Decrease In Cortical Blood Flow Research Articles

Circumscribing Laser Cuts Attenuate Seizure Propagation in a Mouse Model of Focal Epilepsy.

In partial onset epilepsy, seizures arise focally in the brain and often propagate. Patients frequently become refractory to medical management, leaving neurosurgery, which can cause neurologic deficits, as a primary treatment. In the cortex, focal seizures spread through horizontal connections in layers II/III, suggesting that severing these connections can block seizures while preserving function. Focal neocortical epilepsy is induced in mice, sub-surface cuts are created surrounding the seizure focus using tightly-focused femtosecond laser pulses, and electrophysiological recordings are acquired at multiple locations for 3-12 months. Cuts reduced seizure frequency in most animals by 87%, and only 5% of remaining seizures propagated to the distant electrodes, compared to 80% in control animals. These cuts produced a modest decrease in cortical blood flow that recovered and left a ≈20-µm wide scar with minimal collateral damage. When placed over the motor cortex, cuts do not cause notable deficits in a skilled reaching task, suggesting they hold promise as a novel neurosurgical approach for intractable focal cortical epilepsy.

Pilot study: use of contrast-enhanced ultrasonography in feline renal transplant recipients.

Objectives The study aims were to evaluate the feasibility of contrast-enhanced ultrasonography in feline renal transplant recipients in the post-transplantation period and to report findings in a case with presumptive delayed allograft ischemia. Methods Cats were imaged postoperatively using contrast harmonic ultrasonography after a bolus injection of a microbubble contrast medium. Time/mean pixel intensity curves were generated for cortical and medullary regions of interest in the renal allograft in each cat. Arrival time, time to peak, wash-in slope, wash-out slope, mean transit time and renal blood flow were calculated for each area. Results Within the renal cortices of cats without ureteral obstruction 1 day post-transplantation, arrival time was 2.0-6.3 s, time to peak was 3.6-30.1 s, wash-in rate was 2.45-41.14 mean pixel intensity (MPI)/s, wash-out rate was -2.01 to -0.47 MPI/s and blood flow was 6.1-106.5 MPI/s. Ratio mean transit time was 0.29-1.29. Typical cortical and medullary perfusion patterns were observed in these cats. In one cat with delayed graft ischemia followed by presumptive acute transplant rejection, dynamic and heterogeneous cortical and medullary perfusion was demonstrated. Decreases in cortical blood flow were paralleled by elevated serum creatinine. Conclusions and relevance Contrast-enhanced ultrasonography can be used in feline renal transplant recipients and provides both qualitative and quantitative data regarding renal allograft perfusion.

CT Perfusion and CT Angiography in children and juvenile patients during an attack of migraine with aura

Aims: The pathophysiology of migraine is not yet fully understood and stroke has to be included in differential diagnosis. The neurogenic theory is confirmed by neuroimaging studies with functional MRI during auras indicating that the decreases in cortical bloodflow are not sufficient to cause ischemia and the subsequent vasodilatation is observed well after the beginning of headache. Neuroimaging descriptions during migraine attacks are limited to MRI, but this technology is not widely available on a 24h basis. Recent developments in CT technology allows high speed volumetric data acquisition and generation of perfusion maps.

Renal and Systemic Effects of Endothelin-1 in Diabetic-Hypertensive Rats

The Cohen-Rosenthal Diabetic Hypertensive rat (CRDH) is a unique animal model in which genetic hypertension and diabetes developed after crossbreeding of Cohen diabetic rats sensitive substrain (CDR) and spontaneously hypertensive rats (SHR). The present study examined: 1) The acute effects of ET-1 on the systemic and renal hemodynamics in CRDH rats, CDR, and SHR; 2) The expression of ET-1 and its receptors in the renal tissue of CRDH rats. Intravenous injection of ET-1 (1.0 nmol/kg) into anesthetized SHR rats resulted in a significant immediate depressor response (mean arterial pressure (MAP) decreased from 165 ± 3 to 124 ± 12 mmHg, p < 0.0001) followed by a minor hypertensive phase (MAP increased to 170 ± 2 mmHg). Simultaneously, the administration of ET-1 caused a significant decrease in renal blood flow (RBF) from 5.8 ± 0.9 ml/min to 3.2 ± 0.5 ml/min (p = 0.026). These responses were blunted in CRDH rats and CDR. Analysis of intra-renal blood flow by laser-Doppler in CRDH rats revealed that ET-1 injection caused a decrease in cortical blood flow (Δ = −12 ± 2.9%). However, in contrast to its well-known renal medullary vasodilatory effect, ET-1 produced a significant decline in the medulla blood flow (Δ = −17.5 ± 3.4%) (p = 0.0125). These findings suggest that CDR and CRDH rats have reduced sensitivity to vascular and renal action of ET-1. Furthermore, in the CRDH rats, the expected ET-1-induced medullary vasodilatation was abolished and even reversed into prolonged vasoconstriction.

