Using a double heart model, the effect of the reoxygenated coronary effluent of an isolated guinea pig heart on a sequentially perfused second heart was studied under control conditions and after 10 min ischaemia of the first heart. Investigation of the modulating role of known autacoids took place by using free radical scavengers, an NO synthase inhibitor and adenosine receptor antagonists. In order to identify the chemical nature of cardiac metabolites, the coronary effluent was also subjected to different chemical treatment modes. RESULTS: No haemodynamic changes were observed during sequential perfusion under control conditions. After 10 min of global ischaemia in heart I, a marked decrease in LVP (-22%), LVdP/dtmax (-43%), LVdP/dtmin (-41%) and coronary perfusion pressure (-25%) was measured in heart II during sequential perfusion. The negative inotropic effect was rapid in onset and reversible within 5 min; free radicals, nitric oxide and adenosine were not involved. Storage of the coronary effluent of the first heart up to 24 h, heating, or protease treatment did not modify its cardiodepressant effects on the second sequentially perfused heart. CONCLUSIONS: These results suggest the release--from an isolated heart after ischaemia during reperfusion--of a cardiodepressant mediator which induces a potent reversible negative inotropic effect on a sequentially perfused heart. The mediator is stable and in all probability not a protein.

Adenosine Deaminase↗
PubMed2003

Anti-thrombotic activity of PDR, a newly synthesized L-Arg derivative, on three thrombosis models in rats.

The possibility of a newly synthesized L-arginine derivative, polyaspartoyl-L-arginine (PDR), as a novel anti-thrombotic agent and its mode of action were investigated. The anti-platelet effects of PDR in rats ex vivo, anti-thrombotic effects in three thrombosis models in rats and its effect on some autacoids (nitric oxide [NO], thromboxane [TXA2] and prostacyclin [PGI2]) were studied. PDR (i.g.) significantly inhibited ADP-, collagen- or thrombin-induced rat platelet aggregation. In arteriovenous shunt model and ferric chloride-induced arterial thrombosis model in rats, PDR (i.g.) significantly reduced the thrombus weight. In electrical stimulation-induced arterial thrombosis in rats, PDR (i.v.) dose-dependently prolonged the thrombus occlusion time (OT). PDR increased the concentration of NO in plasma. In contrast with aspirin (ASA), PDR did not influence on the TXA2 and PGI2 levels in plasma. In conclusion, PDR is provided with significant inhibitory effect on platelet aggregation and prevention effect on platelet related thrombosis, which is probably attributed to its inhibition on platelet function by L-arginine-NO pathway. The results demonstrate that PDR is a novel, oral and venous effective platelet aggregation inhibitor and has a possibility used as an anti-thrombotic agent.

Adenosine Diphosphate↗
PubMed2000

Role of prostaglandins in hypertension.

The role of prostaglandins (PGs) in hypertension (HT) is reviewed, emphasising their biochemical characteristics, physiological effects and functions, especially in the cardiovascular area, and the current evidence of their participation in the antihypertensive activity of a balanced mechanism to maintain normal blood pressure. Also, the clinical use of PGs and the future of such autacoids in the treatment of HT and other diseases or conditions is mentioned.

Animals↗
PubMed1991

Mediators of the direct effects of amino acids on the rat kidney.

1. The response of the isolated rat kidney to a mixed amino acid solution was examined in the presence of three renal autacoid inhibitors, indomethacin (a cyclo-oxygenase inhibitor), sulpiride (a dopamine antagonist) and L-nitroarginine methyl ester (an inhibitor of nitric oxide synthesis). 2. Increasing the concentration of the mixed amino acid solution perfusing the kidney from 2 to 8 mmol/l (n = 6) produced a sustained increase in renal perfusate flow (P less than 0.01) and reversed the time-dependent fall in [14C]inulin clearance (P less than 0.01) demonstrated in kidneys perfused with 2 mmol/l mixed amino acids alone. A significant increase in the fractional sodium reabsorption and decrease in the fractional albumin excretion was also observed. 3. Indomethacin (10(-4) mol/l, n = 6) produced partial (50%) inhibition of the effect of mixed amino acids on [14C]inulin clearance, but did not influence their ability to increase renal perfusate flow. 4. Sulpiride (0.7 mumol min-1 kg-1, n = 6) produced partial inhibition of the effect of mixed amino acids on both [14C]inulin clearance and renal perfusate flow by 60% and 50%, respectively. Sulpiride also entirely inhibited the reduction in fractional albumin excretion. 5. L-Nitroarginine methyl ester (10(-4) mol/l, n = 6) completely inhibited the effect of mixed amino acids on [14C]inulin clearance, but did not inhibit the increase in renal perfusate flow, even though the basal vascular resistance was markedly enhanced. L-Nitroarginine methyl ester also inhibited the increase in fractional sodium reabsorption produced by the mixed amino acids. 6. It is concluded that prostaglandins, dopamine and nitric oxide may all have a role to play in the direct effect of mixed amino acids on renal function. This does not, however, preclude further modification by additional stimuli generated in vivo.

Albumins↗
PubMed1979

Pharmacology of Schultz-Dale reaction in canine lung strip in vitro: possible model for allergic asthma.

1 Isolated lung parenchymal strips of the dog contracted in response to histamine > carbachol > prostaglandin F(2alpha) (PGF(2alpha)) > bradykinin (Bk) > 5-hydroxytryptamine (5-HT). The order of the relative activity of these agents on the tracheobronchial smooth muscles (TBSM) was carbachol > 5-HT > histamine; PGF(2alpha) and Bk were inactive. Thus there are marked differences in the responsiveness of the smooth muscle of central (trachea and bronchus) and peripheral (lung strip) airways to autonomic and autacoid agents.2 Lung strips and TBSM partially contracted by carbachol, histamine or horse plasma, were relaxed by isoprenaline, PGE(1) and PGE(2).3 Lung strips from dogs sensitized to horse-plasma contracted in response to antigen (Schultz-Dale anaphylactic reaction). Tachyphylaxis or desensitization to subsequent antigen challenge was invariably observed; it was followed after 1 to 2 h of rest by partial recovery of the anaphylactic response.4 Mepyramine selectively antagonized responses to histamine without altering responses to carbachol and antigen.5 Metiamide, an H(2)-receptor antagonist, did not influence responses to histamine, carbachol or horse plasma.6 Indomethacin was found to be ineffective as an inhibitor of the Schultz-Dale anaphylactic reaction.7 The results showed the presence of H(1)-histamine receptors mediating constriction in the peripheral airways of the dog. Histamine and PGF(2alpha) appear to have no important role in the anaphylactic reaction in this tissue. The involvement of slow reacting substance of anaphylaxis (SRS-A) and endoperoxides (thromboxanes) in allergic reactions of canine lung is strongly suggested.

Anaphylaxis↗