N omega-nitro-L-arginine influences cerebral metabolism in awake sheep.

Cerebral vasodilation in hypoxia may involve endothelium-derived relaxing factor-nitric oxide (NO). An inhibitor of NO formation, N omega-nitro-L-arginine (LNA, 100 micrograms/kg i.v.), was given to conscious sheep (n = 6) during normoxia and again in hypocapnic hypoxia (arterial PO2 approximately 38 Torr). Blood samples were obtained from the aorta and sagittal sinus, and cerebral blood flow (CBF) was measured with 15-microns radiolabeled microspheres. During normoxia, LNA elevated (P < 0.05) mean arterial pressure from 82 +/- 3 to 88 +/- 2 (SE) mmHg and cerebral perfusion pressure (CPP) from 72 +/- 3 to 79 +/- 3 mmHg, CBF was unchanged, and cerebral lactate release (CLR) rose temporarily from 0.0 +/- 1.9 to 13.3 +/- 8.7 mumol.min-1 x 100 g-1 (P < 0.05). The glucose-O2 index declined (P < 0.05) from 1.67 +/- 0.16 to 1.03 +/- 0.4 mumol.min-1 x 100 g-1. Hypoxia increased CBF from 59.9 +/- 5.4 to 122.5 +/- 17.5 ml.min-1 x 100 g-1 and the glucose-O2 index from 1.75 +/- 0.43 to 2.49 +/- 0.52 mumol.min-1 x 100 g-1 and decreased brain CO2 output, brain respiratory quotient, and CPP (all P < 0.05), while cerebral O2 uptake, CLR, and CPP were unchanged. LNA given during hypoxia decreased CBF to 77.7 +/- 11.8 ml.min-1 x 100 g-1 and cerebral O2 uptake from 154 +/- 22 to 105.2 +/- 12.4 mumol.min-1 x 100 g-1 and further elevated mean arterial pressure to 98 +/- 2 mmHg (all P < 0.05), CLR was unchanged, and, surprisingly, brain CO2 output and respiratory quotient were reduced dramatically to negative values (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Methylene blue inhibits hypoxic cerebral vasodilation in awake sheep.

Cerebral vasodilation in hypoxia may involve endothelium-derived relaxing factor-nitric oxide. Methylene blue (MB), an in vitro inhibitor of soluble guanylate cyclase, was injected intravenously into six adult ewes instrumented chronically with left ventricular, aortic, and sagittal sinus catheters. In normoxia, MB (0.5 mg/kg) did not alter cerebral blood flow (CBF, measured with 15-microns radiolabeled microspheres), cerebral O2 uptake, mean arterial pressure (MAP), heart rate, cerebral lactate release, or cerebral O2 extraction fraction (OEF). After 1 h of normobaric poikilocapnic hypoxia (arterial PO2 40 Torr, arterial O2 saturation 50%), CBF increased from 51 +/- 5.8 to 142 +/- 18.8 ml.min-1 x 100 g-1, cerebral O2 uptake from 3.5 +/- 0.25 to 4.7 +/- 0.41 ml.min-1 x 100 g-1, cerebral lactate release from 2 +/- 10 to 100 +/- 50 mumol.min- x 100 g-1, and heart rate from 107 +/- 5 to 155 +/- 9 beats/min (P < 0.01). MAP and OEF were unchanged from 91 +/- 3 mmHg and 48 +/- 4%, respectively. In hypoxia, 30 min after MB (0.5 mg/kg), CBF declined to 79.3 +/- 11.7 ml.min-1 x 100 g-1 (P < 0.01), brain O2 uptake (4.3 +/- 0.9 ml.min-1 x 100 g-1) and heart rate (133 +/- 9 beats/min) remained elevated, cerebral lactate release became negative (-155 +/- 60 mumol.min-1 x 100 g-1, P < 0.01), OEF increased to 57 +/- 3% (P < 0.01), and MAP (93 +/- 5 mmHg) was unchanged. The sheep became behaviorally depressed, probably because of global cerebral ischemia. These results may be related to interference with a guanylate cyclase-dependent mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phorbol myristate acetate-induced injury of isolated perfused rat lungs: neutrophil dependence

