The role of prostacyclin (PGI2) in metabolic hyperemia

We explored the possibility that prostacyclin might be the dilator metabolite of postprandial hyperemia. In canine free-flow preparations, effects of prostacyclin were compared with effects of actively absorbed nutrients on hemodynamic and metabolic parameters in the small intestine. Prostacyclin was infused directly into the superior mesenteric artery for 10 minutes at 1.0 nanograms/kg-min. In absorptive study an isosmotic solution of glucose (1.0 g/l) dissolved in 0.9% NaCl was perfused through the gut lumen for 20 minutes. Prostacyclin increased total blood flow to the intestinal segment and decreased oxygen extraction, while not significantly changing either oxygen consumption or PS-product. Active cotransport of glucose and sodium increased total blood flow, oxygen extraction, oxygen consumption and PS-product.In constant flow canine gut preparations, intraarterial prostacyclin infusion decreased arterial pressure, oxygen extraction, oxygen consumption and mesenteric vascular resistance but increased venous pressure. Absorption of glucose and sodium increased oxygen extraction but decreased mesenteric vascular resistance while not affecting other parameters significantly.Since responses to prostacyclin did not coincide with responses to metabolically dependent transport of glucose and sodium, we conclude that the dilator metabolite of postprandial hyperemia is probably not prostacyclin.     

Effects of somatostatin on intestinal circulation and oxygen consumption

The effects of intraarterial administration of somatostatin upon intestinal blood flow, intestinal capillary surface area, oxygen consumption and intestinal motor activity were measured in anesthetized dogs. Blood flow to the segment of distal ileum was measured with an electromagnetic blood flow meter, and arteriovenous oxygen difference (AVO2) was determined spectrophotometrically. Intestinal oxygen consumption was calculated as the product of AVO2 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 radiolabelled microspheres. Intestinal motor activity was monitored from changes in intraluminal pressure. Somatostatin induced a dose-related decrease in intestinal blood flow, capillary surface area and intestinal oxygen consumption. A significant increase in intestinal motor activity was also observed. The data of this study indicate that somatostatin acts on smooth muscle of both arterioles and precapillary sphincters and results in a potent vasoconstriction in the intestinal microcirculation.     

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.     

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.     

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.     

Effects of hypo- and hyper-capnia on myocardial blood flow and metabolism during epinephrine infusion in the dog

We have previously demonstrated a 40% increase in myocardial blood flow (MBF) during hypercapnia but no significant decrease of MBF during hypocapnia. The present study was undertaken to evaluate if epinephrine infusion, which increases both myocardial oxygen consumption (MVo2) and myocardial performance, might influence the effects of hypocapnia and hypercapnia on MBF. Induction of hypocapnia was performed by hyperventilation in closed-chest dogs anesthetized with pentobarbital. By adding carbon dioxide to the inspiratory gas, normocapnia and hypercapnia were created. Epinephrine infusion (0.8 microgram X kg-1 X min-1) increased MBF and cardiac output (CO) by 90 and 140%, respectively, while MVo2 was increased by 45%. Epinephrine had a direct coronary vasodilating effect in excess of myocardial needs evidenced by increased oxygen content of the coronary sinus blood. During epinephrine infusion, induction of hypocapnia effected no change of MBF, while myocardial oxygen extraction increased significantly. Although oxygen saturation (So2) and Po2 in the coronary sinus blood decreased, these values remained well above those with hypocapnia without epinephrine infusion, thereby excluding impaired oxygen supply to the heart. Hypercapnia induced an increase of MBF by nearly 40% despite the coronary vasodilatation already induced by epinephrine infusion.     

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.     

