Transmural distribution of metabolic abnormalities and glycolytic activity during dobutamine-induced demand ischemia

The heterogeneity across the left ventricular wall is characterized by higher rates of oxygen consumption, systolic thickening fraction, myocardial perfusion, and lower energetic state in the subendocardial layers (ENDO). During dobutamine stimulation-induced demand ischemia, the transmural distribution of energy demand and metabolic markers of ischemia are not known. In this study, hemodynamics, transmural high-energy phosphate (HEP), 2-deoxyglucose-6-phosphate (2-DGP) levels, and myocardial blood flow (MBF) were determined under basal conditions, during dobutamine infusion (DOB: 20 microg x kg(-1) x min(-1) iv), and during coronary stenosis + DOB + 2-deoxyglucose (2-DG) infusion. DOB increased rate pressure products (RPP) and MBF significantly without affecting the subendocardial-to-subepicardial blood flow ratio (ENDO/EPI) or HEP levels. During coronary stenosis + DOB + 2-DG infusion, RPP, ischemic zone (IZ) MBF, and ENDO/EPI decreased significantly. The IZ ratio of creatine phosphate-to-ATP decreased significantly [2.30 +/- 0.14, 2.06 +/- 0.13, and 2.04 +/- 0.11 to 1.77 +/- 0.12, 1.70 +/- 0.11, and 1.72 +/- 0.12 for EPI, midmyocardial (MID), and ENDO, respectively], and 2-DGP accumulated in all layers, as evidenced by the 2-DGP/PCr (0.55 +/- 0.12, 0.52 +/- 0.10, and 0.37 +/- 0.08 for EPI, MID, and ENDO, respectively; P < 0.05, EPI > ENDO). In the IZ the wet weight-to-dry weight ratio was significantly increased compared with the normal zone (5.9 +/- 0.5 vs. 4.4 +/- 0.4; P < 0.05). Thus, in the stenotic perfused bed, during dobutamine-induced high cardiac work state, despite higher blood flow, the subepicardial layers showed the greater metabolic changes characterized by a shift toward higher carbohydrate metabolism, suggesting that a homeostatic response to high-cardiac work state is characterized by more glucose utilization in energy metabolism.     

Transmural gradients in Na/K pump activity and [Na+]I in canine ventricle

There are well-documented differences in ion channel activity and action potential shape between epicardial (EPI), midmyocardial (MID), and endocardial (ENDO) ventricular myocytes. The purpose of this study was to determine if differences exist in Na/K pump activity. The whole cell patch-clamp was used to measure Na/K pump current (I(P)) and inward background Na(+)-current (I(inb)) in cells isolated from canine left ventricle. All currents were normalized to membrane capacitance. I(P) was measured as the current blocked by a saturating concentration of dihydro-ouabain. [Na(+)](i) was measured using SBFI-AM. I(P)(ENDO) (0.34 +/- 0.04 pA/pF, n = 17) was smaller than I(P)(EPI) (0.68 +/- 0.09 pA/pF, n = 38); the ratio was 0.50 with I(P)(MID) being intermediate (0.53 +/- 0.13 pA/pF, n = 19). The dependence of I(P) on [Na(+)](i) or voltage was essentially identical in EPI and ENDO (half-maximal activation at 9-10 mM [Na(+)](i) or approximately -90 mV). Increasing [K(+)](o) from 5.4 to 15 mM caused both I(P)(ENDO) and I(P)(EPI) to increase, but the ratio remained approximately 0.5. I(inb) in EPI and ENDO were nearly identical ( approximately 0.6 pA/pF). Physiological [Na(+)](i) was lower in EPI (7 +/- 2 mM, n = 31) than ENDO (12 +/- 3 mM, n = 29), with MID being intermediate (9 +/- 3 mM, n = 22). When cells were paced at 2 Hz, [Na(+)](i) increased but the differences persisted (ENDO 14 +/- 3 mM, n = 10; EPI 9 +/- 2 mM, n = 10; and MID intermediate, 11 +/- 2 mM, n = 9). Based on these results, the larger I(P) in EPI appears to reflect a higher maximum turnover rate, which implies either a larger number of active pumps or a higher turnover rate per pump protein. The transmural gradient in [Na(+)](i) means physiological I(P) is approximately uniform across the ventricular wall, whereas transporters that utilize the transmembrane electrochemical gradient for Na(+), such as Na/Ca exchange, have a larger driving force in EPI than ENDO.     

