Assessment of cerebral blood flow and CO2 reactivity after controlled cortical impact by perfusion magnetic resonance imaging using arterial spin-labeling in rats

We measured CBF and CO2 reactivity after traumatic brain injury (TBI) produced by controlled cortical impact (CCI) using magnetic resonance imaging (MRI) and spin-labeled carotid artery water protons as an endogenous tracer. Fourteen Sprague-Dawley rats divided into TBI (CCI; 4.02 +/- 0.14 m/s velocity; 2.5 mm deformation), sham, and control groups were studied 24 hours after TBI or surgery. Perfusion maps were generated during normocarbia (Paco2 30 to 40 mm Hg) and hypocarbia (PaCO2 15 to 25 mm Hg). During normocarbia, CBF was reduced within a cortical region of interest (ROI, injured versus contralateral) after TBI (200 +/- 82 versus 296 +/- 65 mL.100 g-1.min-1, P < 0.05). Within a contusion-enriched ROI, CBF was reduced after TBI (142 +/- 73 versus 280 +/- 64 mL.100 g-1.min-1, P < 0.05). Cerebral blood flow in the sham group was modestly reduced (212 +/- 112 versus 262 +/- 118 mL.100 g-1.min-1, P < 0.05). Also, TBI widened the distribution of CBF in injured and contralateral cortex. Hypocarbia reduced cortical CBF in control (48%), sham (45%), and TBI rats (48%) versus normocarbia, P < 0.05. In the contusion-enriched ROI, only controls showed a significant reduction in CBF, suggesting blunted CO2 reactivity in the sham and TBI group. CO2 reactivity was reduced in the sham (13%) and TBI (30%) groups within the cortical ROI (versus contralateral cortex). These values were increased twofold within the contusion-enriched ROI but were not statistically significant. After TBI, hypocarbia narrowed the CBF distribution in the injured cortex. We conclude that perfusion MRI using arterial spin-labeling is feasible for the serial, noninvasive measurement of CBF and CO2 reactivity in rats.     

Cerebral blood flow during hypoxemia and hemodilution in rabbits: different roles for nitric oxide?

Hypoxemia and anemia are associated with increased CBF, but the mechanisms that link the changes in PaO2 or arterial O2 content (CaO2) with CBF are unclear. These experiments were intended to examine the contribution of nitric oxide. CaO2 in pentobarbital-anesthetized rabbits was reduced to approximately 6.5 mL O2/dL by hypoxemia (PaO2 approximately 24 to 26 mm Hg) or hemodilution with hetastarch (hematocrit approximately 14% to 15%). Animals with normal CaO2 (approximately 17.5 to 18 mL O2/dL) served as controls. In part I, each animal was given 3, 10, and 30 mg/kg N omega-nitro-L-arginine methyl ester (L-NAME) intravenously (total 43 mg/kg) to inhibit production of nitric oxide. Forebrain CBF was measured with radioactive microspheres approximately 15 to 20 minutes after each dose. Baseline CBF was greater in hypoxemic rabbits (111 +/- 31 mL x 100 g-1 x min-1, mean +/- SD) than in hemodiluted (70 +/- 22 mL x 100 g-1 min-1) or control animals (39 +/- 12 mL x 100 g-1 min-1). L-NAME (which reduced brain tissue nitric oxide synthase activity by approximately 65%) reduced CBF in hypoxemic animals to 80 +/- 23 mL x 100 g-1 x min-1 (P < 0.0001), but had no significant effect on CBF in either anemic or control animals. In four additional rabbits, further hemodilution to a CaO2 of approximately 3.5 mL O2/dL increased baseline CBF to 126 +/- 21 mL x 100 g-1 min-1, but again there was no effect of L-NAME. In part II, animals were anesthetized as above, and a close cranial window was prepared. The cyclic GMP (cGMP) content of the artificial CSF superfusate was measured under baseline conditions, and then after the reduction of CaO2 to approximately 6.5 mL O2/dL by either hypoxemia or hemodilution. Concentrations of cGMP did not change during either control conditions or after hemodilution. However, cGMP increased significantly with the induction of hypoxemia. The cGMP increase in hypoxemic animals could be blocked with L-NAME. These results suggest that nitric oxide plays some role in hypoxemic vasodilation, but not during hemodilution.     

