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British Journal of Pharmacology Mar 2014Application of cannabinoids and endocannabinoids to perfused vascular beds or individual isolated arteries results in changes in vascular resistance. In most cases, the... (Review)
Review
UNLABELLED
Application of cannabinoids and endocannabinoids to perfused vascular beds or individual isolated arteries results in changes in vascular resistance. In most cases, the result is vasorelaxation, although vasoconstrictor responses are also observed. Cannabinoids also modulate the actions of vasoactive compounds including acetylcholine, methoxamine, angiotensin II and U46619 (thromboxane mimetic). Numerous mechanisms of action have been proposed including receptor activation, potassium channel activation, calcium channel inhibition and the production of vasoactive mediators such as calcitonin gene-related peptide, prostanoids, NO, endothelial-derived hyperpolarizing factor and hydrogen peroxide. The purpose of this review is to examine the evidence for the range of receptors now known to be activated by cannabinoids. Direct activation by cannabinoids of CB1 , CBe , TRPV1 (and potentially other TRP channels) and PPARs in the vasculature has been observed. A potential role for CB2, GPR55 and 5-HT1 A has also been identified in some studies. Indirectly, activation of prostanoid receptors (TP, IP, EP1 and EP4 ) and the CGRP receptor is involved in the vascular responses to cannabinoids. The majority of this evidence has been obtained through animal research, but recent work has confirmed some of these targets in human arteries. Vascular responses to cannabinoids are enhanced in hypertension and cirrhosis, but are reduced in obesity and diabetes, both due to changes in the target sites of action. Much further work is required to establish the extent of vascular actions of cannabinoids and the application of this research in physiological and pathophysiological situations.
LINKED ARTICLES
This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6.
Topics: Animals; Blood Vessels; Cannabinoids; Humans; Molecular Sequence Data
PubMed: 24329566
DOI: 10.1111/bph.12560 -
Medicine Dec 2022Hypotension is frequent after spinal anesthesia, especially in elderly patients. Whether pre-emptive methoxamine infusion is effective and safe to prevent spinal...
The efficacy and safety of pre-emptive methoxamine infusion in preventing hypotension by in elderly patients receiving spinal anesthesia: A PRISMA-compliant protocol for systematic review and meta-analysis.
BACKGROUND
Hypotension is frequent after spinal anesthesia, especially in elderly patients. Whether pre-emptive methoxamine infusion is effective and safe to prevent spinal anesthesia-induced hypotension is still a controversial issue, to dress this knowledge lack, we performed a systemic review and meta-analysis to evaluated it.
PARTICIPANTS
Elderly patients undergoing spinal anesthesia.
INTERVENTIONS
Administration of methoxamine prior to spinal anesthesia.
METHODS
We searched PUBMED, Cochrane Library, EMBASE, China National Knowledge Infrastructure, Wanfang Database, and VIP Database, Chinese BioMedical Literature & Retrieval System from January 1st 1978 to February 28th 2022. Primary outcomes of interests included hemodynamic parameters, such as systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate. Secondary outcomes of interests included the incidence of intraoperative hypotension, bradycardia, nausea and vomiting, vasopressors requirement, intraoperative blood loss. For continuous or dichotomous variables, treatment effects were calculated as weighted mean difference or odds ratio, respectively.
RESULTS
Our search yielded 8 randomized controlled trials including 480 patients, and 240 patients were allocated into methoxamine group and 240 into control group. Meta-analysis demonstrated that pre-emptive methoxamine infusion in preventing hypotension by in elderly patients receiving spinal anesthesia had higher blood pressures, lower heart rates. Compared with the control group, the incidence of perioperative hypotension in elderly patients was lower, and elderly patients had less requirement for vasopressor in methoxamine group.
CONCLUSION
This meta-analysis demonstrated that pre-emptive methoxamine infusion in elderly patients receiving spinal anesthesia can improve blood pressure, slow down heart rate, reduce the incidence of hypotension and requirement for vasopressor. However, these findings should be interpreted rigorously. Further well-conducted trials are required to confirm this.
