pituitrin and Stroke

Stroke is a life-threatening condition in which accurate diagnoses and timely treatment are critical for successful neurological recovery. The current acute treatment strategies, particularly non-invasive interventions, are limited, thus urging the need for novel therapeutical targets. Arginine vasopressin (AVP) receptor antagonists are emerging as potential targets to treat edema formation and subsequent elevation in intracranial pressure, both significant causes of mortality in acute stroke. Here, we summarize the current knowledge on the mechanisms leading to AVP hyperexcretion in acute stroke and the subsequent secondary neuropathological responses. Furthermore, we discuss the work supporting the predictive value of measuring copeptin, a surrogate marker of AVP in stroke patients, followed by a review of the experimental evidence suggesting AVP receptor antagonists in stroke therapy. As we highlight throughout the narrative, critical gaps in the literature exist and indicate the need for further research to understand better AVP mechanisms in stroke. Likewise, there are advantages and limitations in using copeptin as a prognostic tool, and the translation of findings from experimental animal models to clinical settings has its challenges. Still, monitoring AVP levels and using AVP receptor antagonists as an add-on therapeutic intervention are potential promises in clinical applications to alleviate stroke neurological consequences.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine; Arginine Vasopressin; Glycopeptides; Nervous System Diseases; Stroke; Vasopressins

Topics: Arrhythmias, Cardiac; Atrial Fibrillation; Catecholamines; Drug Therapy, Combination; Humans; Length of Stay; Myocardial Ischemia; Randomized Controlled Trials as Topic; Renal Replacement Therapy; Shock, Septic; Stroke; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Brain edema formation is a major cause of brain damages and the high mortality of ischemic stroke. The aim of this review is to explore the relationship between ischemic brain edema formation and vasopressin (VP) hypersecretion in addition to the oxygen and glucose deprivation and the ensuing reperfusion injury.. Pertinent studies involving ischemic stroke, brain edema formation, astrocytes, and VP were identified by a search of the PubMed and the Web of Science databases in January 2016. Based on clinical findings and reports of animal experiments using ischemic stroke models, this systematic review reanalyzes the implication of individual reports in the edema formation and then establishes the inherent links among them.. This systematic review reveals that cytotoxic edema and vasogenic brain edema in classical view are mainly under the influence of a continuous malfunction of astrocytic plasticity. Adaptive VP secretion can modulate membrane ion transport, water permeability, and blood-brain barrier integrity, which are largely via changing astrocytic plasticity. Maladaptive VP hypersecretion leads to disruptions of ion and water balance across cell membranes as well as the integrity of the blood-brain barrier. This review highlights our current understandings of the cellular mechanisms underlying ischemic brain edema formation and its association with VP hypersecretion.. VP hypersecretion promotes brain edema formation in ischemic stroke by disrupting hydromineral balance in the neurovascular unit; suppressing VP hypersecretion has the potential to alleviate ischemic brain edema.

Topics: Animals; Astrocytes; Brain; Brain Edema; Brain Ischemia; Humans; Phenotype; Prognosis; Risk Factors; Signal Transduction; Stroke; Up-Regulation; Vasopressins

Although many approaches have been tried in the attempt to reduce the devastating impact of stroke, tissue plasminogen activator for thromboembolic stroke is the only proved, effective acute stroke treatment to date. Vasopressin, an acute-phase reactant, is released after brain injury and is partially responsible for the subsequent inflammatory response via activation of divergent pathways. Recently there has been increasing interest in vasopressin because it is implicated in inflammation, cerebral edema, increased intracerebral pressure, and cerebral ion and neurotransmitter dysfunctions after cerebral ischemia. Additionally, copeptin, a byproduct of vasopressin production, may serve as a promising independent marker of tissue damage and prognosis after stroke, thereby corroborating the role of vasopressin in acute brain injury. Thus, vasopressin antagonists have a potential role in early stroke intervention, an effect thought to be mediated via interactions with aquaporin receptors, specifically aquaporin-4. Despite some ambiguity, vasopressin V1a receptor antagonism has been consistently associated with attenuated secondary brain injury and edema in experimental stroke models. The role of the vasopressin V2 receptor remains unclear, but perhaps it is involved in a positive feedback loop for vasopressin expression. Despite the encouraging initial findings we report here, future research is required to characterize further the utility of vasopressin antagonists in treatment of stroke.