Cerebral blood flow velocity in relation to cerebral blood flow, cerebral metabolic rate for oxygen, and electroencephalogram analysis during isoflurane anesthesia in dogs

The purpose of this study was to correlate changes in cerebral blood flow velocity (Vmean) with cerebral blood flow (CBF) during isoflurane anesthesia in dogs. The relation between cerebral oxygen consumption (CMRO2) and electroencephalogram (EEG) analysis also was investigated. Blood flow velocity was measured in the middle cerebral artery using a pulsed transcranial Doppler (TCD). CBF was measured with radioactive microspheres. EEG was measured over both hemispheres and median EEG frequency (median frequency) was calculated after fast Fourier transformation. Baseline anesthesia was maintained with 50% nitrous oxide in oxygen and 50 micrograms.kg-1 x h-1 fentanyl. Animals of Group I (control, n = 6) were not given isoflurane. Data were recorded at baseline, and at 30, 60, and 90 min. There was no significant change in any variable over time. In Group II (n = 7), data were recorded at baseline and at 1%, 2%, and 3% end-tidal isoflurane. Mean arterial pressure was maintained at baseline levels by phenylephrine infusion. CBF increased from 70.8 +/- 10.6 mL.100g-1 x min-1 at baseline to 146.1 +/- 36.9 mL.100 g-1 x min-1 with 3% isoflurane (P < 0.01). Vmean increased from 38.3 +/- 6.7 cm/s to 65.6 +/- 9.7 cm/s (P < 0.01). The correlation between relative changes in CBF and Vmean was r = 0.94 (P < 0.01). With 1% isoflurane the EEG shifted to slow-wave, high-voltage activity, and median frequency decreased from 5.9 +/- 0.7 Hz to 1.4 +/- 0.4 Hz (P < 0.05). Median frequency was not decreased further during 2% and 3% isoflurane anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of systemic corticoid and antihistamine alone or in combination on elements of the response to a two dose nasal allergen challenge

Adenosine, an endogenous vasodilator, induces a cerebral vasodilation at hypotensive infusion rates in anaesthetized humans. At lower doses (< 100 micrograms kg-1 min-1), adenosine has shown to have an analgesic effect. This study was undertaken to investigate whether a low dose, causing tolerable symptoms of peripheral vasodilation affects the global cerebral blood flow (CBF). In nine healthy volunteers CBF measurements were made using axial magnetic resonance (MR) phase images of the internal carotid and vertebral arteries at the level of C2-3. Quantitative assessment of CBF was also obtained with positron emission tomography (PET) technique, using intravenous bolus [15O]butanol as tracer in four of the subject at another occasion. During normoventilation (5.4 +/- 0.2 kPa, mean +/- s.e.m.), the cerebral blood flow measured by magnetic resonance imaging technique, as the sum of the flows in both carotid and vertebral arteries, was 863 +/- 66 mL min-1, equivalent to about 64 +/- 5 mL 100 g-1 min-1. The cerebral blood flow measured by positron emission tomography technique, was 59 +/- 4 mL 100 g-1 min-1. All subjects had a normal CO2 reactivity. When adenosine was infused (84 +/- 7 micrograms kg-1 min-1.) the cerebral blood flow, measured by magnetic resonance imaging was 60 +/- 5 mL 100 g-1 min-1. The end tidal CO2 level was slightly lower (0.2 +/- 0.1 kPa) during adenosine infusion than during normoventilation. In the subgroup there was no difference in cerebral blood flow as measured by magnetic resonance imaging or positron emission tomography. In conclusion, adenosine infusion at tolerable doses in healthy volunteers does not affect global cerebral blood flow in unanaesthetized humans.     

Prevention of cerebrovasospasm following subarachnoid hemorrhage in rabbits by the platelet-activating factor antagonist, E5880

Recently, an important role of platelet-activating factor (PAF), an inflammation mediator, has been demonstrated in the genesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). In the current study, the authors examined whether intravenous administration of the novel PAF antagonist, E5880, can prevent vasospasm following SAH in rabbits. A vasospasm model was produced in three groups of rabbits using two subarachnoid injections of autologous arterial blood, followed by intravenous administration of distilled water (control), a low dose of E5880 (0.1 mg/kg in distilled water), or a high dose of E5880 (0.5 mg/kg in distilled water). Neurological deterioration was largely prevented in the rabbits that received E5880. Basilar artery constriction was also reduced by both doses of E5880. Histological examination at autopsy predominantly showed ischemic changes in the brain. Animals in each E5880-treated group exhibited ischemic changes less frequently than those in the control group. Plasma thromboxane B2 concentrations were reduced in rabbits treated with E5880. Platelet-activating factor was immunolocalized in the intima and media of the basilar artery in the control group. The PAF immunoreactivity demonstrated in the basilar artery was decreased in the E5880 groups in a dose-dependent manner. Thus, this study provides evidence that PAF may play a role in the pathogenesis of vasospasm after SAH and that intravenous administration of E5880 is a promising approach in preventing vasospasm.     

