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PubMed1991

Effects of typhus rickettsiae on peritoneal and alveolar macrophages: rickettsiae stimulate leukotriene and prostaglandin secretion.

Monolayers of mouse resident peritoneal macrophages were incubated with typhus rickettsiae, and macrophage secretion of leukotriene B4 (LTB4) was assessed. Macrophages incubated with native rickettsiae, but not those incubated with hemolytically inactivated rickettsiae, secreted significantly more LTB4 than did sham-treated macrophages. Antirickettsial antiserum was opsonic and blocked hemolysis, and macrophages incubated with rickettsiae in the presence of antiserum did not secrete more LTB4 than those incubated with buffer alone. Native rickettsiae also stimulated alveolar macrophages to secrete LTB4 and prostaglandin E2 (PGE2), but inactivated rickettsiae had no effect. Finally, because trifluoperazine did not alter macrophage LTB4 secretion in the presence of rickettsiae, but inhibited PGE2 secretion, it was suggested that the mechanisms by which rickettsiae stimulated production of these autacoids may have differed.

Analysis of Variance↗

PubMed1998

Therapeutic options directed against platelet activating factor, eicosanoids and bradykinin in sepsis.

Various autacoids, including the eicosanoids, platelet activating factor (PAF) and bradykinin, have been implicated in the pathogenesis of sepsis and septic shock. The precise role of these compounds as mediators of the diffuse inflammatory state characteristic of sepsis remains to be determined, but, in animal models, beneficial effects have been observed as a result of treatment with various inhibitors of eicosanoid biosynthesis or antagonists of PAF or bradykinin receptors. To date, however, it has been impossible to translate these encouraging results from animal models into convincingly positive results in the clinical setting.

Bradykinin↗

PubMed1998

Vitamin E and atherosclerosis.

Vitamin E was advocated as an effective treatment for heart disease by Dr. Even Shute of London, Ontario more than 50 years ago. His pioneering claims, which were unacceptable to the medical community at large, have been confirmed by recent findings from epidemiologic studies and clinical trials. This review integrates our current knowledge of atherogenesis with the biological functions of vitamin E. The response-to-injury hypothesis explains atherosclerosis as a chronic inflammatory response to injury of the endothelium, which leads to complex cellular and molecular interactions among cells derived from the endothelium, smooth muscle and several blood cell components. Inflammatory and other stimuli trigger an overproduction of free radicals, which promote peroxidation of lipids in LDL trapped in the subendothelial space. Products of LDL oxidation are bioactive, and they induce endothelial expression and secretion of cytokines, growth factors and several cell surface adhesion molecules. The last-mentioned are capable of recruiting circulating monocytes and T lymphocytes into the intima where monocytes are differentiated into macrophages, the precursor of foam cells. In response to the growth factors and cytokines, smooth muscle cells proliferate in the intima, resulting in the narrowing of the lumen. Oxidized LDL can also inhibit endothelial production of prostacyclin and nitric oxide, two potent autacoids that are vasodilators and inhibitors of platelet aggregation. Evidence is presented that vitamin E is protective against the development of atherosclerosis. Vitamin E enrichment has been shown to retard LDL oxidation, inhibit the proliferation of smooth muscle cells, inhibit platelet adhesion and aggregation, inhibit the expression and function of adhesion molecules, attenuate the synthesis of leukotrienes and potentiate the release of prostacyclin through up-regulating the expression of cytosolic phospholipase A2 and cyclooxygenase. Collectively, these biological functions of vitamin E may account for its protection against the development of atherosclerosis.

Animals↗

PubMed1999

Role of thromboxane in the altered vascular reactivity of pregnant rats with adriamycin nephropathy.