Topics: Brain Edema; Hemostatics; Humans; Stroke; Vasopressins

Arginine vasopressin (AVP or antidiuretic hormone) is one of the key hormones in the human body responsible for a variety of cardiovascular and renal functions. It has so far escaped introduction into the routine clinical laboratory due to technical difficulties and preanalytical errors. Copeptin, the C-terminal part of the AVP precursor peptide, was found to be a stable and sensitive surrogate marker for AVP release. Copeptin behaves in a similar manner to mature AVP in the circulation, with respect to osmotic stimuli and hypotension. During the past years, copeptin measurement has been shown to be of interest in a variety of clinical indications, including cardiovascular diseases such as heart failure, myocardial infarction, and stroke. This review summarizes the recent progress on the diagnostic use of copeptin in cardiovascular and renal diseases and discusses the potential use of copeptin measurement in the context of therapeutic interventions with vasopressin receptor antagonists.

Topics: Arginine Vasopressin; Biomarkers; Blood Volume; Cardiovascular Diseases; Cardiovascular System; Glycopeptides; Heart Failure; Humans; Kidney; Kidney Diseases; Myocardial Infarction; Prognosis; ROC Curve; Shock, Cardiogenic; Stroke; Vasopressins

Topics: Anorexia; Arousal; Brain Mapping; Circadian Rhythm; Corticotropin-Releasing Hormone; Depression; Glucocorticoids; Humans; Hydrocortisone; Hypothalamic Hormones; Hypothalamo-Hypophyseal System; Hypothalamus; Magnetic Resonance Imaging; Models, Neurological; Models, Psychological; Mood Disorders; Neuropsychological Tests; Neurotransmitter Agents; Oxytocin; Paraventricular Hypothalamic Nucleus; Phototherapy; Pituitary-Adrenal System; Prefrontal Cortex; Receptors, Glucocorticoid; Receptors, Neurotransmitter; Sleep Initiation and Maintenance Disorders; Stress, Physiological; Stroke; Thyroid Gland; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon; Vasopressins

Topics: Adrenocorticotropic Hormone; Arginine Vasopressin; Brain Edema; Cerebrovascular Disorders; Cortisone; Drug Therapy; Humans; Hydrocortisone; Stroke; Vasopressins

Abnormal patterns of diurnal blood pressure variation have been reported to be related to advanced target organ damage and poor cardiovascular prognosis. We studied silent cerebrovascular disease and stroke events in older Japanese patients with different nocturnal blood pressure dipping. There was a J-shaped relationship of nocturnal dipping status with silent cerebral infarcts detected by brain magnetic resonance imaging at baseline, and with stroke incidence during the follow-up period. The extreme-dippers (with marked nocturnal blood pressure dipping) and the risers (with higher nocturnal blood pressure than awake blood pressure) had a higher prevalence of silent cerebral infarcts and a poorer stroke prognosis than those with appropriate nocturnal blood pressure dipping (dippers). The extreme-dippers tended to have predominant systolic hypertension and increased blood pressure variability. Several factors affect the diurnal blood pressure variation pattern. The non-dipping pattern is associated with autonomic nervous dysfunction and poor sleep quality due to nocturnal behavior and sleep apnea. The extreme-dippers might have increased arterial stiffness with reduced circulating blood volume in addition to an excessive morning surge due to alpha-adrenergic hyperactivity. Anti-hypertensive medication that normalizes the diurnal blood pressure variation might improve the cardiovascular prognosis in high-risk hypertensive patients.

Topics: Aged; Aged, 80 and over; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cerebrovascular Disorders; Circadian Rhythm; Follow-Up Studies; Humans; Hypertension; Hypotension; Middle Aged; Stroke; Vasopressins

The ability of middle cerebral arteries (MCAs) to utilize intracellular smooth muscle (SM) Ca2+ to produce constriction in response to pressure and agonists was assessed in relation to hemorrhagic stroke development in Wistar-Kyoto stroke-prone (SHRSP) and stroke-resistant (srSHR) spontaneously hypertensive rats.. MCAs were studied with the use of a pressure myograph at 100 mm Hg.. MCAs from srSHR and prestroke SHRSP exhibited pressure-dependent constriction and constricted in response to vasopressin or serotonin in the presence of nifedipine or the absence of [Ca2+]o. MCAs from poststroke SHRSP lost the latter functions and could only constrict in response to vasopressin/serotonin in Krebs' solution containing Ca2+ in the absence of nifedipine. This indicated that the SM could not utilize internal Ca2+ for constriction and maintained constriction by Ca2+ entry through L-type channels. The MCAs of poststroke SHRSP could not constrict to [K+]o-induced depolarization, suggesting that the agonist-induced opening of the L-type channels occurred by mechanisms other than SM depolarization. Depletion of the sarcoplasmic SM Ca2+ stores of MCAs from srSHR with cyclopiazonic acid did not prevent pressure-dependent constriction.. Stroke in SHRSP produced a defect in the ability of MCAs to constrict in response to vasopressin or serotonin via the use of an intracellular source of Ca2+. This could be promoted by an inability of the SM to release intracellular Ca2+, by the depletion of internal Ca2+ stores, or by a decrease in the contractile sensitivity to Ca2+ released from the internal stores.

