Dose-related ethanol intake, Cx43 and Nav1.5 remodeling: Exploring insights of altered ventricular conduction and QRS fragmentation in excessive alcohol users.

BACKGROUND: Chronic, excessive ethanol intake has been linked with various electrical instabilities, conduction disturbances, and even sudden cardiac death, but the underlying cause for the latter is insufficiently delineated. METHODS: We studied surface electrocardiography (ECG) in a community-dwelling cohort with moderate-to-heavy daily alcohol intake (grouped as >90g/day, ≤90g/day, and nonintake). RESULTS: Compared with nonintake, heavier alcohol users showed markedly widened QRS duration and higher prevalence of QRS fragmentation (64.3%, 50.9%, and 33.7%, respectively, χ2 12.0, both p<0.05) on surface ECG across the 3 groups. These findings were successfully recapitulated in 14-week-old C57BL/6 mice that were chronically given a 4% or 6% alcohol diet and showed dose-related slower action potential upstroke, reduced resting membrane potential, and disorganized or decreased intraventricular conduction (all p<0.05). Immunodetection further revealed increased ventricular collagen I depots with Cx43 downregulation and remodeling, together with clustered and diminished membrane Nav1.5 distribution. Administration of Cx43 blocker (heptanol) and Nav1.5 inhibitor (tetrodotoxin) in the mice each attenuated the suppression ventricular conduction compared with nonintake mice (p<0.05). CONCLUSIONS: Chronic excessive alcohol ingestion is associated with dose-related phenotypic intraventricular conduction disturbances and QRS fragmentation that can be recapitulated in mice. The mechanisms may involve suppressed gap junction and sodium channel functions, together with enhanced cardiac fibrosis that may contribute to arrhythmogenesis.

Membrane Proteomics of Impaired Energetics and Cytoskeletal Disorganization in Elderly Diet-Induced Diabetic Mice.

Diabetic cardiomyopathy is a well-recognized complication of diabetes, but its pathophysiology is unclear. We aimed to investigate the mechanisms underlying cardiac dysfunction in an elderly type 2 diabetic (T2DM) mouse model, using membrane proteomic analyses. Elderly mice were fed a high fat diet for 12 weeks to induce T2DM, and myocardial structure and function were assessed by echocardiography. Cardiomyocytes were isolated by Langendorff perfusion and subjected to iTRAQ-based quantitative membrane proteomic profiling, immunoblotting, and real-time quantitative reverse-transcriptase polymerase chain reaction. Compared to controls, elderly T2DM mice showed worse systolic function, more myocardial fibrosis and up-regulation of several heart failure markers (all p < 0.05). Cardiomyocyte membrane proteomic profiling revealed that 417 proteins had differential expressions related to perturbations in several biological processes in T2DM mice compared with the control. The most up-regulated proteins were involved in oxidative phosphorylation, whereas many down-regulated proteins were involved in cytoskeletal regulation. Differential protein expression correlated with myocardial systolic velocity by tissue Doppler. In addition, cardiomyocyte immunofluorescence staining showed greater disorganization of thick/parallel F-actin stress fibers and marked reduction in F-to-G-actin ratio in T2DM vs control (p < 0.05), which paralleled worsened myocardial systolic velocity. We concluded that cardiac contractile dysfunction in elderly T2DM mice was associated with impaired energetics and cytoskeletal disorganization.

Genetic Polymorphisms of Alcohol Metabolizing Enzymes and Alcohol Consumption are Associated With Asymptomatic Cardiac Remodeling and Subclinical Systolic Dysfunction in Large Community-Dwelling Asians.

