Cerebral Blood Flow and Oxidative Metabolism in Conscious Fischer-344 Rats of Different Ages

Abstract: The cerebral metabolic rates for O₂ and for glucose were measured in conscious, fasted male Fischer-344 rats at the ages of 3, 12, and 24 months, and cerebral blood flow was determined with ¹⁴C-iodoantipyrine. The metabolic rates for oxygen and glucose were obtained by multiplying blood flow by the O₂ and glucose concentration differences, respectively, between blood in the femoral artery and in the superior sagittal sinus. Mean cerebral blood flow and the metabolic rates for oxygen and glucose did not differ significantly (p > 0.05) between 3 and 12 or between 12 and 24 months. Nor did the arteriovenous differences for O₂ and for glucose change significantly with age. Because the superior sagittal sinus drains blood mainly from the cerebral cortex, the results indicate that average cerebral cortical oxidative metabolism, and the coupling ratios between the cerebral metabolic rate for oxygen and cerebral blood flow and between the cerebral metabolic rate for glucose and cerebral blood flow, do not change significantly with age in the Fischer-344 rat.     

Effect of metabolic acidosis on fetal renal haemodynamics

The effects of metabolic acidosis on renal haemodynamics and intrarenal blood flow distribution was studied in two groups of chronically-catheterized fetal sheep between 122 and 130 days of gestation. One group (experimental group) was studied before and during infusion of 1.1 M lactic acid, whereas the second group received on infusion of dextrose 5% (w/v) in water and served as a time-control group. Infusion of lactic acid for 2 h decreased fetal arterial pH from 7.37 +/- 0.01 to 6.95 +/- 0.02, did not change arterial blood pressure, but produced a significant decrease in renal blood flow (41 +/- 3 to 33 +/- 7 ml/min, P less than 0.05) and a significant increase in renal vascular resistance (1.42 +/- 0.13 to 1.86 +/- 0.18 mmHg/ml/min, P less than 0.05). Moreover, a significant decline in cortical blood flow was also observed in the outer portion of the renal cortex during lactic acidosis. Taken together, these results suggest that metabolic acidosis produces significant changes in fetal renal haemodynamics not associated with changes in arterial blood pressure.     

Ovine fetal electrocortical activity and regional cerebral blood flow

Fetuses of 12 near-term sheep were prepared for microsphere determination of cerebral blood flow. Experiments were performed 5 days postsurgery. The regional blood flows were measured in successive high (HV), low (LV) and high voltage electrocorticographic states. Comparisons were made between the observations made in the LV and averaged flanking HV cycles. Total cerebral blood flow was 95 +/- 8, 119 +/- 11 and 100 +/- 9 ml/min/100 g in HV, LV and HV, respectively. Low voltage electrocortical activity increased average cerebral blood flow by 22% (P less than 0.01). Significant changes were seen in all regions except the occipital cortex. The maximum change was observed in the thalamus in which the flows were 152 +/- 23, 243 +/- 35 and 138 +/- 20 ml/min/per 100 g tissue, respectively. The increase was 68% (P less than 0.001). The percent changes seen in the cerebrum are as follows: Frontal grey + 18%, frontal white + 22%, parietal white + 22%, temporal + 18%. A + 17% change was seen in the cord (P less than 0.03). It is concluded that in low voltage electrocortical activity all of the brain, except the occipital region, shows an increase in cerebral blood flow. This is probably secondary to a variance in cerebral activity. This preparation may be useful in localizing function in the fetal brain.     