Changes in cerebrospinal fluid and cerebrovascular endothelin concentrations during hypotension and hypertension in newborn piglets with induced sterile meningitis

The effects of sterile meningitis on endothelin-1 (ET-1) and big ET-1 concentrations during hypotension and hypertension were studied in the cerebrospinal fluid and plasma of newborn piglets. Cerebrospinal fluid was obtained via cisterna magna puncture, and blood was obtained from the sagittal sinus vein and left subclavian artery. The study group consisted of 14 newborn piglets injected with 0.5 mL heat-killed group B streptococcus (GBS) (10(9) colony forming unit (cfu) equivalents), into the right cerebral lateral ventricle; the control group consisted of 10 newborn piglets injected with sterile normal saline, in a similar fashion. Hypotension (mean arterial blood pressure (MABP) 20-59 mmHg; 1 mmHg = 133.3 Pa) and hypertension (MABP 110-140 mmHg) were induced 1.5-2 h apart in random sequence in each animal, by inflating balloon-tipped catheters placed at the aortic root and descending aorta, respectively. Cerebral blood flow (CBF) was measured using radiolabeled microspheres, 15 min before and after injection of GBS or saline (normotension), during the hypotension and hypertension episodes, and during recovery normotension, immediately prior to cerebrospinal fluid and blood sampling. ET-1 and big ET-1 concentrations (pg/mL) were measured using radioimmunoassay kits. The combined effect of induced sterile meningitis and induced hypotension resulted in a significant rise in the concentration of cerebrospinal fluid ET-1 (control, 5.1 +/- 0.1; GBS, 9.3 +/- 0.2 pg/mL; p < 0.01), cerebrospinal fluid big ET-1 (control, 0; GBS, 18.1 +/- 2.7 pg/mL; p < 0.01), and sagittal sinus (cerebrovascular) big ET-1 (control, 15.5 +/- 4.2; GBS, 47.5 +/- 9.6 pg/mL; p < 0.01). In contrast, the combined effect of induced sterile meningitis and induced hypertension resulted in a marked elevation in cerebrovascular ET-1 concentrations (control, 9.5 +/- 0.9; GBS, 28.5 +/- 6.1 pg/mL; p < 0.01), with no significant change in cerebrospinal fluid concentrations. In addition, cerebrovascular production of ET-1 increased dramatically during hypertension in the GBS group (control, 0; GBS, 161.7 +/- 13.2 pg.min-1.100 g-1; p < 0.001), and was maintained during the recovery period (133.7 +/- 10.8 pg.min-1.100 g-1). Cerebrovascular ET-1 concentrations correlated significantly with total CBF and MABP in both groups of animals (control, r = 0.49, p < 0.002; GBS, r = 0.64, p < 0.0001), but the response was of a much greater magnitude in the GBS group. There was an inverse relationship between cerebrovascular big ET-1 concentrations and total CBF (r = -0.53, p < 0.0001) and MABP (r = -0.71, p < 0.0001) in the GBS group. In the MABP range of 60-110 mmHg a positive relationship was observed between cerebrovascular ET-1 concentrations and cerebral vascular resistance, in the control group only (r = 0.59, p < 0.002). The combined insult of induced sterile meningitis and induced hypotension or hypertension may be associated with increased cerebrovascular ET-1 and (or) big ET-1 concentrations. Changes in these vasoactive agents may contribute to pressure passivity of CBF in the newborn with meningitis.     

Cerebral blood flow is increased throughout 12 h of hypoxaemia in the mid-gestation ovine fetus

The changes in regional cerebral blood flow (CBF) in response to prolonged hypoxaemia were measured using coloured microspheres in the 0.6-gestation ovine fetus (n = 5). Fetal hypoxaemia was induced for 12 h by reducing maternal uterine blood flow with an adjustable clamp. CBF (mL min-1 100 g-1) was increased (P < 0.05) from control values (38.7 +/- 3.5) to 105.6 +/- 5.6 at 6 h of hypoxaemia, and to 121.9 +/- 23.1 at 12 h of hypoxaemia. One hour after fetal hypoxaemia had ceased, CBF (54.0 +/- 3.3) had decreased (P < 0.05) towards control values indicating incomplete cardiovascular recovery. Cerebral vascular resistance at 6 h and 12 h of hypoxaemia was lower (P < 0.05) than control values, and returned to control values 1 h after fetal hypoxaemia had ceased. Cerebral oxygen delivery at 6 h and 12 h of hypoxaemia was not significantly different from control values, but was higher (P < 0.05) 1 h after hypoxaemia had ceased. It is concluded that CBF is sufficiently increased during prolonged hypoxaemia in the mid-gestation fetus to maintain cerebral oxygen delivery.     