AIMS: Excessive consumption of alcoholic beverages is associated with cardiac remodeling and cardiomyopathy. We examined the possible association of alcohol use, common Asian genetic variants in genes involved in alcohol metabolism, and cardiac structures/functions alterations. METHODS: A prospective, community-dwelling survey among individuals with available complete echocardiography examined the associations of alcohol use, cardiac structure/functions, and three common alcohol metabolizing genetic variants, including aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 1B (ADH1B) and cytochrome P450 (CYP) isoform 2E1 (CYP2E1). RESULTS: Among 1577 participants (mean age: 53 ± 9, 59.7% female), we observed that in subjects with more frequent weekly ethanol intake showed greater left ventricle (LV) mass, more impaired diastolic functions, and reduced global longitudinal strain (GLS), systolic (SRs) and early diastolic strain rates (SRe) (P<0.05). After propensity matching for clinical confounders (n = 330:30 for frequent users and non-users), frequent alcohol use and subjects carrying ALDH2 (A/G or A/A), ADH1B (A/A) or CYP2E1(T/C or T/T) polymorphisms were all associated with worse GLSRs and GLSRe, with combined alcohol use and any given genetic variant aggravated these associations (all P < 0.05). Finally, we observed Gene-Gene synergistic effects on LV functional decline in frequent alcohol users by using linear mixed effect model (all interaction P < 0.05). CONCLUSIONS: Among East Asians, even moderate alcohol consumption can confer subclinical adverse effects on cardiac systolic functions, which was most pronounced in subjects carrying common variants in alcohol metabolizing genes. These findings challenge the notion of beneficial influences of less heavy ethanol consumption on the heart, especially among East Asians. SHORT SUMMARY: This study evaluated the association of level of alcohol consumption and genetic variants in genes involved in alcohol metabolism with changes in cardiac function in East Asians. Even moderate alcohol use conferred subclinical adverse effects on cardiac systolic functions, which were most pronounced in subjects carrying common alcohol metabolizing genes.

Slow conduction and gap junction remodeling in murine ventricle after chronic alcohol ingestion.

BACKGROUND: Long-term heavy alcohol drinkers are prone to the development of cardiac arrhythmia. To understand the mechanisms, we evaluated the cardiac structural and electrophysiological changes in mice chronically drinking excessive alcohol. RESULTS: Male C57BL/6J mice were given 36% alcohol in the drinking water. Those given blank water were used as control. Twelve weeks later, the phenotypic characteristics of the heart, including gap junctions and electrical properties were examined. In the alcohol group the ventricles contained a smaller size of cardiomyocytes and a higher density of capillary networks, compared to the control. Western blots showed that, after drinking alcohol, the content of connexin43 (Cx43) protein in the left ventricle was increased by 18% (p < 0.05). Consistently, immunoconfocal microscopy demonstrated that Cx43 gap junctions were up-regulated in the alcohol group with a disorganized distribution, compared to the control. Optical mapping showed that the alcohol group had a reduced conduction velocity (40 ± 18 vs 60 ± 7 cm/sec, p < 0.05) and a higher incidence of ventricular tachyarrhythmia (62% vs 30%, p < 0.05). CONCLUSION: Long-term excessive alcohol intake resulted in extensive cardiac remodeling, including changes in expression and distribution of gap junctions, growth of capillary network, reduction of cardiomyocyte size, and decrease of myocardial conduction.

Heart failure enhances arrhythmogenesis in pulmonary veins.

1. Heart failure (HF) predisposes to atrial fibrillation (AF) as a result of substrate remodelling. The present study aimed to investigate the impact of HF on the electrical remodelling of the pulmonary veins (PV) and left atrium (LA). 2. The electrical activity was recorded in LA and PV from control rabbits and rabbits with rapid ventricular pacing-induced HF, using a multi-electrode array system and conventional microelectrodes. 3. Compared with the control-PV (n = 21), the HF-PV (n = 13) had a higher incidence and frequency of rapid pacing-induced spontaneous activity (85 vs 29%, P = 0.005; 3.5 ± 0.2 vs 1.7 ± 0.1 Hz, P < 0.001) and high-frequency irregular electrical activity (92 vs 38%, P = 0.01; 23 ± 1 vs 19 ± 1 Hz, P = 0.003), greater depolarized resting membrane potential (-59 ± 1 vs -70 ± 2 mV, P < 0.001), higher incidence of early afterdepolarizations (EAD; 69 vs 6%, P = 0.001) and delayed afterdepolarizations (DAD; 92 vs 25%, P = 0.001), and slower conduction velocity (38 ± 2 vs 63 ± 2 cm/s, P < 0.05). In comparison to the HF-LA, the HF-PV had a higher incidence of spontaneous activity and high-frequency irregular electrical activity (85 vs 39%, P = 0.04; 92 vs 46%, P = 0.03), and higher incidence of EAD and DAD, and those differences were not found between the control-LA and control-PV. The control-PV with high-frequency irregular electrical activity had a higher incidence of DAD and spontaneous activity as compared with those without it. 4. HF contributed to an increased automaticity, triggered activity and conduction disturbance in the PV. The PV possessed more arrhythmogenic properties, which might play an important role in the genesis of AF in HF.