Activation of beta3 adrenergic receptor decreases DNA synthesis in human skin fibroblasts via cyclic GMP/nitric oxide pathway.

BACKGROUND: Evidences have shown that beta1 and beta2 adrenoceptors co-exist in human fibroblasts, but it is not yet clear the functional expression of beta3 adrenoceptor in these cells. The aim of this study was to investigate the expression and biological effect of beta3 adrenoceptor activation in human skin fibroblast and the different signaling pathways involved in its effect. Methods: For this purpose in vitro cultures of human skin fibroblast were established from human foreskin and grown in Dulbecco's modified Eagle's medium. The effect of ZD 7114 (beta3 agonist) on cell DNA synthesis, radioligand binding assay, cyclic GMP and cyclic AMP accumulation and nitric oxide synthase (NOS) activity were evaluated. RESULTS: 3H-CGP binding to human fibroblast membranes was a saturable process to a single class of binding site. The equilibrium parameters were: Kd 20+/-3 pM and Bmax 222+/-19 fmol/mg protein. Ki values showed that these cells express a high number of beta(3)adrenoceptor subtypes. ZD 7114 stimulation of beta3 adrenoceptor exerts a concentration-dependent inhibition of DNA synthesis and cAMP accumulation with parallel increase in NOS activity that led to cGMP accumulation. All these effects were blocked by the beta3 adrenoceptor antagonist (SR 59230A). The effect of ZD 7114 on DNA synthesis significantly correlated with its action either on cAMP or NOS-cGMP signaling system. Inhibitors of NOS activity and NO-sensitive guanylate cyclase prevented the inhibitory effect of ZD 7114 on DNA synthesis. In addition, the beta3 adrenoceptor-dependent increase in cGMP and activation of NOS were blocked by the inhibition of phospholipase C (PLC), calcium/calmodulin (CaM), endothelial NOS activity and cGMP accumulation. CONCLUSIONS: beta3 adrenoceptor activation exerts inhibitory effect on human fibroblast DNA synthesis as a result of the activation of NO-cGMP pathway and the inhibition of adenylate cyclase activity. The mechanism appears to occurs secondarily to stimulation of PLC and CaM. This in turn triggers cascade reaction leading to increase production of NO-cGMP with decrease in cAMP accumulation.     

Cellular and subcellular alternans in the canine left ventricle

Previous studies indicate that action potential duration (APD) alternans is initiated in the endocardial (END) and midmyocardial (MID) regions rather than the epicardium (EPI) in the canine left ventricle (LV). This study examines regional differences in the rate dependence of Ca(2+) transient characteristics under conditions that give rise to APD and associated T wave alternans. The role of the sarcoplasmic reticulum (SR) was further evaluated by studying Ca(2+) transient characteristics in myocytes isolated from neonates, where an organized SR is poorly developed. All studies were performed in cells and tissues isolated from the canine LV. Isolated canine ENDO, MID, and EPI LV myocytes were either field stimulated or voltage clamped, and Ca(2+) transients were measured by confocal microscopy. In LV wedge preparations, increasing the basic cycle length (BCL) from 800 to 250 ms caused alternans to appear mainly in the ENDO and MID region; alternans were not observed in EPI under these conditions. Ca(2+) transient alternans developed in response to rapid pacing, appearing in EPI cells at shorter BCL compared with MID and ENDO cells (BCL=428 +/- 17 vs. 517 +/- 29 and 514 +/- 21, respectively, P < 0.05). Further increases in pacing rate resulted in the appearance of subcellular alternans of Ca(2+) transient amplitude, which also appeared in EPI at shorter BCL than in ENDO and MID cells. Ca(2+) transient alternans was not observed in neonate myocytes. We conclude that 1) there are distinct regional differences in the vulnerability to rate-dependent Ca(2+) alternans in dog LV that may be related to regional differences in SR function and Ca(2+) cycling; 2) the development of subcellular Ca(2+) alternans suggests the presence of intracellular heterogeneities in Ca(2+) cycling; and 3) the failure of neonatal cells to develop Ca(2+) alternans provides further support that SR Ca(2+) cycling is a major component in the development of these phenomena.     