Global alteration in perfusion response to increasing oxygen consumption in patients with single-vessel coronary artery disease

BACKGROUND: Recent evidence suggests that, in coronary artery disease (CAD), myocardial blood flow (MBF) regulation is abnormal in regions supplied by apparently normal coronary arteries. However, the relation between this alteration and MBF response to increasing metabolic demand has not been fully elucidated. METHODS AND RESULTS: MBF was assessed at baseline, during atrial pacing tachycardia, and after dipyridamole (0.56 mg/kg IV over 4 minutes) in 9 normal subjects and in 24 patients with ischemia on effort, no myocardial infarction, and isolated left anterior descending (n = 19) or left circumflex (n = 5) coronary artery stenosis (> or = 50% diameter narrowing). Perfusion of both poststenotic (S) and normally supplied (N) areas was measured off therapy by positron emission tomography and [13N]ammonia. Normal subjects and CAD patients showed similar rate-pressure products at baseline, during pacing, and after dipyridamole. In CAD patients, MBF was lower in S than in N territories at rest (0.68 +/- 0.14 versus 0.74 +/- 0.18 mL.min-1.g-1, respectively, P < .05), during pacing (0.92 +/- 0.29 versus 1.16 +/- 0.40 mL.min-1.g-1, respectively, P < .01), and after dipyridamole (1.18 +/- 0.34 versus 1.77 +/- 0.71 mL.min-1.g-1, respectively, P < .01). However, normal subjects showed significantly higher values of MBF both at rest (0.92 +/- 0.13 mL.min-1.g-1, P < .05 versus both S and N areas), during pacing tachycardia (1.95 +/- 0.64 mL.min-1.g-1, P < .01 versus both S and N areas), and after dipyridamole (3.59 +/- 0.71 mL.min-1.g-1, P < .01 versus both S and N areas). The percent change in flow was strictly correlated with the corresponding change in rate-pressure product in normal subjects (r = .85, P < .01) but not in either S (r = .04, P = NS) or N regions (r = .08, P = NS) of CAD patients. CONCLUSIONS: Besides epicardial stenosis, further factors may affect flow response to increasing metabolic demand and coronary reserve in patients with CAD.     

The neuroprotective effect of the glycine site antagonist 3R-(+)-cis-4-methyl-HA966 (L-687,414) in a rat model of focal ischaemia

BACKGROUND: Cardiovascular conditioning reduces resting myocardial oxygen demand by lowering systolic blood pressure and heart rate. Lower myocardial oxygen demand at rest would be expected to be associated with a decrease in resting myocardial blood flow and, consequently, an increase in myocardial flow reserve as the ratio of hyperemic to resting blood flow. However, the effect of controlled exercise together with a low-lipid diet on myocardial blood flow and flow reserve has not been examined in humans. METHODS AND RESULTS: Myocardial blood flow at rest and after dipyridamole-induced hyperemia (0.56 mg/kg i.v.) was quantified with [13N]ammonia and positron emission tomography in 13 volunteers before and upon completion of a 6-week program of cardiovascular conditioning and a low-fat diet. Exercise capacity and serum lipid profiles were also assessed at the start and finish of the program. Eight normal volunteers of similar age not participating in the conditioning program served as a control group. Cardiovascular conditioning lowered the resting rate-pressure product (8859 +/- 2128 versus 7450 +/- 1496, P < .001), serum cholesterol (217 +/- 36 versus 181 +/- 26 mg/dL), LDL cholesterol (140 +/- 32 versus 114 +/- 24 mg/dL), and triglycerides (145 +/- 53 versus 116 +/- 33 mg/dL, all P < .05). Exercise tolerance (metabolic equivalent of the task, METs) improved significantly from 10.0 +/- 3.0 to 14.4 +/- 3.6 (P < .01). Resting blood flow decreased (0.78 +/- 0.18 versus 0.69 +/- 0.14 mL.g-1.min-1, P < .05), whereas hyperemic blood flow increased (2.06 +/- 0.35 versus 2.25 +/- 0.40 mL.g-1.min-1, P < .05), resulting in an improved myocardial flow reserve (2.82 +/- 1.07 versus 3.39 +/- 0.91, P < .05). Overall, the myocardial flow reserve was significantly related to exercise performance (METs). In the control group, no changes in resting rate-pressure product, serum cholesterol levels, exercise performance, resting or hyperemic myocardial blood flow, or flow reserve were observed. CONCLUSIONS: Short-term cardiovascular conditioning together with a low-fat diet results in an improved myocardial flow reserve by lowering resting blood flow and increasing coronary vasodilatory capacity. These changes are associated with an improved exercise capacity and may offer a protective effect in patients with coronary artery disease.     

A system to simulate gas exchange in humans to control quality of metabolic measurements