Atrial gap junctions, NF-kappaB and fibrosis in patients undergoing coronary artery bypass surgery: the relationship with postoperative atrial fibrillation.

OBJECTIVES: We examined the role of atrial gap junctions, NF-kappaB and fibrosis in the occurrence of postoperative atrial fibrillation (AF) in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: Forty-five patients with sinus rhythm were randomly assigned to the beating heart (n = 22) or cardioplegic cardiac arrest (n = 23) technique for surgery. Of them, 14 patients experienced post-CABG AF. Atrial samples taken before and after CABG surgery were analyzed. RESULTS: During surgery, Cx43 and Cx40 proteins were significantly reduced (both p < 0.05) in the arrested heart group, but only mildly decreased in the beating heart group. However, the change of either connexin was not associated with AF. In contrast, patients with AF had a higher baseline expression of NF-kappaB and more fibrosis compared to those without AF (both p < 0.05). CONCLUSIONS: CABG surgery with the beating heart technique attenuated the reduction of atrial Cx43 and Cx40 compared to the cardioplegic cardiac arrest technique. Atrial inflammation and fibrosis status before surgery, but not the changes of connexins during surgery, were associated with the occurrence of post-CABG AF.

On the mechanisms of arrhythmias in the myocardium of mXinalpha-deficient murine left atrial-pulmonary veins.

We have previously shown that left atrial-pulmonary vein tissue (LA-PV) can generate reentrant arrhythmias (atrial fibrillation, AF) in wild-type (mXinalpha+/+) but not in mXinalpha-null (mXinalpha-/-) mice. With the present experiments, we investigated the arrhythmogenic activity and the underlying mechanisms in mXinalpha+/+ vs. mXinalpha-/- LA-PV. Electrical activity and conduction velocity (CV) were recorded in LA-PV by means of a MED64 system. CV was significantly faster in mXinalpha+/+ than in mXinalpha-/- LA-PV and it was increased by 1 muM isoproterenol (ISO). AF could be induced by fast pacing in the mXinalpha+/+ but not in mXinalpha-/- LA-PV where automatic rhythms could occur. ISO increased the incidence of AF in Xinalpha+/+ whereas it increased that of automatic rhythms in mXinalpha-/- LA-PV. In LA-PV with the right atrium attached (RA-LA-PV), automatic rhythms occurred in all preparations. In mXinalpha+/+ RA-LA-PV simultaneously treated with ISO, strophanthidin and atropine, the incidence of the automatic rhythm was about the same, but AF increased significantly. In contrast, in mXinalpha-/- RA-LA-PV under the same condition, the automatic rhythm was markedly enhanced, but still no AF occurred. Conventional microelectrode techniques showed a longer APD(90) and a less negative maximum diastolic potential (MDP) in mXinalpha-/- than mXinalpha+/+ LA-PV tissues. Whole-cell current clamp experiments also showed a less negative MDP in mXinalpha-/- vs. mXinalpha+/+ LA-PV cardiomyocytes. The fact that AF could be induced by fast pacing under several conditions in mXinalpha+/+ but not in mXinalpha-/- LA-PV preparations appears to be due to a slower CV, a prolonged APD(90), a less negative MDP and possibly larger areas of conduction block in mXinalpha-/- myocardial cells. In contrast, the non-impairment of automatic and triggered rhythms in mXinalpha-/- preparations may be due to the fact that the mechanisms underlying these rhythms do not involve cell-to-cell conduction.

