Penetrating Arterioles Research Articles

Topological basis for the robust distribution of blood to rodent neocortex

The maintenance of robust blood flow to the brain is crucial to the health of brain tissue. We examined the pial network of the middle cerebral artery, which distributes blood from the cerebral arteries to the penetrating arterioles that source neocortical microvasculature, to characterize how vascular topology may support such robustness. For both mice and rats, two features dominate the topology. First, interconnected loops span the entire territory sourced by the middle cerebral artery. Although the loops comprise <10% of all branches, they maintain the overall connectivity of the network after multiple breaks. Second, >80% of offshoots from the loops are stubs that end in a single penetrating arteriole, as opposed to trees with multiple penetrating arterioles. We hypothesize that the loops and stubs protect blood flow to the parenchyma from an occlusion in a surface vessel. To test this, we assayed the viability of tissue that was sourced by an individual penetrating arteriole following occlusion of a proximal branch in the surface loop. We observed that neurons remained healthy, even when occlusion led to a reduction in the local blood flow. In contrast, direct blockage of a single penetrating arteriole invariably led to neuronal death and formation of a cyst. Our results show that the surface vasculature functions as a grid for the robust allocation of blood in the event of vascular dysfunction. The combined results of the present and prior studies imply that the pial network reallocates blood in response to changing metabolic needs.

Effect of Hyperglycemia on Brain Penetrating Arterioles and Cerebral Blood Flow Before and After Ischemia/Reperfusion

The effect of preexisiting hyperglycemia on cerebral blood flow (CBF) and brain penetrating arterioles before and after 2 h of ischemia and 30 min of reperfusion was determined. Male Wistar rats that were either hyperglycemic (50 mg/kg streptozotocin; n=24) or normoglycemic (n=24) were subjected to transient ischemia by filament occlusion or nonischemic. CBF was measured prior to ischemia using microspheres and during transient ischemia using laser Doppler. Edema was compared by wet/dry weights. Constriction to apamin, TRAM-34, and L-NNA, inhibitors of small- and intermediate-conductance calcium-activated potassium channels (SK and IK) and nitric oxide, were compared in penetrating arterioles from the ischemic hemisphere to investigate changes in basal tone and endothelium-dependent vasodilator responses. Preexisiting hyperglycemia did not affect CBF in non-ischemic animals or after transient ischemia; however, edema was significantly greater. Ischemia and reperfusion caused decreased basal tone in penetrating arterioles similarly in normoglycemic and hyperglycemic animals that was restored by apamin, and further increased by TRAM-34 and L-NNA. The restoration of tone in penetrating arterioles by apamin and TRAM-34 suggests that transient ischemia activates SK and IK channels in penetrating arterioles. This effect of ischemia was not different between normoglycemic and hyperglycemic animals, suggesting that it was related to ischemia and reperfusion rather than hyperglycemia.

Soluble amyloid-β, effect on cerebral arteriolar regulation and vascular cells

BackgroundEvidence indicates that soluble forms of amyloid-β (Aβ) are vasoactive, which may contribute to cerebrovascular dysfunction noted in patients with Alzheimer's Disease and cerebral amyloid angiopathy. The effects of soluble Aβ on penetrating cerebral arterioles - the vessels most responsible for controlling cerebrovascular resistance - have not been studied.ResultsFreshly dissolved Aβ1-40 and Aβ1-42, but not the reverse peptide Aβ40-1 constricted isolated rat penetrating arterioles and diminished dilation to adenosine tri-phosphate (ATP). Aβ1-42 also enhanced ATP-induced vessel constriction. Aβ1-40 diminished arteriolar myogenic response, and an anti-Aβ antibody reduced Aβ1-40 induced arteriolar constriction. Prolonged Aβ exposure in vessels of Tg2576 mice resulted in a marked age-dependent effect on ATP-induced vascular responses. Vessels from 6 month old Tg2576 mice had reduced vascular responses whereas these were absent from 12 month old animals. Aβ1-40 and Aβ1-42 acutely increased production of reactive oxygen species (ROS) in cultured rat cerebro-microvascular cells. The radical scavenger MnTBAP attenuated this Aβ-induced oxidative stress and Aβ1-40-induced constriction in rat arterioles.ConclusionsOur results suggest that soluble Aβ1-40 and Aβ1-42 directly affect the vasomotor regulation of isolated rodent penetrating arterioles, and that ROS partially mediate these effects. Once insoluble Aβ deposits are present, arteriolar reactivity is greatly diminished.