CaMKII inhibition reduces arrhythmogenic Ca2+ events in subendocardial cryoinjured rat living myocardial slices

Spontaneous Ca²⁺ release (SCR) can cause triggered activity and initiate arrhythmias. Intrinsic transmural heterogeneities in Ca²⁺ handling and their propensity to disease remodeling may differentially modulate SCR throughout the left ventricular (LV) wall and cause transmural differences in arrhythmia susceptibility. Here, we aimed to dissect the effect of cardiac injury on SCR in different regions in the intact LV myocardium using cryoinjury on rat living myocardial slices (LMS). We studied SCR under proarrhythmic conditions using a fluorescent Ca²⁺ indicator and high-resolution imaging in LMS from the subendocardium (ENDO) and subepicardium (EPI). Cryoinjury caused structural remodeling, with loss in T-tubule density and an increased time of Ca²⁺ transients to peak after injury. In ENDO LMS, the Ca²⁺ transient amplitude and decay phase were reduced, while these were not affected in EPI LMS after cryoinjury. The frequency of spontaneous whole-slice contractions increased in ENDO LMS without affecting EPI LMS after injury. Cryoinjury caused an increase in foci that generates SCR in both ENDO and EPI LMS. In ENDO LMS, SCRs were more closely distributed and had reduced latencies after cryoinjury, whereas this was not affected in EPI LMS. Inhibition of CaMKII reduced the number, distribution, and latencies of SCR, as well as whole-slice contractions in ENDO LMS, but not in EPI LMS after cryoinjury. Furthermore, CaMKII inhibition did not affect the excitation–contraction coupling in cryoinjured ENDO or EPI LMS. In conclusion, we demonstrate increased arrhythmogenic susceptibility in the injured ENDO. Our findings show involvement of CaMKII and highlight the need for region-specific targeting in cardiac therapies.     

Myofibrillar adaptations during cardiac hypertrophy

The main purpose of this study was to determine the transmural adaptive changes that occur in cell size, myofibrils, and myosin isoforms from the endocardium (ENDO) to the epicardium (EPI) of the left ventricle (LV) of the rat heart during compensatory hypertrophy. Hypertrophy was induced by supra-renal aortic constriction for periods of 2, 7, 15 and 30 days. Percent left ventricular hypertrophy averaged 63±9.7% at 30 days following constriction. A significant (p <0.05) transmural gradient in the V₃ myosin isoform (9±0.7% ENDO vs. 5±1.8% EPI) was initially observed at 7 days and was still evident by 30 days (25±3.6% ENDO vs 15±2.0% EPI). Cell cross-sectional area was also greater (p <0.05) in the ENDO than in the EPI at 7,15 and 30 days. MF diameter was determined only at 30 days and was found to be similar to control values in both the hypertrophied ENDO (sham 1.24±0.05 vs hyp 1.18±0.09 m) and EPI (sham 1.17±0.08 vs hyp 1.06±0.08 m). The combined effects of cardiac myocyte hypertrophy with no change in MF diameter resulted in a calculated increase of approximately 70% in the number of myofibrils per myocyte both in the ENDO and EPI. It was concluded that the adaptive strategy of the left ventricular free wall to pressure overload was to initially increase myocyte cross-sectional area and then switch myosin expression from V₁ to V₃, both of which proceeds transmurally from the sub-endocardium towards the sub-epicardium. Along with these transmural adaptations, myofibrils increased in number while maintaining myofibrillar diameter with the apparent intent of conserving diffusion distance for calcium from the sarcoplasmic reticulum to the innermost contractile filaments of the myofibrils.     

Improvement in pump function with endocardial biventricular pacing increases with activation time at the left ventricular pacing site in failing canine hearts

