Cellular targets of inhalational anaesthetic- and opioid receptor agonist-induced cardioprotection

Several anaesthetics and anaesthetic adjuvants have been shown to limit the extent of myocardial injury due to ischaemia and reperfusion, a protective phenomenon known as anaesthetic-induced cardioprotection. Inhalational anaesthetics and opioid receptor agonists are among the key players in anaesthetic-induced cardioprotection. However, the mechanisms underlying anaesthetic-induced cardioprotection are not fully understood, and as such there are currently no concrete guidelines regarding the choice of anaesthetic protocols designed to enhance cardioprotection. This mini-review provides insights into the mechanisms through which the cardioprotection due to inhalational agents and opioid receptor agonists occurs, and discusses the clinical implications thereof. The mechanisms underlying this cardioprotection are diverse and remain unresolved, but several cellular signaling cascades involve key targets such as receptors, sarcolemmal- and mitochondrial ATP-sensitive K+ channels, the mitochondrial permeability transition pore, glycogen synthase kinase-3 beta, nitric oxide, and anti-apoptotic factors. Such factors represent potential therapeutic targets in promoting anaesthetic-induced cardioprotection.Keywords:anaesthetic,cardiac, cardioprotection, inhalational agents, opioid recepto

Cardioprotective and anti-arrhythmic effects of magnesium pretreatment against ischaemia/reperfusion injury in isoprenaline-induced hypertrophic rat heart

The effects of magnesium (Mg2+) on ischaemic complications of pathological cardiac hypertrophy are unclear. In this study, we investigated effects of Mg2+ pretreatment on ischaemia/reperfusion (I/R) injury in isoprenaline (ISO)-induced hypertrophic hearts. Wistar rats were treated for 7 days with different combinations of ISO (1.25 mg/kg) subcutaneously, MgSO4 (270 mg/kg) intraperitoneally, or vehicle (saline). On the eighth day, hearts were either subjected to regional I/R during Langendorff perfusion or histologically stained with haematoxylin and eosin and Masson’s trichrome. Haemodynamic and electrocardiographic parameters were recorded using the PowerLab data-acquisition system. Infarcts were identified by triphenyltetrazolium chloride staining. Plasma Mg2+ was measured using photometric assays. Mg2+ pretreatment significantly decreased I/R-induced infarct size (p = 0.001) and the overall arrhythmia score (p < 0.001) of I/R-induced ventricular ectopics, ventricular tachycardia, and ventricular fibrillation in hypertrophic hearts, but not non-hypertrophied hearts. Mg2+ also improved post-I/R left ventricular developed pressure in hypertrophic hearts. However, Mg2+ did not reverse the ISO-induced myocyte thickening and interstitial fibrosis or increases in heart weight. Plasma Mg2+ was not different among treatment groups. These results suggest that Mg2+ pretreatment may protect against I/R-induced injury and malignant arrhythmias in hypertrophic hearts, possibly via mechanisms unrelated to long-lasting changes in plasma Mg2+ or prevention of structural changes such as fibrosis

Cardioprotective effect of fingolimod against calcium paradox-induced myocardial injury in the isolated rat heart

Fingolimod (FTY720) inhibits Ca2+-permeable, Mg2+-sensitive channels called transient receptor potential melastatin 7 (TRPM7), but its effects on Ca2+ paradox (CP)-induced myocardial damage have not been evaluated. We studied the effect of FTY720 on CP-induced myocardial damage, and used other TRPM7 channel inhibitors nordihydroguaiaretic acid (NDGA) and Mg2+ to test if any effect of FTY720 was via TRPM7 inhibition. Langendorff-perfused Wistar rat hearts were treated with FTY720 or NDGA and subjected to a CP protocol consisting of Ca2+ depletion followed by Ca2+ repletion. Hearts of rats pre-treated with MgSO4 were also subjected to CP. Hemodynamic parameters were measured using an intraventricular balloon, and myocardial infarct size was quantified using triphenyltetrazolium chloride stain. TRPM7 proteins in ventricular tissue were detected using immunoblot analysis. FTY720, but not NDGA, decreased CP-induced infarct size. Both FTY720 and NDGA minimized the CP-induced elevation of left ventricular end-diastolic pressure, but only FTY720 ultimately improved ventricular developed pressure. Mg2+ pre-treatment had effect neither on CP-induced infarct size, hemodynamic parameters during CP, nor the level TRPM7 protein expression in ventricular tissue. Overall, FTY720 attenuated CP-induced myocardial damage, with potential therapeutic implications on Ca2+-mediated cardiotoxicity. However, the cardioprotective mechanism of FTY720 seems to be unrelated to TRPM7 channel modulation

Beneficial effects of magnesium treatment on heart rate variability and cardiac ventricular function in diabetic rats

