Loss of endothelium and receptor-mediated dilation in pial arterioles of rats fed a short-term high salt diet. (1/2638)

A high salt diet often is regarded as an accessory risk factor in hypertension, coincidental to the deleterious effect of high blood pressure on vasodilator function. The aim of this study was to determine whether short-term ingestion of a high salt diet per se impairs vasodilator function in the cerebral circulation independent of blood pressure changes. Adult Sprague-Dawley rats were fed a normal salt (0.8%) or high salt (4%) diet for 3 days. Mean arterial pressures were similar in the normal and high salt groups (123+/-2 and 125+/-2 mm Hg, respectively). Subsequently, the responses of the in situ pial arterioles to acetylcholine, iloprost, and sodium nitroprusside were determined in cranial windows using intravital videomicroscopy. Pial arterioles of rats fed normal and high salt diets showed similar resting diameters of 69+/-2 and 72+/-3 microm, respectively, but their reactivity patterns to vasodilator stimuli were markedly different. Arterioles of rats fed a normal salt diet dilated progressively up to 17+/-3% in response to the endothelium-dependent agent acetylcholine (10(-9) to 10(-6) mol/L) and dilated by 22+/-2% in response to the prostaglandin I2 receptor agonist iloprost (3x10(-11) mol/L). In contrast, pial arterioles of rats fed a high salt diet constricted by 4+/-3% and 8+/-2% in response to acetylcholine and iloprost, respectively. Sodium nitroprusside (10(-6) mol/L), a nitric oxide donor, dilated pial arterioles of rats fed low and high salt diets by a similar amount (19+/-3% and 16+/-2%, respectively), suggesting that signaling mechanisms for dilation distal to the vascular smooth muscle membrane were intact after high salt intake. These results provide the first evidence that the short-term ingestion of a high salt diet may severely impair the vasodilator function of the in situ cerebral microcirculation independent of blood pressure elevation.  (+info)

The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. (2/2638)

Primary headache syndromes, such as cluster headache and migraine, are widely described as vascular headaches, although considerable clinical evidence suggests that both are primarily driven from the brain. The shared anatomical and physiologic substrate for both of these clinical problems is the neural innervation of the cranial circulation. Functional imaging with positron emission tomography has shed light on the genesis of both syndromes, documenting activation in the midbrain and pons in migraine and in the hypothalamic gray in cluster headache. These areas are involved in the pain process in a permissive or triggering manner rather than as a response to first-division nociceptive pain impulses. In a positron emission tomography study in cluster headache, however, activation in the region of the major basal arteries was observed. This is likely to result from vasodilation of these vessels during the acute pain attack as opposed to the rest state in cluster headache, and represents the first convincing activation of neural vasodilator mechanisms in humans. The observation of vasodilation was also made in an experimental trigeminal pain study, which concluded that the observed dilation of these vessels in trigeminal pain is not inherent to a specific headache syndrome, but rather is a feature of the trigeminal neural innervation of the cranial circulation. Clinical and animal data suggest that the observed vasodilation is, in part, an effect of a trigeminoparasympathetic reflex. The data presented here review these developments in the physiology of the trigeminovascular system, which demand renewed consideration of the neural influences at work in many primary headaches and, thus, further consideration of the physiology of the neural innervation of the cranial circulation. We take the view that the known physiologic and pathophysiologic mechanisms of the systems involved dictate that these disorders should be collectively regarded as neurovascular headaches to emphasize the interaction between nerves and vessels, which is the underlying characteristic of these syndromes. Moreover, the syndromes can be understood only by a detailed study of the cerebrovascular physiologic mechanisms that underpin their expression.  (+info)

Transforming growth factor-alpha acting at the epidermal growth factor receptor reduces infarct volume after permanent middle cerebral artery occlusion in rats. (3/2638)

Transforming growth factor-alpha (TGF-alpha) is a ligand for the epidermal growth factor (EGF) receptor (EGFR), and is more abundant than EGF in the brain. The authors studied whether administration of exogenous TGF-alpha into the brain can protect neurons against ischemia in a model of permanent middle cerebral artery (MCA) occlusion in the rat, and whether any effect of TGF-alpha was mediated by EGFR by administering 4,5-dianilinophthalimide (DAPH), a protein-tyrosine kinase inhibitor with high selectivity for EGFR. Rats received either TGF-alpha (10 or 25 ng), DAPH (100 ng), DAPH plus TGF-alpha (25 ng), or vehicle in the ipsilateral first ventricle. Drugs were administered twice: 30 minutes before and 30 minutes after MCA occlusion, and infarct volume was evaluated 24 hours later. Transforming growth factor-alpha at the dose of 25 ng caused a statistically significant reduction of infarct volume (60%) in relation to ischemic rats administered vehicle. This reduction was no longer seen when TGF-alpha was administered in combination with DAPH. The present results show that TGF-alpha can protect neurons from ischemic damage, and that this effect is mediated by EGFR. It is suggested that activation of EGFR-mediated intracellular signalling pathways contributes to the survival of neural cells susceptible to ischemic injury.  (+info)

