Hyperglycemia and blood-brain barrier glucose transport.
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Animals↗
Biomedical subjects
D A Pelligrino
Publications and source records attributed to D A Pelligrino.
Diminished muscarinic receptor-mediated cerebral blood flow response in streptozotocin-treated rats.
Endothelium-dependent vascular relaxation in the brain may be impaired in the streptozotocin-treated chronically hyperglycemic diabetic (D) rat. To study this, we measured regional cerebral blood flow (rCBF) changes induced by intracarotid (ic) or intravenous (iv) infusions of the blood-brain permeant muscarinic receptor (MR) agonist oxotremorine (Oxo). In nondiabetic (ND) rats, both ic and iv Oxo resulted in significant (P less than 0.05) rCBF increases from values obtained during saline infusions in the regions analyzed. The maximum rCBF values measured during Oxo (expressed as percent iv or ic saline value) were 358-403% in the cortex (CX), 236-260% in the subcortex (SC), 162-186% in the brain stem (BS), and 143-158% in the cerebellum (CE). The iv or ic Oxo response in D vs. ND rats was reduced by 60-70% in the CX and SC, lost in the BS, and unchanged in the CE. The CBF response was associated with no change in cortical CMRO2 and was completely blocked during ic atropine-Oxo co-infusion or iv co-infusion of Oxo with the nitric oxide (NO) synthesis inhibitor L-nitroarginine methyl ester, demonstrating, respectively, no role for metabolic activation, the exclusive role of MR values, and the critical role for the release of the putative endothelium-dependent relaxation factor NO in mediating this effect. These findings indicate a significant, but regionally variable, impairment of the mechanism for endothelium-dependent vascular relaxation in the diabetic brain.
Animals↗
Chronic hyperglycemic diabetes in the rat is associated with a selective impairment of cerebral vasodilatory responses.
Diabetes has been reported to impair vasodilatory responses in the peripheral vascular tissue. However, little is known about vasodilatory function in the diabetic brain. We therefore studied, in the N2O-sedated, paralyzed, and artificially ventilated rat, the effects of chronic hyperglycemic diabetes on the cerebral blood flow (CBF) responses to 3 acutely imposed vasodilatory stimuli: hypoglycemia (HG) (plasma glucose = 1.6-1.9 mumol ml-1), hypoxia (HX) (PaO2 = 35-38 mm Hg), or hypercarbia HC) (PaCO2 = 75-78 mm Hg). In addition, we evaluated the somatosensory evoked potential (SSEP) and plasma catecholamine changes in rats exposed to acute glycemic reductions. Diabetes was induced via streptozotocin (STZ, 60 mg kg-1 i.p.). All results in diabetic rats were compared to those obtained in age-matched nondiabetic controls. The animals were studied at 6-8 weeks (HG experiments) or 4-6 months (HG, HX, and HC experiments) post-STZ. Values for CBF were obtained for the cortex (CX), subcortex (SC), brainstem (BS), and cerebellum (CE) employing radiolabeled microspheres. Up to three CBF determinations were made in each animal. In 6-8 week diabetics vs. controls, CBF increased to a lesser value in the CX, SC, and BS (p less than 0.05). Thus, in the diabetics, going from chronic hyperglycemia to acute hypoglycemia, CBF values (in ml 100 g-1 min-1 +/- SD) increased (p less than 0.05) from 89 +/- 22 to 221 +/- 57 in the CX, from 82 +/- 21 to 160 +/- 52 in the SC, and from 79 +/- 34 to 237 +/- 125 in the BS. In controls, going from normoglycemia to acute hypoglycemia, the CBF changes (p less than 0.05) were 128 +/- 27 to 350 +/- 219 (CX), 117 +/- 11 to 358 +/- 206 (SC), and 130 +/- 29 to 452 +/- 254 (BS). CBF changes and absolute values in the CE were similar in the two groups. At 4-6 months post-STZ, a complete loss of the hypoglycemic CBF response was found in the CX, SC, and CE. In the BS, a CBF response to hypoglycemia was seen in the diabetic rats, with the CBF increasing from 114 +/- 28 (hyperglycemia) to 270 +/- 204 ml 100 g-1 min-1 (p less than 0.05), compared to a change from 147 +/- 36 (normoglycemia) to 455 +/- 299 ml 100 g-1 min-1 (p less than 0.05) in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Continuous infusion of interpleural bupivacaine maintains effective analgesia after cholecystectomy.
Twenty-five patients who had undergone elective cholecystectomy were prospectively randomized to receive via an interpleural catheter either a continuous infusion of 0.25% bupivacaine at 0.125 mL.kg-1.h-1 (n = 13) or repeated bolus injections (n = 12) of 0.5% bupivacaine with epinephrine 1:200,000 at 0.4 mL/kg every sixth hour. Adequacy of pain relief was measured by the amount of patient-controlled analgesia morphine required postoperatively and by patient scores on a visual analog scale obtained every sixth hour. Two venous blood samples for measurements of serum bupivacaine levels were obtained from patients in the continuous group at hours 6 and 24; four blood samples were obtained from patients in the bolus group, both immediately before and 30 min after injections at hours 6 and 24. Among the patients receiving the bolus injections, morphine was required 62 +/- 15 (SEM) times over the 24-h study period with total morphine dosage averaging 30 +/- 15 mg. Corresponding values for patients in the continuous groups were 35 +/- 10 times and 23 +/- 5 mg of morphine. The difference was not, however, statistically significant, but when activity during the 2-h time periods immediately before reinjection were examined, patients in the bolus group required and received significantly more morphine than did those in the continuous group (P less than 0.05). Patients in the continuous group had visual analog scale scores that averaged 2.9 +/- 0.6 over the 24-h study period. Patients within the bolus group had visual analog scale scores before and again 30 min after injection that averaged 5.8 +/- 0.8 and 1.8 +/- 0.5, respectively (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Brain glucose utilization and transport and cortical function in chronic vs. acute hypoglycemia.