Exercise responses in pregnant sheep: oxygen consumption, uterine blood flow, and blood volume

In an attempt to explore the acute maternal responses to exercise we measured oxygen consumption, uterine blood flow, and blood volume in 13 chronically catheterized pregnant sheep at rest and while exercising on a treadmill. With maximal exercise O2 consumption increased 5.6 times, from a resting value of 5.8 +/- 0.3 (SE) to 32.1 +/- 2.8 ml X min -1 X kg -1, cardiac output increased 2.7 times, from 149 +/- 8 to 404 +/- 32 ml X min -1 X kg -1, and arteriovenous oxygen content difference increased 2.1 times, from 3.9 +/- 0.2 to 8.0 +/- 0.4 ml X dl -1. Total uterine blood flow decreased from a mean resting value of 292 +/- 6 to 222 +/- 19 ml X min -1 X kg fetus -1 near exhaustion during prolonged (40 min) exercise at 70% maximal oxygen consumption. Maternal blood volume decreased 14% (P less than 0.01) from 67.5 +/- 3.7 to 57.8 +/- 3.6 ml X kg -1 during this exercise period, with a 20% decrease in plasma volume without a change in red cell volume. We conclude that uterine blood flow decreases during maternal exercise. However, hemoconcentration helps to maintain a relatively constant oxygen delivery to the uterus.     

Increased oxygen consumption associated with breathing activity in fetal lambs

To examine the relationship between fetal O2 consumption and fetal breathing movements, we measured O2 consumption, umbilical blood flow, and cardiovascular and blood gas data before, during, and after fetal breathing movements in conscious chronically catheterized fetal lambs. During fetal breathing movements, O2 consumption increased by 30% from a control value of 7.7 +/- 0.7 (SE) ml X min-1 X kg-1. Umbilical blood flow was 210 +/- 21 ml X min-1 X kg-1 before fetal breathing movements; in 9 of 16 samples it increased by 52 +/- 12 ml X min-1 X kg-1, while in the other 7 it decreased by 23 +/- 9 ml X min-1 X kg-1. Umbilical arterial and venous O2 partial pressures and pH fell during fetal breathing movements, and the fall was greater when umbilical blood flow was decreased. Partial CO2 pressure rose in both vessels, and again the increase was greatest when umbilical blood flow fell during fetal breathing movements. Also associated with a fall in umbilical blood flow was the transition from low-amplitude irregular to large-amplitude regular fetal breathing movements. It is concluded that fetal breathing movements increase fetal O2 demands and are associated with a transient deterioration in fetal blood gas status, which is most severe during large-amplitude breathing movements.     

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.     

The effects of erythrocythemia on blood viscosity,maximal systemic oxygen transport capacity and maximal rates of oxygen consumption in an amphibian

Graded erythrocythemia was induced by isovolemic loading of packed red blood cells in the toad, Bufo marinus. Blood viscosity, hematocrit, hemoglobin concentration, maximal aortic blood flow rate and maximal rates of oxygen consumption were determined after each load. Blood viscosity was related to hematocrit in the expected exponential manner; ln eta = 0.43 + 0.035 Hct. Maximal blood flow rates in the dorsal aorta were inversely proportional to blood viscosity and fit predictions of the Poiseuille-Hagen flow formula. The effect of increased blood viscosity was to reduce aortic pulse volume, but not maximal heart rate. Maximal systemic oxygen transport capacity (aortic blood flow rate X hemoglobin concentration X O2 binding capacity of hemoglobin) was linearly correlated with the maximal rate of oxygen consumption. These date indicate that optimal hematocrit theory is applicable for maximal blood flow rates in vivo, and that systemic oxygen transport is the primary limitation to aerial VO2 max in amphibians.     

