Adenosine mediation of mesenteric blood flow.

The mesenteric circulation is regulated by multiple mechanisms, there is sufficient reason to support the suspicion that local metabolic factors are especially important in the control of intestinal vasculature. Of these, adenosine, a purine nucleoside and mesenteric vasodilator, may be the messenger of the intestinal tissue to signal appropriate responses of the intestinal vessels. The evidence supporting the candidacy of the nucleoside as a local regular of mesenteric circulation may be summarized, as follows: Adenoside is present in the tissue of the gut in measurable quantities. Exogenous adenosine is a powerful dilator of mesenteric resistance vessels. Blockade of adenosine receptors in the mesenteric circulation interferes significantly with three autoregulatory phenomena, i.e., postprandial hyperemia, pressure-flow autoregulation, and reactive hyperemia. The evidence which weakens the role of adenosine as mesenteric vasoregulator includes: Findings in several reports that adenosine depressed intestinal oxygen consumption. The failure of adenosine receptors to inhibit some autoregulatory hyperemias of the gut and the rather limited amount of evidence regarding tissue adenosine release in autoregulatory responses of the gut's vasculature.     

Effects of intravenous infusion of prostacyclin (PGI2) in man

Prostacyclin infused intravenously in human volunteers induces ex vivo inhibition of platelet aggregation, tachycardia and hypotension. The inhibition of platelet aggregation is obtained with slightly lower doses than those which exhibit cardiovascular effects.The cardiovascular effects disappeared within a few minutes after discontinuing the infusion of prostacyclin but the platelet effects were longer lasting.Prostacyclin did not have any effect on platelet count, platelet factor 3, accelerated partial thromboplastin time, prothrombin time, euglobulin clot lysis time, fibrinogen degradation products, blood glucose concentration or urine sodium potassium ratio.     

Differential effects of prostaglandins and arachidonic acid on gastric circulation and oxygen consumption

Experiments were carried out on anesthetized dogs to compare the effects of prostaglandin E₂ (PGE₂), prostacyclin (PGI₂) and arachidonic acid (AA) administered intraarterially on gastric blood flow and oxygen consumption during constant arterial pressure perfusion and constant flow perfusion of the stomach. Both PGE₂ and PGI₂ increased total blood flow and oxygen consumption both in the resting stomach and following histamine stimulation although the effects of PGE₂ on the oxygen consumption in stimulated stomach were not statistically significant. On the contrary, AA decreased both gastric blood flow and oxygen consumption in the histamine stimulated stomach. To determine if these compounds can influence gastric oxygen consumption independently of their effects on blood flow, the experiments with constant flow perfusion were performed. Both PGE₂ and PGI₂ decreased both the perfusion pressure and oxygen consumption in the resting as well as in the histamine-stimulated stomach whereas AA increased perfusion pressure and decreased oxygen consumption during histamine administration. Effects of AA were blocked by indomethacin suggesting that not AA itself but some of its metabolites, most likely thromboxanes were responsible for the hemodynamic and metabolic changes resulting from the contraction of gastric arterioles and precapillary sphincters. On the contrary, both PGE₂ and PGI₂ caused gastric hyperemia and an increase in oxygen consumption in the resting stomach, but decreased the latter parameter in the stimulated stomach, most probably as a result of secretory inhibition overcoming direct vascular effects of these compounds.     

Leukocytes, oxygen radicals, and myocardial injury due to ischemia and reperfusion

Ischemic myocardium generates stimuli for neutrophil chemotaxis before the final extent of irreversible ischemic injury is attained. Reperfusion accelerates the infiltration of ischemic myocardium by neutrophils. Oxygen radicals released by the activated neutrophils may exacerbate the tissue damage caused by ischemia. Neutrophil depletion by antiserum was shown to limit infarct size in dogs undergoing coronary occlusion for 90 minutes followed by reperfusion for 6 or 72 hours, but not in dogs undergoing occlusion for 4 hours. Prostacyclin, which inhibits the generation of superoxide anions by neutrophils, also limited canine myocardial injury despite no effect on collateral blood flow. Iloprost, an analogue of prostacyclin that inhibits neutrophils also reduced infarct size, while SC39902, an analogue that does not inhibit neutrophils, did not alter infarct size. The results suggest that oxygen radicals released by activated neutrophils play a role in the pathophysiology of myocardial injury due to ischemia followed by reperfusion.     

