Effect of hypoxia on percent of arteriolar and capillary beds perfused in the rat brain.

The effects of moderate and severe hypoxia on quantitative regional morphometric indexes of the total and perfused arteriolar and capillary network were studied in the rat brain to determine whether diffusion distances were reduced in hypoxia. Fluorescein isothiocyanate (FITC)-labeled dextran was injected into the femoral vein of conscious control and hypoxic rats. After 20 s, the animal was decapitated and the head was frozen in liquid N2. Sections from eight brain regions were photographed to detect the perfused microvessels and then stained for alkaline phosphatase to visualize the total vascular network. There were significant increases in percent perfused arteriolar and capillary morphology between the two groups of hypoxic animals and control animals. In control rats, the percent of capillaries perfused averaged 45.6 +/- 0.6% (mean +/- SE). In moderate hypoxia 63.4 +/- 1.8% of the vessels were perfused and in severe hypoxia 89.4 +/- 0.1% were perfused. The percentage of arterioles perfused changed similarly. There were no significant differences in any index of total or percent perfused arteriolar or capillary morphometry among the regions within any group. During severe hypoxia, a greater percentage of the capillary reserves was utilized. These results demonstrate a uniform response to hypoxia in the capillary and arteriolar network of the conscious rat brain.

Effect of hemorrhage on regional morphometric indexes of cerebral capillarity.

This study was performed to determine whether the brain can increase the number of perfused capillaries and arterioles supplying it regionally during hemorrhage. This was done using a technique to simultaneously determine total and perfused regional arteriolar and capillary morphology. Conscious Long-Evans rats served as unbled controls or were bled 65 mmHg or to 40-45 mmHg and stabilized for 30 min. Regional cerebral blood flow was determined using [14C]iodoantipyrine in half of these animals and fluorescein isothiocyanate-dextran was injected in the other half for determination of perfused cerebral microvascular morphometric indexes. The total microvasculature was labeled postmortem via an alkaline phosphatase stain. Regional cerebral blood flow was significantly increased in animals bled to 65 mmHg. During hemorrhage to 40-45 mmHg, cerebral blood flow was reduced 50% (from 59 +/- 28 to 26 +/- 11 ml X min-1 X 100 g-1, mean +/- SD) with no regional redistribution. For all treatments, total capillary density ranged from 400 to 500 capillaries/mm2, and in controls 47% were perfused. Animals bled to 65 mmHg did not mobilize their unperfused microvascular reserve even though they showed a slight tendency to do so. During hemorrhage to 40-45 mmHg, this percent increased significantly to 57% with the largest increase occurring in the pons. Approximately 51% of arterioles were perfused in controls and this was not different compared with the percent perfused during hemorrhage. Despite the overall lack of mobilization of unperfused arterioles, some regions within the brain significantly mobilized their reserves with severe hemorrhage, e.g., hippocampus (78%), hypothalamus (67%), and medulla (73%).(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in perfused capillary morphometry in awake vs anesthetized brain.

This study quantitatively compared various indices of perfused capillary morphometry in pentobarbital-anesthetized and awake rat brains. We hypothesized that barbiturate anesthesia would reduce intraregional differences in percent perfused capillary volume and surface area. A high-molecular-weight FITC-labeled Dextran was injected intravenously into awake or barbiturate-anesthetized (50 mg/kg i.p.) rats. After 20 s, the animal was decapitated and the head frozen in liquid N2. Nine brain regions were isolated and mounted in a microtome cryostat. Sections, 2 microns thick, were photographed with a fluorescent microscope to detect the perfused capillaries. The sections were stained for alkaline phosphatase to visualize the total capillary network. Standard morphometric techniques were employed to determine the total and perfused volume (Vv), surface area (Sv) per mm3 and diameter (D) from the photographs. There were no significant differences in any index of total capillary morphometry among the regions in the anesthetized brain. Approximately half of the average total capillary bed was perfused and there were no significant differences in percent perfused Vv or Sv between awake and anesthetized brains. There were significant differences among the various brain regions in the perfused capillary bed of the awake rat. The percent perfused capillary Vv and Sv in the awake rat was significantly greater in the thalamus and anterior cortex than in other brain regions. In awake rats, the percent perfused capillary Vv ranged from 67.9 +/- 4.7% (mean +/- S.E.M.) in the thalamus to 26.1 +/- 4.3% in the posterior cortex. Thus, while the average percent perfused indices of capillary morphometry were not altered by anesthesia, regional differences in these indices among the examined regions were abolished with anesthesia.