CONTRIBUTION OF PROSTANOID TP RECEPTORS TO THE PRESSOR AND INTRARENAL HAEMODYNAMIC RESPONSE TO ENDOTHELIN

Previous studies have shown that endothelin (ET)-1 stimulates thromboxane (Tx)A(2) production and so we hypothesized that inhibiting prostanoid TP receptors would prevent the pressor and intrarenal haemodynamic response to an acute infusion of ET-1. 2. Male Sprague-Dawley rats were anaesthetized with Inactin (Sigma Chemical, St Louis, MO, USA; 50 mg/kg) and catheters were inserted into the femoral artery and vein for recording mean arterial pressure (MAP) and infusion of ET-1 and receptor antagonists, respectively. A jugular vein catheter was used for the infusion of bovine serum albumin (6.2% in saline) during surgery (1.25% bodyweight). The pressor response to a 1 h infusion of ET-1 (6 pmol/kg per min) was determined in rats that had been pretreated with vehicle (0.9% NaCl) or the TP receptor antagonist SQ29548 (2 mg/kg per h). Laser Doppler single-optic fibres were implanted in the left kidney for the measurement of medullary blood flow (MBF) and cortical blood flow (CBF). 3. Prostanoid TP receptor blockade completely inhibited the acute pressor response to ET-1; the change in MAP was 14 2% versus -3 4% in vehicle and SQ29548 groups, respectively (P<0.05). Endothelin-1 reduced CBF (-15.2 3.3%), a response that was not significantly changed by SQ29548 (-6.2 7.6%). Similarly, the ET-1-mediated response in MBF was not altered by the TP receptor antagonist (7.7 4.9 vs 6.5 5.2%). 4. To determine the influence of the ET(B) receptor in modulating the response to ET-1 during TP receptor blockade, additional groups were pretreated with A-192621, an ET(B) receptor-selective antagonist (10 mg/kg, i.v.). A-192621 potentiated the increase in MAP produced by ET-1 (32 5%; P<0.05 vs ET-1 alone). SQ29548 significantly inhibited, but did not completely block, the increase in MAP produced by ET-1 during ET(B) antagonist treatment (18 4%; P<0.05). Endothelin-1-induced decreases in CBF were significantly enhanced in rats that were pretreated with A-192621, whereas ET-1 also significantly decreased MBF following A-192621 treatment. During ET(B) receptor blockade, TP receptor inhibition had no effect on the ET-1-mediated response of CBF and MBF. 5. These results suggest that TP receptor activation is not involved in the renal haemodynamic responses to ET-1. However, TP receptor activation contributes to the acute pressor response to ET-1, but does not account for the potentiated increase in MAP during ET(B) receptor blockade.