The efficacy of frequency-specific acupuncture stimulation on extracellular dopamine concentration in striatum--a rat model study.

Acupuncture is a practice that has existed in Chinese society for thousands of years. Today, it is gaining greater acceptance and integration into medical practices of the western world. Its mechanism, however, remains elusive. Our study shows that only specific stimulation frequencies at specific acupoints will induce dopamine release in the corpus striatum, as demonstrated by in vivo microdialysis performed on Sprague-Dawley rats. In the first trial, electroacupuncture (EA) stimulation at 15 Hz and 15 mA was conducted at six different points on the upper limbs of the experimental rats. These points mimic acupoints along six different meridians in the human body. Only Point 2 (corresponding to Pericardium 7) induced a response. In the second trial, EA stimulation at varying frequencies of 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30 Hz, and 15 mA were conducted through Point 2. Stimulation at 6 and 15 Hz induced an immediate response; 21 Hz induced a response only after the ceasing of stimulation. All other frequencies failed to induce a response. The data point to the importance of frequency-specific stimulation at specific acupoints for the release of neurotransmitters in the brain. We speculate that each meridian entails a stimulus of a specific frequency and intensity, which induces the release of its associated neurotransmitters or cytokines. This is a concept with far-reaching clinical implications for acupuncture therapy, including the treatment of dopamine-related disorders.

Heterogeneity of propagation of excitation in epicardium of pulmonary veins ostia in rabbit during cooling.

OBJECTIVE: The purpose of this research was to study the propagation of the excitation wave along epicardium in the area of the pulmonary veins ostia in rabbit in normal conditions and while cooling. METHODS: The excitation wave spreading along epicardium in the area of pulmonary veins ostia in the left atrium at 36-37 degrees C and when cooling to 32 degrees C was studied by the method of electrocardiochronotopography in rabbit of Chinchilla species, five months age. The size of the registering surface of the electrode was 1.08 x 1.08 cm. RESULTS: The time of depolarization when cooling from 36 degrees C to 32 degrees C changes unevenly in various zones of pulmonary veins. On the epicardium of pulmonary veins area at temperature reduction from 36 degrees C to 33 degrees C, change in the direction of excitation and essential reduction of depolarization time, and its significant increase under further cooling to 32 degrees C were observed. In the middle part of the left atrium at temperature reduction, change in the main direction of the excitation wave propagation, shift of the location of the areas of the latest depolarization were revealed and the front become more homogeneous. CONCLUSION: In the area of the left atrium base the heterogeneity of the front of depolarization at temperature reduction was revealed.

Changes in ionic currents and reduced conduction velocity in hypertrophied ventricular myocardium of Xin alpha-deficient mice.

OBJECTIVE: mXin alpha, a downstream target gene of Nkx2.5 transcription factor, was shown to encode a proline-rich and Xin repeats-containing protein which localizes to the intercalated disc of adult hearts. Our previous voltage-clamp studies have shown that the ventricular myocytes of mXin alpha -deficient mice exhibited a significant reduction in K+ currents (Ito and IK1), L-type Ca2+ currents, and maximum diastolic potential, leading to the development of early afterdepolarization (EAD) and arrhythmias. However, changes in cationic inward currents could also contribute to the genesis of EAD and arrhythmias in mXin alpha -deficient mice. METHODS: The present study aims to characterize changes in Na+ currents on depolarization and transient inward currents (Iti) on repolarization. Conduction velocity (CV) on the frontal surface of ventricles were also measured and compared. RESULTS: Results of optical mapping on the Langendorff-perfused hearts at 37oC revealed a 36% reduction of CV in mXin alpha -/- ventricle. Pacing (3 Hz)-induced tachyarrhythmias were more frequently found and ventricular fibrillation (VF, 21 Hz for 5 min) occurred in one out of 8 mXin alpha-/- heart. When perfused at 30 degrees C, no VF was observed in both types of preparations. Voltage-clamp study on isolated ventricular myocytes at 37 degrees C shows increase in INa and Iti in mXin alpha -/- cardiomyocytes thus could explain the occurrence of re-entrant triggered arrhythmias. CONCLUSION: The present results revealed that the CV was slower, but INa and Iti were increased in mXin alpha -/-cardiomyocytes thus were prone to reentrant triggered arrhythmias. Hypothermia could reduce the occurrence of arrhythmias.