Cerebral blood flow in intoxicated newborn piglets

Ethanol exposure in the neonatal period causes impaired brain growth and altered adult behaviour in rats. One possible mechanism may be altered cerebral perfusion caused by ethanol intoxication. We assessed the effects of ethanol on cerebral blood flow and its autoregulation in 2-day-old piglets. Piglets received ethanol (1.4 g/kg) or an equivalent volume of dextrose 5% in water over 30 min. One hour later, cerebral blood flow was measured using the microsphere technique at resting, elevated, and decreased mean arterial blood pressure. Ethanol-treated piglets had total cerebral blood flows of 88 +/- 14, 82 +/- 10, and 82 +/- 12 mL X 100 g-1 X min-1 (mean +/- SE) at mean arterial blood pressures of 12.4 +/- 1.1, 15.7 +/- 1.5, and 8.2 +/- 0.9 kPa. Corresponding values in control piglets were 82 +/- 14, 78 +/- 4, and 82 +/- 7 mL X 100 g-1 X min-1 at mean arterial blood pressures of 10.5 +/- 1.5, 14.0 +/- 1.2, and 7.7 +/- 1.1 kPa. At resting arterial blood pressures, regional blood flows to basal ganglia, cortex, brainstem, and cerebellum in ethanol-treated piglets were 123 +/- 21, 90 +/- 16, 94 +/- 17, and 77 +/- 12 mL X 100 g-1 X min-1, respectively. Corresponding regional blood flows for the control piglets were 118 +/- 16, 85 +/- 15, 76 +/- 16, and 76 +/- 16 mL X 100 g-1 X min-1. Blood flow to basal ganglia was greater than to other brain regions in both ethanol-treated and control piglets (P less than 0.01).(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.     

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)     

Down-Regulation of AMPA Glutamate Receptors Reduces Cerebrocortical Metabolic Response to Stimulation

We tested the hypothesis that chronic stimulation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) glutamate receptors with an agonist causes down-regulation of the receptor protein and a decrement in basal and/or stimulated cerebral O2 consumption. Male Wistar rats were intradurally infused with 10 microM AMPA by an osmotic pump at a rate of 1 microl/h for 6 days. As a result, the specific binding of (S)-[3H]-5-fluorowillardiine to AMPA receptors in the cerebral cortex decreased 46% from 2.7 +/- 0.3 to 1.5 +/- 0.6 (density units). Under isoflurane anesthesia and after topical stimulation to the right cerebral cortex with 10(-3) M AMPA, cerebral blood flow (14C-iodoantipyrine method) and O2 consumption (cryomicrospectrophotometrically determined) were determined in control and down-regulated rats. Down-regulation of AMPA receptors did not alter basal O2 consumption. In control, after agonist stimulation, the O2 consumption in the ipsilateral cortex increased by 34%, (4.7 +/- 0.5 ml O2 x min(-1) x 100 g(-1) compared to 3.5 +/- 0.4 in the contralateral cortex). In the down-regulated rats, the O2 consumption did not significantly increase (4.0 +/- 1.5 ml O2 x min(-1) x 100 g(-1) compared to 3.3 +/- 1.7 in the contralateral cortex) after AMPA. In conclusion, following chronic simulation, AMPA receptors underwent down-regulation, but such down-regulation did not alter basal cerebrocortical blood flow or O2 consumption. AMPA down-regulation reduced the agonist stimulated increase in cortical O2 consumption.     

Fetal pulmonary vasodilation and vasoreactivity during metabolic acidaemia

We studied the pulmonary vascular response to progressive metabolic acidaemia and to an abrupt increase in oxygen tension during metabolic acidaemia in 8 chronically-prepared fetal sheep. Left pulmonary artery blood flow was measured by electromagnetic flow transducer. Two and a half hour infusion of NH4Cl into the fetal inferior vena cava caused pH to fall to 6.94 +/- 0.01 from 7.37 +/- 0.01 (P less than 0.001). During this period of progressive metabolic acidaemia, left pulmonary artery blood flow increased from a baseline value of 60 +/- 8 to 105 +/- 14 ml.min-1 (P less than 0.002). Pulmonary artery pressure did not change significantly and calculated pulmonary vascular resistance fell indicating fetal pulmonary vasodilation. PO2 rose significantly (19.8 +/- 0.7 to 24.1 +/- 1.8 torr; P less than 0.03) and oxygen saturation fell (54.6 +/- 2.8% to 38.9 +/- 3.5%; P less than 0.001) confirming a rightward shift of the oxyhaemoglobin dissociation curve. During acidaemia, administration of 100% oxygen to the ewe further increased fetal PO2 to 37.9 +/- 2.3 torr within 10 min (P less than 0.001) and this increase in PO2 was accompanied by an increase in left pulmonary artery blood flow (P less than 0.001), a fall in pulmonary artery pressure (P less than 0.03) and a decrease in pulmonary vascular resistance (P less than 0.001) indicating further vasodilation. The response of the fetal pulmonary circulation to a 2-h period of increased oxygen tension was qualitatively similar in acidaemic and non-acidaemic fetuses. We conclude that the progressive metabolic acidaemia imposed by these experimental conditions increases pulmonary blood flow likely through an increase in fetal PO2 and that metabolic acidaemia does not block the normal vasodilatory response to an increase in oxygen tension.     