Dually Supplied T-Junctions in Arteriolo-Arteriolar Anastomosis in Mice

The functional role of arteriolo-arteriolar anastomosis (AAA) between the middle cerebral artery (MCA) and anterior cerebral artery in local hemodynamics is unknown, and was investigated here. Blood flow in AAAs was examined using fluorescein isothiocyanate-labeled red blood cells (RBCs) as a flow indicator in 16 anesthetized C57BL/6J mice before and after MCA occlusion up to 7 experimental days. We observed paradoxical flow in AAAs; labeled RBCs entered from both the MCA and anterior cerebral artery sides and the opposing flows met at a branching T-junction, where the flows combined and passed into a penetrating arteriole. The dually fed T-junction was not fixed in position, but functionally jumped to adjacent T-junctions in response to changing hemodynamic conditions. On MCA occlusion, RBC flow from the MCA side immediately stopped. After a period of "hesitation," blood started to move retrogradely in one of the MCA branches toward the MCA stem. The retrograde blood flow was statistically significantly (P<0.05), serving to feed blood to other MCA branches after a lag period. In capillaries, MCA occlusion induced immediate RBC disappearance in the ischemic core and to a lesser extent in the marginal zone near AAAs. At day 3 after ischemia, we recognized the beginning of remodeling with angiogenesis centering on AAAs. AAAs appear to play a key role in local hemodynamic homeostasis, both in the normal state and in the development of collateral channels and revascularization during ischemia.

Mechanism of ATP-Induced Local and Conducted Vasomotor Responses in Isolated Rat Cerebral Penetrating Arterioles

Background: Adenosine triphosphate (ATP), a potent vascular regulator in the cerebral circulation, initiates conducted vasomotor responses which may be impaired after pathological insults. We analyzed the mechanism of ATP-induced local vasomotor responses and their effect on conducted vasomotor responses in rat cerebral penetrating arterioles. Methods: Arterioles were cannulated and their internal diameter monitored. Vasomotor responses to ATP were observed in the presence or absence of inhibitors, or after endothelial impairment. Smooth muscle membrane potentials were measured in some vessels. Results: Microapplication of ATP produced a biphasic response (constriction followed by dilation), which resulted in conducted dilation preceded by a membrane hyperpolarization. α,β-methylene-ATP or pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) blunted the ATP-mediated constriction and enhanced local and conducted dilation. N^ω-monomethyl-L-arginine, endothelial impairment and N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH) reduced the local dilation caused by ATP. The conducted dilation was attenuated by MS-PPOH and endothelial impairment, but not N^ω-monomethyl-L-arginine or indomethacin. Conclusion: ATP-induced conducted dilation is preceded by membrane hyperpolarization. Local ATP induces initial local constriction via smooth-muscle P_2X1 and subsequent dilation via endothelial P_2Y receptors. Nitric oxide, cytochrome P450 metabolites, and intermediate and large conductance K_Ca channels mediate dilation caused by ATP. ATP-induced conducted dilation is dependent upon both the endothelium and cytochrome P450 metabolites.