Light to Moderate Habitual Alcohol Consumption Is Associated with Subclinical Ventricular and Left Atrial Mechanical Dysfunction in an Asymptomatic Population: Dose-Response and Propensity Analysis.

BACKGROUND: The effects of light to moderate alcohol consumption on cardiac mechanics remain poorly understood. The aim of this study was to investigate the dose-response relationship between alcohol consumption and left ventricular (LV) and left atrial (LA) function using myocardial deformation. METHODS: In total 3,946 asymptomatic participants (mean age, 49.7 ± 10.7 years; 65% men) were consecutively studied using comprehensive echocardiography and two-dimensional speckle-tracking in a cross-sectional, retrospective manner. Global LV longitudinal and circumferential strain and LA strain were assessed and related to habitual alcohol consumption pattern (fewer than one, one to six, or more than six drinks per week) before and after propensity matching. RESULTS: With increasing weekly alcohol consumption, participants displayed greater LV eccentric remodeling, impaired diastolic function, and more attenuated global longitudinal strain, LA strain (adjusted coefficients, -1.07 [95% CI, -1.95 to -0.19] and -3.73 [95% CI, -5.36 to -2.11]), and early diastolic strain rates (adjusted coefficients, 0.07 [95% CI, 0.03-0.11] and 0.33 [95% CI, 0.24-0.42]) for one to six and more than six drinks per week, respectively (P < .05 for all) in a dose-response manner. Participants with recent alcohol abstinence displayed cardiac mechanics intermediate between those of nondrinkers and current drinkers. After propensity matching (n = 1,140), participants currently consuming more than one drink per week continued to have significantly attenuated global longitudinal strain and all LA mechanics compared with those consuming fewer than one drink per week (P < .05 for all). CONCLUSIONS: Habitual alcohol consumption, even at light to moderate doses, is associated with both reduced LV and LA mechanics in a dose-dependent manner. Whether such observations are reversible or related to future atrial fibrillation deserves further study.

Differential expression of connexin43 gap junctions in cardiomyocytes isolated from canine thoracic veins.

We investigated the phenotypic features of cardiomyocytes, including the gap junctions, in the myocardial sleeve of thoracic veins. Single cardiomyocytes, isolated from the canine pulmonary veins (PV) and superior vena cava (SVC) using digestive enzymes, were examined by immunoconfocal microscopy using antisera against connexin43 (Cx43), Cx40, and other cell markers. The results showed that isolated cardiomyocytes displayed rod shapes of various sizes, ranging from <50 microm to >200 microm in length, and all the cells expressed alpha-actinin and vinculin. Gap junctions made of various amounts of Cx43 and Cx40 were found at the cell borders. These two connexins were extensively co-localized. Comparison between the thoracic veins showed that cells of the SVC contained more Cx43 gap junctions (total Cx43 gap junctions area per cell surface area, 4.0 +/- 0.2% vs 1.5 +/- 0.2%; p<0.01). In addition, for single-nucleus cells, those from the PV were longer (103.7 +/- 3.6 vs 85.0 +/- 3.1 microm; p<0.01) but narrower (14.4 +/- 0.5 vs 16.9 +/- 0.9 microm; p<0.01). In conclusion, canine thoracic veins contain cardiomyocytes with differences in shape and gap junctions, suggesting that the electrical conduction properties may be different between the thoracic veins.

A nanopatterned cell-seeded cardiac patch prevents electro-uncoupling and improves the therapeutic efficacy of cardiac repair.