The present experiments were designed to compare the behavior of cerebral blood flow (CBF) during acute moderate and severe hypotensive episodes induced by either ventricular tachycardias (VT) or by hemorrhage. Using the microsphere method CBF was determined in 20 Sprague-Dawley rats during sinus rhythm (Group A), in 28 animals during high-rate VT (Group B) and in 10 animals after hemorrhage (Group C). According to the decrease in blood pressure and with respect to the lower threshold of cerebral autoregulation Group B was divided into 2 subgroups (B1: 80-130 mmHg; B2: 50-80 mmHg) retrospectively. While CBF remained constant in Group B1 (0.98 +/- 0.3 ml g-1 min-1 vs. 1.01 +/- 0.32 in controls, NS), CBF decreased markedly during severely hypotensive VT in Group B2 (0.52 +/- 0.2 ml g-1 min-1, p < 0.001 vs. A; p < 0.05 vs. C) and during hypovolemic hypotension in Group C (0.77 +/- 0.22 ml g-1 min-1 vs. A; NS). Cerebrovascular resistance and autoregulation indices indicated a maintenance of CBF regulation during hypovolemic hypotension and a failure during normovolemic hypotension. These findings indicate that the autoregulatory ability of the brain is substantially more stable during hypovolemic hypotension than during normovolemic hypotension. Therefore, the hemodynamic sequelae of acute hypotensive episodes on CBF depend on the underlying cause of hypotension.     

Effect of aerosol heparin on the development of hypoxic pulmonary hypertension in the guinea pig

Chronic hypoxia produces pulmonary artery hypertension through vasoconstriction and structural remodeling of the pulmonary vascular bed. The present study was designed to test the effect of heparin administered via aerosol on the development of hypoxic pulmonary hypertension. Anesthetized, intubated, and mechanically ventilated guinea pigs received an aerosol of either 2 ml normal saline (hypoxic control, HC) or 4,500 units of heparin diluted in 2 ml normal saline via an ultrasonic nebulizer (hypoxic heparin, HH). After 24 h of recovery, the animals were placed in a hypoxic chamber (10% O2) for 10 days. Animals kept in room air served as normoxic controls (NC). Hypoxia increased mean pulmonary artery pressure from 11 +/- 1 (SEM) mm Hg in NC to 24 +/- 1 mm Hg in HC (p < 0.05). Pulmonary artery pressure was significantly lower in HH-treated animals (20 +/- 1 mm Hg, p < 0.05 versus HC) as was the total pulmonary vascular resistance (0.15 +/- 0.01 in HH versus 0.20 +/- 0.01 mm Hg/ml/min in HC, p < 0.05). There was no difference in cardiac output (146 +/- 12 in HH versus 126 +/- 7 ml/min in HC), hematocrit (57 +/- 2 in HH versus 56 +/- 2% in HC), partial thromboplastin time (30 +/- 2 in HH versus 32 +/- 3 s in HC), prothrombin time (46 +/- 1 in HH versus 48 +/- 4 s in HC) or room air arterial blood gas values after 10 days of hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrarenal vascular effects of angiotensin I and angiotensin II

The effects of angiotensin I (250 pmol) and angiotensin II (7.5 pmol) on total renal blood flow and its cortical distribution were examined in 25 dogs anesthetized with pentobarbital. These peptides were administered as bolus injections directly into the left renal artery. Right and left renal blood flows were measured with noncannulating electromagnetic flow probes. The distribution of renal cortical blood flow was measured with 15-micrometers radioactive microspheres. Because angiotensin I is converted to angiotensin II extrarenally as well as intrarenally, the distribution of renal blood flow in response to the bolus injection of angiotensin agonists was measured before these peptides could have recirculated through the kidney. This maneuver precluded the possibility that blood flow changes were due to the extrarenal formation of vasoactive metabolites of angiotensin I or angiotensin II. Control total renal blood flow averaged 3.0 +/- 0.1 ml.min-1.g kidney wt-1 and was decreased 25% by both angiotensin I and angiotensin II. Outer renal cortical flow (zone I) was 5.1 +/- 0.3 ml.min-1.g-1 and was decreased to 3.9 +/- 0.3 ml.min-1.g-1 by both angiotensin I and angiotensin II. On the average, angiotensin I decreased inner cortical renal blood flow from a control of 1.8 +/- 0.2 to 1.2 +/- 0.2 ml.min-1.g-1; angiotensin II decreased inner cortical renal blood flow from a control of 1.9 +/- 0.2 to 1.4 +/- 0.2 ml.min-1.g-1. Analysis on a per-experiment basis revealed that angiotensin I, compared with angiotensin II, produced a proportionally greater decrease in inner cortical renal blood flow relative to its effects on outer cortical blood flow.     

Pulsatile versus nonpulsatile flow. No difference in cerebral blood flow or metabolism during normothermic cardiopulmonary bypass in rabbits