BACKGROUND: Pregnant rats with adriamycin nephropathy (ADRP rats) develop hypertension and have an increased vascular reactivity to noradrenaline in the isolated mesenteric bed in vitro. We have shown previously that the administration of daltroban, a specific thromboxane receptor antagonist, prevented hypertension in ADRP rats. METHODS: We measured the effect of daltroban (10(-5) mol/l) on the vasoconstrictory response to noradrenaline (1-10 micromol/l) in the isolated mesenteric bed of ADRP rats at the end of pregnancy, as compared with normal pregnant and adriamycin-treated virgin rats. In further experiments, we measured the changes of flow induced by increasing concentrations of the thromboxane analogue, U46619 (10(-7)-10(-6) mol/l). Finally, changes of flow were assessed in arteries maximally constricted with U46619 (10(-6) mol/l), during perfusion in the presence of increasing concentrations of daltroban (10(-7)-10(-5) mol/l). RESULTS: Daltroban diminished the response to noradrenaline in all groups, shifting the concentration-effect curve to the right. However, at maximal concentrations of noradrenaline, daltroban was ineffective in all rats, except in ADRP animals. The vasoconstrictory response to U46619 was significantly reduced in all pregnant rats, both normal and adriamycin-treated. Daltroban progressively released the vasoconstriction induced by U46619 in all groups. However, this vasodilator response was attenuated in the adriamycin-treated rats, the slopes of their curves being smaller than those of the respective untreated groups (0.038 +/- 0.006 in virgin rats vs 0.063 +/- 0.011 in controls, P < 0.05; and 0.015 +/- 0.005 in ADRP vs 0.028 +/- 0.008 in normal pregnancy, P < 0.05). CONCLUSIONS: The findings could be explained by enhanced occupancy of thromboxane receptors by an endogenous agonist, possibly PGH2, as a consequence of either increased levels of the autacoid or increased number of affinity receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1990

Changes of arterial prostaglandin E2 during haemodialysis.

The absence of a reduction in peripheral vascular resistance secondary to hypervolaemia leads to so-called volume hypertension. In order to study whether a deficient formation of the vasodilator autacoid prostaglandin E2 (PGE2) contributes to the preservation of inadequate vascular tone during extracellular volume expansion, arterial plasma PGE2 and the stable PGE2 metabolite 13,14-dihydro-15-keto-PGE2 (PGE2-M) were determined in 13 oligoanuric women on chronic haemodialysis. Prior to treatment eight of them had hypervolaemia and hypertension (mean arterial pressure (MAP) 128 +/- 3 mmHg (mean +/- SE] and five patients had hypervolaemia of a similar degree but were not hypertensive (MAP: 99 +/- 4 mmHg P less than 0.005). Before haemodialysis the arterial PGE2 and PGE2-M concentrations were less (P less than 0.05) in hypertensive (11 observations in eight patients) than in normotensive patients (ten observations in five patients). As blood pressure decreased during the course of haemodialysis of volume hypertensive patients, the concentration of PGE2 and PGE2-M increased (P less than 0.02) by 104 +/- 43% and 89 +/- 32%, respectively. In normotensive patients neither blood pressure nor the concentration of PGE2 and PGE2-M were found to change during treatment. Since volume hypertension was associated with reduced values and dialysis induced normalisation of blood pressure with increased arterial values of PGE2 and PGE2-M, we hypothesise that the development of hypertension associated with fluid overload of haemodialysed patients may be related to a decreased release of prostaglandin E2.

Adolescent↗

PubMed1990

Estimation of platelet-activating factor receptors in the endometrium of the pregnant rabbit: regulation of ligand availability and catabolism by bovine serum albumin.