Effect of withdrawal from chronic naltrexone on regional cerebral oxygen consumption in the cat.

This investigation determined the effects of withdrawal from chronic naltrexone administration on average and regional cerebral blood flow, oxygen extraction and oxygen consumption. The relationship between the effects of withdrawal from chronic administration of this opiate receptor antagonist, which may increase the numbers of postsynaptic opiate receptors, and these parameters was investigated. Fourteen adult mongrel cats were administered subcutaneous injections of 1 mg/kg naltrexone HCl or 1 ml 0.9% saline twice daily for 21 days. Two days later, regional cerebral blood flow was monitored using radioactively tagged microspheres. The animals were sacrificed and prepared for microspectrophotometric analysis of regional cerebral venous and arterial oxygen saturation. Regional cerebral oxygen consumption was calculated as the product of cerebral blood flow and oxygen extraction for each area examined. After 2 days of withdrawal from chronic naltrexone treatment, the blood pressure, heart rate and blood gas parameters did not change significantly when compared to saline-treated animals. Average cerebral blood flow was significantly increased from 47.9 +/- 3.4 ml/min/100 g (mean +/- S.E.M.) in the control group to 80.3 +/- 6.5 (ml/min/100 g) in the chronic naltrexone-treated group. Flow was significantly increased in the cortex, lenticulate nuclei, thalamus and pons. Neither average cerebral oxygen consumption, which increased slightly, nor cerebral oxygen extraction, which decreased slightly, were significantly altered by treatment. The distribution of flow among the examined regions was, however, significantly altered in the animals 2 days after receiving chronic naltrexone injections. These changes were not restricted to brain regions dense in neuronal opiate receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of locus coeruleus stimulation on regional cerebral oxygen consumption in the cat.

Regional cerebral oxygen consumption was determined during stimulation of the intra-axial noradrenergic pathway to quantitate the metabolic effects of this manipulation on cerebral oxygen extraction, cerebral blood flow (CBF) and its regional distribution. Regional arterial and venous oxygen saturation were examined microspectrophotometrically. Regional CBF was examined using radioactively tagged microspheres (15 +/- 3 microns in diameter). Oxygen consumption was calculated as the regional product of CBF and oxygen extraction. Bipolar concentric electrodes were stereotaxically implanted bilaterally in the locus coeruleus of alpha-chloralose anesthetized, artificially respired adult mongrel cats. The control group was killed after hemodynamic and CBF measurements were taken. The experimental group was sacrificed after these same measurements were taken before and during 10 min of bilateral locus coeruleus stimulation. The cats' heads were simultaneously sawed in 3 places and quickly frozen in liquid nitrogen-cooled propane. Systolic blood pressure was significantly increased during treatment. The heterogeneity of venous oxygen saturation was significantly reduced by stimulation. Average CBF and oxygen consumption were significantly decreased to 57% and 59% of control, respectively. Oxygen consumption was significantly reduced in the hypothalamus from 1.5 +/- 0.3 to 0.9 +/- 0.3 ml O2/min/100 g and from 3.5 +/- 0.9 to 1.2 +/- 0.4 ml O2/min/100 g in the cerebellum by treatment. Changes in the neuronal and/or synthetic cerebral activity produced regional decreases in cerebral oxygen consumption and secondarily altered CBF. These changes are probably due to interaction of the intraparenchymal noradrenergic pathways with other systems or processes in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of naltrexone on regional brain oxygen consumption in the cat.

Cerebral blood flow was measured by 141Ce and 85Sr microsphere accumulation, and oxygen saturation of arterial and venous blood within 9 regions of the brain was determined by microspectrophotometric measurement in chloralose anesthetized cats. Extraction was calculated as the difference between oxygen content of arterial and venous blood. Oxygen consumption was computed as the product of blood flow and oxygen extraction. Global and regional comparisons were made between 7 anesthetized cats and 7 anesthetized cats given 1 mg/kg naltrexone HCl i.v. Naltrexone treatment reduced total brain oxygen consumption by 48% at 20 min after intravenous injection. Analysis of the anterior and posterior cortex, lenticulate nuclei, hippocampus, thalamus, hypothalamus, medulla, pons and cerebellum indicated that the oxygen consumption of the pons and hypothalamus was reduced to the greatest extent. The decreased oxygen consumption reduced blood flow in the whole brain, and the pons. The oxygen supply to consumption ratio was not altered by naltrexone except in the hypothalamus where an even greater excess of oxygen was delivered. These observations are interpreted as indicating that opiate receptor blockade is associated with reduced brain metabolism and that this response is not restricted to regions of high opiate receptor concentration.