BACKGROUND: Although pulsatile and nonpulsatile cardiopulmonary bypass (CPB) do not differentially affect cerebral blood flow (CBF) or metabolism during hypothermia, studies suggest pulsatile CPB may result in greater CBF than nonpulsatile CPB under normothermic conditions. Consequently, nonpulsatile flow may contribute to poorer neurologic outcome observed in some studies of normothermic CPB. This study compared CBF and cerebral metabolic rate for oxygen (CMRO2) between pulsatile and nonpulsatile CPB at 37 degrees C. METHODS: In experiment A, 16 anesthetized New Zealand white rabbits were randomized to one of two pulsatile CPB groups based on pump systolic ejection period (100 and 140 ms, respectively). Each animal was perfused at 37 degrees C for 30 min at each of two pulse rates (150 and 250 pulse/min, respectively). This scheme created four different arterial pressure waveforms. At the end of each perfusion period, arterial pressure waveform, arterial and cerebral venous oxygen content, CBF (microspheres), and CMRO2 (Fick) were measured. In experiment B, 22 rabbits were randomized to pulsatile (100-ms ejection period, 250 pulse/min) or nonpulsatile CPB at 37 degrees C. At 30 and 60 min of CPB, physiologic measurements were made as before. RESULTS: In experiment A, CBF and CMRO2 were independent of ejection period and pulse rate. Thus, all four waveforms were physiologically equivalent. In experiment B, CBF did not differ between pulsatile and nonpulsatile CPB (72 +/- 6 vs. 77 +/- 9 ml.100 g-1.min-1, respectively (median +/- quartile deviation)). CMRO2 did not differ between pulsatile and nonpulsatile CPB (4.7 +/- 0.5 vs. 4.1 +/- 0.6 ml O2.100 g-1.min-1, respectively) and decreased slightly (0.4 +/- 0.4 ml O2.100 g-1.min-1) between measurements. CONCLUSIONS: During CPB in rabbits at 37 degrees C, neither CBF nor CMRO2 is affected by arterial pulsation. The absence of pulsation per se is not responsible for the small decreases in CMRO2 observed during CPB.     

18F-2-deoxyglucose deposition and regional flow in pigs with chronically dysfunctional myocardium. Evidence for transmural variations in chronic hibernating myocardium

BACKGROUND: Hibernating myocardium in patients with collateral-dependent myocardium is characterized by relative reductions in resting flow and increases in the uptake of 18F-2-deoxyglucose (FDG) in the fasting state. We performed the present study to examine whether these key physiological alterations could be produced in a porcine model of chronic coronary occlusion and to assess whether the adaptations consistent with hibernation varied across the myocardial wall. METHODS AND RESULTS: We chronically instrumented pigs (n = 18) with a fixed occluder on the proximal left anterior descending coronary artery (LAD). Three months later, ventricular function, regional myocardial perfusion, and FDG deposition (by excised tissue counting or positron emission tomography) were assessed in pigs after an over-night fast in the closed-chest anesthetized state. Total LAD occlusion with angiographic collaterals was present in the majority of animals. Left ventriculography showed severe anterior hypokinesis, and resting perfusion was significantly reduced in the hibernating LAD region in comparison with the normal remote regions (subendocardium: 0.80 +/- 0.06 versus 1.07 +/- 0.06 mL.min-1.g-1, P < .001; full-thickness: 0.87 +/- 0.04 versus 0.99 +/- 0.06 mL.min-1.g-1, P < .01). There was a twofold increase in full-thickness fasting FDG uptake in the dysfunctional LAD region (1.8 +/- 0.2 by positron emission tomography versus 1.9 +/- 0.1 by ex vivo counting). Ex vivo tissue counting revealed a pronounced transmural variation in FDG uptake in the hibernating region (LAD/normal), which averaged 2.5 +/- 0.2 in the subendocardium, 1.9 +/- 0.2 in the midmyocardium, and 1.4 +/- 0.1 in the subepicardium. CONCLUSIONS: These results demonstrate that pigs instrumented with a proximal LAD stenosis develop hibernating myocardium characterized by relative reductions in resting function and perfusion in association with increased uptake of FDG in the fasting state. The transmural variations in relative resting flow and FDG uptake suggest that myocardial adaptations consistent with hibernation are most pronounced in the subendocardial layers and vary in relation to local coronary flow reserve.     

Chemical modulation of in situ intrinsic cardiac neurones influences myocardial blood flow in the anaesthetised dog

OBJECTIVE: The aim was to determine whether modulation of intrinsic cardiac neurones influences the distribution of myocardial blood flow in canine anaesthetised open chest experimental preparations. METHODS: Intrinsic cardiac neurones were modified by locally applied nicotine (100 micrograms) or bradykinin (50 micrograms) while changes were recorded in cardiac haemodynamics and myocardial blood flow (radiolabelled microspheres). Right and left ventricular intramyocardial tissue pressures were measured with high fidelity microtip transducers. RESULTS: Control injections of saline (vehicle; 0.1 ml) into active loci did not produce cardiovascular responses. Nicotine modulation of intrinsic cardiac neurones did not change coronary artery conductance, but total myocardial blood flow [116(SEM 17) v 532(97) ml.min-1.100 g-1; p = 0.001 v baseline] and oxygen consumption [7.92(1.10) v 20.14(1.86) ml.min-1.100 g-1; p = 0.001] increased in direct relation to heart rate-blood pressure product changes. Locally administered bradykinin increased coronary artery conductance [2.62(0.39) v 4.71(1.07) ml.min-1.100 g-1.mm Hg-1], total myocardial blood flow, to 263(72) ml.min-1.100 g-1, and oxygen consumption, to 14.9(4.4) ml.min-1.100 g-1; however, heart rate-blood pressure product did not change. CONCLUSIONS: These results support earlier findings that intrinsic neurones are involved in cardiac regulation. Furthermore, modification of intrinsic cardiac neurones by nicotine or bradykinin significantly alters the distribution of myocardial blood flow, possibly because of increased myocardial metabolism.     