The effect of vasopressin on fetal oxygenation in sheep

To examine the effects of vasopressin on fetal oxygenation the hormone was infused intravenously for 1 h (1.4-3.5 mU X min-1 X kg fetal weight-1) to chronically catheterized fetal lambs in utero (113-137 days gestation). Arterial pressure rose (48.3 to 59.6 mmHg) (1 mmHg = 133.322 Pa) and heart rate fell (185.3 to 141.0 beats/min) during the infusion. There was a significant increase in fetal arterial PO2 (20.0 to 23.1 mmHg) and significant declines in pH (7.414 to 7.381) and base excess. Umbilical blood flow rose, and the percentage increase in flow (23%) was identical to the proportional rise in arterial pressure. Accompanying the rise in umbilical blood flow was a rise in umbilical oxygen delivery. But as there was no change in fetal oxygen consumption, fractional oxygen extraction by the fetus fell significantly (0.31 to 0.25). These data indicate that the vasopressin-induced rise in fetal vascular PO2 results from an increase in umbilical oxygen delivery and concomitant fall in fractional extraction. Fetal vasopressin levels are greatly elevated during hypoxia, and under conditions of reduced oxygen supply, the effects of the hormone on umbilical oxygen delivery and vascular PO2 could have definite survival value.     

Dynamic changes in organ blood flow and oxygen consumption during acute asphyxia in fetal sheep

The effects of acute asphyxia on both the time course of blood flow changes in central and peripheral organs, including the skin, and the time course of changes in oxygen consumption were studied in 9 unanaesthetized fetal sheep in utero at 130 +/- 2 days of gestation during 4-min arrest of uterine blood flow. Blood flow distribution and total oxygen consumption were determined at 1-min intervals during asphyxia using isotope-labelled microspheres (15 micrograms diameter) and by calculating the decline of the arterial O2 content, respectively. During asphyxia peripheral blood flow including that to the skin, scalp, and choroid plexus decreased rapidly, whereas blood flow to the heart, brain stem and (in surviving fetuses only) adrenals increased slowly. Total oxygen consumption fell exponentially with time and was closely correlated with the fall in both arterial oxygen content and peripheral blood flow; the time courses of these changes were very similar to those of the decreasing blood flows to the skin and scalp. Blood flow within the brain was redistributed at the expense of the cerebrum and the choroid plexus; the total blood flow to the brain did not change. In the 5 fetuses that died during the recovery period adrenal blood flow failed to increase and, at the nadir of asphyxia, peripheral vessels dilated and central vessels constricted. We conclude that in fetal sheep near term during acute asphyxia the time course of changes in blood flow to central and peripheral organs is different; total oxygen consumption depends on arterial O2 content and peripheral blood flow; total blood flow to the brain does not change, but is redistributed towards the brain stem at the expense of the cerebrum and choroid plexus; fetal death is preceded by a failure of adrenal blood flow to increase, by peripheral vasodilatation, and by central vasoconstriction and skin blood flow validly indicates rapid changes in the distribution of blood flow and the changes in oxygen consumption that accompany it.     

Postprandial intestinal blood flow, metabolic rates, and exercise in Chinook salmon (Oncorhynchus tshawytscha)

Following a relatively large meal (2% body mass of dry pellets), intestinal blood flow in chinook salmon (Oncorhynchus tshawytscha) increased significantly, up to 81%, between 14 and 29 h postprandially. Also, 15 h postprandially, oxygen consumption (M(2)) was elevated by 128% compared with a measurement of routine M(2) made after 1 wk of fasting. The postprandial increase in MO(2) (the heat increment) was 33 micromol O(2) min(-1) kg(-1). Because intestinal blood flow is known to decrease during swimming activity in fish, we therefore tested the hypothesis that swimming fish would have to make a trade-off between maximum swimming activity and digestive activity by comparing the swimming performance and metabolic rates of fed and fasted chinook salmon. As expected, MO(2) increased exponentially with swimming velocity in both fed and fasted fish. Moreover, the heat increment was irreducible during swimming, such that MO(2) remained approximately 39 micromol O(2) min(-1) kg(-1) higher in fed fish than in fasted fish at all comparable swimming speeds. However, maximum M dot o2 was unaffected by feeding and was identical in both fed and fasted fish (approximately 250 micromol O(2) min(-1) kg(-1)), and, as a result, the critical swimming speed (U(crit)) was 9% lower in the fed fish. Three days after the fish were fed and digestion was completed, MO(2) and U(crit) were not significantly different from those measured in fasted fish. The ability of salmonids to maintain feeding metabolism during prolonged swimming performance is discussed, and it is suggested that reduced swimming performance may be due to postprandial sparing of intestinal blood to support digestion, thereby limiting the allocation of blood flow to locomotory muscles.     