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)     

Difference in glutamate release between retina and cerebral cortex following ischemia

The difference in ischemic tolerance between the retina and cerebral cortex may be attributable to a difference in glutamate release during ischemia. Glutamate release in the retina and the cerebral cortex was compared in rats. A dialysis electrode for real-time glutamate measurement was perfused with L-glutamate oxidase, and the current evoked between two voltage-clamped electrodes was detected. Two electrodes were implanted in the retina through the choroid and cerebral cortex in 12 anesthetized rats, each mounted on a stereotaxic frame. Global ischemia was induced by ligation on both carotid arteries and hypotension was induced by blood withdrawal. Under control conditions, the glutamate concentration in the retina was 164 +/- 231 (mean +/- standard deviation) microM, being significantly higher (P < 0.05) than that in the cerebral cortex (83 +/- 105 microM). In 10 of the 12 animals, the glutamate concentration in the retina decreased to a minimum of 134 +/- 149 microM (P < 0.01, compared with the value for the cerebral cortex), but that in the cortex increased to 410 +/- 305 microM (averaged highest value). Immediately after the start of reperfusion, the glutamate concentration in the cortex decreased rapidly to 101 +/- 27 microM, but that in the retina increased gradually to almost the control level (148 +/- 204 microM). In the other two animals, the glutamate concentration remained unchanged. In conclusion, glutamate release in the retina does not proceed as rapidly as that in the cerebral cortex during 20 min of ischemia, and in fact decreases. This opposite trend shown by the two organs may be due to the slow depletion rate of ATP in the retina. This may explain the differing neuronal tolerance to ischemia in these two organs.     

Mechanism for pressor response to nonexertional heating in the conscious rat

The purpose of this study was to determine the systemic hemodynamic mechanism(s) underlying the pressor response to nonexertional heat stress in the unrestrained conscious rat. After a 60-min control period [ambient temperature (Ta) 24 degrees C], male Sprague-Dawley rats (260-340 g) were exposed to a Ta of 42 degrees C until a colonic temperature (Tc) of 41 degrees C was attained. As Tc rose from control levels (38.1 +/- 0.1 degrees C) to 41 degrees C, mean arterial blood pressure (carotid artery catheter, n = 33) increased from 124 +/- 2 to 151 +/- 2 mmHg (P less than 0.05). During this period, heart rate increased (395 +/- 5 to 430 +/- 6 beats/min, P less than 0.05) and stroke volume remained unchanged. As a result, ascending aorta blood flow velocity (Doppler flow probe, n = 8), used as an index of cardiac output, did not change from control levels during heating, but there was a progressive Tc-dependent increase in systemic vascular resistance (+30% at end heating, P less than 0.05). This systemic vasoconstrictor response was associated with decreases in blood flow (-31 +/- 9 and -21 +/- 5%) and increases in vascular resistance (94 +/- 16 and 53 +/- 8%; all P less than 0.05) in the superior mesenteric and renal arteries (n = 8 each) and increases in plasma norepinephrine (303 +/- 37 to 1,237 +/- 262 pg/ml) and epinephrine (148 +/- 28 to 708 +/- 145 pg/ml) concentrations (n = 12, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Low-intensity training produces muscle adaptations in rats with femoral artery stenosis.

The effectiveness of a mild-intensity exercise program to induce adaptations within skeletal muscle of animals with peripheral arterial insufficiency was evaluated using an isolated perfused hindlimb preparation at a muscle blood flow similar to the peak found in vivo. Adult rats were subjected to bilateral femoral artery stenosis sufficient to limit peak blood flow during exercise but not alter resting blood flow. Stenosed-trained (Sten-Trained) rats walked on a treadmill at an easily achieved speed (20 m/min with a 15% grade) 5 days wk. Exercise tolerance improved from 10 min initially to 2 h/day. Non-stenosed-sedentary (Non-Sten-Sed) and stenosed-sedentary (Sten-Sed) animals were limited to cage activity. Oxygen delivery to the contracting muscles was similar among groups (7.0 +/- 0.4, 7.3 +/- 0.6, and 6.6 +/- 0.6 mumol.min-1.g-1 in Non-Sten-Sed, Sten-Sed, and Sten-Trained, respectively; n = 13 each). Force development was better maintained by Sten-Trained muscle (P less than 0.001) during a sequence of tetanic contraction conditions. Peak oxygen consumption was greater (P less than 0.05) in the Sten-Trained (5.23 +/- 0.34 mumol.min-1.g-1) than in Non-Sten-Sed (4.08 +/- 0.35) and Sten-Sed (4.34 +/- 0.37) rats. The increased peak oxygen extraction (P less than 0.05) by the muscle of the Sten-Trained rats (82.5 +/- 7.1% of oxygen inflow vs. 58.7 +/- 4.7 and 57.4 +/- 5.0%, respectively) was probably related to the increased muscle capillarity and mitochondrial enzyme activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduced cholecystokinin in the brain of LEC rats with hepatic encephalopathy.