肠缺血再灌注时肠内给予不同营养物对肠粘膜ATP含量的影响

将SD大鼠分组 ,先制作空肠袋 ,分别向袋内注射不同营养物 :10mmol/L丙氨酸 ,10mmol/L葡萄糖 ,10mmol/L甘露醇或 5mmol/L丙氨酸 +5mmol/L葡萄糖的混合液 ,用动脉夹阻断肠系膜上动脉血流 6 0min后 ,再恢复灌流 6 0min。分别于阻断血流 6 0min和恢复灌注 6 0min测定肠粘膜ATP含量。研究结果显示 ,缺血再灌注能显著降低肠粘膜ATP含量 ,给予丙氨酸或葡萄糖 /丙氨酸混合液使肠粘膜ATP含量进一步降低 (P <0 .0 1) ,而给予葡萄糖能显著增加肠粘膜ATP含量 (P <0 .0 1)。结论 :缺血再灌注过程中 ,肠内给予葡萄糖能改善肠粘膜ATP含量 ,对缺血再灌注损伤的肠道提供保护作用     

Evidence for additional mediator in prostaglandin-induced choleresis

PGA1 and PGF2alpha were administered to isolated perfused porcine and canine livers to determine whether these hormones could induce hepatic choleresis. PGA1 (25 microgram/kg/10 min) decreased portal venous resistance, but had no effect on bile flow, oxygen, pyruvate, or lactate consumption in canine livers. PGF2alpha increased portal venous resistance and weight gain while decreasing bile flow and oxygen consumption in canine livers. At high doses (50 microgram/kg/10 min) these effects resulted in irreversible outflow block. At low doses (5 microgram/kg/10 min) these trends were reversible. Porcine livers did not exhibit the outflow block syndrome after PGF2alpha administration (100 microgram/kg/10 min); however, choleresis was not observed. Thus, the in-vivo choleretic effects of prostaglandins previously reported are probably mediated partially or wholly by extrahepatic release of other hormones, neurological stimulation or alterations in mesenteric blood flow.     

Effects of prostaglandin F2 alpha and prostacyclin on pulmonary microcirculation in the cat

In pulmonary microcirculation, using a new X-ray television system, we measured the effects of prostaglandin F2 alpha (PGF2 alpha) and prostacyclin on the internal diameter (ID), flow velocity, volume flow, and transit times of a contrast medium in small arteries (Ta) and veins (Tv) in anesthetized cats. The ID of the arteries and veins ranged from 100 to 500 micron. PGF2 alpha, 0.3, 1, and 3 micrograms/kg, predominantly decreased ID on the arterial side in a dose-dependent manner but increased flow velocity 27-62%. Consequently, volume flow was kept relatively constant. With PGF2 alpha, Ta and Tv were decreased 18-41% and 4-15%, respectively. Prostacyclin, 2 and 4 micrograms/kg, uniformly dilated the ID of small arteries 9-16% but did not change small veins. With prostacyclin, flow velocity was unchanged or decreased, whereas volume flow was increased significantly, 27-32%. No significant changes of Ta and Tv were observed in response to prostacyclin. When both prostaglandins, PGF2 alpha and prostacyclin, were administered, they canceled each other with respect to the ID of small pulmonary arteries. Prostacyclin also prevented the PGF2 alpha-induced vasoconstriction of the pulmonary venous microcirculation.     