We compared regional brain capillary permeability-surface area products for glucose transfer (PSin), cerebral glucose utilization (rCMRGlc) rates, and brain tissue glucose levels (GlCbr) in N2O-sedated, paralyzed, and artificially ventilated rats during normoglycemia (NG), insulin-induced acute hypoglycemia (AH), or chronic hypoglycemia (CH) [hypoglycemic plasma glucose (Glcp) = 2.2-2.3 mumol/ml]. In addition, a comparative assessment of brain function in AH vs. CH was performed employing somatosensory-evoked response (SSER) technology. A double-label (3H and 14C) 2-deoxy-D-glucose method was used for the simultaneous assessment of PSin and rCMRGlc. Compared with normoglycemic controls, AH resulted in significant 40-50% reductions in rCMRGlc in 10 of 11 regions analyzed (cerebellum unchanged). In CH vs. AH, significantly higher values for rCMRGlc, Glcbr/Glcp ratios, and PSin were seen in 8, 8, and 5 regions, respectively. No differences in rCMRGlc were observed when comparing CH vs. NG groups. Furthermore, CH rats were able to sustain normal SSER at levels of hypoglycemia (1.5 mumol/ml) that, when imposed acutely, resulted in attenuated SSER. Thus CH is associated with an enhanced blood-brain glucose transport capacity in many (but not all) brain regions. This in turn increases rCMRGlc and improves the general cerebral function compared with that seen during AH.
Acute Disease↗
Role of cerebrospinal fluid [H+] in ventilatory deacclimatization from chronic hypoxia.
Once ventilatory acclimatization begins in sea level residents sojourning at high altitude, abrupt restoration of normal oxygen tensions will not restore ventilation to normal. We have investigated the role of cerebrospinal fluid (CSF) [H(+)] in this sustained hyperventilation by measuring CSF acid-base status in seven men (lumbar) and five ponies (cisternal) in normoxia, first at sea level and then periodically over 13-24 h of "deacclimatization" after 3-5 d in hypoxia (P(B) = 440 mm Hg). After 1 h deacclimatization, hyperventilation continued at a level only slightly less than that obtained in chronic hypoxia (+1-2 mm Hg Pa(CO2)), whereas CSF pH was either equal (in man) or alkaline (in pony, +0.02, P < 0.01) to sea level values. Between 1 and 12-13 h deacclimatization in all humans and ponies Va fell progressively (Pa(CO2) increased 4-7 mm Hg) and CSF pH became increasingly more acid (-0.02 to -0.05, P < 0.01). Between 12 and 24 h of normoxic deacclimatization in ponies, Pa(CO2) rose further toward normal, coincident with an increasing acidity in CSF (-0.02 pH). Similar negative correlations were found between changes in arterial pH and Va throughout normoxic deacclimatization. We conclude that [H(+)] in the lumbar or cisternal CSF is not the mediator of the continued hyperventilation and its gradual dissipation with time during normoxic deacclimatization from chronic hypoxia. These negative relationships of Va to CSF [H(+)] in normoxia are analogous to those previously shown during acclimatization to hypoxia.
Acclimatization↗
The brain's role in exercise hyperpnea.
Three aspects concerning the role of the central nervous system in the control of exercise hyperpnea are reviewed. First, the integration of sensory input stresses the concept of multiple sites of integration--with the end result that both adequate gas exchange and near-optimal mechanical response of the lung and chest wall are achieved during exercise. Secondly, the potential role of the "central" [H+] chemoreceptor is discussed--in terms of the mechanisms available for the protection of brain ECF [H+] and the stimulus-response characteristics of this important chemical sensor and a critical analysis of how it may be evaluated. Finally, the question of forebrain influences on exercise hyperpnea and the "sensation" of ventilatory effect is discussed, with particular emphasis on the multi-purpose regulation of breathing in athletic endeavors.
Brain↗
Effects of hypocapnia PCO2 gradients between CSF and cerebral capillary blood.
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Alkalosis, Respiratory↗
Dependence of CSF on plasma bicarbonate during hypocapnia and hypoxemic hypocapnia.
We have previoulsy shown pH compensation to be similar in CSF and arterial blood during chronic hypoxemic hypocapnia in man and pony, and postulated that the compensatory reduction in CSF [HCO3] was dependent upon corresponding changes in [HCO3]a. We tested this hypothesis in anesthetized, paralyzed dogs by determining the effects of 7 or 14 hours of hypocapnia (PaCO2 20 and 30 mm Hg), hypoxemia (PaO2 30, 38 and 48 mm Hg) and hypocapnic hypoxemia on CSF acid-base status. [hco3]a was either permitted to fall normally or was held near control levels by NaHCO3 infusion. In hypocapnia and hypoxemic hypocapnia, the decrease in [HCO3] and % pH compensation in CSF were less than or equal to that in arterial blood. Most (51-89%) of the compensatory decrease in CSF [HCO3] was prevented by preventing the corresponding reduction in [HCO3]a. This dependence of changes in CSF on plasma [HCO3] required a concurrent decrease in CSF PCO2, but was largely independent of variations in plasma pH. A minor but significant portion of the decrease in CSF [HCO3] was achieved independently of corresponding changes in [HCO3]a. The contribution of this local mechanism to CSF [HCO3] regulation increased with increasing severity of hypocapnia or hypoxemia and was usually associated with a selective increase in CSF lactate. It was concluded that [HCO3] regulation in the CSF during hypoxemic hypocapnia was primarily dependent upon, and therefore limited by, the concomitant decrease in plasma [HCO3].
Acid-Base Equilibrium↗