The heart is an extremely sophisticated organ with nanoscale anisotropic structure, contractility and electro-conductivity; however, few studies have addressed the influence of cardiac anisotropy on cell transplantation for myocardial repair. Here, we hypothesized that a graft's anisotropy of myofiber orientation determines the mechano-electrical characteristics and the therapeutic efficacy. We developed aligned- and random-orientated nanofibrous electrospun patches (aEP and rEP, respectively) with or without seeding of cardiomyocytes (CMs) and endothelial cells (ECs) to test this hypothesis. Atomic force microscopy showed a better beating frequency and amplitude of CMs when cultured on aEP than that from cells cultured on rEP. For the in vivo test, a total of 66 rats were divided into six groups: sham, myocardial infarction (MI), MI + aEP, MI + rEP, MI + CM-EC/aEP and MI + CM-EC/rEP (n ≥ 10 for each group). Implantation of aEP or rEP provided mechanical support and thus retarded functional aggravation at 56 days after MI. Importantly, CM-EC/aEP implantation further improved therapeutic outcomes, while cardiac deterioration occurred on the CM-EC/rEP group. Similar results were shown by hemodynamic and infarct size examination. Another independent in vivo study was performed and electrocardiography and optical mapping demonstrated that there were more ectopic activities and defective electro-coupling after CM-EC/rEP implantation, which worsened cardiac functions. Together these results provide comprehensive functional characterizations and demonstrate the therapeutic efficacy of a nanopatterned anisotropic cardiac patch. Importantly, the study confirms the significance of cardiac anisotropy recapitulation in myocardial tissue engineering, which is valuable for the future development of translational nanomedicine.

Heat shock protein inducer modifies arrhythmogenic substrate and inhibits atrial fibrillation in the failing heart.

BACKGROUND: Geranylgeranylacetone (GGA) has been reported up-regulating heat shock protein (HSP) expression, and protecting against atrial remodeling. This study aimed to investigate the effects of GGA on atrial electrophysiology and inducibility of atrial fibrillation (AF) in heart failure (HF) model. METHODS AND RESULTS: HF rabbits were created 4 weeks after coronary artery ligation. Monophasic action potential recordings and multielectrode array were used to record the electrophysiological characteristics of left atrium (LA) in normal, or HF rabbits with (HF-GGA) and without (HF-control) oral administration of GGA (200 mg/kg, 24 h before experiments). The mRNA and protein expressions of ionic channels were measured by Western blot and PCR. HF-GGA LA (n = 10), similar to normal LA (n = 10) had a shorter action potential duration (APD) and effective refractory period than HF-control LA (n = 10). HF-GGA LA had less triggered activity and APD alternans (20% vs. 100%, P = 0.001), lower maxima slope of restitution curve of APD (0.94 ± 0.04 vs.1.69 ± 0.04, P < 0.001), and less inducibility of AF (50% vs. 100%, P = 0.033) than HF-control LA. HF-GGA LA had a shorter activation time and higher conduction velocity than HF-control LA. HF-GGA LA had a higher mRNA expression of Cav1.2, Nav1.5, Kir2.1, Kv1.4, Kv7.1, Kv11.1, sarcoplasmic reticulum Ca(2+)-ATPase, and higher phosphorylation of phospholamban than HF-control LA. CONCLUSIONS: GGA decreases triggered activity, dispersion of APD and inducibility of AF in failing heart through induction of HSP, and modulation of ionic channels and calcium homeostasis.

Temporal changes in cardiac force- and flow-generation capacity, loading conditions, and mechanical efficiency in streptozotocin-induced diabetic rats.