Characterization of the PGI2/IP system in cultured rat mesangial cells

Mesangial cells play an important role in glomerular function. They are an important source of cyclooxygenase (COX)-derived arachidonic acid metabolites, including prostaglandin E(2) and prostacyclin. Prostacyclin receptor (IP) mRNA was amplified from cultured mesangial cell total RNA by RT-PCR. While the prostaglandin E(2) receptor subtype EP(2) was not detected, EP(1,3,4) mRNA was amplified. Also, IP protein was noted in mesangial cells, proximal tubules, inner medullary collecting ducts, and the inner and outer medulla. But no protein was detected in whole cortex preparations. Prostacyclin analogues: cicaprost and iloprost, increased cAMP levels in mesangial cells. On the other hand, arginine-vasopressin and angiotensin II increased intracellular calcium in mesangial cells, but cicaprost, iloprost and prostaglandin E(2) had no effect. Moreover, a 50% inhibition of cicaprost- and iloprost-cAMP stimulation was observed upon mesangial cell exposure to 25 and 35 mM glucose for 5 days. But no change in IP mRNA was observed at any glucose concentration or time exposure. Although 25 mM glucose had no effect on COX-1 protein levels, COX-2 was increased up to 50%. In contrast, PGIS levels were reduced by 50%. Thus, we conclude that the prostacyclin/IP system is present in cultured rat mesangial cells, coupling to a cAMP stimulatory pathway. High glucose altered both enzymes in the PGI(2) synthesis pathway, increasing COX-2 but reducing PGIS. In addition, glucose diminished the cAMP response to prostacyclin analogues. Therefore, glucose attenuates the PGI(2)/IP system in cultured rat mesangial cells.     

Decreased vascular prostacyclin in experimental diabetes.

Prostacyclin is a potent inhibitor of platelet aggregation. Its release from the aorta of streptozotocin-diabetic rats is reduced. High rates of prostacyclin production appear to be incompatible with high blood glucose levels. It is possible that decreased prostacyclin release may be related to vascular complications in diabetes.     

Effects of substance P on intestinal circulation and oxygen consumption

The effects of intra-arterial administration of substance P upon intestinal blood flow, oxygen consumption, intestinal motor activity, and distribution of blood flow to the compartments of the gut wall were measured in anesthetized dogs. Blood flow to the segment of distal ileum was measured with an electromagnetic blood flow meter and A-VO2 was measured spectrophotometrically. Oxygen uptake was calculated as the product of A-VO2 and total blood flow. The clearance of 86Rb was measured to estimate the density of the perfused intestinal capillaries. Changes in blood flow distribution were estimated from the distribution of radiolabeled microspheres. Motor activity was monitored from changes in intraluminal pressure. Substance P induced a dose-related increase in intestinal blood flow, oxygen consumption, and intestinal motor activity. A significant increase in 86Rb clearance and increase in blood flow to the muscles was also observed. The results of these studies indicate that substance P relaxes intestinal arterioles and precapillary sphincters thereby inducing intestinal hyperemia and increased oxygen consumption. These changes, at least in part, might be due to the increased intestinal motility with enhanced metabolic demands of the muscularis for oxygen.     

Prostacyclin does not change during an oxygen induced increase in pulmonary blood flow in the fetal lamb

The role of prostacyclin in mediating the increase in pulmonary blood flow caused by an increase in oxygen tension in the fetal lamb was investigated. Plasma concentrations of 6-keto-PGF1 alpha, the hydrolysis product of prostacyclin, were measured during an increase in pulmonary blood flow caused by a rise in oxygen tension in eight intrauterine fetal lambs. Fetal oxygen tension was increased by placing the pregnant ewes in a hyperbaric chamber and having them breathe 100% oxygen at three atmospheres absolute pressure. This increased fetal PaO2 from 27 +/- 3 to 60 +/- 6 torr (mean +/- S.E., p less than or equal to 0.0001) and increased the proportion of right ventricular output distributed to the fetal lungs from 6 +/- 2 to 45 +/- 7% (mean +/- S.E., p less than or equal to 0.001). However, the fetal plasma concentration of 6-keto-PGF1 alpha did not change, 186 +/- 26 to 208 +/- 40 pg/ml (mean +/- S.E.). Indomethacin decreased plasma concentrations of 6-keto-PGF1 alpha in each of three fetuses but did not decrease the proportion of right ventricular output distributed to their lungs. The increase in pulmonary blood flow caused by an increase in oxygen tension in the fetal lamb is not associated with an increase in plasma concentrations of 6-keto-PGF1 alpha. Prostacyclin does not appear to be involved in the increase in pulmonary blood flow caused by the increase in oxygen tension at birth.     