The Effects of Carbon Dioxide versus Ioxaglate in the Rat Kidney

The renal medulla seems to be particularly vulnerable to vascular injection of iodinated contrast media, particularly in patients with preexisting renal dysfunction. The gas carbon dioxide is frequently used as an alternative to iodinated contrast medium in these patients. In this study, the renal effects of CO(2) are investigated and compared with those of the iodinated contrast medium ioxaglate. Cortical and outer medullary blood flow (measured by laser Doppler flowmetry) and oxygen tension (Po(2); measured by oxygen microelectrodes) were recorded in anesthetized Sprague-Dawley rats given an intraarterial injection of ioxaglate (320 mgI/kg body weight), a volume-matched dose of CO(2), or Ringer solution. Injection of CO(2) induced a pronounced and transient decrease in cortical blood flow and Po(2) (approximately -45%), whereas outer medullary blood flow and Po(2) were transiently increased (+21% and +29%, respectively). In contrast, injection of ioxaglate did not influence cortical blood flow and caused outer medullary blood flow to decrease by 17%. Ioxaglate injection also resulted in a decrease in cortical and outer medullary Po(2) (-15% and -33%, respectively). Ringer solution affected none of the recorded parameters. Although injection of CO(2) markedly affected regional renal blood flow and Po(2), there were qualitatively different effects in the cortex and outer medulla compared with those seen after injection of ioxaglate. The pronounced decrease in medullary blood flow and Po(2) observed after injection of ioxaglate was absent in the animals injected with CO(2). This might suggest beneficial effects of the use of CO(2) instead of iodinated contrast media in patients with increased risk of developing renal failure.

Effects of Endothelin-1 on Systemic and Renal Hemodynamics in Hypertensive-Diabetic Rats (CRDH), Diabetic Rats (CDR), and Hypertensive Rats (SHR)

The Cohen-Rosenthal diabetic hypertensive rat is a unique animal model in which genetic hypertension and diabetes developed after crossbreeding of a sensitive substrain of Cohen diabetic rats and spontaneously hypertensive rats (SHR) and feeding them a copper-poor sucrose diet. This study examined the acute effects of endothelin-1 on the systemic and renal hemodynamics in Cohen-Rosenthal diabetic hypertensive rats, Cohen diabetic rats and spontaneously hypertensive rats. Intravenous injection of endothelin- 1 (1.0 nmol/kg) into anesthetized SHR resulted in a significant immediate depressor response in mean arterial pressure [from 165 +/- 3 mmHg to 124 +/- 12 mmHg (P < 0.0001)] followed by a minor hypertensive phase (mean arterial pressure increased to 170 +/- 2 mmHg). Simultaneously, the administration of endothelin-1 caused a significant decrease in renal blood flow from 5.8 +/- 0.9 mL/minute to 3.2 +/- 0.5 mL/minute (P = 0.026). These responses were blunted in Cohen-Rosenthal diabetic hypertensive rats and Cohen diabetic rats. Analysis of intrarenal blood flow by laser-Doppler in Cohen-Rosenthal diabetic hypertensive rats revealed that endothelin-1 injection caused a decrease in cortical blood flow (Delta = -12 +/- 2.9%). However, in contrast to its well known renal medullary vasodilatory effect, endothelin-1 produced a significant decline in the medulla blood flow (Delta = -17.5 +/- 3.4%) (P = 0.0125). These findings suggest that Cohen diabetic rats and Cohen-Rosenthal diabetic hypertensive rats have reduced sensitivity to the vascular and renal action of endothelin-1. Furthermore, in the Cohen-Rosenthal diabetic hypertensive rats the expected endothelin- 1-induced medullary vasodilation was abolished and even reversed into prolonged vasoconstrictor response.

Differential Regulation of ETA and ETB in the Renal Tissue of Rats with Compensated and Decompensated Heart Failure

Endothelin-1 (ET-1) exerts its biological actions through two receptor subtypes: endothelin-A (ETA) receptor and endothelin-B (ETB) receptor. We demonstrated previously that ET-1 induces systemic and renal cortical vasoconstriction via ETA whereas ETB mediates medullary vasodilation. Congestive heart failure (CHF) is characterized by increased vascular resistance and impaired renal hemodynamic and excretory function. While the pathophysiological effects of ET-1 in CHF are well established, the status of ETA and ETB in the kidney is poorly characterized. The present study examined the immunostaining and localization of ETA and ETB in the renal cortex and medulla of rats with experimental CHF induced by aorto-caval fistula. Rats with CHF were further subdivided, based on their daily urinary sodium excretion, into rats with compensated (urinary sodium excretion > 1200 microEq/day) and decompensated CHF (urinary sodium excretion < 200 microEq/day). ETA is predominantly localized to the cortex mainly in the peritubular capillaries, and is upregulated in rats with compensated and decompensated CHF compared with sham controls. In contrast, ETB is preferentially expressed in the outer and inner medulla, mainly in the vasa recta, the thick ascending limb of Henle's loop and the collecting duct. While compensated CHF is associated with upregulation of ETB in the collecting duct and vasa recta, decompensated CHF is accompanied with enhanced ETB abundance in the vasa recta and remarkable downregulation of this receptor subtype in the collecting duct. The findings suggest that upregulation of ETA may lead to a decrease in cortical blood flow while upregulation of ETB in the vasa recta probably contributes to the preservation of medullary blood flow. Furthermore, downregulation of ETB in the collecting duct, only in rats with decompensated CHF, could contribute to sodium retention in that subgroup.