Background: Diabetes mellitus induces life-threatening cardiovascular complications such as cardiac autonomic neuropathy and ventricular dysfunction and is associated with hypomagnesemia. In this study, we investigated the short-term effects of magnesium (Mg2+) treatment on streptozotocin (STZ)-induced diabetic cardiac complications. Methods: Adult Wistar rats were treated once with STZ (50 mg/kg, intraperitoneally [ip]) or vehicle (citrate) and then daily for 7 days with MgSO4 (270 mg/kg, ip) or saline. On the eighth day, in vivo tail-pulse plethysmography was recorded for heart rate variability (HRV) analysis, and ex vivo Langendorff-based left ventricular (LV) pressure–volume parameters were measured using an intraventricular balloon. Measurements of plasma lipid and Mg2+ levels as well as blood glucose and cardiac tissue Mg2+ levels were also performed. Results: Treatment with Mg2+ prevented diabetes-induced alterations in the standard deviation of the averages of normal-to-normal (NN) intervals (SDANN), root mean square differences of successive NN intervals (RMSSD), heart rate, and low-frequency (LF) power–high-frequency (HF) power ratio. In addition, Mg2+ restored orthostatic stress-induced changes in SDANN, RMSSD, and LF–HF ratio in diabetic rats. In isolated hearts, Mg2+ reversed the diabetes-induced decrease in LV end-diastolic elastance and the right shift of end-diastolic equilibrium volume intercept, without altering LV-developed pressure or end-systolic elastance. However, Mg2+ did not prevent the elevation in blood glucose, total cholesterol, and triglycerides or the decrease in high-density lipoprotein cholesterol in diabetes. Plasma- or cardiac tissue Mg2+ was not different among the treatment groups. Conclusion: These results suggest that Mg2+ treatment may attenuate diabetes-induced reduction in HRV and improve LV diastolic distensibility, without preventing hyperglycemia and dyslipidemia. Thus, Mg2+ may have a modulatory role in the early stages of diabetic cardiovascular complications

The effect of sphingosine‐1‐phosphate on the endothelial glycocalyx during ischemia‐reperfusion injury in the isolated rat heart

Objective: Sphingosine‐1‐phosphate is a natural metabolite that is cardioprotective, but its effects on endothelial glycocalyx damage during ischemia‐reperfusion are unknown. Therefore, we investigated the effect of sphingosine‐1‐phosphate on the endothelial glycocalyx during ischemia‐reperfusion. Methods: Isolated hearts from Wistar rats were perfused on a Langendorff system with Krebs‐Henseleit buffer and pretreated with sphingosine‐1‐phosphate (10 nmol/L) before ischemia‐reperfusion. Infarct size was measured by triphenyl tetrazolium chloride staining (n ≥ 6 per group). Cardiac edema was assessed by calculating total water content (n = 7 per group) and histologically quantifying the interstitial compartment (n ≥ 3 per group). The post‐ischemic coronary release of syndecan‐1 was quantified using ELISA. Syndecan‐1 immunostaining intensity was assessed in perfusion‐fixed hearts (n ≥ 3 per group). Results: Pretreatment with sphingosine‐1‐phosphate decreased infarct size in isolated hearts subjected to ischemia‐reperfusion (P = .01 vs ischemia‐reperfusion). However, sphingosine‐1‐phosphate had no effect on syndecan‐1 levels in the coronary effluent or on the intensity of the syndecan‐1 immunostaining signal in cardiac tissue. Heart total water content was not significantly different between control and ischemic groups but was significantly decreased in hearts treated with sphingosine‐1‐phosphate alone. Conclusion: These results suggest that sphingosine‐1‐phosphate‐induced cardioprotection against ischemia‐reperfusion injury is not mediated by the maintenance of syndecan‐1 in the endothelial glycocalyx

Ethanolamine is a novel STAT-3 dependent cardioprotective agent

Ethanolamine is a biogenic amine found naturally in the body as part of membrane lipids and as a metabolite of the cardioprotective substances, sphingosine-1-phosphate (S1P) and anandamide. In the brain, ethanolamine, formed from the breakdown of anandamide protects against ischaemic apoptosis. However, the effects of ethanolamine in the heart are unknown. Signal transducer and activator of transcription 3 (STAT-3) is a critical prosurvival factor in ischaemia/reperfusion (I/R) injury. Therefore, we investigated whether ethanolamine protects the heart via activation of STAT-3. Isolated hearts from wildtype or cardiomyocyte specific STAT-3 knockout (K/O) mice were pre-treated with ethanolamine (Etn) (0.3 mmol/L) before I/R insult. In vivo rat hearts were subjected to 30 min ischaemia/2 h reperfusion in the presence or absence of 5 mg/kg S1P and/or the FAAH inhibitor, URB597. Infarct size was measured at the end of each protocol by triphenyltetrazolium chloride staining. Pre-treatment with ethanolamine decreased infarct size in isolated mouse or rat hearts subjected to I/R but this infarct sparing effect was lost in cardiomyocyte specific STAT-3 deficient mice. Pre-treatment with ethanolamine increased nuclear phosphorylated STAT-3 [control 0.75 ± 0.08 vs. Etn 1.50 ± 0.09 arbitrary units; P < 0.05]. Our findings suggest a novel cardioprotective role for ethanolamine against I/R injury via activation of STAT-3

Defining and unpacking the core concepts of pharmacology : A global initiative

The authors acknowledge the contribution of the expert group members who contributed their expertise to the study and Professor Martin Kingsbury for his invaluable guidance on concept mapping.Peer reviewe

Identifying the core concepts of pharmacology education : a global initiative

Background and Purpose: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry or physiology, lacks a consensus list of such core concepts . Experimental approach: We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two-part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents. Key Results: The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology. Conclusion and Implications: This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts

Lower limb anatomy wiki

The Lower Limb Wiki was created in 2011 as part of an Anatomy & Physiology class project for 1st year Physiotherapy and Occupational Therapy students at the University of Cape Town. Each student wrote a Wiki page. The Lower Limb Wiki was created in 2011 as part of an Anatomy & Physiology class project for 1st year Physiotherapy and Occupational Therapy students at the University of Cape Town. Each student wrote a wiki age. This site is now open to the public and as with any Wiki can be edited by non-members and members

The upper limb anatomy wiki

Funded by The Centre for Educational Technology at the University of Cape Town.The Upper Limb Wiki was created in 2010 as part of an Anatomy & Physiology class project for 1st year Physiotherapy and Occupational Therapy students at the University of Cape Town. It is a comprehensive resource looking at the anatomy of the upper limb in human physiology. Each student involved in the course wrote a wiki page and two Physiotherapy students worked over their vacations to improve the Wiki