Prevention of cerebrovascular disorders with adrenergic substances]

The author suggests an experimental model of cerebrovascular disorders of the neurogenic (adrenergic) nature following the administration of KCl into the lateral ventricles of the brain of cats or dogs. Surgical desympathization considerably reduced the spasms of the cerebral vessels caused by the central effect of KCl. Dihydroergotoxin, phenoxybenzamine, tropaphene, guanethidine and nialamide produced both the therapeutic and the prophylactic influence under the mentioned experimental disorders of the cerebral circulation.     

Functional structure and cerebrovascular circulation of the vestibulo-ocular formations of the brain stem of the human cerebrum

This work is dedicated to the study of anatomo-physiological peculiarities of the construction and cerebrovascular circulation of the vestibulo-ocular formations of the brain stem of the human cerebrum. The analysis of anatomo-physiological data enable to convince that the arches of the vertical and horizontal vestibulo-ocular reflexes include many structures of the brain stem of the human cerebrum, which are located along its longitude from the superior colliculi to caudal sections of brain stem. There is an existence of separate mechanisms of horizontal and vertical vestibulo-ocular interaction. The peculiarity of cerebrovascular circulation of main vestibulo-ocular structures is their profuse vascularisation chiefly by branches of the vertebro basilar system of arteries, which widely connected between each other, providing sufficiently profuse circulation in normal conditions of vital activity. The anatomical information above has great importance for the correct interpretation of the symptoms of infarctions in vertebro-basilar pool of the cerebrum, diagnostics and expert appreciation of these pathological states.     

Cerebrovascular effects of met- and leu-enkephalins

Met- and leu-enkephalines have a two-phase influence on the brain blood supply: initial short-term blood flow increase is replaced by the decrease of cerebral blood flow. Enkephalines are established to possess a pronounced depressive influence on neurogenic spasms of cerebral vessels and somatosympathetic and vasomotor reflex both under systemic administration and administration into brain lateral ventricles. Bicucullin has no effect on leuenkephaline action on cerebral circulation and its nervous control, while naloxone either removes or reduces the effects. Hence, opiate receptors take part in the realization of cerebrovascular effects of opioid peptides. The data obtained show the brain opioid system involvement in the regulation of brain circulation.     

Angiotensin and Cerebral Blood Flow

1.General properties of the cerebral circulation.2.Cerebral blood flow autoregulation in hypertension, in stroke, and during the aging process.3.The Angiotensin system.4.Angiotensin receptor subtypes.5.Angiotensin receptors and actions of Angiotensin II in the brain: interactions between the brain and circulating Angiotensin II.6.The cerebrovascular Angiotensin system.7.Effects of Angiotensin II on cerebrovascular reactivity.8.Angiotensin and cerebrovascular flow.9.Effects of therapeutic modulation of the Angiotensin II system on cerebrovascular regulation in health and disease.10.Conclusions.     

Changes in cerebral oxygenation and blood flow during LBNP in spinal cord-injured individuals.

Spinal cord-injured (SCI) individuals, having a sympathetic nervous system lesion, experience hypotension during sitting and standing. Surprisingly, they experience few syncopal events. This suggests adaptations in cerebrovascular regulation. Therefore, changes in systemic circulation, cerebral blood flow, and oxygenation in eight SCI individuals were compared with eight able-bodied (AB) individuals. Systemic circulation was manipulated by lower body negative pressure at several levels down to -60 mmHg. At each level, we measured steady-state blood pressure, changes in cerebral blood velocity with transcranial Doppler, and cerebral oxygenation using near-infrared spectroscopy. We found that mean arterial pressure decreased significantly in SCI but not in AB individuals, in accordance with the sympathetic impairment in the SCI group. Cerebral blood flow velocity decreased during orthostatic stress in both groups, but this decrease was significantly greater in SCI individuals. Cerebral oxygenation decreased in both groups, with a tendency to a greater decrease in SCI individuals. Thus present data do not support an advantageous mechanism during orthostatic stress in the cerebrovascular regulation of SCI individuals.     

Role of the locus coeruleus in the development of cerebrovascular disorders in acute myocardial ischemia

Experiments on rats were made to examine the total cerebral blood flow during locus coeruleus (LC) stimulation, acute myocardial ischemia and in the presence of acute myocardial ischemia after LC precoagulation . LC electric stimulation caused a decrease in the cerebral blood flow. The most profound cerebrovascular disorders were observed in animals with acute myocardial ischemia without LC precoagulation and were followed by cardiac arrhythmias. Cerebrovascular hemodynamic disorders occurring in acute myocardial ischemia were prevented by LC coagulation. It is suggested that the cerebrovascular disorders are consequent on the formation in the LC of the hyperactive determinant structure and play a role of a secondary pathogenetic factor in heart regulation disorders.     