Topics: Humans; Aged; Methoxamine; Anesthesia, Spinal; Systematic Reviews as Topic; Meta-Analysis as Topic; Hypotension; Vasoconstrictor Agents; Bradycardia; Double-Blind Method; Randomized Controlled Trials as Topic
PubMed: 36626487
DOI: 10.1097/MD.0000000000032262 -
Yakugaku Zasshi : Journal of the... May 2010It is widely accepted that vascular endothelium regulates vasoconstriction via release of endothelium-derived relaxing factors (EDRF). The mesenteric circulation, which... (Review)
Review
It is widely accepted that vascular endothelium regulates vasoconstriction via release of endothelium-derived relaxing factors (EDRF). The mesenteric circulation, which is the largest vascular bed, influences regulation of systemic blood pressure. However, the role of EDRF in the modulation of vascular tone in peripheral mesenteric circulation has not been extensively studied. Therefore, our recent studies investigated the role of the vascular endothelium in the regulation of methoxamine (alpha(1)-adrenoceptor agonist)-induced vasoconstriction and their age-related changes in rat mesenteric vascular beds. In mesenteric vascular beds with intact endothelium isolated from 8 week-old rats, the initial maximum vasoconstriction induced by continuous perfusion of methoxamine was time-dependently decreased during 3 hour-perfusion. Neither nitric oxide synthase inhibitor nor cyclooxygenase inhibitor altered this time-dependent reduction of methoxamine-induced vasoconstriction. Endothelium removal, K(+)-channel inhibitors and gap junction inhibitor significantly inhibited the time-dependent reduction of methoxamine-induced vasoconstriction. In the preparations with intact endothelium from 16 week-old rats, the time-dependent reduction of methoxamine-induced vasoconstriction disappeared. Furthermore, endothelium removal and treatment with cyclooxygenase inhibitor, thromboxane A(2) receptor antagonist or superoxide dismutase mimetic significantly reduced the methoxamine-induced vasoconstriction in the preparations from 16 week-old rats. These findings suggest that vascular endothelium acts to depress methoxamine-induced vasoconstriction by releasing endothelium-derived hyperpolarizing factor (EDHF), and dysfunction in this endothelial modulation develops with ageing.
Topics: Adrenergic alpha-Agonists; Aging; Animals; Endothelium, Vascular; Endothelium-Dependent Relaxing Factors; Gap Junctions; In Vitro Techniques; Mesenteric Arteries; Methoxamine; Microcirculation; Potassium Channels; Rats; Reactive Oxygen Species; Time Factors; Vasoconstriction
PubMed: 20460871
DOI: 10.1248/yakushi.130.723 -
European Review For Medical and... 2016Hypotension is a common complication of spinal anesthesia for cesarean delivery. Atropine is a vagus nerve blocker that can antagonize vagus excitation to mitigate the... (Comparative Study)
Comparative Study Randomized Controlled Trial
Comparison of the treatment effects of methoxamine and combining methoxamine with atropine infusion to maintain blood pressure during spinal anesthesia for cesarean delivery: a double blind randomized trial.
OBJECTIVE
Hypotension is a common complication of spinal anesthesia for cesarean delivery. Atropine is a vagus nerve blocker that can antagonize vagus excitation to mitigate the reflex bradycardia. We aimed to assess the effect of methoxamine-atropine therapy in treating spinal anesthesia hypotension for cesarean section.
PATIENTS AND METHODS
This is a double-blind randomized controlled study. Women under spinal anesthesia for elective caesarean delivery received boluses of methoxamine 2 mg alone (Group M, n = 40), or with addition of atropine 0.1 mg (Group MA1, n = 40), atropine 0.2 mg (Group MA2, n = 40) or atropine 0.3 mg (Group MA3, n = 40) upon a maternal systolic pressure ≤ 80% of baseline. The primary endpoint was systolic blood pressure and the secondary endpoints were maternal heart rates, instant neonatal heart rates, umbilical artery pH and umbilical artery base excess.
RESULTS
Changes in systolic blood pressure were similar among the four groups. The incidences of bradycardia in groups M and MA1 were significantly higher than those in group MA2 and MA3. The fetal heart rates after delivery in groups MA2 and MA3 were higher than those in group M and MA1 but within the normal range. The acid-base status had no difference in the four groups.
CONCLUSIONS
Methoxamine-atropine combination has a similar efficacy to methoxamine alone but has an increased hemodynamic stability and a less adverse effect occurrence.