Effect of morphine on regional cerebral oxygen consumption and supply.

The effects of acute opiate receptor stimulation on regional cerebral oxygen consumption and blood flow were examined in 9 regions of the artificially respired, alpha-chloralose-anesthetized cat. Regional cerebral arterial and venous oxygen saturation were examined microspectrophotometrically and regional cerebral blood flow was monitored using radioactively tagged microspheres (15 +/- 3 micron in diameter). Oxygen consumption was calculated as the product of flow and oxygen extraction. In 8 cats, after control cerebral blood flow was obtained, and in 8 experimental cats after this same measurement was obtained before and 40 min after the administration of 1.5 mg/kg morphine sulfate; the cats' heads were simultaneously sawed in 3 places and quickly frozen in liquid nitrogen-cooled propane. Systolic and diastolic blood pressure were significantly decreased by treatment. The heterogeneity of venous oxygen saturation was significantly reduced by morphine. Average cerebral blood flow, oxygen extraction and consumption were not altered significantly by morphine. Regional cerebral blood flow in the hypothalamus, thalamic oxygen extraction, and hypothalamic and thalamic oxygen consumption were significantly decreased by treatment. This low dose of morphine may produce changes in cerebral neuronal and/or synthetic activity which lowers oxygen consumption in some regions rich in opiate receptors, while not affecting overall brain oxygen supply or consumption.

2,5-Dimethoxy-4-methylamphetamine (DOM)- a central component of its cardiovascular effects in rats; involvement of serotonin.

The hallucinogen DOM produces a rise in blood pressure and heart rate when injected into the cerebral ventricles of anesthetized rats. These effects are abolished in rats with transected spinal cords but are unaffected by prior treatment with hexamethonium. Central but not peripheral administration of the serotonin antagonist BOL reduces the response. Tachyphylaxis to the response develops rapidly and is accompanied by a decrease in the ability of 5-HT to induce a centrally mediated cardiovascular change. It is concluded that the response is mediated by direct stimulation of central 5HT receptors. Tachyphylaxis may be the result of irreversible binding of DOM to 5-HT receptors or to 5-HT receptor densensitization.

Immediate vs. long-term desmethylimipramine or chlorimipramine: effects on regional cerebral blood flow.

The immediate vs. long-term effects of desmethylimipramine (DMI) or chlorimipramine (CMI) on cerebral blood flow (CBF) were determined in 17 rabbit brain regions using radioactively tagged microspheres (15 +/- 3 micron in diameter). A single administration of either drug did not alter average CBF or its regional distribution 1 h later. Desmethylimipramine, an agent which primarily blocks re-uptake in presynaptic noradrenergic neurons, significantly increased CBF when administered daily for 21 consecutive days. The regional effects of DMI were not restricted to those areas dense in noradrenergic receptors. Flow was significantly increased in the hypothalamus, olfactory cortex, globus pallidus-putamen and midbrain. These flow increases probably reflect integrated cerebral metabolic, synthetic and/or functional activity which were associated with altered receptor sensitivity and/or number, rather than a direct cerebral vasodilatory effect. In contrast, CMI, a tricyclic antidepressant which primarily blocks presynaptic re-uptake in serotonergic neurons, and produced sedation, had little effect on CBF when administered daily for 21 consecutive days. The immediate effects of these agents on presynaptic re-uptake was not associated with altered CBF. The long-term antidepressant activity of these two agents on receptor sensitivity was probably not correlated with CBF, as evidenced by the lack of effect which CMI had on this parameter. Rather, CBF response appears to be correlated with the therapeutic spectrum of DMI which increases psychomotor activity in retarded depression.

Effects of phenoxybenzamine or N-methyl chlorpromazine on regional cerebral blood flow: comparison of central and peripheral alpha adrenergic receptor antagonism.

