Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Focal brain ischemia is the most common event leading to stroke in humans. To understand the molecular mechanisms associated with brain ischemia, we applied the technique of mRNA differential display and isolated a gene that encodes a recently discovered peptide, adrenomedullin (AM), which is a member of the calcitonin gene-related peptide (CGRP) family. Using the rat focal stroke model of middle cerebral artery occlusion (MCAO), we determined that AM mRNA expression was significantly increased in the ischemic cortex up to 17.4-fold at 3 h post-MCAO (P < 0.05) and 21.7-fold at 6 h post-MCAO (P < 0.05) and remained elevated for up to 15 days (9.6-fold increase; P < 0.05). Immunohistochemical studies localized AM to ischemic neuronal processes, and radioligand (125I-labeled CGRP) displacement revealed high-affinity (IC50 = 80.3 nmol) binding of AM to CGRP receptors in brain cortex. The cerebrovascular function of AM was studied using synthetic AM microinjected onto rat pial vessels using a cranial window or applied to canine basilar arteries in vitro. AM, applied abluminally, produced dose-dependent relaxation of preconstricted pial vessels (P < 0.05). Intracerebroventricular (but not systemic) AM administration at a high dose (8 nmol), prior to and after MCAO, increased the degree of focal ischemic injury (P < 0.05). The ischemia-induced expression of both AM mRNA and peptide in ischemic cortical neurons, the demonstration of the direct vasodilating effects of the peptide on cerebral vessels, and the ability of AM to exacerbate ischemic brain damage suggests that AM plays a significant role in focal ischemic brain injury.
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PMID:Discovery of adrenomedullin in rat ischemic cortex and evidence for its role in exacerbating focal brain ischemic damage. 852 87

This study was conducted to investigate the effect of intracerebroventricular administration of adrenomedullin (13-52) [ADM(13-52)], a novel hypotensive peptide, on the hemodynamic parameters of anesthetized rats. ADM(13-52) was administered centrally in a dose of 0.4-3.2 nmol/kg. It provoked marked, prolonged and dose-dependent increases in mean arterial blood pressure, heart rate, stroke volume, cardiac index, left ventricular pressure, left ventricular dp/dtmax and dp/dtmin, but reduction in total peripheral resistance index. In addition, intracerebroventricular administration of ADM(13-52; 1.6 nmol/kg) provoked a marked increase in renal sympathetic nerve activity. Intracerebroventricular administration of artificial cerebrospinal fluid had no effect on the hemodynamic parameters and renal sympathetic nerve activity. The results indicate that ADM(13-52) exerts a central action on the cardiovascular system. The mechanisms of hemodynamic changes induced by central ADM(13-52) were preliminarily analyzed in this study. ADM might play a role in the central control of the cardiovascular system, although the confirmed mechanisms and the physiological implications are undetermined.
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PMID:Hemodynamic effects of centrally administered adrenomedullin (13-52) in anesthetized rats. 868 13