High affinity receptors have been demonstrated for the potent phospholipid autacoid, platelet-activating factor (PAF C18:0; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) in a variety of tissues, including the endometrium. Because of the relative instability of PAF and our previous demonstration that lyso-PAF (1-O-alkyl-2-lyso-sn-glycero-3-phosphorylcholine), the major metabolite of PAF, displaced [3H]PAF from endometrial PAF receptor sites, we have examined the ability of bovine serum albumin (BSA) to prevent degradation of PAF and have characterized PAF and lyso-PAF binding sites in purified rabbit endometrial membranes isolated on Day 6 of pregnancy. In buffer containing the phospholipase A2 inhibitors, quinacrine (10 microM) and dibromoacetophenone (2 microM), and 0.25% BSA, 87.4 +/- 3.2% of added [3H]PAF C18:0 remained intact after incubation at 25 degrees C for 150 min. The metabolic products, lyso-PAF and 1-O-alkyl-2-acyl-sn-glycero-3-phosphorylcholine (alkylacyl-GPC), only amounted to 5.2 +/- 3.2 and 3.3 +/- 1.1, respectively. At the same concentration, rabbit serum albumin (RSA) also significantly protected [3H]PAF C18:0 from metabolism, but bovine gamma globulin (BGG) was ineffective. The presence of 0.25% BSA, however, did not protect [3H]lyso-PAF C18:0 from extensive catabolism: the major product formed was [3H]alkylacyl-GPC. Insignificant amounts of [3H]PAF were formed. Under the same conditions (25 degrees C, 150 min) in the presence of 0.25% BSA, saturation analysis revealed the presence of two types of PAF C18:0 receptors in the endometrial membranes. Type 1 sites had a Kd of 0.42 +/- 0.03 nM (mean +/- SD; n = 3) and binding capacity of 0.11 +/- 0.01 pmol/mg protein. Type 2 receptor sites had a Kd of 5.96 +/- 0.35 nM and a binding capacity of 1.59 +/- 0.22 pmol/mg protein. Thus, in the presence of BSA, the binding capacities of the two classes of receptors were markedly reduced compared to values generated previously in its absence. The Kd of the Type 1 sites was not significantly changed by the presence of BSA. A single class of saturable high-affinity binding sites was demonstrable for lyso-PAF C18:0: Kds ranged from 0.76 +/- 0.58 to 11.1 +/- 0.62 nM, depending on which method of analysis was used (Eadie-Hofstee, Scatchard-Rosenthal, or the Lundon nonlinear method). The binding capacities were equally varied, ranging from 0.15 +/- 0.08 to 15.17 +/- 4.95 pmol/mg protein.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Activity of platelet-activating factor acetylhydrolase in the mouse uterus during the estrous cycle, throughout the preimplantation phase of pregnancy, and throughout the luteal phase of pseudopregnancy.

Platelet-activating factor (PAF) is a potent autacoid produced by the embryo and the endometrium during early pregnancy. Its actions in vivo are dependent upon its half-life, which in turn is largely governed by its metabolism. PAF:acetylhydrolase is a major metabolic enzyme for PAF and is widespread in body tissues and fluids. This study was an examination of the activity of this enzyme in the uterus (uterine luminal fluids and endometrial scrapings) of mice in the periovulatory period, throughout the preimplantation phase of pregnancy, and throughout the luteal phase of pseudopregnancy. PAF:acetylhydrolase activity was found in uterine washings and endometrial tissue; it was dependent upon incubation time and protein concentration and was destroyed by boiling. The activity was not affected by cations (Mg2+ and Ca2+) and was not inhibited by bromophenacyl bromide, a phospholipase A2 inhibitor. The specific and total activity changed dramatically throughout the reproductive cycle. Total tissue activity did not change significantly during the follicular phase. On the day after ovulation, tissue activity was lower in naturally mated mice and was maintained at this level until Day 4; there was no difference in this value between pregnant and pseudopregnant animals. On days 5 and 6 of pseudopregnancy the total tissue activity increased, reaching a peak on Day 6 of 4609 pmol acetate released.min-1, approximately 780% higher than the value obtained on Day 4. Activity then decreased so that by Day 8 it was not different from preovulatory levels. For uterine luminal fluids, total activity significantly decreased during the follicular phase. This continued throughout the preimplatation phase with minimum activity being reached on Days 3 and 4 (7.68 pmol acetate.min-1 on Day 4 pseudopregnancy).(ABSTRACT TRUNCATED AT 250 WORDS)

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1996

Lipid mediator networks in cell signaling: update and impact of cytokines.