Topics: Adult; Anesthesia, Spinal; Atropine; Blood Pressure; Cesarean Section; Double-Blind Method; Drug Therapy, Combination; Female; Fetal Blood; Heart Rate; Humans; Hypotension; Infant, Newborn; Infusions, Intravenous; Methoxamine; Pregnancy; Treatment Outcome; Young Adult
PubMed: 26914134
DOI: No ID Found -
Journal of Vascular Research 2016Voltage-gated potassium (Kv) channels formed by Kv7 (KCNQ) α-subunits are recognized as crucial for vascular smooth muscle function, in addition to their established... (Comparative Study)
Comparative Study
Voltage-gated potassium (Kv) channels formed by Kv7 (KCNQ) α-subunits are recognized as crucial for vascular smooth muscle function, in addition to their established roles in the heart (Kv7.1) and the brain (Kv7.2-5). In vivo, Kv7 α-subunits are often regulated by KCNE subfamily ancillary (β) subunits. We investigated the effects of targeted germline Kcne4 deletion on mesenteric artery reactivity in adult male and female mice. Kcne4 deletion increased mesenteric artery contractility in response to α-adrenoceptor agonist methoxamine, and decreased responses to Kv7.2-7.5 channel activator ML213, in male but not female mice. In contrast, Kcne4 deletion markedly decreased vasorelaxation in response to isoprenaline in both male and female mice. Kcne4 expression was 2-fold lower in the female versus the male mouse mesenteric artery, and Kcne4 deletion elicited only moderate changes of other Kcne transcripts, with no striking sex-specific differences. However, Kv7.4 protein expression in females was twice that in males, and was reduced in both sexes by Kcne4 deletion. Our findings confirm a crucial role for KCNE4 in regulation of Kv7 channel activity to modulate vascular tone, and provide the first known molecular mechanism for sex-specificity of this modulation that has important implications for vascular reactivity and may underlie sex-specific susceptibility to cardiovascular diseases.
Topics: Adrenergic alpha-1 Receptor Agonists; Anilides; Animals; Bridged Bicyclo Compounds; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Genotype; KCNQ Potassium Channels; Male; Mesenteric Arteries; Methoxamine; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Phenotype; Potassium Channels, Voltage-Gated; Sex Factors; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents
PubMed: 27710966
DOI: 10.1159/000449060 -
Pharmacology Research & Perspectives Oct 2022α2-adrenoceptors, (α2A, α2B and α2C-subtypes), are Gi-coupled receptors. Central activation of brain α2A and α2C-adrenoceptors is the main site for α2-agonist...
α2-adrenoceptors, (α2A, α2B and α2C-subtypes), are Gi-coupled receptors. Central activation of brain α2A and α2C-adrenoceptors is the main site for α2-agonist mediated clinical responses in hypertension, ADHD, muscle spasm and ITU management of sedation, reduction in opiate requirements, nausea and delirium. However, despite having the same Gi-potency in functional assays, some α2-agonists also stimulate Gs-responses whilst others do not. This was investigated. Agonist responses to 49 different α-agonists were studied (CRE-gene transcription, cAMP, ERK1/2-phosphorylation and binding affinity) in CHO cells stably expressing the human α2A, α2B or α2C-adrenoceptor, enabling ligand intrinsic efficacy to be determined (binding K /Gi-IC ). Ligands with high intrinsic efficacy (e.g., brimonidine and moxonidine at α2A) stimulated biphasic (Gi-Gs) concentration responses, however for ligands with low intrinsic efficacy (e.g., naphazoline), responses were monophasic (Gi-only). ERK1/2-phosphorylation responses appeared to be Gi-mediated. For Gs-mediated responses to be observed, both a system with high receptor reserve and high agonist intrinsic efficacy were required. From the Gi-mediated efficacy ratio, the degree of Gs-coupling could be predicted. The clinical relevance and precise receptor conformational changes that occur, given the structural diversity of compounds with high intrinsic efficacy, remains to be determined. Comparison with α1 and β1/β2-adrenoceptors demonstrated subclass affinity selectivity for some compounds (e.g., α2:dexmedetomidine, α1:A61603) whilst e.g., oxymetazoline had high affinity for both α2A and α1A-subtypes, compared to all others. Some compounds had subclass selectivity due to selective intrinsic efficacy (e.g., α2:brimonidine, α1:methoxamine/etilefrine). A detailed knowledge of these agonist characteristics is vital for improving computer-based deep-learning and drug design.