Spontaneous intracerebral haemorrhage in adults: a literature overview

A large number of reports have analysed epidemiology, pathogenesis, symptomatology, diagnostics and options for medical and surgical treatment of intracerebral haemorrhage. Nevertheless, management still remains controversial. The purpose of the present review is to summarise the clinical data and derive a current updated management concept as a result. The analysis was based on a Medline search to November 2006 for the term "intracerebral haemorrhage" (ICH). The clinical query functions were optimised for aetiology, diagnosis and therapy to limit the results. A total of 103 articles were found eligible for review. Race, age and sex influence the occurrence of ICH. Moreover, hypertension and alcohol consumption are the paramount risk factors. The most frequent pathophysiological mechanism of ICH seems to be a degenerative vessel wall change and, in consequence, rupture of small penetrating arteries and arterioles of 50-200 microm in diameter. The symptomatology depends on the size of ICH, possible rebleeding and the occurrence of hydrocephalus or seizures. The outcome is worse with concomitant occurrence of intraventricular haemorrhage. Treatment with recombinant factor VIIa (rFVIIa) within four hours after the onset of ICH limits the growth of haematoma, reduces mortality and improves functional outcome. Minimally invasive surgery tends to improve functional outcome. A systematic knowledge of currently available data on epidemiology, pathogenesis and symptomatology, the use of diagnostics and the different conservative and surgical treatment options can lead to a balanced management strategy for patients with ICH.

ATP‐induced local and conducted vasomotor mechanisms in isolated rat cerebral penetrating arterioles

Background ATP is a regulator in the cerebral circulation and initiates conducted vasomotor responses. We analyzed the mechanism of ATP-induced local and conducted vasomotor responses in rat cerebral penetrating arterioles. Methods Arterioles were cannulated and their internal diameter monitored with a video microscope. Vasomotor responses to micro-application of ATP were obtained in the presence or absence of inhibitors. Intracellular membrane potentials of smooth muscle cells were measured in some vessels. Results Topical micro-application of ATP produced a biphasic response (constriction followed by dilation), resulting in conducted vasomotor responses. Conducted dilation was preceded by membrane hyperpolarization. a.b-methylene-ATP or pyridoxal phosphate-6-azophenyl-2′,4′-disulphonic acid blunted the ATP-mediated constriction and enhanced the dilation. No-monomethyl-L-arginine, clotrimazole, and endothelial impairment inhibited the local dilation of ATP. In contrast, the conducted dilation was attenuated by clotrimazole, MS-PPOH and endothelial impairment, but not No-monomethyl-L-arginine. Conclusions Our results indicate that 1) ATP-induced conducted dilation is preceded by hyperpolarization; 2) ATP induces initial local constriction via smooth muscle P2X1 and secondary dilation via endothelial P2Y2 receptors in the cerebral arterioles; 3) Nitric oxide and cytochrome P-450 metabolites contribute to local dilation of ATP; 4) ATP-induced conducted dilation is regulated by the endothelium and cytochrome P-450 metabolites. NIH HL57540 (HHD) and NS30555 (RGD and HHD).

Cilostazol, an Inhibitor of Type 3 Phosphodiesterase, Produces Endothelium-Independent Vasodilation in Pressurized Rabbit Cerebral Penetrating Arterioles

We investigated the effects of cilostazol, a potent inhibitor of cGMP-inhibited cAMP phosphodiesterase, on mechanical activity of isolated pressurized rabbit cerebral penetrating arterioles with special reference to the function of the endothelium. Both cilostazol and milrinone, another inhibitor of cAMP phosphodiesterase, produced vasodilation of the cerebral penetrating arterioles in a dose-dependent manner. Pretreatment with selective inhibitors of cyclooxygenase or nitric oxide synthase, or chemical denudation of the endothelial cells caused no significant effect on the cilostazol-mediated vasodilation of the cerebral arterioles. A selective large-conductance calcium-activated potassium channel inhibitor, iberiotoxin, and a selective protein kinase A inhibitor, H-89, caused no significant effect on the cilostazol-mediated vasodilation. In the cerebral arterioles, low concentration (10^–6M) of cilostazol or milrinone caused a significant shift of the dose-vasodilatory response curve for adenosine to the left. These findings suggest that cilostazol produces vasodilation independent of the presence of the endothelium or activation of endogenous vasodilative prostaglandins, nitric oxide, calcium-activated potassium channel and protein kinase A. In conclusion, the vasodilator action of cilostazol may, in part, contribute to the beneficial effect of preventing lacunar cerebral infarction in patients with functional damage of the endothelium in cerebral penetrating arterioles.