Recently, attention has been focused on comparing left ventricular (LV) endocardial (ENDO) with epicardial (EPI) pacing for cardiac resynchronization therapy. However, the effects of ENDO and EPI lead placement at multiple sites have not been studied in failing hearts. We hypothesized that differences in the improvement of ventricular function due to ENDO vs. EPI pacing in dyssynchronous (DYSS) heart failure may depend on the position of the LV lead in relation to the original activation pattern. In six nonfailing and six failing dogs, electrical DYSS was created by atrioventricular sequential pacing of the right ventricular apex. ENDO was compared with EPI biventricular pacing at five LV sites. In failing hearts, increases in the maximum rate of LV pressure change (dP/dt; r = 0.64), ejection fraction (r = 0.49), and minimum dP/dt (r = 0.51), relative to DYSS, were positively correlated (P < 0.01) with activation time at the LV pacing site during ENDO but not EPI pacing. ENDO pacing at sites with longer activation delays led to greater improvements in hemodynamic parameters and was associated with an overall reduction in electrical DYSS compared with EPI pacing (P < 0.05). These findings were qualitatively similar for nonfailing hearts. Improvement in hemodynamic function increased with activation time at the LV pacing site during ENDO but not EPI pacing. At the anterolateral wall, end-systolic transmural function was greater with local ENDO compared with EPI pacing. ENDO pacing and intrinsic activation delay may have important implications for management of DYSS heart failure.     

Calcium channel binding in nerves and muscle of canine small intestine

Using [3H]-nitrendipine (Nit) and [125I]-omega conotoxin (w-CTX), the cellular and subcellular distribution of calcium channel subtypes in the homogenates of canine small intestinal circular muscle was studied. Nit. bound to the membranes from the circular smooth muscle cells (PM) and to the synaptosomal membranes from the deep muscular plexus (DMP); the Kd and Bmax values of Nit binding from these two sources were similar (Kd 0.4 +/- 0.16 nM and 0.77 +/- 0.24 nM; Bmax 206 +/- 22 and 192 +/- 39 fmol/mg of protein in DMP and PM respectively). w-CTX, however, bound only to the DMP (Kd 18.41 +/- 7.5 pM, Bmax 265 +/- 36 fmol/mg of protein). In DMP, nifedipine (10(-6) M) failed to interact with the binding of w-CTX; similarly, no modulation of Nit binding with unlabelled w-CTX (10(-7) M) could be detected. Therefore w-CTX and Nit binding sites represent two distinct, non-interactive and differentially distributed binding sites in canine small intestine.     

Noradrenergic agonists and antagonists: effects on avoidance behaviour in rats

The effects of various agonists and antagonists of both alpha and beta adrenoceptors on the acquisition of avoidance behaviour were investigated in the rat. Clonidine, a selective agonist of alpha 2 adrenoceptors depressed avoidance acquisition whilst yohimbine, an antagonist of these receptors produced an opposite effect. Prazosin which showed postsynaptic alpha 1 adrenoceptor blocking activity reduced avoidance behaviour. A similar effect was produced by propranolol, a non-selective antagonist of beta adrenoceptors. On the other hand, salbutamol preferentially stimulating beta 2 adrenoceptors facilitated avoidance behaviour. In general, the results show a fairly good correlation between avoidance acquisition and efficacy of noradrenergic neurotransmission.     

Characterization of Rat Cerebral Cortical Beta Adrenoceptor Subtypes Using (-)-[125I]-Iodocyanopindolol

Abstract

(-)-[¹²⁵I]-Iodocyanopindolol ((-)ICYP), used to characterize beta adrenoceptors on membrane preparations from rat cerebral cortex, was shown to have affinity for both beta adrenoceptors and serotonin receptors. Therefore, 10 µM serotonin was added to the assays to prevent (-)ICYP binding to serotonin receptors. Under these conditions, (-)ICYP binding to the cortical membrane preparation was reversible and saturable, and the association reaction was very slow. The dissociation reaction was also very slow, and revealed two affinity states corresponding to a high and a low affinity state. Scatchard analysis showed a single class of binding sites with an equilibrium dissociation constant (K_D) of 20.7 pM, and a maximal density of binding sites (B_max) of 95.1 fmol/mg membrane protein. Displacement binding analyses revealed a potency series of (-) isoproterenol greater than (-) epinephrine equal to (-) norepinephrine, suggesting a predominance of the beta₁ adrenoceptor subtype. Detailed competition ligand binding studies with the selective beta₁ adrenoceptor antagonist ICI-89406 and the selective beta₂ adrenoceptor antagonist ICI-118551, showed that about 70% of the beta adrenoceptor population in the rat cortex is of the beta₁ subtype with the remainder being of the beta₂ subtype.