Biomembranes serve barrier functions and serve as a store for precursors of rapidly generated, structurally diverse intracellular and extracellular lipid-derived mediators (LM). Cell activation is accompanied by remodeling of membrane components that appear to be essential in signal transduction. Phospholipases (PLA2, PLC, PLD, sphingomyelinase) are pivotal in the generation of these LM including eicosanoids, platelet activating factor (PAF), diacylglycerides, ceramide, and other newly discovered bioactive autacoids. Cytokines exert a dramatic multilevel impact both in regulating enzymes in individual LM pathways and in generating LM central to their action. Here, we provide an overview and update of recent progress in this area with emphasis on the effect of cytokines on LM networks. The generation of eicosanoids (prostaglandins, leukotrienes, and lipoxins), oxygenated lipids, and PAF remain the focus of rational drug design targets given their established roles in cell-cell communication and as mediators in inflammation and pathophysiologic events. Key enzymes in these pathways are cloned, sequenced, and their subcellular organization is investigated with surprising findings implicating involvement of the nuclear membrane at the functional level. Several LM receptors are identified and cloned, and results from transgenic animals have emerged for several key enzymes. Novel bioactive eicosanoids were discovered, including 15-epi-lipoxins, isoprostanes, and isoleukotrienes, that offered new concepts to consider in formation of LM and the actions of nonsteroidal anti-inflammatory drugs. Together, these findings indicate that LM play critical and essential roles in both signal transduction and cell-cell communication and will continue to be important pathways to be considered in novel therapeutic approaches.-Serhan, C. N., Haeggström, J. Z., Leslie, C. C. Lipid mediator networks in cell signaling: update and impact of cytokines.

Animals↗

PubMed1989

Endothelium-derived nitric oxide: actions and properties.

Vascular smooth muscle relaxation in response to chemically diverse naturally occurring neurotransmitters and autacoids has been attributed to the formation and/or release of one or more vascular endothelium-derived relaxing factors (EDRFs) distinct from prostacyclin. The chemical, biochemical, and pharmacological properties of one such EDRF resemble closely the properties of nitric oxide (NO). Thus, both arterial and venous EDRFs as well as authentic NO cause heme-dependent activation of soluble guanylate cyclase, endothelium-independent vascular and nonvascular smooth muscle relaxation accompanied by tissue cyclic GMP formation, and inhibition of platelet aggregation and adhesion to endothelial cell surfaces. EDRF from artery, vein, and freshly harvested and cultured aortic endothelial cells was recently identified as NO or a labile nitroso species as assessed by chemical assay and bioassay. Endothelium-derived NO (EDNO) has an ultrashort half-life of 3-5 s due to spontaneous oxidation to nitrite and nitrate, both of which have only weak biological activity. EDNO can be synthesized from L-arginine and possibly other basic amino acids and polypeptides, perhaps by oxidative metabolic pathways that could involve polyunsaturated fatty acid-derived oxygen radicals. Inorganic nitrite could serve as both a stored precursor and an inactivation product of EDNO. EDNO and related EDRFs may serve physiological and/or pathophysiological roles in the regulation of local blood flow and platelet function.

Animals↗

PubMed2002

Isoflurane-induced cerebral hyperemia is partially mediated by nitric oxide and epoxyeicosatrienoic acids in mice in vivo.