Nitric oxide and renal nerves: Comparison of effects on renal circulation and sodium excretion in anesthetized rats

An array of vasoconstrictor and vasodilator agents have the potential to control intrarenal circulation; however, their relative functional importance is unclear. We compared here the importance of nitric oxide and renal nerves in studies involving sequential blockade of nitric oxide synthesis and renal denervation. In anesthetized rats, N-nitro-L-arginine methylester (L-NAME) was used for nonselective inhibition of nitric oxide synthesis and 7-nitroindazole (7-NI) for inactivation of neuronal isoform of nitric oxide synthase (nNOS). Acute unilateral renal denervation was performed noninvasively enabling observation of rapid changes. Renal cortical and medullary blood flow was determined by laser Doppler flowmetry. L-NAME decreased medullary blood flow and cortical blood flow, by 22% to 24%, whereas after 7-NI, medullary blood flow decreased by 22% and cortical blood flow about 10% (all changes significant). In untreated rats denervation significantly increased cortical blood flow (10% to 15%) but not medullary blood flow. In rats treated with L-NAME denervation partly prevented the post-inhibitor decrease in cortical blood flow but not in medullary blood flow. After 7-NI treatment, the decrease in cortical blood flow and medullary blood flow did not occur or a partial restoration of flow was seen. The denervation natriuresis was intact under L-NAME but attenuated following 7-NI. A reduction of medullary blood flow after 7-NI, similar as after L-NAME, suggests that nitric oxide generated by nNOS is mainly responsible for adequate perfusion of the medulla whereas activity of nNOS and other isoform(s) is required to maintain cortical blood flow. Renal denervation partly restored cortical blood flow reduced by nitric oxide blockade. For medullary blood flow, such restoration was seen only after inactivation of nNOS alone, suggesting an intrinsic interaction of this isoform and renal nerves.

Differential regulation of renal endothelin eta and etb receptors in rats withexperimental heart failure

P-94 Key Words: Endothelin Receptors, Kidney, Heart Failure

Renal vascular effects of frusemide in the rat: influence of salt loading and the role of angiotensin II.

We showed recently that post-frusemide (furosemide) natriuresis was associated with a major depression of medullary circulation. In the present study, prior to administration of frusemide the tubular transport of NaCl was modified by loading the animals with 5% saline to elucidate a possible interrelation between the tubular and vascular effects of the drug. Moreover, a possible involvement of the renin-angiotensin system was examined by pharmacological blockade using captopril, an inhibitor of angiotensin converting enzyme (1 mg x kg(-1), I.V.), or losartan, a selective inhibitor of angiotensin AT1 receptor (10 mg x kg(-1), I.V.). The effects of frusemide (0.25 mg x kg(-1) I.V., then the same dose given over 1 h) on renal medullary and cortical circulation (using laser-Doppler flowmetry) and renal excretion of sodium (U(Na)V), water and total solutes were measured in anaesthetised rats. With no pre-treatment, frusemide decreased the medullary flow (36.6 +/- 6.0%) significantly more than the cortical flow (10.1 +/- 1.0%; P < 0.001). The difference between the medulla and cortex was not significant in rats which showed high U(Na)V after hypertonic saline loading (2.0 +/- 0.4 vs. 0.4 +/- 0.1 micromol x min(-1) in non-loaded rats): 21.1 +/- 3.9% and 15.8 +/- 1.5%, respectively. At very high U(Na)V (9.5 +/- 1.1 micromol x min(-1)) the post-frusemide decrease in blood flow tended to be smaller in the medulla (7.6 +/- 7.7%) than in the cortex (16.2 +/- 2.6%). The fall in medullary blood flow was attenuated by pre-treatment with captopril (22.0 +/- 3.3%) and abolished by pre-treatment with losartan (2.8 +/- 11.8%). The decrease in cortical blood flow was not changed by hypertonic saline or angiotensin II blockers. The abolition of the post-frusemide depression of medullary blood flow by previous salt loading confirms the proposed link between tubular transport status and vasoconstriction. A similar modification of the response by blockade of the renin-angiotensin system suggests that the system is involved in the mechanism of medullary vasoconstriction.