We conclude that since (-)ICYP binds to both beta adrenoceptors and serotonin receptors, it is important to prevent the binding of (-)ICYP to serotonin receptors by adding a suppressing ligand like excess cold serotonin when assaying beta adrenoceptors. We have presented the first such characterization of rat cerebral cortical beta adrenoceptors with (-)ICYP in this study.     

Inverse regulation of alpha-2 and beta-2 adrenoceptors in salt-sensitive hypertension: an hypothesis

A high salt diet leads to up-regulation of alpha-2 adrenoceptors and down-regulation of beta-2 adrenoceptors in normotensive subjects. Although the increase in blood pressure with a high salt diet is not related to the magnitude of the alpha-2 or beta-2 adrenoceptor changes alone, it is related to the increase in the ratio of the receptor changes (operative alpha/beta adrenoceptor ratio). An increase in the operative alpha/beta adrenoceptor ratio with a high salt intake results in vasoconstriction and reduced vasodilatation at resistance vessels, as well as increased renal proximal tubular sodium reabsorption. An influence of heredity on this relationship is supported by four lines of evidence: 1) salt-sensitivity of blood pressure occurs predominantly in subjects with a family history of hypertension; 2) studies in twin children document the influence of genetic variance on salt-sensitivity of blood pressure; 3) subjects with a family history of hypertension have a significantly lower salivary sodium concentration and an altered urinary sodium excretion after salt loading compared to subjects with no such history; 4) salt-sensitivity of blood pressure may be associated with specific genetic markers. On the basis of these observations, we propose the hypothesis that enhanced inverse alpha-beta-adrenoceptor regulation in response to a high salt intake may be responsible for salt sensitivity in the normal population, and may contribute to the development of essential hypertension in susceptible individuals. This alteration is likely to be genetically mediated.     

Binding of the hydrophilic beta-adrenergic antagonist [3H]CGP-12177 to cardiac tissue slices: characterization and ontogenetic studies in dogs

A new technique was developed to characterize the binding of a hydrophilic beta-adrenergic antagonist, [3H]CGP-12177, to 1-mm thick slices of canine cardiac tissue. This technique was used to quantify the density (Bmax) and the affinity (Kd) of these receptors in the right ventricular conus (RVC) and the left ventricle (LV) at day 1 to 6 weeks of age, and in the adult. Binding was found to be reversible, saturable, stereospecific, of high affinity, and thermolabile. There was an increase in the density of beta-adrenergic receptors between day 1 (Bmax = 2.2 +/- 0.3 fmol/mg tissue in RVC and 2.9 +/- 0.8 fmol/mg tissue in the LV) and 2 weeks of age postnatally, after which it remained constant until 6 weeks of age (Bmax = 7.5 +/- 0.4 and 6.8 +/- 0.9 fmol/mg tissue in RVC and LV, respectively); however, by 6 weeks of age it had not reached adult levels (10.3 +/- 1.0 fmol/mg tissue). The affinity of these receptors did not change between early neonatal life (Kd = 1.3 +/- 0.4 nM) and adulthood (Kd = 1.4 +/- 0.2 nM). The density of beta-adrenergic receptors in the RVC was similar to that in the LV. This new method of quantifying beta-adrenergic receptors in cardiac tissue is simple and fast, and requires minimal tissue handling. It proved to be useful in studying the development of cardiac beta-adrenergic receptors with age.     

Agonist-Induced Regulation of Adrenoceptor Subtypes in Cerebral Cortical Slices

Cerebral cortical slices from rat brain were incubated at 37 degrees C for 2 h in the presence of isoproterenol, noradrenaline, or adrenaline, and binding affinities and densities of adrenoceptor subtypes were subsequently examined in homogenized tissue. The density of alpha 2- and total beta-adrenoceptors was estimated using the radioligands [3H]rauwolscine and [3H]dihydroalprenolol (DHA), respectively. The percentages of beta 1- and beta 2-adrenoceptors were defined by inhibiting the binding of [3H]DHA with the beta 1-selective antagonist metoprolol. Exposure of slices to noradrenaline and adrenaline significantly decreased the maximal number of binding sites (Bmax) of alpha 2-adrenoceptors (48 and 37% respectively) without significantly affecting affinity; isoproterenol had no effect. Exposure to isoproterenol, noradrenaline, and adrenaline significantly decreased the Bmax of beta-adrenoceptors (by 60, 34, and 24%, respectively) but did not affect the affinity. Isoproterenol and adrenaline significantly decreased the density of beta 1-adrenoceptors by 75 and 24% and beta 2-adrenoceptors by 23 and 28%, respectively. Noradrenaline significantly decreased the density of beta 1-adrenoceptors by 42% without affecting the number of beta 2-adrenoceptors. These findings indicate that subtypes of adrenoceptors in rat cerebral cortex are differentially regulated by adrenergic agonists.     