Intestinal blood flow and oxygen consumption

In this study, we examined the effects of both pharmacologically and mechanically induced increases in intestinal blood flow on intestinal oxygen consumption. Intraarterial infusions of prostacyclin (1-20 ng X kg-1 X min-1) significantly increased both blood flow and oxygen consumption under free flow conditions. However, the increase in oxygen consumption appears to be due to the corresponding increase in blood flow rather than a direct effect of prostacyclin on intestinal metabolism. This conclusion is supported by the finding that a mechanically induced increase in intestinal blood flow (60%) can also produce an increase in intestinal oxygen consumption (24%). These findings support the hypothesis that intestinal oxygen consumption is flow-dependent over a wide range of blood flows.     

Alteration of growth yield by overexpression of phosphoenolpyruvate carboxylase and phosphoenolpyruvate carboxykinase in Escherichia coli.

Phosphoenolpyruvate and oxaloacetate are key intermediates at the junction between catabolism and biosynthesis. Alteration of carbon flow at these branch points will affect the growth yield and the formation of products. We attempted to modulate the metabolic flow between phosphoenolpyruvate and oxaloacetate by overexpressing phosphoenolpyruvate carboxylase and phosphoenolpyruvate carboxykinase from a multicopy plasmid under the control of the tac promoter. It was found that overexpression of phosphoenolpyruvate carboxylase decreased the rates of glucose consumption and organic acid excretion, but the growth and respiration rates remained unchanged. Consequently, the growth yield on glucose was improved. This result indicates that the wild-type level of phosphoenolpyruvate carboxylase is not optimal for the most efficient glucose utilization in batch cultures. On the other hand, overexpression of phosphoenolpyruvate carboxykinase increased glucose consumption and decreased oxygen consumption relative to those levels required for growth. Therefore, the growth yield on glucose was reduced because of a higher rate of fermentation product excretion. These data provide useful insights into the regulation of central metabolism and facilitate further manipulation of pathways for metabolite production.     

Angiotensin II mediates systemic rebound hypertension after cessation of prostacyclin infusion in sheep

Prostacyclin(or epoprostenol), an arachidonic acid metabolite, is aneffective treatment for patients with primary pulmonary hypertension.Interruption of chronic prostacyclin infusion can result in recurrentsymptoms of dyspnea and fatigue. The etiology of this phenomenon isunknown. We hypothesized that sympathoadrenal activation could lead toincreased vascular tone after abrupt termination of the infusion. Toevaluate this effect, we monitored six chronically instrumented, awakesheep during and after infusion of prostacyclin. Prostacyclin decreasedmean arterial pressure (MAP) by 14% and increased cardiac output by33%. After the infusion ceased, MAP rebounded 23% above baseline, andcardiac output decreased by 28% from peak values within 10 min. Wewere unable to demonstrate an increase in norepinephrine levels aftercessation of prostacyclin, nor did -adrenergic blockade affectpostinfusion hemodynamics. However, plasma renin activity increased>10-fold at peak infusion and remained elevated for up to 2 h afterdiscontinuation of prostacyclin. Coinfusion of the angiotensinII-receptor antagonist L-158,809 resulted in complete abrogation of thepostcessation rise in MAP. We conclude that renin-angiotensin systemactivation is primarily responsible for systemic hypertension occurringafter abrupt cessation of prostacyclin infusion in sheep and thatangiotensin II receptor blockade prevents this response. Our data donot support a role for sympathetic nervous system activation in thesystemic pressor response after prostacyclin infusion.