Adrenomedullin, a potent hypotensive peptide, reduces blood pressure and pulmonary vascular resistance, and increases pulmonary blood flow. The mRNA for adrenomedullin and its receptor is highly expressed in the lung, suggesting a regulatory role for adrenomedullin in the pulmonary circulation. To investigate the clinical significance of adrenomedullin in patients with pulmonary hypertension, we studied the relationship between plasma levels of adrenomedullin and pulmonary haemodynamics. Venous, arterial and pulmonary arterial blood samples were obtained during cardiac catheterization and plasma levels of adrenomedullin were measured by specific radioimmunoassay in 33 consecutive patients with severe pulmonary hypertension (12 cases of primary pulmonary hypertension, 21 with chronic thromboembolic pulmonary hypertension; age 49+/-16 years, mean pulmonary arterial pressure 50+/-15mmHg). In addition, plasma levels of adrenomedullin were measured before and after acute nitric oxide inhalation. The changes in plasma adrenomedullin during the follow-up period of 10.3+/-4.3 months were also evaluated (n=5). Sixty-two healthy subjects served as the control group. Adrenomedullin was measured in an antecubital vein in the controls. Plasma levels of adrenomedullin were significantly higher in the patients with pulmonary hypertension than in the control subjects (10.1+/-8.7 versus 4.9+/-1.1pmol/l, P<0.01). Plasma levels of adrenomedullin, expressed as their natural logarithm, were significantly correlated with mean right atrial pressure (r=0.71, P<0.01), stroke volume (r=-0.63, P<0.01), total pulmonary resistance (r=0.60, P<0.01), mean pulmonary arterial pressure (r=0.37, P<0.05), and the natural logarithm of plasma atrial natriuretic peptide (r=0. 63, P<0.01). Plasma levels of adrenomedullin did not change significantly after nitric oxide inhalation, but significantly increased in association with the elevation of the total pulmonary resistance during the long-term follow-up period. These results suggest that plasma levels of adrenomedullin increase in proportion to the extent of pulmonary hypertension.
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PMID:Increased plasma levels of adrenomedullin in patients with pulmonary hypertension. 985 4

Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM) are potent dilators of human brain arteries, and they have been implicated in the neurogenic inflammation underlying migraine headache and in the evolution of stroke, respectively. However, little is known about the presynaptic and postsynaptic distribution of their respective receptors in the human cerebrovascular bed and trigeminovascular system. In the current study, the expression of mRNA for ADM and the two cloned human CGRP1 receptors (identified here as A-CGRP1 receptors [Aiyar et al., 1996] and K-CGRP1 receptors) [Kapas and Clark, 1995] were evaluated in human brain vessels and trigeminal ganglia. Further, the ability of CGRP and ADM to activate adenylate cyclase in cerebromicrovascular and astroglial cell cultures was determined, and the receptors involved were characterized pharmacologically. Isolated human pial vessels, intracortical microvessels, and capillaries, as well as cultures of brain endothelial (EC), smooth muscle (SMC), and astroglial (AST) cells, all expressed mRNA for the two cloned CGRP1 receptors; however, message for the K-CGRP1 receptor was barely detectable in microvascular tissues and cells. In contrast, only isolated capillaries and cultured AST exhibited message for the ADM receptor. In human trigeminal ganglia, mRNA for ADM and the two CGRP1 receptors was systematically present. The CGRP dose-dependently increased (up to 50-fold) cAMP formation in cell cultures, an effect significantly blocked by 0.1 to 10 micromol/L of the CGRP1 receptor antagonist CGRP8-37. The ADM receptor agonist, ADM13-52 (1 micromol/L), similarly increased cAMP production in all cell types, and this response was virtually abolished by 1 micromol/L CGRP8-37. Low concentrations (1 to 10 micromol/L) of the ADM receptor antagonist ADM22-52 blocked the ADM13-52-induced cAMP formation in AST (26% at 10 micromol/L, P < 0.05), whereas they potentiated this response in brain EC and SMC (40% and 100%, P < 0.001, respectively). Even at a higher dose (50 micromol/L), ADM22-52 inhibited the ADM13-52 effect in vascular cells (45%) much less effectively than in AST (95%). These results indicate that both CGRP and ADM can affect human brain vessels through a CGRP1 receptor, and they further suggest the presence of functional ADM receptors in human astroglial cells.
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PMID:Functional calcitonin gene-related peptide type 1 and adrenomedullin receptors in human trigeminal ganglia, brain vessels, and cerebromicrovascular or astroglial cells in culture. 1056 74