Targeting Therapeutics Across the Blood Brain Barrier (BBB), Prerequisite Towards Thrombolytic Therapy for Cerebrovascular Disorders—an Overview and Advancements

Cerebral tissues possess highly selective and dynamic protection known as blood brain barrier (BBB) that regulates brain homeostasis and provides protection against invading pathogens and various chemicals including drug molecules. Such natural protection strictly monitors entry of drug molecules often required for the management of several diseases and disorders including cerebral vascular and neurological disorders. However, in recent times, the ischemic cerebrovascular disease and clinical manifestation of acute arterial thrombosis are the most common causes of mortality and morbidity worldwide. The management of cerebral Ischemia requires immediate infusion of external thrombolytic into systemic circulation and must cross the blood brain barrier. The major challenge with available thrombolytic is their poor affinity towards the blood brain barrier and cerebral tissue subsequently. In the clinical practice, a high dose of thrombolytic often prescribed to deliver drugs across the blood brain barrier which results in drug dependent toxicity leading to damage of neuronal tissues. In recent times, more emphasis was given to utilize blood brain barrier transport mechanism to deliver drugs in neuronal tissue. The blood brain barrier expresses a series of receptor on membrane became an ideal target for selective drug delivery. In this review, the author has given more emphasis molecular biology of receptor on blood brain barrier and their potential as a carrier for drug molecules to cerebral tissues. Further, the use of nanoscale design and real-time monitoring for developed therapeutic to encounter drug dependent toxicity has been reviewed in this study.KEY WORDS: blood brain barrier (BBB), cerebral ischemic disorders, drug delivery, earthworm protease, neurodegenerative disorder, thrombolytic     

Hypoxic regulation of the fetal cerebral circulation.

Fetal cerebrovascular responses to acute hypoxia are fundamentally different from those observed in the adult cerebral circulation. The magnitude of hypoxic vasodilatation in the fetal brain increases with postnatal age although fetal cerebrovascular responses to acute hypoxia can be complicated by age-dependent depressions of blood pressure and ventilation. Acute hypoxia promotes adenosine release, which depresses fetal cerebral oxygen consumption through action of adenosine on neuronal A1 receptors and vasodilatation through activation of A2 receptors on cerebral arteries. The vascular effect of adenosine can account for approximately half the vasodilatation observed in response to hypoxia. Hypoxia-induced release of nitric oxide and opioids can account for much of the adenosine-independent cerebral vasodilatation observed in response to hypoxia in the fetus. Direct effects of hypoxia on cerebral arteries account for the remaining fraction, although the vascular endothelium contributes relatively little to hypoxic vasodilatation in the immature cerebral circulation. In contrast to acute hypoxia, fetal cerebral blood flow tends to normalize during acclimatization to chronic hypoxia even though cardiac output is depressed. However, uncompensated chronic hypoxia in the fetus can produce significant changes in brain structure and function, alteration of respiratory drive and fluid balance, and increased incidence of intracranial hemorrhage and periventricular leukomalacia. At the level of the fetal cerebral arteries, chronic hypoxia increases protein content and depresses norepinephrine release, contractility, and receptor densities associated with contraction but also attenuates endothelial vasodilator capacity and decreases the ability of ATP-sensitive and calcium-sensitive potassium channels to promote vasorelaxation. Overall, fetal cerebrovascular adaptations to chronic hypoxia appear prioritized to conserve energy while preserving basic contractility. Many gaps remain in our understanding of how the effects of acute and chronic hypoxia are mediated in fetal cerebral arteries, but studies of adult cerebral arteries have produced many powerful pharmacological and molecular tools that are simply awaiting application in studies of fetal cerebral artery responses to hypoxia.     

Disorders of Autonomic Control under Conditions of Long-Term Psychoemotional Stress: a Risk Factor and a Predictor of Unfavorable Clinical Course of Cerebral Insult

We describe the results of an analysis of the morbidity, clinical course, and mortality resulting from cerebral insult developing under conditions of acute (Spitak earthquake) and long-term (long-lasting energy crisis, military actions, social deprivation, etc.) psychoemotional stresses acting upon a large human population (on the territory of the entire country, Armenia). It is concluded that autonomic disorders related to acute psychoemotional stress play the role of a risk factor responsible for an increase in the frequency of nonfatal disorders of cerebral circulation. At the same time, the respective disorders induced by long-term stress should be considered a predictor of an unfavorable (sometimes fatal) clinical course of cerebral insult. Hypotheses on the influence of changes in fundamental neurophysiological mechanisms of the autonomic nervous system, which result from the effects of psychoemotional stress, on the clinical result of cerebrovascular diseases and, in particular, of cerebral insult are discussed.     