Regional myocardial blood flow and glucose utilization during fasting and physiological hyperinsulinemia in humans

We investigated the effect of insulin on total and regional myocardial blood flow (MBF) and glucose uptake (MGU) in healthy subjects (50 +/- 5 yr) by means of positron emission tomography (PET) with oxygen-15-labeled water (H(2)(15)O) and fluorine-18 labeled fluorodeoxyglucose ((18)FDG) before and during physiological hyperinsulinemia (40 mU.min(-1).m(-2)). Twelve male subjects were included in the study. During hyperinsulinemia, MBF increased from 0.91 +/- 0.28 to 1.01 +/- 0.31 ml.min(-1).g(-1) (n = 7 patients, P = 0.05; n = 112 regions, P < 0.005). Intersubject variability ranged from -3.0 to +41%. MGU increased from 0.11 +/- 0.08 (n = 5) to 0.56 +/- 0.08 micromol.min(-1).g(-1) (P < 0.0001, n = 7). MBF and insulin-mediated MGU were higher in the septum and anterior and lateral wall along short-axis regions of the heart. During hyperinsulinemia, MBF was also higher in the apex and midventricle compared with the base. MBF and MGU were positively correlated before (r = 0.66, P < 0.0001) and during hyperinsulinemia (r = 0.24, P < 0.05). These results provide evidence that insulin stimulates MBF in normal human hearts and appears to involve mainly those regions of the heart where insulin-mediated MGU is higher. Furthermore, regional distribution of insulin-stimulated MBF and MGU does not appear to be uniform across the left ventricular wall of healthy subjects.     

Two types of inositol trisphosphate binding in cardiac microsomes.

Two distinct types of [3H]IP3 binding were found in canine cardiac microsomes with high (Kd = 21 nM, Bmax = 0.66 pmol/mg) and low affinity (Kd = 230 nM, Bmax = 2.9 pmol/mg). Also found were low affinity [3H]IP4 binding (Kd = 190 nM, Bmax = 4.5 pmol/mg) and high affinity [3H]IP6 binding (Kd = 10 nM, Bmax = 4.9 pmol/mg). The rank order of potency to displace these radioligands indicates that binding of IP3 and IP6 is ligand-specific. Sucrose gradient centrifugation of the detergent-solubilized cardiac microsomes indicates that the molecular size of the cardiac high affinity IP3 receptor is similar to that of the aortic smooth muscle IP3 receptor and smaller than that of the ryanodine receptor which migrates more rapidly. The IP4 and IP6 binding migrates more slowly than the IP3 receptor.     

Identification of a high-affinity receptor for interleukin-1 beta in rat brain

A single type of high-affinity binding sites for IL-1 beta was identified in the rat hypothalamus (Kd = 1.0 +/- 0.2 nM) and cerebral cortex (Kd = 1.3 +/- 0.2 nM), but not in the pituitary. The maximum binding capacity (Bmax) in the hypothalamus (Bmax = 75.4 +/- 10.8 fmol/mg protein) was 4 times greater than in the cerebral cortex (Bmax = 17.2 +/- 1.5 fmol/mg protein). Neither various neuropeptides nor IL-2 appeared to influence the binding of [125I]IL-1 beta to the hypothalamic membrane preparations. The potency of unlabeled IL-1 alpha to replace the binding of [125I]IL-1 beta to the hypothalamic membrane preparations was considerably less than that of unlabeled IL-1 beta. These findings indicate that IL-1 beta receptors are heterogeneously distributed in the central nervous system and that IL-1 alpha does not bind with IL-1 beta receptors in the brain.     