Levels of cholecystokinin (CCK) immunoreactivity and distribution of CCK immunoreactive cells were studied in the cerebral cortex of LEC (Long Evans Cinnamon) rats with hepatic encephalopathy. CCK immunoreactivity in water extract of cerebral cortex of LEC rats with hepatic encephalopathy (n = 7) was 41.5 +/- 2.6 (mean +/- S.E.M. pmol/g wet wt.) and that of LEC rats without encephalopathy (n = 8) was 67.1 +/- 6.9, the difference being significant (P less than 0.01). CCK immunoreactive cells assessed by immunohistochemistry were also markedly decreased in the cortex of LEC rats with hepatic encephalopathy of stage IV. Thus, CCK reduction was observed in the cerebral cortex of LEC rats with hepatic encephalopathy which are provided as a model for analysis of the pathogenesis of acute hepatic encephalopathy.     

Cariporide enables hemodynamically more effective chest compression by leftward shift of its flow-depth relationship

When given during closed-chest resuscitation, cariporide (4-isopropyl-methylsulfonylbenzoyl-guanidine methanesulfonate; a selective inhibitor of the Na(+)/H(+) exchanger isoform-1) enables generation of viable perfusion pressures with less depth of compression. We hypothesized that this effect results from greater blood flows generated for a given depth of compression. Two series of 14 rats each underwent 10 min of untreated ventricular fibrillation followed by 8 min of chest compression before defibrillation was attempted. Compression depth was adjusted to maintain an aortic diastolic pressure (ADP) between 26 and 28 mmHg in the first series and between 36 and 38 mmHg in the second series. Within each series, rats were randomized to receive cariporide (3 mg/kg) or NaCl (0.9%; control) before chest compression was started. Blood flow was measured using 15-mum fluorescent microspheres. Less depth of compression was required to maintain the target ADP when cariporide was present in both series 1 (13.6 +/- 1.2 vs. 16.6 +/- 1.2 mm; P < 0.001) and series 2 (15.3 +/- 1.0 vs. 18.9 +/- 1.5 mm; P < 0.001). Despite less compression depth, the cardiac index in cariporide-treated rats was comparable to control rats in series 1 (11.1 +/- 0.7 vs. 11.3 +/- 1.4 ml.min(-1).kg(-1); P = not significant) but higher in series 2 (15.5 +/- 2.3 vs. 9.9 +/- 1.4 ml.min(-1).kg(-1); P < 0.05). Increases in compression depth (from series 1 to series 2) increased myocardial, cerebral, and adrenal blood flow in cariporide-treated rats. We conclude that cariporide enhances the efficacy of closed-chest resuscitation by leftward shift of the flow-depth relationship.     

Changes in regional cerebral blood flow distribution during postexercise hypotension in humans.