Endothelium-derived relaxing factor participates in the increased blood flow in response to pentagastrin in the rat stomach mucosa

The stimulation of gastric-acid secretion by pentagastrin, a synthetic analogue of the endogenous peptide gastrin, is associated with an increased blood flow to the stomach mucosa, commonly referred to as functional hyperaemia. There are at least two potent vasodilator substances, the local release of which from endothelial cells could contribute to this hyperaemia, endothelium-derived relaxing factor (EDRF) and prostacyclin. EDRF has been identified as nitric oxide, released enzymatically from the guanidino group of L-arginine. In the present studies, the involvement of prostacyclin in the pentagastrin-induced increase in stomach blood flow was eliminated by using the cyclo-oxygenase inhibitor indomethacin. Thus this work was designed to elucidate the participation of EDRF/NO in the pentagastrin-induced hyperaemia and not its relative importance to prostacyclin. The increase in blood flow to the gastric mucosa in response to pentagastrin was measured by laser Doppler flowmetry in situ. Inhibition of EDRF/NO biosynthesis with the L-arginine analogues NG-monomethyl-L-arginine (MeArg) or N omega-nitro-L-arginine (NO2Arg) significantly attenuated (by more than 80%) the increase in mucosal blood flow in response to pentagastrin. However, infusions of the natural substrate L-arginine reversed the inhibitor effect of MeArg on pentagastrin-induced increase in mucosal blood flow. Local intra-arterial injections of the endothelium-independent vasodilator glyceryl trinitrate produced a dose-related increase in blood flow to the rat stomach mucosa that was unaffected by infusion of MeArg. Thus, in the absence of prostacyclin, EDRF/NO participates in the pentagastrin-induced increase in blood flow to the rat stomach mucosa.     

Diaspirin cross-linked hemoglobin improves oxygen extraction capabilities in endotoxic shock.

We studied the effects of diaspirin cross-linked hemoglobin (DCLHb), a cell-free hemoglobin derived from human erythrocytes, on blood flow distribution and tissue oxygen extraction capabilities in endotoxic shock. Eighteen pentobarbital sodium-anesthetized, mechanically ventilated dogs received 2 mg/kg of E. coli endotoxin, followed by saline resuscitation to restore cardiac filling pressures to baseline levels. The animals were randomly divided into three groups: six served as control, six received DCLHb at a dose of 500 mg/kg (group 1) and six DCLHb at a dose of 1,000 mg/kg (group 2). Cardiac tamponade was then induced by saline injection in the pericardial sac to progressively reduce cardiac index and thereby allow study of tissue oxygen extraction capabilities. DCLHb had a dose-dependent vasopressor effect but did not significantly alter cardiac index or regional blood flow. During cardiac tamponade, critical oxygen delivery was 12.8 +/- 0.7 ml. kg(-1). min(-1) in the control group, but 8.6 +/- 0.9 and 8.2 +/- 0.7 ml. kg(-1). min(-1) in groups 1 and 2, respectively (both P < 0.05 vs. control group). The critical oxygen extraction ratio was 39.1 +/- 3.1% in the control group but 58.7 +/- 12.8% and 60.2 +/- 9.0% in groups 1 and 2, respectively. We conclude that DCLHb can improve whole body oxygen extraction capabilities during endotoxic shock in dogs.     