The effect of leukocyte depletion on acute lung injury produced by intravenous or intratracheal phorbol myristate acetate (PMA) administration was studied in isolated perfused rat lungs. Vascular endothelial permeability was assessed by use of the capillary filtration coefficient (Kf,c). A predicted pulmonary capillary pressure (Ppc,p) was calculated from measurements of postcapillary resistances. These parameters were measured before and 90 min after the administration of PMA, either intratracheally or intravascularly. When blood elements were present both intratracheal and intravascular PMA caused an increased Kf,c [0.27 +/- 0.02 vs. 0.99 +/- 0.22 and 0.25 +/- 0.05 vs. 0.64 +/- 0.15 (SE) ml.min-1.cmH2O-1.100 g-1, respectively; P less than 0.05] and an increased Ppc,p (8.3 +/- 0.4 vs. 74.7 +/- 18.3 and 8.7 +/- 0.8 vs. 74.2 +/- 25.1 cmH2O, respectively; P less than 0.05). Removal of circulating leukocytes abolished the increased Kf,c when PMA was given intratracheally (0.35 +/- 0.06 vs. 0.23 +/- 0.07 ml.min-1.cmH2O-1.100 g-1) or intravascularly (0.39 +/- 0.07 vs. 0.33 +/- 0.07 ml.min-1.cmH2O-1.100 g-1). In the absence of neutrophils, Ppc,p slightly increased with intratracheal PMA, from 6.9 +/- 0.5 to 10.5 +/- 1.1 cmH2O (P less than 0.05), but was unchanged at 90 min with intravascular PMA. Depletion of circulating neutrophils with an antineutrophil serum failed to block the Kf,c change with intratracheal PMA (from 0.24 +/- 0.03 to 0.42 +/- 0.09 ml.min-1.cmH2O-1.100 g-1; P less than 0.05). Ppc,p also increased from 6.9 +/- 0.6 to 19.8 +/- 6.7 cmH2O (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure

Coronary blood flow (CBF) and myocardial oxygen consumption (MVO(2)) are reduced in dogs with pacing-induced congestive heart failure (CHF), which suggests that energy metabolism is downregulated. Because nitric oxide (NO) can inhibit mitochondrial respiration, we examined the effects of NO inhibition on CBF and MVO(2) in dogs with CHF. CBF and MVO(2) were measured at rest and during treadmill exercise in 10 dogs with CHF produced by rapid ventricular pacing before and after inhibition of NO production with N(G)-nitro-L-arginine (L-NNA, 10 mg/kg iv). The development of CHF was accompanied by decreases in aortic and left ventricular (LV) systolic pressure and an increase in LV end-diastolic pressure (25 +/- 2 mmHg). L-NNA increased MVO(2) at rest (from 3.07 +/- 0.61 to 4.15 +/- 0.80 ml/min) and during exercise; this was accompanied by an increase in CBF at rest (from 31 +/- 2 to 40 +/- 4 ml/min) and during exercise (both P < 0.05). Although L-NNA significantly increased LV systolic pressure, similar increases in pressure produced by phenylephrine did not increase MVO(2). The findings suggest that NO exerts tonic inhibition on respiration in the failing heart.     

Blood-brain barrier to hydrogen ion during acute metabolic acidosis in piglets

The present study investigates the integrity of the blood-brain barrier to H+ or HCO3- during acute plasma acidosis in 35 newborn piglets anesthetized with pentobarbital sodium. Cerebrospinal fluid acid-base balance, cerebral blood flow (CBF), and cerebral oxygenation were measured after infusion of HCl (0.6 N, 0.191-0.388 ml/min) for a period of 1 h at a constant arterial PCO2 of 35-40 Torr. HCl infusion resulted in decreased arterial pH from 7.38 +/- 0.01 to 7.00 +/- 0.02 (P less than 0.01). CBF measured by the tracer microsphere technique was decreased by 12% from 69 +/- 6 to 61 +/- 4 ml.min-1.100 g-1 (P less than 0.05). Infusion of 0.6 N NaCl as a hypertonic control had no effect on CBF. Cerebral metabolic rate for O2 and O2 extraction was not significantly changed from control (3.83 +/- 0.20 ml.min-1.100 g-1 and 5.7 +/- 0.6 ml/100 ml, respectively) during acid infusion. Cerebral venous PO2 was increased from 41.6 +/- 2.1 to 53.8 +/- 4.0 Torr by HCl infusion (P less than 0.02) associated with a shift in O2-hemoglobin affinity of blood in vivo from 38 +/- 2 to 50 +/- 1 Torr. Cisternal cerebrospinal fluid pH decreased from 7.336 +/- 0.014 to 7.226 +/- 0.027 (P less than 0.005), but cerebrospinal fluid HCO3- concentration was not changed from control (25.4 +/- 1.0 meq/l). These data suggest that there is a functional blood-brain barrier in newborn piglets, that is relatively impermeable to HCO3- or H+ and maintains cerebral perivascular pH constant in the face of acute severe arterial acidosis. (ABSTRACT TRUNCATED AT 250 WORDS)     