A role for the angiotensin IV/AT 4 system in mediating natriuresis in the rat

Angiotensin II (AngII) or Angiotensin IV (AngIV) was infused into the renal artery of anesthetized rats while renal cortical blood flow was measured via laser Doppler flowmetry. The infusion of AngII produced a significant elevation in mean arterial pressure (MAP) with an accompanying decrease in cortical blood flow, glomerular filtration rate (GFR), urine volume, and urine sodium excretion. The infusion of AngIV induced significant increases in renal cortical blood flow and urine sodium excretion, without altering MAP, GFR, and urine volume. Pretreatment infusion with a specific AT 1 receptor antagonist, DuP 753, blocked or attenuated the subsequent AngII effects, while pretreatment infusion with the specific AT 4 receptor antagonist, Divalinal-AngIV, blocked the AngIV effects. These results support distinct and opposite roles for AngII and AngIV, i.e. AngII acts as an anti-natriuretic agent, while AngIV acts as a natriuretic agent.

Cerebral blood flow and metabolism in silent brain infarction and related cerebrovascular disorders

The appropriate management of silent stroke requires better understanding of the haemodynamic status in the brain. However, only a few studies have examined cerebral blood flow and metabolism in subjects with silent stroke. Positron emission tomography demonstrated a slight decrease in cortical blood flow with an increase in oxygen extraction fraction (ie misery perfusion) in subjects with silent brain infarction, whereas both cerebral blood flow and oxygen metabolism decreased in patients with symptomatic brain infarction (matched hypoperfusion). These findings confirm that brain circulation is haemo-dynamically compromised in subjects with silent stroke. Another important point is that subcortical silent stroke may induce a reduction in cortical blood flow and metabolism by a disconnection mechanism (ie diaschisis) between the cortex and the subcortical structures. Silent infarction is not innocuous in terms of compromised cerebral circulation, which may lead to cognitive decline or subsequent clinical stroke. In the future, further developments in functional imaging will permit a more sophisticated analysis of brain circulation and metabolism in silent stroke.

Role of NO and cytochrome P-450-derived eicosanoids in ET-1-induced changes in intrarenal hemodynamics in rats.

Endothelin-1 (ET-1) produces potent renal effects that we have previously shown to be dependent on cytochrome P-450 (CYP450) metabolites of aracidonic acid (24) This study evaluated the role of these metabolites in the effects produced by ET-1 on renal blood flow (RBF), cortical blood flow (CBF), medullary blood flow (MBF), and mean arterial blood pressure (MBP). ET-1 (20-200 pmol/kg) increased MBP, renal vascular resistance (RVR), and MBF but reduced CBF and RBF in a dose-dependent manner. The decreases in CBF and RBF, and increases in MBP and RVR were blunted by BMS-182874, an ET(A) receptor antagonist or BQ-788, an ET(B) receptor antagonist. Similarly, indomethacin, an inhibitor of cyclooxygenase activity, or 12,12-dibromododecenoic acid (DBDD), a CYP450-dependent inhibitor of production of 20-hydroxyeicosatetraenoic acid (20-HETE), blunted these effects. ET-3 elicited dose-related reduction in CBF and increase in MBF. Indomethacin accentuated the reduction in CBF and attenuated the increase in MBF, as did DBDD. ET-1-induced increase in MBF was attenuated by BQ-788, N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, indomethacin, or DBDD. DBDD inhibited the hemodynamic effects of L-NAME. Miconazole, the inhibitor of CYP450-dependent epoxygenase activity, was without effect. These results indicate that hemodynamic changes produced by ET-1 are mediated by vasoconstrictor prostanoids and/or prostanoid-like substances, possibly, 20-HETE via activation of ET(A) and ET(B) receptors. However, the increase in MBF is mediated by vasodilator prostanoids or by NO via ET(B) receptor activation.