     

Defibrotide modulates prostaglandin production in the rat mesenteric vascular bed

Defibrotide 1 microM, a polydeoxyribonucleotide extracted from mammalian organs, reduced the contractile responses to noradrenaline (NA) in the rat isolated and perfused mesenteric vascular bed, in intact as well as in de-endothelialized preparations. Defibrotide was without effect on the acetylcholine-induced relaxations of U-46619-precontracted mesenteric vascular beds. Moreover, defibrotide increased 6-keto prostaglandin (PG) F(2alpha) (stable metabolite of prostacyclin) release sixfold in the presence, but not in the absence of the endothelium, with no modification on the release of other prostanoids. Defibrotide also inhibited the NA-induced increase in PGF(2alpha) release, in both intact and de-endothelialized mesenteric vascular beds. In conclusion, the present results show that defibrotide modulates PG production in the mesenteric bed and that the observed inhibition of the contractile responses should be due to the impairment of the NA-induced increase in PGF(2alpha) release.     

The effects of mefenamic acid on postprandial intestinal carbohydrate metabolism

The effects of mefenamic acid on the food-induced changes in intestinal carbohydrate metabolism were determined in an attempt to elucidate the mechanism(s) by which inhibition of prostaglandin synthesis enhances the postprandial increases in intestinal blood flow and oxygen consumption. The data show that when the luminal perfusate was was changed from saline to a nutrient/bile solution, there was an increase in carbohydrate utilization, which was offset by absorption of glucose from the lumen. Intravenous administration of mefenamic acid significantly increased both carbohydrate absorption and metabolism when food was placed in the lumen. Changes in carbohydrate absorption and metabolism have been shown to play an important role in determining the magnitude of glucose induced changes in intestinal blood flow and oxygen consumption. Therefore, it is possible that the ability of mefenamic acid to enhance significantly the food-induced increases in blood flow and oxygen consumption may be due in part to its effects on intestinal carbohydrate absorption and utilization.     

The effects of mefenamic acid on postprandial intestinal carbohydrate metabolism

The effects of mefenamic acid on the food-induced changes in intestinal carbohydrate metabolism were determined in an attempt to elucidate the mechanism(s) by which inhibition of prostaglandin synthesis enhances the postprandial increases in intestinal blood flow and oxygen consumption. The data show that when the luminal perfusate was changed from saline to a nutrient/bile solution, there was an increase in carbohydrate utilization, which was offset by absorption of glucose from the lumen. Intravenous administration of mefenamic acid significantly increased both carbohydrate absorption and metabolism when food was placed in the lumen. Changes in carbohydrate absorption and metabolism have been shown to play and important role in determining the magnitude of glucose induced changes in intestinal blood flow and oxygen consumption. Therefore, it is possible that the ability of mefenamic acid to enhance significantly the food-induced increases in blood flow and oxygen consumption may be due in part to its effects on intestinal carbohydrate absorption and utilization.     

Effect of the prostacyclin synthetase inhibitor tranylcypromine on uterine blood flow in pregnancy

Prostacyclin is a potent vasodilator in a number of vascular beds including the uterus. However, the role of prostacyclin in maintaining uterine blood flow during pregnancy is not well established. Recent reports have appeared suggesting that tranylcypromine can selectively inhibit prostacyclin synthesis. Thus, the present study was undertaken using an unanesthetized chronically catheterized pregnant sheep preparation to evaluate the effects of direct intra-arterial infusions of tranylcypromine on the uterine vasculature of late-term pregnant ewes. Infusions of 1, 3 and 10 mg/min of tranylcypromine led to dose-related reduction in uterine blood flow (16, 21 and 47 percent, respectively) and increased blood pressure (7, 10 and 23 percent, respectively). However, these alterations were not associated with reductions in the uterine production rates of the prostacyclin metabolite, 6-keto-PGF_1α, as determined by unextracted plasma RIA. In addition, pre-treatment of animals with the α-adrenergic blocking agent, phenoxybenzamine, almost totally abolished uterine and systemic blood pressure responses to tranylcypromine. These data suggest that tranylcypromine either releases or elevates levels of an alpha adrenergic stimulant which constricts the uterine and systemic vasculature and does not alter prostacyclin levels at the dose tested.     