Role of iNOS in the vasodilator responses induced by L-arginine in the middle cerebral artery from normotensive and hypertensive rats. (4/2638)

1. The substrate of nitric oxide synthase (NOS), L-arginine (L-Arg, 0.01 microM - 1 mM), induced endothelium-independent relaxations in segments of middle cerebral arteries (MCAs) from normotensive Wistar-Kyoto (WKY) and hypertensive rats (SHR) precontracted with prostaglandin F2alpha (PGF2alpha). These relaxations were higher in SHR than WKY arteries. 2. L-N(G)-nitroarginine methyl ester (L-NAME) and 2-amine-5,6-dihydro-6-methyl-4H-1,3-tiazine (AMT), unspecific and inducible NOS (iNOS) inhibitors, respectively, reduced those relaxations, specially in SHR. 3. Four- and seven-hours incubation with dexamethasone reduced the relaxations in MCAs from WKY and SHR, respectively. 4. Polymyxin B and calphostin C, protein kinase C (PKC) inhibitors, reduced the L-Arg-induced relaxation. 5. Lipopolysaccharide (LPS, 7 h incubation) unaltered and inhibited these relaxations in WKY and SHR segments, respectively. LPS antagonized the effect polymyxin B in WKY and potentiated L-Arg-induced relaxations in SHR in the presence of polymyxin B. 6. The contraction induced by PGF2alpha was greater in SHR than WKY arteries. This contraction was potentiated by dexamethasone and polymyxin B although the effect of polymyxin B was higher in SHR segments. LPS reduced that contraction and antagonized dexamethasone- and polymyxin B-induced potentiation, these effects being greater in arteries from SHR. 7. These results suggest that in MCAs: (1) the induction of iNOS participates in the L-Arg relaxation and modulates the contraction to PGF2alpha; (2) that induction is partially mediated by a PKC-dependent mechanism; and (3) the involvement of iNOS in such responses is greater in the hypertensive strain.  (+info)

Two similar cases of encephalopathy, possibly a reversible posterior leukoencephalopathy syndrome: serial findings of magnetic resonance imaging, SPECT and angiography. (5/2638)

Two young women who had encephalopathy that resembled reversible posterior leukoencephalopathy syndrome are presented. The brain magnetic resonance imaging (MRI) of these patients exhibited similar T2-high signal lesions, mostly in the white matter of the posterior hemispheres. Xe-SPECT during the patients' symptomatic period showed hypoperfusion in the corresponding areas, and angiography demonstrated irregular narrowing of the posterior cerebral artery. Clinical manifestations subsided soon after treatment, and the abnormal radiological findings also were almost completely resolved. Thus, we concluded that transient hypoperfusion followed by ischemia and cytotoxic edema might have had a pivotal role in these cases.  (+info)

Age and stimulus dependency of visually evoked cerebral blood flow responses. (6/2638)

BACKGROUND AND PURPOSE: During visual stimulation, the increased metabolic demand is coupled with an increase of cerebral blood flow velocity (pCBFV) in the posterior cerebral artery (PCA). Investigation of the visually evoked flow responses (VEFR, expressed as percentage of increase from baseline pCBFV values) was suggested for different conditions of vasoneuronal disorders in the absence of any systematic investigation in healthy subjects. METHODS: We investigated VEFRs from both PCAs to various increasingly complex paradigms (diffuse light, alternating checkerboard patterns, and a color video movie stimulation; 5, 10, 20, and 30-second intervals) in 60 healthy volunteers (mean age, 41.5+/-14.9 years; range, 24 to 80 years; 28 male, 32 female) at different recording sites (P1 versus P2 segments of PCAs). RESULTS: With increasing complexity of stimulation, the VEFRs increased significantly (24.3+/-10.3%, 28.5+/-13.5%, and 43.4+/-10.7%, respectively). Twenty-second stimulation intervals yielded maximal responses (41.5+/-13.2%) compared with 5-, 10-, and 30-second intervals (22.6+/-14.1%, P=0.001; 34.4+/-11.7%, P=0.0042; and 35.5+/-9.9%, P=0.0032, respectively). Significantly higher responses were gained from P2 segments than from P1 segments (42.7+/-7.2% versus 28.2+/-7.1%). Although VEFRs tended to decrease in amplitude with age (mean, 41. 7+/-10.5% [20 to 40 years], 35+/-9.2% [40 to 60 years], and 33.9+/-8.6% [60 to 80 years]); without significant sex-related differences, only the percentage decrement of the pulsatility indices during stimulation were significant (mean, 24+/-10.7% [20 to 40 years], 20+/-7.3% [40 to 60 years], and 13+/-11.2% [60 to 80 years]). CONCLUSIONS: For optimal stimulus conditions for maximum VEFRs, a colored video stimulation of 20-second intervals should be used to combine responses not only from the primary visual projection fields (V1 and V2) but also from temporal lobe areas (V3 through V5) often supplied by the PCA.  (+info)