Regional blood flows and cardiac hemodynamics in renovascular and mineralocorticoid hypertensive rats

Regional blood flows and cardiac hemodynamics were studied in 3 models of hypertensive rats: one-kidney DOC-saline, one-kidney, one-clip and two-kidney, one-clip hypertension and in normotensive control rats. All hypertensive models were characterized by increased peripheral vascular resistance and normal cardiac output. Coronary and cerebral blood flows varied among the hypertensive models but did not significantly differ from the normotensive rats. However, coronary blood flow of one-kidney, one-clip rats (8.4 +/- 1.3 ml X min-1 X g-1) was significantly higher than that of the two-kidney one-clip rats (6.5 +/- 1.2 ml X min.-1 X g-1, P less than 0.05). Cerebral blood flow of DOC-saline rats was lower than that of two-kidney one-clip or one-kidney one-clip renovascular rats. Renal blood flows of the unclipped kidney of two-kidney renovascular rats (3.77 +/- 0.85 ml X min-1 X g-1) and DOC-saline rats (2.95 +/- 0.83 ml X min-1 X g-1) were significantly lower than those of normotensive rats (5.92 +/- 1.16 ml X min-1 X g-1, P less than 0.05). In conclusion, although vascular resistance becomes elevated in all models of experimental hypertension, regional vascular resistance and blood flow distribution may differ depending on the vasoconstrictor mechanisms that participate in each model.     

Relation between the O2 supply:demand ratio, MVO2, and adenosine formation in hearts stimulated with inotropic agents

Mooted controllers of adenosine formation in heart are the oxygen supply:demand ratio, myocardial oxygen consumption (MVO2), the cytosolic phosphorylation potential (log[ATP]/[ADP][Pi]). The relationship between these parameters and purine release (adenosine + inosine) into the venous effluent was examined in isovolumic rat hearts perfused at 20 and 12 mL.min-1.g-1 with a glucose containing crystalloid buffer and stimulated with inotropic agents (isoproterenol, norepinephrine, 3-isobutyl-1-methylxanthine, and ouabain). The oxygen supply:demand ratio and MVO2 were continuously determined using an oxygen electrode to monitor oxygen supply and consumption. The phosphorylation potential was calculated from phosphorus metabolite levels determined by 31P-NMR spectroscopy and HPLC analysis. Left ventricular function was assessed as the rate-pressure product. All inotropic agents increased the rate-pressure product, with increases in function being greater in the hearts perfused at 20 mL.min-1.g-1. MVO2 was linearly related to the rate-pressure product at each flow rate; however, the hearts perfused at 20 mL.min-1.g-1 exhibited approximately twofold greater MVO2 values for similar rate-pressure product values. All inotropic agents increased adenosine release into the venous effluent. While there was a significant linear relation between adenosine formation and MVO2 in hearts perfused at both flow rates and stimulated with drugs, the relations differed with adenosine release being approximately fourfold greater in hearts perfused at 12 mL.min-1.g-1 under similar conditions of MVO2. Adenosine formation correlated exponentially with the ratio of oxygen supply:demand under all conditions (r = 0.97) and the relation did not differ significantly between hearts perfused at different rates.(ABSTRACT TRUNCATED AT 250 WORDS)     

Training-induced muscle adaptations: increased performance and oxygen consumption