Somatostatin receptor subtypes sst1, sst2, sst3 and sst5 expression in human pituitary, gastroentero-pancreatic and mammary tumors: comparison of mRNA analysis with receptor autoradiography

The aim of this study was to elucidate further the causative mechanism of abnormal coronary vasomotion in patients with syndrome X. In patients with syndrome X, defined as angina pectoris and documented myocardial ischaemia during stress testing with normal findings at coronary angiography, abnormal coronary vasomotion of either the micro- or the macrocirculation has been suggested as the causative mechanism. Accordingly, we evaluated endothelial function, vasodilator reserve, and perfusion heterogeneity in these patients. Twenty-five patients with syndrome X (definitely normal coronary arteriogram, group A), 15 patients with minimal coronary artery disease (group B) and 21 healthy volunteers underwent [13N]ammonia positron emission tomography at rest, during cold pressor stimulation (endothelial function) and during dipyridamole stress testing (vasodilator reserve). Heterogeneity of myocardial perfusion was analysed by parametric polar mapping using a 480-segment model. In both patient groups, resting perfusion was increased compared to the normal subjects: group A, 127+/-31 ml.min-1.100 g-1; group B, 124+/-30 ml.min-1.100 g-1 normal subjects, 105+/-21 ml.min-1.100 g-1 (groups A and B vs normals, P<0.05). These differences were abolished after correction for rate-pressure product. During cold pressor stimulation, the perfusion responses (ratio of cold pressor perfusion to resting perfusion) were similar among the patients and the control subjects (group A, 1.20+/-0.23; group B, 1.24+/-0.22; normal subjects, 1.23+/-0.14). Likewise, during dipyridamole stress testing, perfusion responses were similar among the three groups (group A, 2.71+/-0.67; group B, 2.77+/-1.29; normal subjects, 2. 91+/-1.04). In group A the heterogeneity of resting perfusion, expressed as coefficient of variation, was significantly different from the volunteers (20.1+/-4.5 vs 17.0+/-3.0, P<0.05). In group B (coefficient of variation 19.4+/-3.9) the difference from normal volunteers was not significant. In this study, patients with syndrome X and patients with minimal coronary artery disease showed normal perfusion responses during cold pressor stimulation and dipyridamole stress testing. Our findings therefore suggest that endothelial dysfunction and impaired vasodilator reserve are of no major pathophysiological relevance in patients with syndrome X. Rather, other mechanisms such as increased sympathetic tone and focal release of vasoactive substances may play a role in the pathogenesis of syndrome X.     

Changes of respiratory chain activity in mitochondrial and synaptosomal fractions isolated from the gerbil brain after graded ischaemia

In this study we have examined (1) the integrated function of the mitochondrial respiratory chain by polarographic measurements and (2) the activities of the respiratory chain complexes I, II-III, and IV as well as the ATP synthase (complex V) in free mitochondria and synaptosomes isolated from gerbil brain, after a 30-min period of graded cerebral ischaemia. These data have been correlated with cerebral blood flow (CBF) values as measured by the hydrogen clearance technique. Integrated functioning of the mitochondrial respiratory chain, using both NAD-linked and FAD-linked substrates, was initially affected at CBF values of approximately 35 ml 100 g-1 min-1, and declined further as the CBF was reduced. The individual mitochondrial respiratory chain complexes, however, showed differences in sensitivity to graded cerebral ischaemia. Complex I activities decreased sharply at blood flows below approximately 30 ml 100 g-1 min-1 (mitochondria and synaptosomes) and complex II-III activities decreased at blood flows below 20 ml 100 g-1 min-1 (mitochondria) and 35-30 ml 100 g-1 min-1 (synaptosomes). Activities declined further as CBF was reduced below these levels. Complex V activity was significantly affected only when the blood flow was reduced below 15-10 ml 100 g-1 min-1 (mitochondria and synaptosomes). In contrast, complex IV activity was unaffected by graded cerebral ischaemia, even at very low CBF levels.     