This investigation compared patterns of regional cerebral blood flow (rCBF) during exercise recovery both with and without postexercise hypotension (PEH). Eight subjects were studied on 3 days with randomly assigned conditions: 1) after 30 min of rest; 2) after 30 min of moderate exercise (M-Ex) at 60-70% heart rate (HR) reserve during PEH; and 3) after 30 min of light exercise (L-Ex) at 20% HR reserve with no PEH. Data were collected for HR, mean blood pressure (MBP), and ratings of perceived exertion and relaxation, and rCBF was assessed by use of single-photon-emission computed tomography. With the use of ANOVA across conditions, there were differences (P < 0.05; mean +/- SD) from rest during exercise recovery from M-Ex (HR = +12 +/- 3 beats/min; MBP = -9 +/- 2 mmHg), but not from L-Ex (HR = +2 +/- 2 beats/min; MBP = -2 +/- 2 mmHg). After M-Ex, there were decreases (P < 0.05) for the anterior cingulate (-6.7 +/- 2%), right and left inferior thalamus (-10 +/- 3%), right inferior insula (-13 +/- 3%), and left inferior anterior insula (-8 +/- 3%), not observed after L-Ex. There were rCBF decreases for leg sensorimotor regions after both M-Ex (-15 +/- 4%) and L-Ex (-12 +/- 3%) and for the left superior anterior insula (-7 +/- 3% and -6 +/- 3%), respectively. Data show that there are rCBF reductions within specific regions of the insular cortex and anterior cingulate cortex coupled with a postexercise hypotensive response after M-Ex. Findings suggest that these cerebral cortical regions, previously implicated in cardiovascular regulation during exercise, may also be involved in PEH.     

Reductions in blood pressure after acute exercise by hypertensive rats

Postexercise reductions in blood pressure at rest have been reported for hypertensive subjects. To determine whether post-exercise hypotension would occur in spontaneously hypertensive rats and to test the hypothesis that any reductions would result because of decreases in regional vascular resistances, hypertensive rats (n = 19) were instrumented with indwelling arterial catheters and Doppler probes to measure regional blood flows from the iliac, superior mesenteric, and renal arteries. Data were collected from animals who performed a 20- and a 40-min treadmill test at between 60 and 70% of their maximum O2 uptake. When the animals ran for 20 min, there was a pre- to postexercise drop in mean arterial pressure (MAP) from 158 +/- 3.6 to 150 +/- 3.6 mmHg (P less than 0.05), which was recorded 30 min after the exercise had ceased. The pre- to postexercise reduction in MAP after 40 min of treadmill running was from 154 +/- 3.1 to 138 +/- 3.0 mmHg (P less than 0.05) as recorded 30 min postexercise. Postexercise heart rate was significantly lower after the 40-min exercise bout, from a preexercise mean of 351 +/- 3 beats/min to 324 +/- 5 beats/min 30 min after the treadmill had stopped. Surprisingly, marked pre- to postexercise reductions in regional vascular resistance were not observed in either the iliac, superior mesenteric, or renal vascular beds. These data demonstrated the existence of postexercise hypotension in genetic hypertensive rats and suggested that reductions in cardiac output were the primary hemodynamic mechanism for this finding.     

The role of alpha-adrenergic receptors in the vasoconstrictor response induced by indomethacin in the kidney.

The effect of indomethacin, an inhibitor of prostaglandin (PG) synthesis, was studied on the renal circulation, Na+ and water excretion in anaesthesized dogs during alpha-receptor inhibition. Indomethacin decreased cortical blood flow (CBFcontr, 454 +/- 142; CBFindo, 332 +/- 51 ml per min per 100 g; p less than 0.02) as well as medullary blood flow (OMBFcontr, 339 +/- 95; OMBFindo, 183 +/- 46 ml per min per 100 g; p less than 0.001), salt and water excretion, further it caused a shift in the intrarenal blood flow distribution toward the cortex. Alpha-blockade prevented the indomethacin-induced vasoconstriction in the cortex (CBF alpha inhibition + indo, 455 +/- 76 ml per min per 100 g) but not in the medullar (OMBF alpha inhibition + indo, 259 +/- 102 ml per min per 100 g, p less than 0.05). Alpha-blockade failed to prevent the indomethacin-induced antidiuresis, antinatriuresis and the intrarenal blood flow redistribution. GFR remained unaffected in all three series of studies. Our experimental findings are in line with the presumption that alpha-receptors are involved in the renal circulatory changes caused by indomethacin, probably as a result of an enhanced NE release during the inhibition of PG production. A NE--PG feed back mechanism is suggested in the regulation of renal circulation. The reduction of salt and water output induced by indomethacin appears to be independent of the alterations in renal haemodynamics, and seems rather to be the result of enhanced Na+ reabsorption, predominantly at the distal segment of the nephron, in the absence of PG, and/or a direct action of indomethacin.     