Diabetes mellitus may result in impaired cardiac contractility, but the underlying mechanisms remain unclear. We aimed to investigate the temporal alterations in cardiac force- and flow-generation capacity and loading conditions as well as mechanical efficiency in the evolution of systolic dysfunction in streptozotocin (STZ)-induced diabetic rats. Adult male Wistar rats were randomized into control and STZ-induced diabetic groups. Invasive hemodynamic studies were done at 8, 16, and 22 wk post-STZ injection. Maximal systolic elastance (E(max)) and maximum theoretical flow (Q(max)) were assessed by curve-fitting techniques, and ventriculoarterial coupling and mechanical efficiency were assessed by a single-beat estimation technique. In contrast to early occurring and persistently depressed E(max), Q(max) progressively increased with time but was decreased at 22 wk post-STZ injection, which temporally correlated with the changes in cardiac output. The favorable loading conditions enhanced stroke volume and Q(max), whereas ventriculoarterial uncoupling attenuated the cardiac mechanical efficiency in diabetic animals. The changes in E(max) and Q(max) are discordant during the progression of contractile dysfunction in the diabetic heart. In conclusion, our study showed that depressed Q(max) and cardiac mechanical efficiency, occurring preceding overt systolic heart failure, are two major determinants of deteriorating cardiac performance in diabetic rats.

Remodeling of myocardial sleeve and gap junctions in canine superior vena cava after rapid pacing.

OBJECTIVE: We studied the response of the superior vena cava (SVC) myocardial sleeve to atrial fibrillation (AF). METHODS AND RESULTS: We examined adult male dogs without pacing (N=6) and after rapid atrial pacing (600 bpm) for 2 weeks (P2w; N=5) and 6-8 weeks (P6-8w; N=5). After pacing, the sleeve was increased in thickness (non-paced vs. either paced group, both P<0.05). This was associated with an increase in proliferative activity, which was higher in the P2w than the P6-8w animals (P<0.05). In addition, collagen content increased, and the component cardiomyocytes become more unevenly oriented and shorter and narrower in shape (non-paced vs. either paced group, both P<0.05). Pacing had different effects on connexin40 (Cx40) and Cx43 gap junctions. There was a 98% increase in Cx43 signal in P2w, and a 74% increase in P6-8w animals (non-paced vs. each paced group, both P<0.05). In contrast, Cx40 signal decreased 47% in P2w but increased 44% in P6-8w animals (non-paced vs. each paced group, both P<0.05). CONCLUSIONS: Rapid atrial pacing results in a specific pattern of remodeling of the canine SVC sleeve, including changes in size and shape, spatial orientation, and gap junction expression profile of the component cardiomyocytes. These changes may co-operatively affect the electrical properties and contribute to the formation and maintenance of the arrhythmogenic substrate of AF.

Magnesium chloride and ruthenium red attenuate the antiallodynic effect of intrathecal gabapentin in a rat model of postoperative pain.

BACKGROUND: Gabapentin, a gamma-aminobutyric acid analog anticonvulsant, has been shown to possess antinociceptive effects in animal models and clinical trials. An endogenous binding site of [3H]gabapentin has been revealed to be the alpha(2)delta subunit of voltage-dependent Ca2+ channels. Magnesium chloride, ruthenium red, and spermine have been shown to modulate [3H]gabapentin binding to this binding site in vitro. In this study, the authors examined whether intrathecal magnesium chloride, ruthenium red, or spermine could affect the antiallodynic effect of intrathecal gabapentin in a rat model of postoperative pain. METHODS: Under isoflurane anesthesia, male Sprague-Dawley rats received an incision over the plantar surface of the right hind paw to produce punctate mechanical allodynia. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before incision, 2 h after incision, and every 30 min after intrathecal coadministration of gabapentin with normal saline or different doses of magnesium chloride, ruthenium red, or spermine for 2 h. RESULTS: Intrathecal gabapentin (30, 100, 200 microg) dose-dependently reduced incision-induced allodynia. Hexahydrated magnesium chloride (5, 10, 20 microg) and ruthenium red (0.2, 2, 20 ng) noncompetitively inhibited the antiallodynic effect of gabapentin. Spermine at doses not inducing motor weakness (30, 60 microg) did not affect the antiallodynic effect of gabapentin. The antiallodynic effect of intrathecal morphine (1.5 microg) was not affected by hexahydrated magnesium chloride (20 microg), ruthenium red (20 ng), or spermine (60 microg). CONCLUSIONS: These results provide behavioral evidence to support that the alpha(2)delta subunit of Ca2+ channels may be involved in the antiallodynic action of intrathecal gabapentin in the postoperative pain model.