Effect of separate hemidiaphragm contraction on left phrenic artery flow and O2 consumption

Phrenic arterial blood flow has been shown to increase during bilateral phrenic nerve stimulation (BPNS). However, the role of unilateral phrenic nerve stimulation [left (LPNS) or right (RPNS)] on the blood flow and O2 consumption of the contralateral hemidiaphragm is not known and is explored here. In six anesthetized, mechanically hyperventilated dogs, left phrenic arterial blood flow (Qlpha) was measured (Doppler technique). Supramaximal (10 V, 30 Hz, 0.25-ms duration) LPNS, RPNS, and BPNS at a pacing frequency 15/min and duty cycle of 0.50 were delivered in separate runs. Left hemidiaphragmatic blood samples for gas analyses were obtained by left phrenic venous cannulation. During RPNS, Qlpha and left hemidiaphragmatic O2 consumption (VO2ldi) did not change significantly compared with control. During LPNS and BPNS, there was a significant increase in Qlpha and VO2ldi (P less than 0.01). There was no significant difference in Qlpha and VO2ldi between LPNS and BPNS (P greater than 0.05). We conclude 1) that there is a complete independence of left-right hemidiaphragmatic circulation both at rest and during diaphragm pacing and 2) that during unilateral stimulation transdiaphragmatic pressure is not related to diaphragmatic blood flow.     

Pharmacologic modification of blood flow in the rabbit microvasculature with prostacyclin and related drugs

The rabbit epigastric free flap was used to investigate the effect of prostacyclin and drugs modifying its synthesis in vivo on microvascular blood flow. Prostacyclin and its analogue carbacyclin caused an increase in flow with a maximal twofold increase at approximately 6.5 and 250 ng/ml, respectively, in the flap. Thromboxane synthetase inhibitors such as dazoxiben hydrochloride, UK-38,485, 7-IHA, and imidazole (up to 7 X 10(-4) M in the flap) as well as the prostaglandins 6-oxo-PGF1 alpha and PGE2 (up to 3.7 and 9.2 ng/ml, respectively, in the flap) all failed to modify the control flow rate in the cutaneous microcirculation. It is concluded that the vasodilatory properties of prostacyclin and carbacyclin, together with their known platelet antiaggregatory properties, warrant further study in problem areas of microsurgery such as flap ischemia. The use of thromboxane synthetase inhibitors had no demonstrable effect on the normal flap, and their effect on the ischemic flap remains to be investigated.     

Integral mechanisms of regulation of oxygen delivery and consumption in human body

With new algorithms of pattern recognition three types of regulation of oxygen delivery and consumption were studied: at normal regulation, hypo- and hyperfunction of heart. It is shown that a surplus systemic blood flow results in increase of arterio-venous shunt flow. Insufficient blood flow results in increase of arterio-venous gradient of blood oxygen content due to the increase of gradient of oxygen content on both sides of capillary wall and to activating of vasomotor function of microcirculatory arterial bed. Quantitative estimations of shunt and capillary blood flow are obtained.     

Effect of short-term energy intake level and exercise on oxygen consumption in men

The influence of short-term energy intake and cycle exercise on oxygen consumption in response to a 1.5 MJ test meal was investigated in ten young, adult men. On the morning after a previous day's "low-energy" intake (LE regimen) of 4.5 MJ, the mean resting oxygen consumption increased by 0.7 ml X kg-1 X min-1 after the test meal (P less than 0.025). After a "high-energy" intake (HE regimen) of 18.1 MJ, the resting measurement was unchanged (+0.4 ml X kg-1 X min-1) after the meal (n.s.). These trends are the reverse of what would be expected if oxygen consumption in response to feeding is a factor in the acute control of body weight. The mean fasting oxygen consumption during cycle exercise at 56% of VO2max (constant work) for both LE and HE prior intakes was not different at 31.1 ml X kg-1 X min-1. Oxygen consumption during exercise increased after feeding by 0.5 ml X kg-1 X min-1 on the LE regimen (n.s.) and decreased by 1.2 ml X kg-1 X min-1 on the HE regimen (n.s.). These results are also the reverse of what would be expected if oxygen consumption in response to exercise is related to short-term energy intake.