BACKGROUND: Despite intense investigation, the mechanism of isoflurane-induced cerebral hyperemia is unclear. The current study was designed to determine the contributions of neuronal nitric oxide synthase, prostaglandins, and epoxyeicosatrienoic acids to isoflurane-induced cerebral hyperemia. METHODS: Regional cerebral cortical blood flow was measured with laser Doppler flowmetry during stepwise increases of isoflurane from 0.0 to 1.2, 1.8, and 2.4 vol% end-tidal concentration in alpha-chloralose-urethane-anesthetized, C57BL/6 mice before and 45 min after administration of the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI, 40 mg/kg, intraperitoneal), the cyclooxygenase inhibitor indomethacin (INDO, 10 mg/kg, intravenous), and the cytochrome P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-proparglyoxyphenyl)hexanoic acid (PPOH, 20 mg/kg, intravenous). RESULTS: Isoflurane increased regional cerebral cortical blood flow by 9 +/- 3, 46 +/- 21, and 101 +/- 26% (SD) at 1.2, 1.8, and 2.4 vol%, respectively. The increases in regional cerebral cortical blood flow were significantly (*P < 0.05) smaller after 7-NI (5 +/- 6, 29 +/- 19*, 68 +/- 15%*) or PPOH (4 +/- 8, 27 +/- 17*, 67 +/- 30%*), but not after administration of INDO (4 +/- 4, 33 +/- 18 [NS], 107 +/- 35% [NS]). The effect of combined treatment with 7-NI, PPOH, and INDO was not additive and was equal to that of either 7-NI or PPOH alone (5 +/- 5, 30 +/- 12*, 76 +/- 24%*). Chronic treatment of mice for 5 days with 7-NI (2 x 40 mg/kg, intraperitoneal) produced similar decreases in regional cerebral cortical blood flow as those seen with acute administration. Neither PPOH nor INDO conferred a significant additional block of the hyperemia in these animals. CONCLUSIONS: Nitric oxide and epoxyeicosatrienoic acids contribute to isoflurane-induced hyperemia. However, only approximately one third of the cerebral hyperemic response to isoflurane is mediated by autacoids. The remaining part of this response appears to be mediated by a direct action of isoflurane on smooth muscle by some yet-unknown mechanism.

Animals↗

PubMed2000

Acadesine and intestinal barrier function after hemorrhagic shock and resuscitation.

OBJECTIVE: To determine actions of the prototype adenosine-regulating agent, acadesine (5-amino-1-[beta-D-ribofuranosyl]imidazole-4-carboxamideriboside; AICAR), on intestinal barrier function after hemorrhagic shock and fluid resuscitation, three series of experiments were performed to measure functional (series 1: intestinal permeability and intramural blood flow), structural (series 2: histology), and biochemical (series 3: tissue concentrations of adenine nucleotides and metabolites) changes. DESIGN: Prospective, controlled animal study. SETTING/SUBJECTS: University laboratory; juvenile crossbred pigs of either gender. INTERVENTIONS: Either AICAR or its saline vehicle were intravenously administered 30 mins before 40% hemorrhage. After 1 hr shock, shed blood plus crystalloid was administered for resuscitation. Data were collected for 1 hr thereafter. MEASUREMENTS AND MAIN RESULTS: In series 1, permeability of the ileum was measured by assaying the portal venous concentration of fluorescein-labeled dextran after placement of this tracer in the lumen. In addition, serosal and mucosal blood flow were monitored with laser-Doppler probes. With vehicle, hemorrhage and resuscitation increased the dextran concentration three-fold and decreased blood flow 50% of the baseline values (both p < .05). AICAR attenuated the permeability increase (p < .05) and attenuated mucosa, but not serosal, ischemia (p < .05). Similar effects were observed with a structurally dissimilar compound-- 4-amino-1-(5-amino-5-deoxy-1-beta-D-ribofuranosyl)-3-bromo-pyrazolo [3,4-d] pyrimidine, a specific adenosine kinase inhibitor-as well as continuous intra-arterial infusion of adenosine. In series 2, AICAR ameliorated the mucosal damage caused by shock/resuscitation (p < .05). In series 3, AICAR increased ileal tissue adenine nucleotides and metabolites during the shock period (p < .05). CONCLUSIONS: AICAR attenuated gut permeability changes, increased mucosal perfusion, and increased tissue adenine nucleotides, which is consistent with preserved intestinal barrier function after hemorrhage and fluid resuscitation. In context with previous studies from this laboratory, these results provide further evidence for a role for adenosine as an endogenous anti-inflammatory autacoid after shock and trauma. Further study is needed to determine the therapeutic potential of adenosine-regulating agents in resuscitation fluids.