C-Reactive Protein and Cerebral Small-Vessel Disease

Stroke places a large burden on healthcare and social services resources in the older adult population. Because the incidence of stroke increases with advancing age, and the population is aging, the number of patients affected by stroke is increasing. See p 900 The burden of stroke goes well beyond those cases that are clinically recognized. Imaging techniques of the brain have revealed a remarkably high prevalence of white matter lesions (WML) and silent brain lacunar infarcts (SBLI). In the National Heart, Lung, and Blood Institute–sponsored Cardiovascular Health Study, SBLI ≥3 mm were found in 31% of all subjects.1 Fewer than 15% of patients with such lesions had a clinical history of stroke. The prevalence of SBLI increased with advancing age; 22% of subjects 65 to 69 years old had SBLI, as compared with 43% in subjects ≥80 years old. WML involving in particular the centrum ovale are a subject of great interest. Partly this is because modern neuroimaging methods detect subcortical WM changes with increasing frequency in people >60 years old and also because these abnormalities may be associated with specific neurobehavioral deficits, including dementing syndromes.2 The descriptive term leukoaraiosis (LA), frequently applied to these neuroimaging abnormalities of the WM, refers to bilateral and either patchy or diffuse areas of hypodensity on CT or hyperintensity on T2-weighted MRI.3 In this issue of Circulation , van Dijk and colleagues4 explore the relationship of C-reactive protein (CRP), a well-known systemic marker of inflammation, with the severity and progression of cerebral WML/LA on MRI scans. The investigators examined the prevalence and incidence of brain WML/LA and SBLI in the prospective cohort of 1033 older adult participants of the population-based Rotterdam Scan study. They confirmed a relationship between inflammation and the severity and progression of cerebral WML/LA and SBLI independent …

Acute amyloid-beta, cerebral penetrating arterioles and oxygen radical

Amyloid-beta (Ab) is the hallmark peptide deposited in amyloid plaques found in Alzheimer's disease. Ab is primarily and continuously produced by astroglia with nano-molar concentrations in the cerebro-spinal fluid (CSF). However, after head trauma, an Ab increase in the CSF into the micro-molar range was observed. The effect of such increased concentrations of Ab on the cerebral micro-vasculature is not known.

Endothelium-dependent flow-induced vasodilation in pressueized rabbit cerebral penetrating arterioles.

Endothelium-dependent flow-induced vasodilation in pressueized rabbit cerebral penetrating arterioles.

Fibrosis and Stenosis of the Long Penetrating Cerebral Arteries: the Cause of the White Matter Pathology in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) the vascular smooth muscle cells are destroyed and granular osmiophilic material is deposited followed by fibrosis of the arterial wall. To verify whether true stenosis of the fibrotic white matter arteries is a key pathogenic event in CADASIL, we analyzed the thickness of walls (expressed as sclerotic index) and luminal diameters of penetrating arterioles in both grey matter and white matter of four CADASIL patients due to the C475T (R133C) mutation in the Notch3 gene and in 9 age-matched controls. We also reconstructed 9 arterioles from 1000 serial sections in two CADASIL patients. The thickness of the arteriolar walls in both grey matter and white matter was significantly increased in the CADASIL patients compared with controls. Furthermore, in CADASIL patients the arteriolar walls were significantly thicker in the white matter than in the grey matter. The distribution curve of arteriolar internal diameters in CADASIL patients shifted towards smaller sizes. In serial sections, the marked increase in the thickness of the white matter penetrating arterioles or their branches did not occur until the internal diameters had decreased to about 20 to 30 pm and external diameters to about 100 to 130 microm. In conclusion, long penetrating arterioles and their branches supplying subcortical structures in CADASIL are stenosed and their walls are thickened. This conforms to the abundance of infarcts and primary ischemic damage in CADASIL patients' white matter.