An isolated perfused rat hindlimb preparation was used to study the impact of local muscle adaptations induced by endurance exercise training on muscle performance and peak muscle oxygen consumption. Rats were trained for 12-15 wk by a running program (30 m/min up a 15% grade for 1 h/day 5 days/wk) shown previously to increase muscle mitochondrial enzyme activity. Sedentary (n = 11) and trained (n = 11) hindlimbs of similar size were perfused with a similar inflow (12.1 ml/min) at a similar oxygen content (18.1 ml O2/100 ml blood). Tetanic contractions (100 ms at 100 Hz) at 4, 8, 15, 30, 45, and 60/min were elicited in consecutive order. Initial tension was better maintained by muscles of trained animals at all frequencies above 4 tetani/min (P less than 0.05). Oxygen consumption (mumol.min-1.g-1) increased similarly in both groups at the lower contraction frequencies but was greater (P less than 0.05) in the trained [3.52 +/- 0.32 (SE)] than in the sedentary (2.44 +/- 0.31) group at 60 tetani/min. The peak oxygen consumption of the trained group (3.93 +/- 0.27) was 20% greater (P less than 0.05) than that of the sedentary group (3.28 +/- 0.28) when peak values for each animal, irrespective of the contraction condition, are compared. Blood flows to the contracting muscle (approximately 100 ml.min-1.g-1) and, therefore, oxygen deliveries (mumol.min-1.g-1) were not different between sedentary (7.99 +/- 0.56) and trained groups (8.35 +/- 0.61). Thus the 20% higher peak oxygen consumption was achieved by a greater oxygen extraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of furegrelate on renal plasma flow after angiotensin II infusion

We had previously shown that selective thromboxane synthetase inhibition with furegrelate increases urinary excretion of 6-ketoPGF1 alpha, the hydrolysis product of prostacyclin after stimulation of renal prostaglandin synthesis with furosemide. The present study assessed the functional significance of this "redirection" of prostaglandin formation using a more physiologic stimulus, angiotensin II. Sprague-Dawley rats (n = 27) were fitted with a transabdominal bladder cannula. Five days later they were given angiotensin II (10 mg.kg-1.min-1) by intravenous infusion. After 30 min, an infusion of furegrelate, 2 mg/kg, then 2 mg.kg-1.h-1, (n = 9); indomethacin, 2 mg/kg, then 2 mg.kg-1.h-1 (n = 9); or vehicle, 250 microL, then 0.018 mL/min (n = 9) was begun for 60 min. Clearance of [14C]para-aminohippuric acid was taken as a measure of renal plasma flow. Angiotensin II raised the mean arterial pressure in all groups. Administration of furegrelate or indomethacin did not change mean arterial pressure or heart rate. Angiotensin II reduced [14C]p-aminohippuric acid clearance by about 32% (1.42 +/- 0.18 to 0.97 +/- 0.07 mL.min-1.100 g-1, p less than 0.05). Furegrelate attenuated this renal vasoconstriction (0.97 +/- 0.07 to 1.38 +/- 0.17 mL.min-1.100 g-1, p less than 0.05), while indomethacin increased it by a further 32% (1.78 +/- 0.12 to 1.20 +/- 0.12 mL.min-1.100 g-1, p less than 0.05). Vehicle alone had no effect. Furegrelate reduced serum thromboxane B2 by 90% (6.52 +/- 0.030 to 0.7 +/- 0.21 ng/100 microL, p less than 0.05), while indomethacin reduced it by 73% (5.9 +/- 0.99 to 1.4 +/- 0.20 ng/100 microL, p less than 0.05). We conclude that furegrelate attenuates the renal vasoconstriction of angiotensin II, presumably by enhancing the formation of vasodilator prostaglandins.     

Effect of hematocrit on cerebral blood flow with induced polycythemia

Cerebral blood flow (CBF) is lowered during polycythemia. Whether this fall is due to an increase in red blood cell concentration (Hct) or to an increase in arterial O2 content (Cao2) is controversial. We examined the independent effects of Hct and Cao2 on CBF as Hct was raised from 30 to 55% in anesthetized 1- to 7-day-old sheep. CBF was measured by the radiolabeled microsphere technique before and after isovolemic exchange transfusion with either oxyhemoglobin-containing erythrocytes (in 5 control animals) or with methemoglobin-containing erythrocytes (in 9 experimental animals). Following exchange transfusion in the control animals, Hct rose (30 +/- 1 vs. 55 +/- 1%, mean +/- SE), Cao2 increased (15.1 +/- 0.8 vs. 26.7 +/- 0.9 vol%), and CBF fell (66 +/- 9 vs. 35 +/- 5 ml X min-1 X 100 g-1). Because the fall in CBF was proportionate to the rise in Cao2, cerebral O2 transport (CBF X Cao2) was unchanged. Following exchange transfusion in the experimental animals, Hct rose (32 +/- 1 vs. 55 +/- 1%) but Cao2 did not change. Nevertheless, CBF still fell (73 +/- 4 vs. 48 +/- 2 ml X min-1 X 100 g-1) and, as a result, cerebral O2 transport also fell. The latter cannot be attributed to a fall in cerebral O2 uptake, as cerebral O2 uptake was unaffected during each of these conditions. Comparison of the two groups of animals showed that approximately 60% of the fall in CBF may be attributed to the increase in red cell concentration alone. It is probable that this effect is due largely to changes in blood viscosity.     