Blockade and reversal of endothelin-induced constriction in pial arteries from human brain. (7/2638)

BACKGROUND AND PURPOSE: Substantial evidence now implicates endothelin (ET) in the pathophysiology of cerebrovascular disorders such as the delayed vasospasm associated with subarachnoid hemorrhage and ischemic stroke. We investigated the ET receptor subtypes mediating vasoconstriction in human pial arteries. METHODS: ET receptors on human pial and intracerebral arteries were visualized with the use of autoradiography, and the subtypes mediating vasoconstriction were identified by means of wire myography. RESULTS: ET-1 was more potent than ET-3 as a vasoconstrictor, indicating an ETA-mediated effect. Similarly, the selective ETB agonist sarafotoxin S6c had no effect on contractile action at concentrations up to 30 nmol/L. The nonpeptide ETA receptor antagonist PD156707 (3 to 30 nmol/L) caused a parallel rightward shift of the ET-1-induced response, yielding a pA2 of 9.2. Consistent with these results, PD156707 (30 nmol/L) fully reversed an established constriction in pial arteries induced by 1 nmol/L ET-1, while the selective ETB receptor antagonist BQ788 (1 micromol/L) had little effect. The calcium channel blocker nimodipine (0.3 to 3 micromol/L) significantly attenuated the maximum response to ET-1 in a concentration-dependent manner without changing potency. In agreement with the functional data, specific binding of [125I]PD151242 to ETA receptors was localized to the smooth muscle layer of pial and intracerebral blood vessels. In contrast, little or no [125I]BQ3020 binding to ETB receptors was detected. CONCLUSIONS: These data indicate an important role for ETA receptors in ET-1-induced constriction of human pial arteries and suggest that ETA receptor antagonists may provide additional dilatory benefit in cerebrovascular disorders associated with raised ET levels.  (+info)

Cerebrovascular alterations in protein kinase C-mediated constriction in stroke-prone rats. (8/2638)

BACKGROUND AND PURPOSE: Cerebrovascular pressure-dependent constriction may involve the smooth muscle production of diacylglycerol, which could facilitate constriction by activating protein kinase C (PKC). A dysfunctional PKC system could promote the loss of pressure-dependent constriction. We attempted to determine whether the alterations in pressure-dependent constriction in the middle cerebral arteries (MCAs) observed in relation to stroke development in Wistar-Kyoto stroke-prone spontaneously hypertensive rats (SHRsp) were associated with defects in the ability of the arteries to constrict in response to PKC activation. METHODS: MCAs were sampled from SHRsp before and after stroke development and in stroke-resistant Wistar-Kyoto spontaneously hypertensive rats. A pressure myograph was used to test the ability of the arteries to constrict in response to a 100 mm Hg pressure step and subsequently to contract in response to phorbol 12,13-dibutyrate in the presence of nifedipine (3 micromol/L). RESULTS: Pressure-dependent constriction and constriction in response to phorbol dibutyrate in the MCAs were inhibited by PKC inhibitors (staurosporine [40 nmol/L], chelerythrine [12 micromol/L], bisindolylmaleimide [5 micromol/L]), declined with age before stroke development in SHRsp, and were absent after stroke. There was a significant relationship between pressure- and phorbol dibutyrate-induced constriction (r=0.815, P<0. 05). CONCLUSIONS: Phorbol esters interact with the same activation site as diacylglycerol to stimulate PKC. An inability to constrict in response to phorbol dibutyrate may reflect unresponsiveness to diacylglycerol and may contribute to the loss of pressure-dependent constriction associated with stroke in the MCAs of SHRsp. The loss of this autoregulatory function before stroke could increase the risk of cerebral hemorrhage.  (+info)

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