Pelvic Castleman's disease presenting as an adnexal tumor

Pelvic Castleman's disease presenting as an adnexal tumor

Mechanism of extracellular K+-induced local and conducted responses in cerebral penetrating arterioles.

Extracellular concentration of potassium ion ([K+]o) may have a significant influence on the cerebral circulation in health and disease. Mechanisms of [K+]o-induced conducted vasomotor responses in cerebral arterioles, possibly linking microvascular regulation to neuronal activity, have not been examined. We analyzed vascular responses to small increases of [K+]o (up to 5 mmol/L) in isolated, cannulated, and pressurized rat cerebral arterioles (36.5+/-1.4 micro m). [K+]o was elevated globally through extraluminal application or locally through micropipette, while arteriolar diameter was measured online. Elevation of [K+]o (5 mmol/L) produced dilation that was inhibited by ouabain but not BaCl2. Locally applied [K+]o (3 to 5 mmol/L) produced a biphasic response (initial constriction followed by dilation), both of which were conducted to the remote site (distance 1142+/-68 microm). Endothelial impairment inhibited conducted but not local biphasic responses. Extraluminal ouabain attenuated local and conducted secondary dilation but not initial constriction. The local biphasic response was unaffected by extraluminal or intraluminal BaCl2. Extraluminal but not intraluminal BaCl2 impaired both conducted constriction and dilation. In rat penetrating arteriole, (1) [K+]o (3 to 5 mmol/L) strongly regulates arteriolar tone and causes conducted vasomotor responses; (2) local responses to elevated [K+]o are endothelium independent but conducted responses are dependent on an intact endothelium; (3) smooth muscle Na+-K+-ATPase activation is the generator of conducted dilation; and (4) smooth muscle inward rectifier potassium channels sustain conduction. Our findings suggest that potassium-induced conducted vasomotor responses may link local neuronal activity to microvascular regulation, which may be attenuated in pathological conditions.

Should patients with lacunar stroke and severe carotid artery stenosis undergo endarterectomy?

The concept of lacunar infarction (LI) has been long recognized, but it was Fisher who first drew attention to the association with distinct clinical syndromes.1–,4 In his original description, LIs were described as small subcortical infarcts affecting the basal ganglia, internal capsule, thalamus or pons, which occurred in association with occlusion of deep penetrating arterioles on a background of hypertensive small‐vessel disease, chiefly lipohyalinosis and microatheroma.1–,4 If this aetiopathogenetic description holds true for all patients, an associated severe ipsilateral carotid artery stenosis (CAS) would be regarded as coincidental rather than causative. Given that severe asymptomatic disease is often best managed medically, as the benefit of carotid endarterectomy (CEA) is marginal and cannot be recommended unless the perioperative complication rate is 70% ipsilateral CAS, irrespective of ischaemic stroke subtype.8 What, then, is the evidence that patients with LI are likely to benefit from this procedure? To answer this question, we performed a search of Medline/PubMed databases, as well as the Cochrane Database of Systematic Reviews, entering the terms ‘lacunar stroke’, ‘lacunar infarction’, ‘lacunes’ and ‘carotid endarterectomy’. References arising from these articles were also searched and in some cases, authors of key articles were contacted directly. LI accounts for one quarter of all ischaemic strokes,9 and differentiation from other stroke subtypes is important, as the prognosis tends to be better in terms of mortality, disability and recurrence.10–,12 Most patients present with one of five classical syndromes (see Table 1) which have a high positive predictive value for LI,1–,4 though other entities such as primary intracerebral haemorrhage occasionally present …