Adrenomedullin is a potent endogenous vasodilating and natriuretic peptide that is similar in structure to calcitonin gene-related peptide (CGRP). The gene involved in the synthesis of adrenomedullin has been localized to a single locus on chromosome 11, with specific sites on the genome to regulate transcription. Adrenomedullin is normally found in human plasma and in other organs. It is thought that one of the clearance sites for this peptide is in the pulmonary circulation. Endothelial cells are assumed to be one of the major sources of plasma adrenomedullin. Adrenomedullin is an important factor in regulating local and systemic vascular tone, by its activity as an autocrine/paracrine and circulating hormone. Depending on the site of action, adrenomedullin seems to bind to a CGRP receptor and send signals by either cyclic adenosine monophosphate or nitric oxide. From the results of experiments in animals, it has become clear that adrenomedullin's effects are species-specific. However, what is commonly seen with adrenomedullin is peripheral vasodilatation, a positive inotropic action, increased cardiac output, and increased stroke volume. In addition, adrenomedullin has actions in the brain, lungs, and kidneys to regulate regional hemodynamics. With these activities defined, recent studies have suggested a potential therapeutic role for adrenomedullin.
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PMID:Adrenomedullin: a vasoactive and natriuretic peptide with therapeutic potential. 1172 67

Adrenomedullin is a potent vasodilator peptide exerting anti-atherosclerotic actions in vitro. We investigated the impact of the severity of atherosclerosis on plasma mature-adrenomedullin (m-AM) levels in 38 patients with chronic ischemic stroke. The variables of carotid artery atherosclerosis assessed using ultrasound measurement, blood pressure, and risk factors were related to m-AM levels. Severe atherosclerosis was associated with a further elevation of the increased m-AM level in patients with high systolic blood pressure. Even in patients with fewer risk factors, the presence of severe atherosclerosis was associated with an increased m-AM level. Thus, atherosclerosis elevates m-AM independent of the blood pressure level or presence of risk factors.
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PMID:Association of plasma adrenomedullin with carotid atherosclerosis in chronic ischemic stroke. 1175 75

Chronic hypotension, defined by a systolic blood pressure < 100 mmHg in the interdialytic period, affects 5-10% of hemodialysis patients, and is more prevalent among patients on long-term hemodialysis. This complication requires a substantial amount of medical and nursing care before and during dialysis to control its symptoms. Chronic hypotension is characterized hemodinamically by preserved cardiac index, heart rate or stroke volume, but reduced total peripheral vascular resistances. Although its pathophysiology is not well defined, a reduced cardiovascular response to vasopressor agents (such as norepinephrine and angiotensin II), associated with a down-regulation of their receptors, as well as an increased production of vasodilators (such as nitric oxide or adrenomedullin) are possibly involved. The treatment of this complication is not well defined and the measures recommended (contention in the lower limbs or the sympathomimetic agent midodrine) are of limited benefit.
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PMID:Chronic hypotension in the dialysis patient. 1224 60

In this paper we review pathophysiologic aspects of heart failure (HF). Mechanisms that normally act to prevent decrease in stroke volume and peripheral pressure are activated in HF and become maladaptive. These mechanisms lead to cardiac stimulation (inotropism, chronopism and lusotropism), peripheral vasoconstriction and sodium and water retention. HF progression is related to a) neurohumoral mechanisms, signaled by neurohumoral messengers; b) inflammatory activation; and c) ventricular remodeling that can be both cause and consequence of HF. We review the main neurohumoral mechanisms, some "regulators" (vasoconstrictors, antinatriuretics, inotropics and proliferatives) and some "counter-regulators" (vasodilators, natriuretics, negative inotropics and antiproliferatives). The first group includes the sympathetic nervous system, the renin angiotensin aldosterone system, arginine-vasopressive and endothelin, while in the second group natriuretic peptides, nitric oxide, bradykinin, vasodilator prostaglandins, the dopaminergic system, adrenomedullin and parasympathetic mechanisms are included. In inflammatory activation we review cytokines and oxidative stress. In ventricular remodeling we review modifications in myocyte function and morphology as well as modifications in the interstitium. Actions and interactions between these systems are the main factors leading to HF progression.
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PMID:[Physiopathology of heart failure]. 1522 47