Adenosine↗

PubMedDate not supplied

Positive inotropic and chronotropic effects and coronary vasodilation in vitro by two antiasthmatic xanthines with different abilities to antagonize adenosine.

The direct actions and the ability to antagonize adenosine of theophylline (1,3-dimethylxanthine) and enprofylline (3-propylxanthine) were examined in isolated guinea pig heart preparations. Enprofylline was approximately six times as potent as theophylline in reducing coronary perfusion pressure, and between three and five times more potent in increasing rate and force of contraction in isolated perfused hearts, spontaneously beating right atrias, and electrically stimulated left atrias. Adenosine reduced the coronary perfusion pressure and had negative inotropic and chronotropic actions. Theophylline (5-75 microM) concentration-dependently antagonized the coronary vasodilation and the negative chronotropic and inotropic actions of adenosine, whereas enprofylline (2.5-75 microM) did not antagonize adenosine. Since adenosine may be a protective autacoid in the heart under select stress conditions, the possibility that adenosine nonblocking xanthines, like enprofylline, may offer therapeutic advantages over theophylline should be investigated.

Adenosine↗

PubMed1986

High beta 1-selectivity and favourable pharmacokinetics as the outstanding properties of bisoprolol.

Bisoprolol, (+/-)1-(4-[(2-isopropoxyethoxy)-methyl]-phenoxy)-3-isopropyl-amino -2- propanol-hemifumarate, is a new, highly selective beta 1-adrenoceptor blocking agent without intrinsic sympathomimetic activity and low to moderate local anaesthetic activity. As demonstrated in binding experiments, and in classical pharmacological studies using rats, guinea pigs, cats, and dogs, bisoprolol markedly differentiated between beta 1-adrenoceptors of the heart, or the renal juxtaglomerular apparatus, and the beta 2-subtype in arterial blood vessels, bronchi, liver, or skeletal muscle. Up to concentrations nearly 100-fold higher than the therapeutic plasma levels in humans, bisoprolol did not affect the functional refractory period of the heart, and was devoid of a direct suppressive effect on myocardial contractility and of calcium antagonistic properties in heart and vascular muscle. The pattern of haemodynamic effects of bisoprolol was typical of beta-blockers and included decreases in blood pressure (BP), heart rate (HR), and cardiac output, concomitant with an increase in calculated total peripheral resistance. In contrast to other beta-blockers, bisoprolol increased renal blood flow in anaesthetized dogs. Bisoprolol lowered BP in hypertensive dogs and rats, attenuated the development of spontaneous hypertension in rats, decreased plasma renin activity and protected the heart from the sequelae of transient ischemia. It did not block presynaptic beta-adrenoceptors in blood vessels. Serum lipids and the serum lipoprotein profile remained unaltered after bisoprolol. Bisoprolol was devoid of affinity for autonomic receptors other than beta-adrenoceptors or for autacoid receptors. This is probably one of the reasons why bisoprolol did not affect the function of the central nervous, respiratory, and gastrointestinal systems in an obvious way. The high beta 1-selectivity of bisoprolol is linked with extremely favourable pharmacokinetic properties. These include nearly complete enteral absorption and virtual absence of liver first-pass metabolism, both resulting in high bioavailability, long plasma half-life, pharmacokinetics that are linear over a wide dose range and independent of age, food intake and hydroxylator status, low plasma protein binding, and a 1:1 ratio of hepatic metabolization to renal elimination of the unaltered substance. This sum of favourable pharmacological and pharmacokinetic properties characterize bisoprolol as an optimized beta-blocker.

Adrenergic beta-Antagonists↗

PubMed1989

Differential vascular sensitivity to luminally and adventitially applied endothelin-1.