L-Arginine normalizes coronary vasomotion in long-term smokers

BACKGROUND: Noninvasive measurements of myocardial blood flow (MBF) with PET revealed an abnormal coronary vasomotor response to cold pressor test in healthy long-term smokers. If coronary endothelial dysfunction accounted for this abnormality, we hypothesized that it could be reversed by L-arginine as the substrate for NO synthase. METHODS AND RESULTS: MBF was quantified with 13N-labeled ammonia and PET in 11 healthy smokers (age, 45+/-10 years; 27+/-10 years of smoking) and in 12 age-matched nonsmokers on 2 separate days. On day 1, MBF was measured at rest and, after intravenous L-arginine, during cold pressor test. On day 2, MBF was measured during cold pressor test and then at rest during L-arginine. Baseline rate-pressure product (RPP) (6559+/-1590 versus 7144+/-1157 bpmxmm Hg) and MBF (0.65+/-0.14 versus 0.73+/-0.13 mL x g-1 x min-1) were similar in nonsmokers and smokers. Cold pressor test increased RPP similarly in both groups (53+/-26% versus 46+/-26%), whereas MBF increased in nonsmokers (to 0.93+/-0.25 mL x g-1 x min-1; P<0.05) but not in smokers (0.80+/-0.16 mL x g-1 x min-1). The percent MBF increase differed between nonsmokers and smokers (44+/-25% versus 11+/-14%; P=0.0017). However, after L-arginine, the magnitude of MBF response to cold pressor test no longer differed between groups (48+/-36% versus 48+/-28%), whereas RPP again increased similarly in the 2 groups (59+/-30% versus 44+/-16%). L-Arginine had no effect on resting MBF in smokers or nonsmokers. CONCLUSIONS: Our findings implicate the coronary endothelium as the major site of the abnormal vasomotor response in long-term smokers. Cold pressor test combined with PET imaging may allow the noninvasive identification of coronary endothelial dysfunction in humans.     

Carotid artery stenosis in peripheral vascular disease

We describe the implementation and validation of a combined dynamic-autoradiographic approach for measuring the regional cerebral blood flow (rCBF) with 15O-butanol. From arterial blood data sampled at a rate of 1 s and list mode data of the cerebral radioactivity accumulated over 100 s, the time shift between blood and tissue curves, the dispersion constant DC, the partition coefficient p, and the CBF were estimated by least squares fitting. Using the fit results, a pixel-by-pixel parametrization of rCBF was computed for a single 40-s (autoradiographic) 15O-butanol uptake image. The mean global CBF found in 27 healthy subjects was 49 +/- 8 ml 100 g-1 min-1. Gray and white matter rCBF were 83 +/- 20 and 16 +/- 3 ml 100 g-1 min-1, respectively, with a corresponding partition coefficient p of 0.77 +/- 0.18 and 0.77 +/- 0.29 ml/g in both compartments. The quantitative images resulted in a significantly higher gray matter rCBF than the autoradiographic images.     

Public health developments in colonial Malaya: colonialism and the politics of prevention

-Previous studies have shown that whereas the nonclipped kidney in two-kidney, one clip (2K1C) rats undergoes marked depletion of renin content and renin mRNA, intrarenal angiotensin II (Ang II) levels are not suppressed; however, the distribution and functional consequences of intrarenal Ang II remain unclear. The present study was performed to assess the plasma, kidney, and proximal tubular fluid levels of Ang II and the renal responses to intrarenal Ang II blockade in the nonclipped kidneys of rats clipped for 3 weeks. The Ang II concentrations in proximal tubular fluid averaged 9.19+/-1.06 pmol/mL, whereas plasma Ang II levels averaged 483+/-55 fmol/mL and kidney Ang II content averaged 650+/-66 fmol/g. Thus, as found in kidneys from normal rats with normal renin levels, proximal tubular fluid concentrations of Ang II are in the nanomolar range. To avoid the confounding effects of decreases in mean arterial pressure (MAP), we administered the nonsurmountable AT1 receptor antagonist candesartan directly into the renal artery of nonclipped kidneys (n=10). The dose of candesartan (0.5 microg) did not significantly decrease MAP in 2K1C rats (152+/-3 versus 148+/-3 mm Hg), but effectively prevented the renal vasoconstriction elicited by an intra-arterial bolus of Ang II (2 ng). Candesartan elicited significant increases in glomerular filtration rate (GFR) (0.65+/-0. 06 to 0.83+/-0.11 mL. min-1. g-1) and renal blood flow (6.3+/-0.7 to 7.3+/-0.9 mL. min-1. g-1), and proportionately greater increases in absolute sodium excretion (0.23+/-0.07 to 1.13+/-0.34 micromol. min-1. g-1) and fractional sodium excretion (0.38+/-0.1% to 1.22+/-0. 35%) in 2K1C hypertensive rats. These results show that proximal tubular fluid concentrations of Ang II are in the nanomolar range and are much higher than can be explained on the basis of plasma levels. Further, the data show that the intratubular levels of Ang II in the nonclipped kidneys of 2K1C rats remain at levels found in kidneys with normal renin content and could be exerting effects to suppress renal hemodynamic and glomerular function and to enhance tubular reabsorption rate.