Catheter Ablation of Idiopathic Premature Ventricular Contractions and Ventricular Tachycardias Originating from the Vicinity of Endocardial and Epicardial Mitral Annulus

Background

Several previous reports have revealed that idiopathic ventricular arrhythmias (VAs), including premature ventricular contractions (PVCs) and ventricular tachycardias (IVTs), can originate from endocardial mitral annulus (ENDO MA). However, these data are limited to ENDO MA VAs, and little is known about the electrocardiographic (ECG) characteristics and the efficacy of radiofrequency catheter ablation (RFCA) via the coronary venous system for the VAs arising from the epicardial MA (EPI MA).

Methodology/Principal Findings

Characteristics of body surface electrocardiogram and electrophysiologic recordings were analyzed in 21 patients with symptomatic PVCs/IVTs originating from the vicinity of MA. Among 597 patients with PVCs/IVTs, the incidence of VAs originating from the ENDO and EPI MA was 3.52% (21 cases). Eleven (52%) from the ENDO MA, and 10 (48%) from the EPI MA. There were different characteristics of ECG of PVCs/VT originating from the ENDO and EPI MA. The prolonged pseudodelta wave time and intrinsicoid deflection time in lead V2 and the precordial maximum deflection index reliably differentiated EPI MA VAs from ENDO MA VAs with high sensitivity and specificity. Successful RFCA in 18 patients could be achieved (85.7% acute procedural success).

Conclusions/Significance

ECG characteristics of PVCs/VTs originating from the different portions of the MA are different, and can help regionalize the origin of these arrhythmias. RFCA within the coronary venous system was relatively effective and safe for the PVCs/IVTs and should be seen as an alternative approach, when the MA PVCs/IVTs could not be eliminated by RFCA from the endocardium.     

Role of brain adrenoceptors in the corticortopin-releasing factor-induced central activation of sympatho-adrenomedullary outflow in rats

We investigated the role played by catecholamine-dependent pathways in modulating the ability of centrally administered corticotropin releasing factor (CRF) to activate sympatho-adrenomedullay outflow, using urethane-anesthetized rats. The CRF (1.5 nmol/animal, i.c.v.)-induced elevations of both plasma noradrenaline and adrenaline were attenuated by phentolamine (a non-selective alpha adrenoceptor antagonist) [125 and 250 microg (0.33 and 0.66 micromol)/animal], Heat (a selective alpha(1) adrenoceptor antagonist) [10 and 30 microg (30 and 90 nmol)/animal, i.c.v.] and clonidine (a selective alpha(2) adrenoceptor agonist) [100 microg (0.375 micromol)/animal, i.c.v.]. On the other hand, the CRF (1.5 nmol/animal, i.c.v.)-induced elevation of both catecholamines was not influenced by RS 79948 (a selective alpha(2) adrenoceptor antagonist) [10 and 30 microg (7.2 and 72 nmol)/animal, i.c.v.]. Furthermore, the CRF (1.5 nmol/animal, i.c.v.)-induced elevation of noradrenaline was attenuated by sotalol (a non-selective beta adrenoceptor antagonist) [125 and 250 microg (0.4 and 0.8 micromol)/animal, i.c.v.], while that of adrenaline was not influenced by sotalol. These results suggest that centrally administered CRF-induced elevation of plasma noradrenaline is mediated by an activation of alpha(1) and beta adrenoceptors in the brain, and that of plasma adrenaline is mediated by an activation of alpha(1) adrenoceptors in the brain. Furthermore, central alpha(2) adrenoceptors are involved in modulating the CRF-induced elevation of both plasma catecholamines.     

Central noradrenergic inhibition of gastric mucosal blood flow and acid secretion in rats

To investigate the role of central noradrenaline (NA) in gastric functions, changes in mucosal blood flow (MBF) and acid secretion following electrical stimulation of the lateral hypothalamic area (LHA) and the effects of NA on these parameters were examined in rats anesthetized with urethane. NA 10 μg/animal injected into the lateral ventricle decreased the basal value of both the gastric MBF and acid output, while the same dose of acetycholine or dopamine was without effect. Repetitive electrical stimulation of LHA at 10 cycles/sec, 0.5 mA, 2 msec for 10 min elicited a significant, reproducible increase in both gastric MBF and acid output. NA 10 μg/animal injected into the lateral ventricle completely blocked these increases induced by the electrical stimulation. These data suggest that a central noradrenergic inhibitory mechanism is involved in regulation of the gastric MBF and acid secretion.