Topics: Animals; Brimonidine Tartrate; CHO Cells; Cricetinae; Cricetulus; Humans; Ligands
PubMed: 36101495
DOI: 10.1002/prp2.1003 -
Progress in Biophysics and Molecular... 2008Cardiovascular diseases are the leading cause of mortality worldwide and about 25% of cardiovascular deaths are due to disturbances in cardiac rhythm or "arrhythmias".... (Review)
Review
Cardiovascular diseases are the leading cause of mortality worldwide and about 25% of cardiovascular deaths are due to disturbances in cardiac rhythm or "arrhythmias". Arrhythmias were traditionally treated with antiarrhythmic drugs, but increasing awareness of the risks of presently available antiarrhythmic agents has greatly limited their usefulness. Most common treatment algorithms still involve small molecule drugs, and antiarrhythmic agents with improved efficacy and safety are sorely needed. This paper reviews the model systems that are available for discovery and development of new antiarrhythmic drugs. We begin with a presentation of screening methods used to identify specific channel-interacting agents, with a particular emphasis on high-throughput screens. Traditional manual electrophysiological methods, automated electrophysiology, fluorescent dye methods, flux assays and radioligand binding assays are reviewed. We then discuss a variety of relevant arrhythmia models. Two models are widely used in testing for arrhythmogenic actions related to excess action potential prolongation, an important potential adverse effect of chemical entities affecting cardiac rhythm: the methoxamine-sensitized rabbit and the dog with chronic atrioventricular block. We then go on to review models used to assess potential antiarrhythmic actions. For ventricular arrhythmias, chemical induction methods, cardiac or neural electrical stimulation, ischaemic heart models and models of cardiac channelopathies can be used to identify effective antiarrhythmic agents. For atrial arrhythmias, potentially useful models include vagally-maintained atrial fibrillation, acute asphyxia with atrial burst-pacing, sterile pericarditis, Y-shaped atria surgical incisions, chronic atrial dilation models, atrial electrical remodelling due to sustained atrial tachycardia, heart failure-related atrial remodelling, and acute atrial ischaemia. It is hoped that the new technologies now available and the recently-developed models for arrhythmia-response assessment will permit the introduction of newer and more effective antiarrhythmic therapies in the near future.
Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disease Models, Animal; Dogs; Drug Discovery; Drug Evaluation, Preclinical; Electrophysiological Phenomena; Humans; In Vitro Techniques; Ion Channels; Myocytes, Cardiac; Rabbits
PubMed: 19038282
DOI: 10.1016/j.pbiomolbio.2008.10.009 -
Acta Neurobiologiae Experimentalis 2022This study aimed to further explore the underlying molecular mechanism of intracerebral hemorrhage (ICH), gene expression profile GSE24265, containing perihematomal...
This study aimed to further explore the underlying molecular mechanism of intracerebral hemorrhage (ICH), gene expression profile GSE24265, containing perihematomal tissues, contralateral grey and white matters were retrieved and analyzed. The data was hierarchically clustered and the differentially expressed genes (DEGs) were screened. Functional analysis and protein interaction analysis of DEG hubs were performed, and the miRNA‑transcription factor (TF)‑target network was built. In addition, the candidate small-molecule compounds that might reverse the expression of an ICH‑linked gene were identified by CMap. This method revealed a total of 408 DEGs. Five modules including chemokinerelated, antigen immune-related, pathogen infection, cell reaction, and positive regulation of tyrosine phosphorylation and MAPK cascade were identified. The expression levels of CCL5, CXCL8, ICAM1, IL-1B, IL-6, VCAM1, and VEGFA were correlated with ICH among the top 10 hub genes obtained in the protein-protein interaction (PPI) network. A total of 237 miRNA‑TF‑target regulatory relationships were obtained, including 6 TFs, 11 miRNAs and 105 target genes. Finally, the CMap database identified Prestwick-1083, xamoterol, ifosfamide, methyldopate, nifurtimox, propranolol, and methoxamine as potential therapeutic agents for ICH while doxorubicin, menadione and azacitidine may increase its pathogenicity. Furthermore, CCL5, CXCL8 and VEGFA may be novel candidate susceptibility genes for ICH. Some small-molecule drugs, including xamoterol may be used for the treatment of ICH.
Topics: Biomarkers; Cerebral Hemorrhage; Computational Biology; Gene Expression Profiling; Gene Regulatory Networks; Humans; MicroRNAs; Xamoterol
PubMed: 35833818
DOI: 10.55782/ane-2022-017 -
Frontiers in Physiology 2021Metabolic syndrome is associated with hypercholesterolemia, cardiac remodeling, and increased susceptibility to ventricular arrhythmias. Effects of diet-induced...