Topics: Animals; Blood Pressure; Calcium; Calcium Channel Blockers; Calcium Channels, L-Type; Disease Models, Animal; Disease Progression; Hypertension; In Vitro Techniques; Middle Cerebral Artery; Muscle, Smooth, Vascular; Myography; Nifedipine; Potassium; Rats; Rats, Inbred SHR; Serotonin; Sodium, Dietary; Stroke; Vasoconstriction; Vasoconstrictor Agents; Vasopressins

Dahl salt-sensitive (DSS) rats fed an 8.7% sodium chloride diet from weaning spontaneously developed hypertension and a 50% mortality rate by 5 weeks. Before death the rats exhibited behavioural signs of stroke and disruption of the blood-brain barrier.. To test the hypothesis that rats exhibiting stroke had middle cerebral arteries (MCAs) that had lost the ability to constrict in response to pressure, and to assess whether this defect was associated with abnormalities in protein kinase C (PKC)-mediated constriction.. MCAs were sampled from DSS rats before and after stroke and from Dahl salt-resistant (DSR) rats fed 8.7% NaCl. Constrictions in response to a 100 mmHg pressure step and to PKC activation by phorbol dibutyrate (PDB) (0.1 micromol/l) in the presence of nifedipine (3 micromol/l) were measured.. MCAs from DSS rats after stroke constricted in response to vasopressin but were unable to constrict in response to pressure or PDB in the presence of nifedipine, whereas those from DSS rats before stroke and from DSR rats constricted in response to all the stimuli. The PKC inhibitors, chelerythrine (12 micromol/l) and bisindolylmaleimide (5 micromol/l) inhibited constrictions in response to pressure and to PDB in the presence of nifedipine.. Constriction of the MCA in response to pressure is dependent on functional PKC signalling. Development of stroke in DSS rats fed a high-salt diet is associated with an inability of the MCAs to constrict in response to pressure, possibly because of the presence of an incompetent PKC system. The inability to constrict in response to pressure may cause blood flow abnormalities that contribute to disruption of the blood-brain barrier in these rats.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Middle Cerebral Artery; Models, Cardiovascular; Nifedipine; Protein Kinase C; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Stroke; Survival Analysis; Time Factors; Vasoconstriction; Vasoconstrictor Agents; Vasopressins

Cerebrovascular pressure-dependent constriction (PDC) is associated with smooth muscle (SM) depolarization and Ca(2+) influx through voltage-gated channels. We studied the alterations in electromechanical contraction in the middle cerebral arteries (MCAs) of stroke-prone Wistar-Kyoto spontaneously hypertensive rats (SHRsp) in relation to the stroke-related loss of PDC.. Constriction to pressure, elevated [K(+)](o) and/or [Ca(2+)](o), and SM membrane potentials (E(m)) were measured in isolated pressurized MCAs of SHRsp and stroke-resistant SHR.. MCAs of SHRsp exhibited an age-related decrease in PDC before hemorrhagic stroke and a loss of PDC after stroke. At 100 mm Hg, the MCAs of poststroke SHRsp maintained partial constriction that was not altered with pressure but was inhibited by nifedipine (1 micromol/L). The MCAs of poststroke SHRsp constricted to vasopressin (0.17 micromol/L) but not to elevated [K(+)](o). When pressure was reduced from 100 to 0 mm Hg, the MCAs from young prestroke SHRsp exhibited SM hyperpolarization (-38 to -46 mV), whereas those of poststroke SHRsp maintained a constant, depolarized E(m) (-34 mV). Alterations in E(m) with varying [K(+)](o) suggested that there was a decrease in SM K(+) conductance in the MCAs of poststroke SHRsp.. The observation that the MCAs of poststroke SHRsp depolarize but do not constrict to elevated [K(+)](o) suggests the presence of dysfunctional voltage-gated Ca(2+) channels. The inability to alter E(m) with pressure or to constrict to depolarization could partially contribute to the loss of PDC in the MCAs of poststroke SHRsp.

Topics: Animals; Calcium; Calcium Channel Blockers; Cerebral Arteries; Electrophysiology; Genetic Predisposition to Disease; Hypertension; In Vitro Techniques; Muscle, Smooth, Vascular; Nifedipine; Potassium; Pressure; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; Stroke; Vasoconstriction; Vasoconstrictor Agents; Vasomotor System; Vasopressins