Capsaicin-sensitive mechanisms are involved in cortical spreading depression-associated cerebral blood flow changes in rats

We tested the hypothesis that capsaicin-sensitive mechanisms play a role in the cortical spreading depression (CSD)-related changes in cortical blood flow (CBF). CBF was measured with laser Doppler flowmetry in anesthetized rats. The animals were treated with capsaicin before (48 h–2 weeks) or during the experiments. This agent is thought to stimulate small-diameter sensory nerve fibers selectively and to deplete stored peptides. In the vehicle-treated group ( n=8), the peak value of the CSD-associated hyperperfusion was 257±12% above the baseline (mean±SEM, P<0.05). In the groups treated with 20 and 40 μg/kg or 20 mg/kg capsaicin, there were only small decreases in CBF. In the groups treated with 100 mg/kg capsaicin, the CSD-associated hyperemia was reduced at 48 h (158±7%, P<0.05). However, at 96 h a transient hyperresponsiveness (390±38%, P<0.05) was observed, which had disappeared by 2 weeks. These results indicate that the manipulation of sensory neuropeptide stores results in a biphasic effect on CSD-induced CBF responses.

Effects of A-192621.1, a specific endothelin-B antagonist, on intrarenal hemodynamic responses to endothelin-1.

The present study examined the effects of A-192621.1, a highly selective endothelin-B- (ETB) receptor antagonist, on the renal hemodynamic and systemic actions of endothelin-1 (ET-1). Intravenous injection of ET-1 (1.0 nmol/kg) into anesthetized rats produced a sustained decrease in renal blood flow (assessed by ultrasonic flowmeter) and a significant increase in renal vascular resistance, as well as an increase in mean arterial pressure. These changes were significantly augmented by pretreatment with A-192621.1 (3.0 mg/kg/h). Analysis of intrarenal blood flow by laser-Doppler flowmeter revealed that ET-1 caused a marked and sustained decrease in cortical blood flow, associated with a transient increase in medullary blood flow. The reduction in cortical blood flow in response to ET-1 was further enhanced by pretreatment with A-192621.1, whereas the ET-1-induced medullary vasodilatation was completely abolished and reversed into a vasoconstrictor response. These findings suggest that the ETB-receptors mediate the systemic and renal vasodilatory actions of ET-1 in the rat, and that their activation may serve as a physiological counterbalance that modulates ET-1-induced vasoconstriction.

Regulation of intrarenal blood flow in experimental heart failure: role of endothelin and nitric oxide.

Congestive heart failure(CHF) is associated with a marked decrease in cortical blood flow and preservation of medullary blood flow. In the present study we tested the hypothesis that changes in the endothelin (ET) and nitric oxide (NO) systems in the kidney may contribute to the altered intrarenal hemodynamics in rats with aortocaval fistula, an experimental model of CHF. Cortical and medullary blood flow were measured simultaneously by laser-Doppler flowmetry in controls and rats with compensated and decompensated CHF. As previously reported [K. Gurbanov, I. Rubinstein, A. Hoffman, Z. Abassi, O. S. Better, and J. Winaver. Am. J Physiol. 271 (Renal Fluid Electrolyte Physiol. 40): F1166-F1172, 1996], administration of ET-1 in control rats produced a sustained cortical vasoconstriction and a transient medullary vasodilatory response. In rats with decompensated CHF, cortical vasoconstriction was severely blunted, whereas ET-1-induced medullary vasodilation was significantly prolonged. This prolonged response was mimicked by IRL-1620, a specific ETB agonist, and partially abolished by NO synthase (NOS) blockade. In line with these findings, expression of ET-1, ETA and ETB receptors, and endothelial NOS (eNOS), assessed by RT-PCR, and eNOS immunoreactivity, assessed by Western blotting, was significantly higher in the medulla than in the cortex. Moreover, expression of ET-1 mRNA in the cortex and eNOS mRNA in the cortex and the medulla increased in proportion to the severity of heart failure. These findings indicate that CHF is associated with altered regulation of intrarenal blood flow, which reflects alterations in expression and activity of the ET and NO systems. It is further suggested that exaggerated NO activity in the medulla contributes to preservation of medullary blood flow in the face of cortical vasoconstriction in CHF.