Metabolic syndrome is associated with hypercholesterolemia, cardiac remodeling, and increased susceptibility to ventricular arrhythmias. Effects of diet-induced hypercholesterolemia on susceptibility to torsades de pointes arrhythmias (TdP) together with potential indicators of arrhythmic risk were investigated in three experimental groups of Carlsson's rabbit model: (1) young rabbits (YC, young control, age 12-16 weeks), older rabbits (AC, adult control, age 20-24 weeks), and older age-matched cholesterol-fed rabbits (CH, cholesterol, age 20-24 weeks). TdP was induced by α-adrenergic stimulation by methoxamine and I block in 83% of YC rabbits, 18% of AC rabbits, and 21% of CH rabbits. High incidence of TdP was associated with high incidence of single (SEB) and multiple ectopic beats (MEB), but the QTc prolongation and short-term variability (STV) were similar in all three groups. In TdP-susceptible rabbits, STV was significantly higher compared with arrhythmia-free rabbits but not with rabbits with other than TdP arrhythmias (SEB, MEB). Amplitude-aware permutation entropy analysis of baseline ECG could identify arrhythmia-resistant animals with high sensitivity and specificity. The data indicate that the TdP susceptibility in methoxamine-sensitized rabbits is affected by the age of rabbits but probably not by hypercholesterolemia. Entropy analysis could potentially stratify the arrhythmic risk and identify the low-risk individuals.
PubMed: 34234694
DOI: 10.3389/fphys.2021.692921 -
BMC Anesthesiology Jun 2020Acute renal injury (AKI) caused by hypotension often occurs in elderly patients after gastrointestinal tumor surgery. Although vasoactive drugs can increase effective... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of continuous intraoperative infusion of methoxamine on renal function in elderly patients undergoing gastrointestinal tumor surgery: a randomized controlled trial.
BACKGROUND
Acute renal injury (AKI) caused by hypotension often occurs in elderly patients after gastrointestinal tumor surgery. Although vasoactive drugs can increase effective filtration pressure, they may increase renal vascular resistance and reduce renal blood flow. The effect of methoxamine on renal function is not clear.
METHODS
After obtaining written informed consent, 180 elderly patients undergoing elective gastrointestinal tumor surgery were randomly allocated into two groups: M group (continuous infusion of methoxamine at 2 μg/kg/min) and N group (continuous infusion of normal saline). The patients' mean arterial pressure was maintained within 20% of baseline by a continuous infusion of methoxamine or normal saline. Maintenance fluid was kept at 5 mL/kg/h. According to Kidney disease improve global outcome (KDIGO) guidelines, creatinine was measured at 1, 2 and 7 days after operation, and urine volume at 6, 12 and 24 h after operation was measured to evaluate the occurrence of AKI. 162 patients were included in the final data analysis.
RESULTS
Significant differences in the incidence of postoperative Acute kidney injury (M group: 7.5%; N group: 18.3%; P < 0.05), the frequency of hypotension (M group: 1 [1-3]; N group: 3 [1-5]; P < 0.05), and the duration of intraoperative hypotension (M group: 2[0-10]; N group: 10 [5-16]; P < 0.05) were identified between the groups. Multivariate logistic regression analyses demonstrated that preoperative creatinine and the frequency of intraoperative hypotension were the common factors leading to the occurrence of postoperative AKI. The results of Cox multivariate analysis showed that age and AKI were independent risk factors for 30-day death.
CONCLUSION
Compared with the intraoperative continuous infusion of placebo and methoxamine, continuous infusion of 2 μg/kg/min methoxamine reduced the incidence of postoperative AKI and other clinical complications in elderly patients undergoing gastrointestinal surgery by raising blood pressure and improved the prognosis of patients.
TRIAL REGISTRATION
Trial registration: Chinese Clinical Trial Registry, ChiCTR1900020536, registered 7 January, 2019.
Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Arterial Pressure; Double-Blind Method; Female; Gastrointestinal Neoplasms; Humans; Infusions, Intravenous; Intraoperative Period; Logistic Models; Male; Methoxamine; Postoperative Complications; Proportional Hazards Models; Prospective Studies
PubMed: 32534584
DOI: 10.1186/s12871-020-01064-0