Control of myocardial oxygen consumption in transgenic mice overexpressing vascular eNOS

Our objective was to investigate the potential role of selective endothelial nitric oxide (NO) synthase (eNOS) overexpression in coronary blood vessels in the control of myocardial oxygen consumption (MVO2). Transgenic (Tg) eNOS-overexpressing mice (eNOS Tg) (n=22) and wild-type (WT) mice (n=24) were studied. Western blot analysis indicated greater than sixfold increase of eNOS in cardiac tissue. Echocardiography in awake mice indicated no difference in cardiac function between WT and eNOS Tg; however, systolic pressure in eNOS Tg mice decreased significantly (126 +/- 2.3 to 109 +/- 2.3 mmHg; P <0.05), whereas heart rate (HR) was not different. Total peripheral resistance (TPR) was also decreased (9.8 +/- 0.8 to 7.6 +/- 0.4 4 mmHg.ml(-1).min; P <0.05) in eNOS Tg. Furthermore, female eNOS Tg mice showed even lower TPR (7.2 +/- 0.4 mmHg.ml(-1).min) compared with male eNOS mice (8.6 +/- 0.5, mmHg.ml.min(-1); P <0.05). Left ventricular slices were isolated from WT and eNOS Tg mice. With the use of a Clark-type oxygen electrode in an airtight bath, MVO2 was determined as the percent decrease during increasing doses (10(-10) to 10(-4) mol/l) of bradykinin (BK), carbachol (CCh), forskolin (10(-12) to 10(-6) mol/l), or S-nitroso-N-acetyl penicillamine (SNAP; 10(-7) to 10(-4) mol/l). Baseline MVO2 was not different between WT (181 +/- 13 nmol.g(-1).min(-1)) and eNOS Tg (188 +/- 14 nmol.g(-1).min(-1)). BK decreased MVO2 (10(-4) mol/l) in WT by 17% +/- 1.1 and 33% +/- 2.7 in eNOS Tg (P < 0.05). CCh also decreased MVO2, 10(-4) mol/l, in WT by 20% +/- 1.7 and 31% +/- 2.0 in eNOS Tg (P <0.05). Forskolin (10(-6) mol/l) or SNAP (10(-4) mol/l) also decreased MVO2 in WT by 24% +/- 2.8 and 36% +/- 1.8 versus eNOS 31% +/- 1.8 and 37% +/- 3.5, respectively. N-nitro-L-arginine methyl ester (10(-3) mol/l) inhibited the MVO2 reduction to BK, CCh, and forskolin by a similar degree (P <0.05), but not to SNAP. Thus selective overexpression of eNOS in cardiac blood vessels in mice enhances the control of MVO2 by eNOS-derived NO.     

Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs

Statin drugs can upregulate endothelial nitric oxide (NO) synthase (eNOS) in isolated endothelial cells independent of lipid-lowering effects. We investigated the effect of short-term simvastatin administration on coronary vascular eNOS and NO production in conscious dogs and canine tissues. Mongrel dogs were instrumented under general anesthesia to measure coronary blood flow (CBF). Simvastatin (20 mg. kg(-1). day(-1)) was administered orally for 2 wk; afterward, resting CBF was found to be higher compared with control (P < 0.05) and veratrine- (activator of reflex cholinergic NO-dependent coronary vasodilation) and ACh-mediated coronary vasodilation were enhanced (P < 0.05). Response to endothelium-independent vasodilators, adenosine and nitroglycerin, was not potentiated. After simvastatin administration, plasma nitrate and nitrite (NO(x)) levels increased from 5.22 +/- 1.2 to 7. 79 +/- 1.3 microM (P < 0.05); baseline and agonist-stimulated NO production in isolated coronary microvessels were augmented (P < 0.05); resting in vivo myocardial oxygen consumption (MVO(2)) decreased from 6.8 +/- 0.6 to 5.9 +/- 0.4 ml/min (P < 0.05); NO-dependent regulation of MVO(2) in response to NO agonists was augmented in isolated myocardial segments (P < 0.05); and eNOS protein increased 29% and eNOS mRNA decreased 50% in aortas and coronary vascular endothelium. Short-term administration of simvastatin in dogs increases coronary endothelial NO production to enhance NO-dependent coronary vasodilation and NO-mediated regulation of MVO(2).     