Cerebroprotective effects of the CO-releasing molecule CORM-A1 against seizure-induced neonatal vascular injury

Endogenous CO, a product of heme oxygenase activity, has vasodilator and cytoprotective effects in the cerebral circulation of newborn pigs. CO-releasing molecule (CORM)-A1 (sodium boranocarbonate) is a novel, water-soluble, CO-releasing compound. We addressed the hypotheses that CORM-A1 1) can deliver CO to the brain and exert effects of CO on the cerebral microvasculature and 2) is cerebroprotective. Acute and delayed effects of topically and systemically administered CORM-A1 on cerebrovascular and systemic circulatory parameters were determined in anesthetized newborn pigs with implanted closed cranial windows. Topical application of CORM-A1 (10(-7)-10(-5) M) to the brain produced concentration-dependent CO release and pial arteriolar dilation. Systemically administered CORM-A1 (2 mg/kg ip or iv) caused pial arteriolar dilation and increased cortical cerebrospinal fluid CO concentration. Systemic CORM-A1 did not have acute or delayed effects on blood pressure, heart rate, or blood gases. Potential cerebroprotective vascular effects of CORM-A1 (2 mg/kg ip, 30 min before seizures) were tested 2 days after bicuculline-induced epileptic seizures (late postictal period). In control piglets, seizures reduced postictal cerebrovascular responsiveness to selective physiologically relevant vasodilators (bradykinin, hemin, and isoproterenol) indicative of cerebrovascular injury. In contrast, in CORM-A1-pretreated animals, no loss of postictal cerebrovascular reactivity was observed. We conclude that systemically administered CORM-A1 delivers CO to the brain, elicits the vasodilator and cytoprotective effects of CO in the cerebral circulation, and protects the neonatal brain from cerebrovascular injury caused by epileptic seizures.     

Abnormalities of the Vertebrobasilar Circulation due to Subclavian Artery Disease

The studies of Hutchinson and Yates on caroticovertebral stenosis have stimulated further interest in cerebrovascular disease. As a consequence, investigation of the four vessels, supplying the brain is now routine in the assessment of patients being considered for surgery for occlusive disease of the vessels. This has led to some interesting and unexpected findings.The effect of subclavian artery disease on the vertebrobasilar circulation was studied in two patients. Angiography showed the vertebral arteries to function as a collateral pathway when an occlusion of the subclavian artery was present proximal to the origin of the vertebral arteries. In one case both the carotid and the vertebral arteries were implicated in the collateral supply. A normal circulation was restored by subclavian endarterectomy.Studies of other workers have shown that such a circulation may reduce the cerebral blood flow by about 40%, but neither patient described in this report had signs or symptoms of cerebrovascular disease. It is evident that our understanding of the effects of cerebrovascular disease is far from complete.     

Distribution and origin of vasoactive intestinal polypeptide (VIP)-immunoreactive,acetylcholinesterase-positive and adrenergic nerves of the cerebral arteries in the bent-winged bat (Mammalia: Chiroptera)

Summary The overall distribution and origins of vasoactive intestinal polypeptide (VIP)-immunoreactive (IR), acetylcholinesterase (AChE)-positive and adrenergic nerves in the walls of the cerebral arteries were investigated in the bent-winged bat. VIP-IR and AChE-positive nerves innervating the bat cerebral vasculature appear to arise mainly from VIP-IR and AChE-positive cell bodies within microganglia found in the nerve bundle accompanying the sympathetic nerve bundle within the tympanic cavity. These microganglia, as well as the nerve bundle containing them, do not emit catecholamine fluorescence, suggesting that they are of the cranial parasympathetic outflow, probably the facial or glossopharyngeal one. The axons from VIP-IR and AChE-positive microganglia run intermingled with sympathetic adrenergic nerves in the same thick fiber bundles, and reach the cranial cavity through the carotid canal. In addition, some of the VIP-IR fibers innervating the vertebro-basilar system, at least the basilar artery, originate from VIP-IR nerve cells located in the wall of this artery.The supply of VIP-IR fibers to the bat major cerebral arteries is the richest among mammals that have been studied, and differs from other mammals in that it is much greater in the vertebro-basilar system than in the internal carotid system: plexuses of VIP-IR nerves are particularly dense along the walls from the posterior ramus to posterior cerebral and basilar arteries. Small pial and intracerebral arteries of the vertebro-basilar system, especially those of the posterior cerebral artery which supply most parts of the diencephalon and cerebrum, are also richly innervated by peripheral VIP-IR fibers. This pattern corresponds well with the innervation pattern of adrenergic and AChE-positive nerves.     