When secreted into the vascular lumen, endothelin-1 (ET-1) potentially may act as a circulating pressor substance. We investigated whether luminal ET-1 can directly stimulate smooth muscle in isolated vascular segments. Rabbit femoral arteries and veins whose luminal and adventitial surfaces could be perfused separately were used. Luminally administered ET-1 (1 nM) induced a vasoconstriction (21 +/- 5% of outer resting diameter) in segments without endothelium whereas in segments with intact endothelium, no significant vasomotor response was observed. In segments without endothelium, however, the vasoconstrictor responses to luminal and abluminal ET-1 were not significantly different. Similar results were obtained in segments of femoral veins. No release of endothelium-derived relaxing factor (EDRF) could be detected (guanylate cyclase assay) in segments of rabbit aorta and vena cava following stimulation with ET-1 whereas there was a slight increase (by 20 +/- 13%) of PGI2 release. It is concluded that the endothelium forms a tight barrier to circulating ET-1 (up to 1 nM) in intact vessels that has no functionally significant effect on endothelial autacoid release.

Animals↗

PubMed1998

Dietary L-arginine normalizes endothelin-induced vascular contractions in cholesterol-fed rabbits.

The endothelium regulates vascular function by releasing the vasodilator autacoid nitric oxide (NO) and the vasoconstrictor peptide endothelin-1 (ET-1). Impaired activity of NO as well as excessive activity of ET-1 have been demonstrated in hypercholesterolemia and atherosclerosis. Because dietary L-arginine can restore NO function and improve abnormal endothelium-dependent relaxation in hypercholesterolemic rabbits, we examined the effects of dietary supplementation with L-arginine in cholesterol-fed rabbits on endothelium-dependent vascular relaxation and ET-1-induced vascular contraction, as well as the systemic synthesis of ET-1. Rabbits were initially fed a diet enriched with 1% cholesterol for 4 weeks, followed by 0.5% cholesterol alone or supplemented with 2% L-arginine in drinking water during the next 12 weeks. Cholesterol feeding impaired endothelium-dependent relaxation of rabbit aortic rings ex vivo and increased urinary immunoreactive ET-1 excretion, along with decreased urinary nitrate excretion, an index of NO production. L-Arginine partially restored endothelium-dependent relaxation in parallel to increased urinary nitrate excretion and decreased urinary immunoreactive ET-1 excretion. Selective inhibition of ET-A receptors with BQ123 partially restored endothelium-dependent relaxation in hypercholesterolemic rabbits but had no effect on arterial rings from rabbits supplemented with L-arginine or from control animals. The contractile vascular response of aortic rings to exogenous ET-1 was increased in rabbits fed a high-cholesterol diet; this enhanced contractility to ET-1 was completely reversed by L-arginine. These data suggest that L-arginine restores endothelial function and normalizes the synthesis and vasoconstrictor response to ET-1 in hypercholesterolemia.

Animals↗

PubMed1999

Renal vascular interaction of angiotensin II and prostaglandins in renovascular hypertension.

The vascular responses to angiotensin II (Ang II) in the renal circulation are increased in kidneys from rats with aortic coarctation compared with sham-operated rats. We have suggested that these differences are related to changes in mediators of the Ang II effect. The aim of this study was to investigate the role of arachidonic acid (AA) metabolites on the Ang II effect in the renal circulation of normotensive and hypertensive rats. We evaluated vascular renal reactivity in the rat isolated perfused kidney. Bolus injection of Ang II (9, 18, 36, 72 ng) increased perfusion pressure in a dose-dependent manner by 16.5+/-4, 23.5+/-4, 35.5+/-7, and 42.5+/-7 mm Hg in sham-operated rats and 50+/-6, 72+/-10, 92+/-6, and 120+/-6 mm Hg in rats with aortic coarctation. Ang II-induced vasoconstriction was prevented in hypertensive rats and potentiated in normotensive rats by the presence of indomethacin (1 microg/ml) in the perfusion solution. Furthermore, the use of the endoperoxide/thromboxane blocker (SQ29548, 1 microM) did not alter the effect of Ang II on the normotensive rats but prevented its effect in hypertensive rats. Moreover, the prostaglandin/ thromboxane (PGH2/TxA2) receptor agonist U46619 increased perfusion pressure to similar values in both kidneys from sham-operated or aortic coarctation rats. Ang II stimulated AA and prostaglandin release from isolated perfused kidneys. However, autacoid release was higher in kidneys from rats with aortic coarctation. In conclusion, we suggest that during the development of hypertension, the AA metabolism of vasoconstrictor prostaglandins is increased, and it mediates the vasoconstrictive effects of Ang II.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2003