Effects of luminal shear stress on cerebral arteries and arterioles

The effect of luminal shear stress was studied in cerebral arteries and arterioles. Middle cerebral arteries (MCA) and penetrating arterioles (PA) were isolated from male Long-Evans rats, mounted in a tissue bath, and pressurized. After the development of spontaneous tone, inside diameters were 186 +/- 5 microm (n = 28) for MCA and 65 +/- 3 microm (n = 37) for PA. MCA and PA constricted approximately 20% with increasing flow. Flow-induced constriction persisted in MCA and PA after removal of the endothelium. After removal of the endothelium, the luminal application of a polypeptide containing the Arg-Gly-Asp amino acid sequence (inhibitor of integrin attachment) abolished the flow-induced constriction. Similarly, an antibody specific for the beta(3)-chain of the integrin complex significantly inhibited the flow-induced constriction. The shear stress-induced constriction was accompanied by an increase in vascular smooth muscle Ca(2+). For example, a shear stress of 20 dyn/cm(2) constricted MCA 8% (n = 5) and increased Ca(2+) from 209 +/- 17 to 262 +/- 29 nM (n = 5). We conclude that isolated cerebral arteries and arterioles from the rat constrict to increased shear stress. Because the endothelium is not necessary for the response, the shear forces must be transmitted across the endothelium, presumably by the cytoskeletal matrix, to elicit constriction. Integrins containing the beta(3)-chain are involved with the shear stress-induced constrictions.

Muscarinic--but not nicotinic--acetylcholine receptors mediate a nitric oxide-dependent dilation in brain cortical arterioles: a possible role for the M5 receptor subtype.

Increases in cortical cerebral blood flow are induced by stimulation of basal forebrain cholinergic neurons. This response is mediated in part by nitric oxide (NO) and reportedly involves both nicotinic and muscarinic receptors, some of which are possibly located in the vessel wall. In the present study, the vasomotor response(s) elicited by acetylcholine (ACh) on isolated and pressurized bovine and/or human intracortical penetrating arterioles were investigated, and pharmacological characterization of the receptor involved in this response was carried out. Acetylcholine (10(-11) to 10(-4) mol/L) dose dependently dilated bovine and human intracortical arterioles at spontaneous tone (respective pD2 values of 6.4+/-0.3 and 7.2+/-0.3 and E(Amax) of 65.0+/-26.8 and 43.2+/-30.1% of the maximal dilation obtained with papaverine) and bovine arterioles after preconstriction with serotonin (pD2 = 6.3+/-0.1, E(Amax) = 80.0+/-17.9% of induced tone). In contrast, nicotine (10(-8) to 10(-4) mol/L) failed to induce any vasomotor response in bovine vessels whether at spontaneous or at pharmacologically induced tone. Application of the nitric oxide synthase (NOS) inhibitor Nomega-nitro-L-arginine (L-NNA; 10(-5) mol/L) elicited a gradual constriction (approximately 20%) of the arterioles, indicating the presence of constitutive NO release in these vessels. Nomega-Nitro-L-argigine (10(-5) to 10(-4) mol/L) also significantly blocked the dilation induced by ACh. The muscarinic ACh receptor (mAChR) antagonists pirenzepine, 4-DAMP, and AF-DX 384 dose dependently inhibited the dilatation induced by ACh (10(-5) mol/L) with the following rank order of potency: 4-DAMP (pIC50 = 9.2+/-0.3) >> pirenzepine (pIC50 = 6.7+/-0.4) > AF-DX 384 (pIC50 = 5.9+/-0.2). These results suggest that ACh can induce a potent, dose-dependent, and NO-mediated dilation of bovine and/or human intracortical arterioles via interaction with an mAChR that best corresponds to the M5 subtype.

Functional heterogeneity of endothelial P2 purinoceptors in the cerebrovascular tree of the rat.