心脏和脑循环功能相互影响的动力学模型

心脏和脑血管疾病是医学研究的热点。本文整合心脏、体循环和脑循环,构建了循环系统的整体动力学模型,力图揭示心脏和脑循环功能的相互影响。结论表明,从血液动力学角度,不但心脏特性变化会对脑循环产生影响,脑血管异常也会对心血管功能（如血压）发生作用。     

A histochemical study of the innervation of the cerebral blood vessels in the domestic fowl

Summary Adrenergic and cholinergic nerves innervating the cerebral arteries of the domestic fowl were examined by specific histochemical techniques.The adrenergic nerve plexuses of the cerebral carotid system are markedly denser than those of other vertebrates observed by similar techniques. They form longitudinally elongated meshworks of fine fibres in the vascular wall of the arterial branches. Those innervating the vertebro-basilar system are less dense and more elongated, and, as the size of the artery diminishes, the fibres of the plexus become coarser. In the small pial and parenchymal arteries they are reduced to a few fibres running parallel to, or spiralling around the vascular axis.The cholinergic nerve plexuses are not as dense as the adrenergic system. The acetylcholinesterase activity is very weak, except in the plexuses innervating the cerebral carotid artery and the proximal portion of the anterior and posterior rami. In the vertebro-basilar system, a few thick nerve bundles run alongside the blood vessels of the vertebral and basilar arteries. Cholinergic nerves enter the cranial cavity along the internal carotid, the vertebral and possibly the cerebro-ethmoidal arteries.Intracerebral capillaries and some arterioles are not innervated with cholinergic and adrenergic fibres of peripheral origin, but with ones arising from parenchymal nerve cells.     

Mechanisms of the Anti-Ischemic Effect of Angiotensin II AT( 1 ) Receptor Antagonists in the Brain

1. Circulating and locally formed Angiotensin II regulates the cerebral circulation through stimulation of AT(1) receptors located in cerebrovascular endothelial cells and in brain centers controlling cerebrovascular flow. 2. The cerebrovascular autoregulation is designed to maintain a constant blood flow to the brain, by vasodilatation when blood pressure decreases and vasoconstriction when blood pressure increases. 3. During hypertension, there is a shift in the cerebrovascular autoregulation to the right, in the direction of higher blood pressures, as a consequence of decreased cerebrovascular compliance resulting from vasoconstriction and pathological growth. In hypertension, when perfusion pressure decreases as a consequence of blockade of a cerebral artery, reduced cerebrovascular compliance results in more frequent and more severe strokes with a larger area of injured tissue. 4. There is a cerebrovascular angiotensinergic overdrive in genetically hypertensive rats, manifested as an increased expression of cerebrovascular AT(1) receptors and increased activity of the brain Angiotensin II system. Excess AT(1) receptor stimulation is a main factor in the cerebrovascular pathological growth and decreased compliance, the alteration of the cerebrovascular eNOS/iNOS ratio, and in the inflammatory reaction characteristic of cerebral blood vessels in genetic hypertension. All these factors increase vulnerability to brain ischemia and stroke. 5. Sustained blockade of AT(1) receptors with peripheral and centrally active AT(1) receptor antagonists (ARBs) reverses the cerebrovascular pathological growth and inflammation, increases cerebrovascular compliance, restores the eNOS/iNOS ratio and decreases cerebrovascular inflammation. These effects result in a reduction of the vulnerability to brain ischemia, revealed, when an experimental stroke is produced, in protection of the blood flow in the zone of penumbra and substantial reduction in neuronal injury. 6. The protection against ischemia resulting is related to inhibition of the Renin-Angiotensin System and not directly related to the decrease in blood pressure produced by these compounds. A similar decrease in blood pressure as a result of the administration of beta-adrenergic receptor and calcium channel blockers does not protect from brain ischemia. 7. In addition, sustained AT(1) receptor inhibition enhances AT(2) receptor expression, associated with increased eNOS activity and NO formation followed by enhanced vasodilatation. Direct AT(1) inhibition and indirect AT(2) receptor stimulation are associated factors normalizing cerebrovascular compliance, reducing cerebrovascular inflammation and decreasing the vulnerability to brain ischemia.8. These results strongly suggest that inhibition of AT(1) receptors should be considered as a preventive therapeutic measure to protect the brain from ischemia, and as a possible novel therapy of inflammatory conditions of the brain.     