Relationship between eicosanoids and endothelin-1 in the pathogenesis of erythropoietin-induced hypertension in uremic rats.

Recent studies suggest a possible link between recombinant human erythropoietin (rhEPO)-induced hypertension and endothelium-derived vasoconstrictor autocoids. The current study was designed to evaluate the role of eicosanoids such as thromboxane (TX) A and prostacyclin (PGI ) and of endothelin-1 (ET-1) and the relationship between these vasoactive substances in rhEPO-induced hypertension in uremic rats. Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 6-week stabilization period. In protocol A, rats were divided into four groups: vehicle, rhEPO (100 u/kg, subcutaneously, three times per week), a selective ET receptor antagonist (ABT-627, 10 mg/kg/d), and rhEPO + ABT-627 for 5 weeks. In protocol B, uremic animals were divided into two groups: rhEPO and rhEPO + a TX receptor antagonist and synthesis inhibitor, ridogrel (25 mg/kg/d), for 5 weeks. At the end of the study, immunoreactive eicosanoid metabolites (TXB and 6-keto-PGF, stable metabolites of TXA and PGI ), and ET-1 were measured in either the thoracic aorta or in the mesenteric arterial bed. After 5/6 nephrectomy, the animals developed uremia, anemia, and hypertension. rhEPO corrected the anemia but aggravated the hypertension. Both drugs were effective in preventing the progression of hypertension in rhEPO-treated rats although ABT-627 was more potent than ridogrel. rhEPO increased the concentration of ET-1 and TXB in blood vessels and ABT-627 decreased tissue levels of both vasopressors. The concentration of 6-keto-PGF was not significantly changed. Ridogrel significantly decreased tissue TXB concentrations but had no effect on ET-1 levels. These results suggest that endothelium-derived vasoconstrictor autacoids (TXA and ET-1) are involved in the pathogenesis of rhEPO-induced hypertension in uremic rats. TXA probably serves as a mediator of the vascular effect of ET-1.

Animals↗

PubMed1997

Central role of vascular smooth muscle hyperreactivity in coronary hyperconstriction after balloon injury in miniature pigs.

BACKGROUND: Coronary constrictive responses to autacoids become augmented 1 week after balloon injury in our swine model. The present study aimed to elucidate the mechanisms of this effect. METHODS: In 12 hypercholesterolaemic miniature pigs, the coronary constrictive response to serotonin was examined angiographically 1 week after injury. After the angiographic study, organ chamber experiments using excised coronary artery were performed to clarify whether functional changes in endothelial cells or in vascular smooth muscle cells contributed to the hyperconstriction. RESULTS: The coronary constrictive response to serotonin in vivo was significantly greater at the previously injured site than at the non-injured site. The degree of the hyperconstriction at the previously injured site exceeded that predicted from a geometric theory. Histological examination demonstrated that the previously injured site was almost covered with regenerated endothelial cells. In vitro studies demonstrated that serotonin caused significantly greater contraction in coronary artery strips, whether with or without endothelium, from the previously injured site than in those from the non-injured site. Endothelium-dependent relaxation in response to serotonin was comparable at the injured and non-injured sites. CONCLUSIONS: These results suggest that the coronary hyperconstriction response to serotonin 1 week after injury results primarily from hyperreactivity of vascular smooth muscle. Whereas any contribution of endothelial dysfunction or the geometric effect may be minimal.

Animals↗