Separate effects of ischemia and reperfusion on vascular permeability in ventilated ferret lungs.

In systemic organs, ischemia-reperfusion injury is thought to occur during reperfusion, when oxygen is reintroduced to hypoxic ischemic tissue. In contrast, the ventilated lung may be more susceptible to injury during ischemia, before reperfusion, because oxygen tension will be high during ischemia and decrease with reperfusion. To evaluate this possibility, we compared the effects of hyperoxic ischemia alone and hyperoxic ischemia with normoxic reperfusion on vascular permeability in isolated ferret lungs. Permeability was estimated by measurement of filtration coefficient (Kf) and osmotic reflection coefficient for albumin (sigma alb), using methods that did not require reperfusion to make these measurements. Kf and sigma alb in control lungs (n = 5), which were ventilated with 14% O2-5% CO2 after minimal (15 +/- 1 min) ischemia, averaged 0.033 +/- 0.004 g.min-1.mmHg-1.100 g-1 and 0.69 +/- 0.07, respectively. These values did not differ from those reported in normal in vivo lungs of other species. The effects of short (54 +/- 9 min, n = 10) and long (180 min, n = 7) ischemia were evaluated in lungs ventilated with 95% O2-5% CO2. Kf and sigma alb did not change after short ischemia (Kf = 0.051 +/- 0.006 g.min-1.mmHg-1.100 g-1, sigma alb = 0.69 +/- 0.07) but increased significantly after long ischemia (Kf = 0.233 +/- 0.049 g.min-1 x mmHg-1 x 100 g-1, sigma alb = 0.36 +/- 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of contraction frequency and duty cycle on diaphragmatic blood flow

The effects of diaphragmatic contraction frequency (no. of intermittent tetanic contractions/min) at a given tension-time index and of duty cycle (contraction time/total cycle time) on diaphragmatic blood flow were measured in anesthetized mongrel dogs during bilateral supramaximal phrenic nerve stimulation. Diaphragmatic blood flow was measured by the radionuclide-labeled microsphere method. Contraction frequency was varied between 10 and 160/min at duty cycles of 0.25 and 0.75. Diaphragmatic blood flow increased with contraction frequency from 1.47 +/- 0.13 ml X min-1 X g-1 (mean +/- SE) at an average of 18/min to 2.65 +/- 0.16 ml X min-1 X g-1 at 74/min (P less than 0.01) with a duty cycle of 0.25 and from 1.32 +/- 0.19 ml X min-1 X g-1 at an average of 15/min to 1.96 +/- 0.15 ml X min-1 X g-1 at 80/min (P less than 0.02) with a duty cycle of 0.75. At higher contraction frequencies diaphragmatic blood flow did not increase further at both duty cycles. In addition, diaphragmatic blood flow was higher with a duty cycle of 0.25 than 0.75 at all contraction frequencies. We conclude that frequency of contraction is a major determinant of diaphragmatic blood flow and that high duty cycle impedes diaphragmatic blood flow.     

Renal function studies in an experimental model of papillary necrosis in the rat

Twenty four hours after i.v. injection of bromoethylamine-hydrobromide (BEA) in rats, a uniform papillary necrosis is observed. The present study investigates the renal functional and the papillary haemodynamics in response to acute volume expansion (12% of body weight) in this model. Renal function studies were performed in hydropenic and volume expanded sham- or BEA-injected rats. In hydropenic normal animals a GFR of 1.97 +/- 0.14 ml/min, an urinary osmolarity (UOsm) of 1 011 +/- 94.5 mOsm/kg and a fractional sodium excretion (FENa) of 0.18 +/- 0.026% were obtained. In contrast, BEA-treated hydropenic animals showed a lower GFR (1.16 +/- 0.14 ml/min), UOsm (469 +/- 30.31 mOsm/kg) and a higher FENa (0.37 +/- 0.06%). In volume expansion a similar UOsm and FENa were obtained in both groups. The papillary plasma flow (PPF) was measured in each of the experimental groups by the albumin accumulation technique. The mean value in hydropenic normal animals was 50.65 +/- 2.12 m 100 g-1 min-1 and increased to 66.02 +/- 2.00 ml 100 g-1 min-1 after volume expansion (P less than 0.001). In BEA rats the PPF was 58.86 +/- 2.33 ml 100 g-1 min-1 in hydropenia (P less than 0.01 vs. control animals) and remained unchanged after volume expansion. Thus, during hydropenia, BEA-induced papillary necrosis results with a salt wasting state and an urinary concentration defect. After volume expansion no disturbance in sodium excretion capacity was observed. These results are compatible with the nephron-heterogeneity concept in the regulation of sodium excretion. The histological lesions cannot be explained by a decreased renal papillary plasma flow.     