Exposure to LBNP results in body fluid shift to lower extremities similarly as under influence of orthostatic stress. In susceptible persons it leads to syncope. For better understanding why certain individuals are more susceptible to orthostatic challenges it seemed necessary to collect more data on hemodynamic and neuroendocrine adjustments occurring before onset of presyncopal symptoms Accordingly, in this study heart rate (HR), blood pressure (BP), stroke volume (SV), cardiac output (CO), hematocrit, plasma catecholamines, adrenomedullin, ACTH and plasma renin activity (PRA) were measured in 24 healthy men during graded LBNP (-15, -30 and -50 mmHg). Thirteen subjects completed the test (HT group) whereas 11 had presyncope signs or symptoms at -30 mmHg or at the beginning of -50 mmHg (LT group). Comparison of these groups showed that LT subjects had lower baseline total peripheral resistance and higher plasma adrenomedullin. During LBNP plasma catecholamine and PRA increases were even greater in LT than in HT group while plasma adrenomedullin elevations were similar in both groups. Plasma ACTH increased only in LT group following presyncope symptoms. Low tolerant group showed more rapid decline of SV and CO than HT subjects from the beginning of LBNP. It is suggested that measurements of SV at the level of LBNP which did not evoke any adverse symptoms may be of predictive value for lower orthostatic tolerance.
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PMID:Hemodynamic and neuroendocrine predictors of lower body negative pressure (LBNP) intolerance in healthy young men. 1598 1

It has been suggested that skeletal nerves fibers may play important roles in neuro-osteogenic interactions. This view is partly based upon information obtained from immunohistochemical studies, chemical and surgical denervation experiments and clinical observations in patients with stroke and spinal cord injury, indicating the presence of a network of nerve fibers in the skeleton and that defective signalling in skeletal nerve fibers affects remodelling of bone. This view is also supported by data showing that functional receptors for signalling molecules in skeletal nerve fibers are expressed in bone cells and that activation of these receptors leads to profound effects on bone forming osteoblasts and bone resorbing osteoclasts. Convincing evidence for a role of neuronal signalling in bone metabolism has been provided by gene deletion approaches in which it has been shown that leptin-sensitive and neuropeptide Y-sensitive receptors in hypothalamus are important for bone remodelling in mice. Recently, gene deletion experiments have shown that calcitonin gene-related peptide (CGRP), one of the neuropeptides present in skeletal nerve fibers, is an important physiological regulator of bone formation at the level of osteoblast activity. CGRP belongs to the calcitonin (CT) family of peptides also including CT, amylin and adrenomedullin, as well as the recently described intermedin and calcitonin receptor-stimulating peptide. These peptides utilize two seven transmembrane G protein-coupled receptors - the calcitonin receptor (CTR) and the calcitonin receptor- like receptor (CRLR) - which can dimerize with three different single transmembrane proteins, making up the RAMP family. Associations between RAMPs and either CTR or CRLR give rise to seven distinct, molecularly characterized, receptors for CT, CGRP, amylin and adrenomedullin. Deletions of the genes for ligands in the CT family of peptides and for one of the receptors have revealed unexpected findings that have changed our view on the role of these peptides in bone remodelling. It was anticipated that deletions of the CT/alpha-CGRP and CTR genes would lead to bone loss, since CT has been shown to inhibit bone resorption in vitro and in vivo and has been used to treat patients with excessive bone resorption. Surprisingly, it was found that CT/alpha-CGRP-/- and CTR+/- mice have increased bone mass due to increased bone formation. Mice with deletion of the amylin gene, however, exhibited bone loss due to enhanced bone resorption. Selective deletion of the alpha-CGRP gene also leads to bone loss, but due to decreased bone formation. Thus, our understanding of the role of the CT family of peptides has been changed dramatically and much more data have to be gained before we fully understand the roles these peptides have in bone biology.
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PMID:Deletions of genes encoding calcitonin/alpha-CGRP, amylin and calcitonin receptor have given new and unexpected insights into the function of calcitonin receptors and calcitonin receptor-like receptors in bone. 1667 92


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