A comparison of the central and peripheral effects of alpha adrenergic receptor antagonism on regional cerebral blood flow was examined utilizing N-methyl chlorpromazine, an alpha adrenergic receptor antagonist which does not cross the blood-brain barrier, or phenoxybenzamine, an alpha adrenergic receptor antagonist which does enter the brain when injected systemically. Regional cerebral blood flow was monitored in 17 brain regions of 16 pentobarbital-anesthetized New Zealand White rabbits using radioactively tagged microspheres (15 +/- 3 micrometer in diameter). There was a significant overall difference in regional cerebral blood flow distribution in the control state. Although phenoxybenzamine had no significant effect on average global cerebral blood flow, this agent significantly redistributed flow among the various regions. Flow was significantly decreased in some cortical regions, the hippocampus and cerebellum, whereas flow was increased in the pons and substantia nigra. There were no significant effects of N-methyl chloropromazine on average global cerebral blood flow or its regional distribution. Central alpha adrenergic receptor blockade probably decreased regional cerebral blood flow in brain regions rich in neuronal alpha adrenoreceptors by decreasing regional metabolic and/or neuronal activity, while increasing metabolic and/or neuronal activity in the pons and substantia nigra via a positive feedback mechanism causing an increased flow rate in these regions. Peripheral alpha adrenergic receptor blockade appears to have little or no effect on regional cerebral blood flow.

Effect of stimulation of ansa subclavia on regional myocardial O2 supply and O2 consumption.

Cardiac sympathetic nerve stimulation produces increases in various indices of cardiac work and metabolism. To determine how these increased O2 demands are met, the effects of stimulation of the ansa subclavia on regional arterial and venous O2 saturation, O2 extraction, blood flow, and O2 consumption were determined in the hearts of 16 pentobarbital-anesthetized open-chest dogs. Microspectrophotometric observations of small regional arteries and veins in quick-frozen hearts to determine regional O2 extraction were combined with regional blood flow measurements with radioactive microspheres to determine regional myocardial O2 consumption by the Fick principle. Ansa subclavia stimulation produced significant increases in maximum rate of pressure development, heart rate, and blood pressure. Under control conditions, venous O2 saturation was lower and O2 extraction higher in the subendocardial compared with the subepicardial region of the left ventricle. While sympathetic stimulation did not alter the mean O2 extraction or venous O2 saturation values, there were no longer significant subepicardial vs. subendocardial differences in these parameters. Flow and O2 consumption in these regions increased proportionally during stimulation. The ratio of O2 supply to O2 consumption was not significantly altered by ansa subclavia stimulation, indicating that sympathetic stimulation produced no adverse effect in either region.

Effect of hypoxic-hypocapnia on cerebral regional oxygen consumption and supply.

The effect of hypoxic-hypocapnia (PaO2, 35 mm Hg, PaCO2, 22 mm Hg) on regional cerebral O2 consumption and supply was determined in 18 alpha-chloralose-anesthetized open-chest adult cats. Regional arterial and venous O2 saturation measurements determined by a microspectrophotometric technique were combined with regional flow measurements by the radioactive microsphere method to calculate cerebral regional O2 consumption. In a control group, after blood flow was determined with 15 +/- 3-microns-diameter microspheres, the heads were quick-frozen and measurements of flow and arterial-venous O2 differences were obtained from nine brain regions. In the experimental group, similar measurements were obtained after the induction of hypoxic-hypocapnia. Cerebral blood flow was significantly lower than the control group during hypocapnia. Cerebral blood flow increased with the induction of hypoxia. Arterial and venous O2 saturation decreased uniformly and to the same extent in the nine examined brain regions. This maintained the arterial-venous O2 saturation difference. O2 extraction and consumption were unaffected. The brain O2 supply/consumption ratio was maintained during hypoxic-hypocapnia indicating adequate and uniform protection in this condition throughout the brain.

Effect of ouabain on O2 supply/demand in normal and ischemic heart.

The effect of ouabain (15 microgram/kg) on subepicardial and sub-endocardial blood flow, oxygenation, and small-vessel blood content was studied in anesthetized open chest rabbits with hearts subjected to acute coronary occlusion. 10 minutes after occlusion, blood flow was 48% lower than in the control region. Ouabain lowered blood flow significantly in the non-occluded region and insignificantly in the occluded area. Small-vessel blood content, a measure of open capillary density, was unaffected by occlusion or ouabain. After occlusion, relative tissue PO2 fell to a greater extent in the affected subendocardium than the affected subepicardium. Ouabain, therefore, appears to be well tolerated in both the control and ischemic regions in terms of oxygen supply and consumption.