脑循环功能检测技术近三十年进展

脑循环功能的异常改变往往早于形态学和影像学改变,这对于脑血管的早期检测以及治疗过程中疗效的评价有显著意义。国内外脑循环功能检测技术的发展已有30年左右的历史,本文综述了脑循环动力学参数的生理背景及脑循环功能检测技术近年来的发展。     

On the atrophy of the internal carotid artery in capybara

Capybara might be a useful model for studying changes in cerebral circulation as the natural atrophy of the internal carotid artery (ICA) occurs in this animal at maturation. In this study, confocal and electron microscopy combined with immunohistochemical techniques were applied in order to reveal the changes in morphology and innervation to the proximal part of ICA in young (6-month-old) and mature (12-month-old) capybaras. Some features of the basilar artery (BA) were also revealed. The ICA of young animals degenerated to a ligamentous cord in mature animals. Immunolabelling positive for pan-neuronal marker protein gene product 9.5 but negative for tyrosine hydroxylase was observed in the proximal part of ICA at both ages examined. Axon varicosities positive for synaptophysin were present in the adventitia of ICA of young animals but were absent in the ligamentous cord of mature animals. In the ICA of young animals, adventitial connective tissue invaded the media suggesting that the process of regression of this artery began within the first 6 months of life. An increase in size of the BA was found in mature animals indicating increased blood flow in the vertebro-basilar system, possibly making capybara susceptible to cerebrovascular pathology (e.g. stroke). Capybara may therefore provide a natural model for studying adaptive responses to ICA regression/occlusion.The financial support of the Graduate Fund, UCL, London, UK (C. Steele) and the Brazilian Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ) Brazil (200516/01-9; A.A.C.M. Ribeiro) is gratefully acknowledged.     

Natriuresis following fourth ventricle perfusion with high-sodium artificial CSF.

Perfusion of the fourth cerebral ventricle with high-sodium artificial cerebrospinal fluid was found to result in an increase in urinary sodium excretion in anesthetized cats. The natriuresis was accompanied by an increase in blood pressure and glomerular filtration rate. However, in animals with the changes in blood pressure and glomerular filtration rate prevented by alpha adrenergic blockade (phenoxybenzamine), the increase in urinary sodium excretion persisted. the data suggest the presence of a neural mechanism in the vicinity of the fourth ventricle sensitive to cerebrospinal fluid sodium levels and capable of affecting urinary sodium excretion independent of changes in blood pressure or glomerular filtration rate. The possible role of the area postrema and adjacent medulla is considered.     

Acute effects of three isoflavone class phytoestrogens and a mycoestrogen on cerebral microcirculation

Phytoestrogens and mycoestrogens are naturally occurring plant and fungus secondary metabolites with estrogen-like structure and/or actions. We aimed to check the hypothesis that phytoestrogens and mycoestrogens, due to their ability to elicit cerebral vasodilation, can induce acute increases in brain blood perfusion. For this purpose, we continuously recorded cerebrocortical perfusion by laser-Doppler flowmetry in anesthetized rats receiving intracarotid infusions (1 mg/kg) of one of the following estrogenic compounds: biochanin A, daidzein, genistein or zearalanone. We have shown the ability of two isoflavone class phytoestrogens (daidzein and biochanin A) and the mycoestrogen zearalanone to induce acute increases in brain blood flow when locally infused into the cerebral circulation of anesthetized rats. The isoflavone genistein failed to induce a significant increase in brain perfusion. No concomitant changes in blood pressure were recorded during the cerebral effects of the estrogenic compounds. Therefore, these microcirculatory effects were due to direct actions of the estrogenic compounds on the cerebrovascular bed.     

Neuronal messengers in the human cerebral circulation

In recent years our knowledge of the nervous control of the cerebral circulation has increased. The use of denervations and retrograde tracing in combination with immunohistochemical techniques has demonstrated that cerebral vessels are supplied with sympathetic, parasympathetic, and sensory nerve fibers and possibly central pathways containing a multiplicity of new transmitter substances in addition to the classical transmitters. The majority of these transmitters are neuropeptides. More recently it has been suggested that a gaseous transmitter, nitric oxide (NO) also could participate in the neuronal regulation of cerebral blood flow. Although little is known about the physiological actions and inter-relationships among all these putative neurotransmitters, their presence within cerebrovascular nerve fibers will make it necessary to revise our view on the mechanisms of cerebrovascular neurotransmission.