The effects of stimulating P2Y1 or P2Y2 purinoceptors on the endothelium of isolated middle cerebral arteries (MCAs), third-order branches of the MCA (bMCAs), and penetrating arterioles (PAs) of the rat were studied. After pressurization and development of spontaneous tone (25% contraction), resting diameters for MCAs, bMCAs, and PAs were 203 +/- 5 (n = 50), 99 +/- 2 (n = 42), and 87 +/- 2 micron (n = 53), respectively. Luminal application of the P2Y1-selective agonist 2-methylthioadenosine 5'-triphosphate elicited dose-dependent dilations (or loss of intrinsic tone) in MCAs but not in bMCAs or PAs. The dilation in MCAs was completely blocked by removal of the endothelium or by nitro-L-arginine methyl ester (10(-5) M), an inhibitor of NO synthase. Luminal application of the P2Y2-selective agonist ATP elicited dilations in MCAs, bMCAs, and PAs. Removal of the endothelium abolished the dilations in all vessel groups. Dilations in MCAs have been shown to involve both NO and endothelium-derived hyperpolarizing factor (EDHF). The dilations in bMCAs and PAs had a minor NO component and prominent EDHF component; that is, 1) the dilations to ATP were not diminished by the combined inhibition of NO synthase and cyclooxygenase, 2) the dilations were accompanied by significant hyperpolarizations of the vascular smooth muscle (approximately 15 mV), and 3) the dilations were completely abolished by the calcium-activated potassium channel blocker charybdotoxin. We concluded that the role of NO in purinoceptor-induced dilations diminishes along the cerebrovascular tree in the rat, whereas the role of EDHF becomes more prominent.

Associations between neuropeptide Y nerve terminals and intraparenchymal microvessels in rat and human cerebral cortex

Neuropeptide Y (NPY) can influence local brain perfusion, possibly via direct relationships with the microvascular bed. To evaluate this possibility, the authors quantitatively analyzed by light and electron microscopy the morphological associations between immunostained NPY neuronal elements and intraparenchymal microvessels in the rat and human cerebral cortex. At the light microscopic level in the rat frontoparietal cortex, about 16% of NPY neurons and large proximal processes as well as a subset of nerve terminals not affected by double sympathectomy were associated with penetrating arterioles and local microvessels. In human temporal cortex, a dense network of NPY nerve fibers was observed, many of which approached and/or contacted intracortical vessels. At the ultrastructural level, 14% of NPY axonal varicosities in the rat cerebral cortex were considered perivascular and associated with capillaries (approximately 70%) or microarterioles (approximately 30%). They were particularly enriched in the immediate vicinity (< 0.25 micron) of the microvessels, where the perivascular astrocytic leaflets represented a frequent target. In human cerebral cortex, NPY varicosities were observed in proximity to microvessels corresponding primarily to capillaries. Perivascular NPY varicosities never established synaptic junctions with vascular or astroglial elements. The results show that central NPY nerve terminals associate with microvessels and perivascular astroglial cells in the rat and human cerebral cortex. Thus, NPY released from these nerves could possibly influence (via a parasynaptic mode of action) vascular and/or astrocytic functions depending on the distribution of NPY receptors in these cellular compartments. These results provide morphological support for the effects of NPY on brain perfusion and homeostasis.

Local and conducted vasomotor responses in isolated rat cerebral arterioles.

We tested the hypothesis that conduction of vasomotor responses occurs in cannulated and isolated rat cerebral penetrating arterioles. Both at the site of stimulation (local) and 500-650 microns distant from it, we observed the diameter responses and time courses thereof to pressure-ejected vasoactive stimuli. ATP locally caused an initial constriction (response onset at 0.3 s, average diameter 85% of control at 450-ms pulse with a maximum at 1.6 s after stimulation) followed by a secondary dilation (111% at 7 s). Conducted vasodilation of 111% was observed over a distance of 520 microns. Prostaglandin F2 alpha (PGF2 alpha) constricted the vessels locally (80%) and caused conducted vasodilation (110%). For both ATP and PGF2 alpha the local constriction occurred simultaneously to the conducted vasodilation. Adenosine dilated the vessels (123%) but produced only inconsistent conducted vasodilation. Hydrogen ions initially constricted the vessels (88%) and then dilated them to 113%. Thus, although ATP and PGF2 alpha are strong promoters of conduction, adenosine and hydrogen ions are not. Paradoxically, ATP and PGF2 alpha caused conducted vasodilation even though the initial local response was a vasoconstriction, indicating that in cerebral arterioles conduction may be mediated through endothelial cell mechanisms rather than through smooth muscle cell communication.