Distribution of blood flow in muscles of miniature swine during exercise

The purpose of this study was to determine how the distribution of blood flow within and among the skeletal muscles of miniature swine (22 +/- 1 kg body wt) varies as a function of treadmill speed. Radiolabeled microspheres were used to measure cardiac output (Q) and tissue blood flows in preexercise and at 3-5 min of treadmill exercise at 4.8, 8.0, 11.3, 14.5, and 17.7 km/h. All pigs (n = 8) attained maximal O2 consumption (VO2max) (60 +/- 4 ml X min-1 X kg-1) by the time they ran at 17.7 km/h. At VO2max, 87% of Q (9.9 +/- 0.5 l/min) was to skeletal muscle, which constituted 36 +/- 1% of body mass. Average total muscle blood flow at VO2max was 127 +/- 14 ml X min-1 X 100 g-1; average limb muscle flow was 135 +/- 17 ml X min-1 X 100 g-1. Within the limb muscles, blood flow was distributed so that the deep red parts of extensor muscles had flows about two times higher than the more superficial white portions of the same muscles; the highest muscle blood flows occurred in the elbow flexors (brachialis: 290 +/- 44 ml X min-1 X 100 g-1). Peak exercise blood flows in the limb muscles were proportional (P less than 0.05) to the succinate dehydrogenase activities (r = 0.84), capillary densities (r = 0.78), and populations of oxidative (slow-twitch oxidative + fast-twitch oxidative-glycolytic) fiber types (r = 0.93) in the muscles. Total muscle blood flow plotted as a function of exercise intensity did not peak until the pigs attained VO2max, although flows in some individual muscles showed a plateau in this relationship at submaximal exercise intensities. The data demonstrate that blood flow in skeletal muscles of miniature swine is distributed heterogeneously and varies in relation to fiber type composition and exercise intensity.     

Cerebral blood flow during submaximal and maximal dynamic exercise in humans

Cerebral blood flow (CBF) in humans was measured at rest and during dynamic exercise on a cycle ergometer corresponding to 56% (range 27-85) of maximal O2 uptake (VO2max). Exercise bouts were performed by 16 male and female subjects, lasted 15 min each, and were carried out in a semisupine position. CBF (133Xe clearance) was expressed as the initial slope index (ISI) and as the first compartment flow (F1). CBF at rest [ISI, 58 (range 45-73); F1, 76 (range 55-98) ml.100 g-1.min-1] increased during exercise [ISI to 79 (57-94) and F1 to 118 (75-164) ml.100 g-1.min-1, P less than 0.01]. CBF did not differ significantly between work loads from 32 (24-33) to 86% (74-96) of VO2max (n = 10). During exercise, mean arterial pressure increased from 84 (60-100) to 101 (78-124) Torr (P less than 0.01) and PCO2 remained unchanged [5.1 (4.6-5.6) vs. 5.4 (4.4-6.3) kPa, n = 6]. These results demonstrate a median increase of 31% (0-87) in CBF by ISI and a median increase of 58% (0-133) in CBF by F1 during dynamic exercise in humans.     