Autoradiographic Identification of Kidney Angiotensin IV Binding Sites and Angiotensin IV-Induced Renal Cortical Blood Flow Changes in Rats

Coleman, J. K. M., L. T. Krebs, T. A. Hamilton, B. Ong, K. A. Lawrence, M. F. Sardinia, J. W. Harding and J. W. Wright. Autoradiographic identification of kidney angiotensin IV binding sites and angiotensin IV-induced renal cortical blood flow changes in rats. Peptides 19(2) 269–277, 1998.—The present investigation initially determined that specific binding sites for the hexapeptide angiotensin IV (AngIV) are present in the rat kidney cortex and outer medulla but not in the inner medulla, using in vitro autoradiographic techniques. This binding site has been termed AT 4, is distinct from the previously characterized AT 1 and AT 2 sites, and does not bind the specific AT 1 receptor antagonist DuP753 or the AT 2 receptor antagonist PD123177. Renal artery infusions of AngIV produced a dose-dependent increase in cortical blood flow without altering systemic blood pressure. In contrast, the infusion of angiotensin II (AngII) induced a dramatic decrease in cortical blood flow, accompanied by a significant elevation in systemic blood pressure. The infusion of [D-Val 1]AngIV, an analog that does not bind at the AT 4 receptor site, and the C-terminal truncated analogs AngIV (1-4) and AngIV (1-5) that possess lower affinity for this site, produced no change in cortical blood flow. The infusion of [Nle 1]AngIV and [Lys 1]AngIV, analogs that bind with high affinity at the AT 4 receptor site, produced increases in cortical blood flow with no influence on blood pressure. Pretreatment with a specific AT 4 receptor antagonist, Divalinal-AngIV, completely blocked AngIV-induced elevations in blood flow, but failed to influence AngII-induced decreases in blood flow, suggesting that these ligands are acting at different receptor sites. Pretreatment with the nitric oxide synthase inhibitor, N G-Monomethyl-L-Arginine, also blocked subsequent AngIV-induced increases in cortical blood flow. These data support the notion that AngIV exerts a unique influence upon renal hemodynamics via the AT 4 receptor subtype, and suggest that AngIV-induced elevations in blood flow may be mediated by nitric oxide.

Effect of stimulation of the nucleus basalis of Meynert and somatic afferents on experimentally-induced decreases in cortical blood flow in anesthetized rats

Platelets play a role in repair of vessels and contain different growth factors, including nerve growth factor (NGF). Since NGF is the most potent growth factor to support survival of cholinergic neurons, we aimed to study the effects of platelet-derived NGF on cholinergic neurons in organotypic brain slices. Brain slices of the nucleus basalis of Meynert (nBM) were cultured with or without NGF (10 ng/ml) or platelet extracts (100 μg/ml) or fresh platelets (108 platelets/ml). In order to enhance NGF in platelets recombinant NGF (100 ng) was loaded into platelets using ultrasound (3 h). Our data show that recombinant NGF markedly supports survival of cholinergic neurons. The addition of fresh platelets showed a tendency for enhancing cholinergic neuron numbers, while platelet extracts had no effects. Ultrasound was highly effective to load recombinant NGF into platelets. The addition of NGF-loaded platelets markedly enhanced cholinergic neuron numbers. In conclusion, our data provide evidence that NGF-derived platelets may counteract cell death of cholinergic neurons.

Pathogenesis of subcortical visuo-spatial neglect. A HMPAO SPECT study

The pathophysiology of neuropsychological disorders due to right deep-seated hemispheric lesions remains a debated point. We undertook this study to check the hypothesis according to which remote cortical dysfunction could be responsible for the occurrence of neglect. Twenty-eight patients presenting with a right-sided subcortical stroke were studied. A neuropsychological battery of tests suitable for assessment of possible visuo-spatial neglect was performed as well as HMPAO SPECT. Neglect was observed in 15 cases out of 28. The lesion's site (at CT and/or MRI) did not allow discrimination between patients without neglect and patients with neglect. The latter however could be distinguished from the former by the presence of a remote decrease in cortical blood flow in the right temporo-parietal region. By suggesting that cortical involvement is necessary for the occurrence of neglect, the results were interpreted according to a network approach in which subcortical neglect is attributed to a cortical deprivation from afferent input in the posterior part of the brain.