Effects of calcitonin gene-related peptide on renal blood flow in the rat

The effects of alpha-rat calcitonin gene-related peptide (alpha-rCGRP) on systemic and renal hemodynamics and on renal electrolyte excretion were examined in normal anesthetized rats. In one group of rats (n = 7), infusions of alpha-rCGRP at doses of 10, 50, 100, and 500 ng/kg/min for 15 min each produced dose-related and significant decreases in mean arterial pressure from a control of 130 +/- 3 mm Hg to a maximal depressor response of 91 +/- 2 mm Hg. During the first three doses of alpha-rCGRP, renal blood flow progressively and significantly increased from a control of 5.0 +/- 0.3 ml/min to a peak level of 6.3 +/- 0.3 ml/min achieved during the 100 ng/kg/min infusion. With the highest infusion rate of 500 ng/kg/min, renal blood flow fell below the control level to 4.5 +/- 0.2 ml/min (P less than 0.05). The responses in renal blood flow and mean arterial pressure were associated with reductions in renal vascular resistance. After cessation of alpha-rCGRP infusions, arterial pressure, renal blood flow, and renal vascular resistance gradually returned toward the baseline values. In another group of rats (n = 9), infusion of alpha-rCGRP for 30 min at 100 ng/kg/min produced a significant reduction in urinary sodium excretion from 0.28 +/- 0.06 to 0.14 +/- 0.5 muEq/min (P less than 0.05). Urine flow and urinary potassium excretion also appeared to decrease, but the changes were not significantly different (P greater than 0.05) from their respective baselines. These results demonstrate that alpha-rCGRP is a potent and reversible hypotensive and renal vasodilatory agent in the anesthetized rat. The data also suggest that alpha-rCGRP may have significant effects on the excretory function of the kidney.     

OXIDATIVE METABOLISM OF THE CEREBRAL CORTEX OF THE RAT IN SEVERE INSULIN-INDUCED HYPOGLYCAEMIA

—Measurements were made of organic phosphates, carbohydrate substrates, amino acids and ammonia in the cerebral cortex, as well as of cerebral blood flow and of cerebral metabolic rate for oxygen and glucose in rats that developed an isoelectric EEG pattern (‘coma’) during insulin-induced hypoglycaemia. The results were compared to those obtained in control animals, as well as in hypoglycaemic animals with an EEG pattern of slow waves and polyspikes. In animals with slow waves and polyspikes, there was a decrease in all citric acid cycle intermediates except succinate and oxaloacetate, and a decrease in the pool size of intermediates. In animals that had an isoelectric EEG for 5–15 min, there were further decreases in citrate, isocitrate, α-ketoglutarate, malate and fumarate, but since the concentration of succinate (and oxaloacetate) increased, the pool size remained the same. In isoelectric animals, the results revealed extensive utilization of amino acids by both transamination and deamination reactions. However, since glycogen had disappeared and the amino acid pattern was constant after the first 5 min of isoelectric EEG, further oxidation must have occurred at the expense of non-carbohydrate, non-amino acid substrates. There were two- to three-fold increases in cerebral blood flow in animals with slow waves and polyspikes and in animals with isoelectric EEG, and no decrease in the cerebral metabolic rate for oxygen. Since less than half of the oxygen consumption could be accounted for in terms of glucose extraction, the data indicate that severe hypoglycaemia is associated with extensive oxidation of endogenous substrates other than carbohydrates and free acids.     

Cerebral artery responses to pressure and flow in uremic hypertensive and spontaneously hypertensive rats

Impaired cerebral blood flow autoregulation is seen in uremic hypertension, whereas in nonuremic hypertension autoregulation is shifted toward higher perfusion pressure. The cerebral artery constricts in response to a rise in either lumen pressure or flow; we examined these responses in isolated middle cerebral artery segments from uremic Wistar-Kyoto rats (WKYU), normotensive control rats (WKYC), and spontaneously hypertensive rats (SHR). Pressure-induced (myogenic) constriction developed at 100 mmHg; lumen flow was then increased in steps from 0 to 98 microl/min. Some vessels were studied after endothelium ablation. Myogenic constriction was significantly lower in WKYU (28 +/- 2.9%) compared with both WKYC (39 +/- 2.5%, P = 0.035) and SHR (40 +/- 3.1%, P = 0.018). Flow caused constriction of arteries from all groups in an endothelium-independent manner. The response to flow was similar in WKYU and WKYC, whereas SHR displayed increased constriction compared with WKYU (P < 0.001) and WKYC (P < 0.001). We conclude that cerebral myogenic constriction is decreased in WKYU, whereas flow-induced constriction is enhanced in SHR.