Intrapulmonary distribution of bronchial blood flow after moderate smoke inhalation

The systemic blood flow to the airways of the left lung was determined by the radioactive microsphere technique before and 17 h after smoke inhalation in six conscious sheep (smoke group) and six sheep insufflated with air alone (sham group). Smoke inhalation caused a sixfold increase in systemic blood flow to the lower trachea (baseline 10.6 +/- 1.7 vs. injury 60.9 +/- 16.1 ml.min-1.100 g-1) and an 11- to 14-fold increase to the intrapulmonary central airways (baseline range 9.5 +/- 1.9 to 13.5 +/- 3.7 ml.min-1.100 g-1 vs. injury 104.6 +/- 32.2 to 187.3 +/- 83.6 ml.min-1.100 g-1). There was a trend for this hyperemic response to be greater as airway diameter decreased from the trachea to 2-mm-diam central airways. In airways smaller than 2 mm, the hyperemic response appeared to diminish. The total systemic blood flow to whole lung is predominantly to small peripheral airways and showed no significant increase from its baseline level of 17.5 +/- 3.7 ml.min-1.100 g-1 in the lung homogenate. Occlusion of the bronchoesophageal artery decreased central airway blood flow 60-80% and peripheral airway blood flow 40-60% in both the sham and the smoke groups.     

Dopamine production by the isolated perfused rat kidney

We used isolated perfused rat kidneys to examine dopamine (DA) production and its relation to renal function. Both innervated and chronically surgically denervated kidneys perfused with a solution containing neither albumin nor tyrosine, excreted 0.2 +/- 0.1 ng DA X min-1 X g wet weight-1 during the 10-min collection period between 30 and 40 min after starting perfusion. When perfused with 6.7% albumin, without tyrosine, innervated kidneys excreted 1.0 +/- 0.06 ng DA X min-1 X g-1 and denervated kidneys excreted 1.0 +/- 0.07 DA X min-1 X g-1. When 0.03 mM tyrosine was included in the albumin perfusate, innervated kidneys excreted 1.2 +/- 0.1 ng DA X min-1 X g-1 (p less than 0.1). Under these conditions DA excretion continued for at least 100 min at which time it was 0.6 ng X min-1 X g-1 and 86 ng/g kidney weight had been excreted. Denervated kidneys perfused with albumin + tyrosine excreted 0.9 +/- 0.13 ng DA X min-1 X g-1. Renal stores of free DA, conjugated DA, and dihydroxyphenylalanine (DOPA) could have provided at the most 30 ng/g of DA. Carbidopa inhibited DA excretion completely. DA excretion did not correlate with renal vascular resistance, inulin clearance, or fractional sodium excretion. In summary, nonneural tissue in isolated perfused kidneys produced DA at the same rate as denervated kidneys in vivo. Less than one-third of the DA produced by isolated kidneys could have come from intrarenal stores of DOPA, free DA, and conjugated DA; the rest was synthesized from unknown precursors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of xanthine oxidase and neutrophils in ischemia-reperfusion injury in rabbit lung

This study evaluated the effect of ischemia-reperfusion (I-R) on pulmonary capillary permeability in isolated rabbit lungs and the roles of xanthine oxidase (XO), aldehyde oxidase (AO), and neutrophils (PMN) in producing this lung injury. Effects of XO and AO were studied by inactivation with a tungsten-enriched diet (0.7 g/kg) and inhibition of XO by allopurinol (100 microM) or AO by menadione (3.5 microM). PMN effects were studied by preventing endothelial adhesion with the monoclonal antibody IB4 (10 microM). Vascular permeability was evaluated by determining the capillary filtration coefficient (Kf,c) measured before and after I-R in all experimental conditions. Reperfusion after 2 h of ischemia significantly increased pulmonary capillary permeability (Kf,c changed from 0.096 +/- 0.014 to 0.213 +/- 0.025 ml.min-1. cmH2O-1.100 g-1), and this increase was blocked by the addition of catalase (50,000 U) at reperfusion (baseline Kf,c was 0.125 +/- 0.023 and 0.116 +/- 0.014 ml.min-1.cmH2O-1.100 g-1). XO inactivation with the tungsten-supplemented diet and XO inhibition with allopurinol prevented the Kf,c increase observed after I-R (0.183 +/- 0.030 to 0.185 +/- 0.033 and 0.126 +/- 0.018 to 0.103 +/- 0.005 ml.min-1.cmH2O-1.100 g-1). Inhibition of AO had no effect on I-R injury (Kf,c 0.108 +/- 0.011 to 0.167 +/- 0.014 ml.min-1.cmH2O-1.100 g-1). Preventing PMN adhesion resulted in significant attenuation of the change in Kf,c associated with I-R (0.112 +/- 0.032 to 0.090 +/- 0.065 ml.min-1.cmH2O-1.100 g-1). We conclude that XO and PMN adherence, but not AO, are involved in the increased capillary permeability associated with I-R.