Biosynthesis of Prostacyclin in Rat Cerebral Microvessels and the Choroid Plexus

Abstract: Microvessels, predominantly capillaries, were isolated from rat cerebrum by a modification of published procedures. The morphology and purity of the preparations were monitored by light and electron microscopy and by enrichment in alkaline phosphatase, γ-glutamyl transpeptidase, and prostacyclin synthetase. A reversed-phase high-pressure liquid chromatographic method was used in the purification of prostaglandins after extraction from aqueous incubation solutions. Prostacyclin synthesis in brain is localized in cerebral blood vessels and capillaries. The endogenous biosynthetic capacity of the isolated cerebral capillary fractions for prostacyclin, measured as its chemically stable breakdown product, 6-keto-prostaglandin F_1α, was 11 ng/mg protein/10 min. Choroid plexus and intact surface vessels synthesized 6-keto-prostaglandin F_1α at 37 and 35 ng/mg protein/10 min, respectively. The prostacyclin-synthesizing enzyme of the cerebral capillaries also converted the exogenously added prostaglandin endoperoxides to 6-keto-prostaglandin F_1α. Comparison of the synthesis of prostaglandins 6-keto-F_1α, E₂, and F_2α showed that 6-keto-prostaglandin F_1α was the major prostaglandin formed in the microvessels, in the larger surface vessels, and in the choroid plexus. Prostaglandin D₂ was not detected. Prostacyclin synthesis by the cerebral vasculature is similar to that in other blood vessels and cultured human endothelial cells. Possible physiological roles of prostacyclin in the cerebral microvasculature are discussed with special regard to the autoregulation of cerebral blood flow.     

Gastrointestinal blood flow in the red Irish lord, Hemilepidotus hemilepidotus: long-term effects of feeding and adrenergic control

Cardiac output, blood flow to the coeliac and mesenteric arteries, dorsal aortic blood pressure and heart rate were recorded simultaneously at rest and postprandial for 6 days in a teleost, the red Irish lord (Hemilepidotus hemilepidotus). We anticipated that gastrointestinal blood flow would increase postprandially, supported by an increase in cardiac output. However, we had no predictions for either the exact time-course of this response, or for the regional distribution of blood flow between to the two major arteries comprising the splanchnic circulation. In resting, unfed animals, blood flow to the coeliac artery and mesenteric artery was 4.1 ± 0.6 ml min⁻¹ kg⁻¹ and 4.9 ± 1.3 ml min⁻¹ kg⁻¹, respectively (mean ± SEM, n=7), which together represented 34% of cardiac output. Feeding increased blood flow to the coeliac and mesenteric arteries in a time-dependent manner. The increase in coeliac artery blood flow preceded that in the mesenteric artery, a finding that is consistent with the coeliac artery supplying blood to the liver and stomach, while the mesenteric artery supplies blood to the stomach and intestine. Coeliac blood flow had increased by 84 ± 18% after 1 day and had a peak increase of 112 ± 40% at day 4 postprandial. Mesenteric blood flow was not significantly elevated at day 1, but had increased by 94 ± 19% at day 4 postprandial. Cardiac output also increased progressively, increasing by a maximum of 90 ± 30% at day 4. Because the increase in cardiac output was adequate to meet the postprandial increase in gut blood flow, the postprandial decreases in vascular resistance for the coeliac and mesenteric circulations mirrored the increases in blood flow. Intra-arterial injections of adrenaline and noradrenaline into resting fish more than doubled coeliac and mesenteric vascular resistances, and blood flow decreased proportionately. This adrenergic vasoconstriction was totally abolished by pretreatment with the α-adrenoceptor antagonist phentolamine, which in itself approximately halved coeliac and mesenteric vascular resistances. These observations indicate a significant α-adrenergic tone in the gastrointestinal circulation of the red Irish lord, the loss of which could not entirely account for the postprandial increase in gastrointestinal blood flow. Other control mechanisms are suggested. Accepted: 17 November 1999