bluuebunny/crossref_metadata_2025 huggingface dataset:
Ventricular arrhythmias in the subacute myocardial infarction period. High-resolution activation and refractory patterns of reentrant rhythms.
Authors: Restivo M , Gough W B , el-Sherif N
Published: June 2012

Patterns of activation, functional conduction block, and effective refractory periods during reentrant activation were investigated in a 4-day postinfarction canine model using a 64-channel high-resolution (1 mm) bipolar electrode array. Lower resolution (3-10 mm) isochronal activation maps of the entire epicardial surface were constructed from 126 sites during the initiation and sustenance of reentry and showed reentrant wave fronts that circulated around arcs of functional conduction block. During initiation of reentry by premature stimulation, high-density recordings from these same regions showed that conduction block occurred abruptly, within 1 mm, and without prior decrement of the impulse. Electrograms recorded in proximity to the arc of block were comprised of two deflections: a local activation potential and an electrotonic potential reflecting activation 1 mm away; the reverse order of activation and electrotonus was observed on the opposite side of the arc of block. The occurrence of functional conduction block during premature stimulation in this model was correlated with abrupt increases in effective refractory periods of 10-120 msec (27 +/- 24 msec; mean +/- SD) within 1 mm or less. Neither the abrupt change of refractoriness nor functional conduction block appeared to depend on differences in excitability, the geometrical characteristics of the surviving epicardial layer, or the orientation of the myocardial fibers. During sustained reentrant activation, high-density recordings along the arcs of block showed split electrograms comprised of local activation and electrotonus, which were identical in morphology to those recorded during the initiation of reentry. The interval between the deflections was shorter at the ends of the arc and increased to a maximum value at the center of the arc. The activation potentials corresponded in time with activation of large isochronal regions on either side of the arc of block. There was evidence that at least part of the arc of block during sustained reentry represented thin discrete zones of constant block due to electrotonic influences of impulse penetration from both sides of the arc. Our results strongly suggest that continuous arcs of functional conduction block are a necessary prerequisite for both the initiation and the sustenance of reentrant activation in subacute canine myocardial infarction. Functional conduction block during the initiation of reentry was due to abrupt changes in refractoriness, within a distance of 1 mm or less.
Baroreflex control of the cutaneous active vasodilator system in humans.
Authors: Kellogg D L , Johnson J M , Kosiba W A
Published: June 2012

Cutaneous arterioles are controlled by vasoconstrictor and active vasodilator sympathetic nerves. To find out whether the active vasodilator system is under baroreceptor control, laser-Doppler velocimetry and the local iontophoresis of bretylium were combined to allow selective study of the active vasodilator system. Each of six subjects had two forearm sites (0.64 cm2) treated with bretylium to abolish adrenergic vasoconstrictor control. Laser-Doppler velocimetry was monitored at those sites and at two adjacent untreated sites. Subjects underwent 3 minutes of lower-body negative pressure (LBNP) and 3 minutes of cold stress to verify blockade of vasoconstrictor nerves. They were then subjected to whole-body heat stress (water-perfused suits), and the 3 minutes of LBNP was repeated. Finally, subjects were returned to normothermia, and LBNP and cold stress were repeated to verify the persistence of blockade. During the application of LBNP in normothermia, cutaneous vascular conductance (CVC) fell at untreated sites by 22.7 +/- 4.7% (p less than 0.01) but was unaffected at bretylium-treated sites (p greater than 0.20). During cold stress, CVC at untreated sites fell by 30.2 +/- 1.7% (p less than 0.01) and at treated sites rose by 0.7 +/- 4.6% (p greater than 0.10). Both control and bretylium-treated sites reflexly vasodilated in response to hyperthermia. With LBNP during hyperthermia, CVC at untreated sites fell by 23.3 +/- 7.1% (p less than 0.05) and at treated sites 17.9 +/- 9.2% (p less than 0.05) with no significant difference between sites (p greater than 0.10). After return to normothermia, neither LBNP application nor cold stress caused CVC to fall at treated sites (p greater than 0.10). Thus, the vasoconstrictor system was blocked by bretylium treatment throughtout the study, whereas the active vasodilator response to heat stress was intact. Because LBNP in hyperthermia induced similar falls in CVC at both sites, we conclude that baroreceptor unloading elicits a withdrawal of active vasodilator tone and that the baroreflex has control of the active vasodilator system.
Functional implications of decreased renal cortical atrial natriuretic peptide binding in experimental diabetes.
Authors: Benigni A , Perico N , Dadan J , Gabanelli M , Galbusera M , Boccardo P , Mennini T , Remuzzi G
Published: June 2012

Glomerular hyperfiltration in streptozotocin-induced diabetes mellitus in rats may be mediated by atrial natriuretic peptide (ANP). We wanted to evaluate plasma levels of ANP and plasma volume in relation to renal ANP receptor density and affinity in rats 6 weeks after induction of diabetes. Plasma levels of immunoreactive ANP were significantly higher in hyperglycemic diabetic (75.2 +/- 8.3 pg/ml) than in control animals (34.7 +/- 8.1 pg/ml; p less than 0.01). Administration of insulin to keep diabetic rats normoglycemic normalized plasma levels of immunoreactive ANP (30.5 +/- 5.2 pg/ml). In contrast, plasma volume did not show significant differences among the groups (hyperglycemic diabetes, 46.6 +/- 3.8; normoglycemic diabetes, 42.4 +/- 3.2; controls, 43.2 +/- 2.0 ml/kg body wt). No correlation was found between plasma levels of immunoreactive ANP and plasma volume. By autoradiography a significant reduction in the number of renal cortical ANP receptors was observed in hyperglycemic diabetic rats as compared with controls. At variance, ANP receptor affinity did not change either in the cortex or in the medulla in hyperglycemic diabetics in comparison with control animals. The pathophysiological implication of cortical ANP receptor down-regulation was underscored by the blunted response of glomerular filtration rate to ANP infusion in diabetic animals as compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Firing characteristics of single-fiber carotid sinus baroreceptors.
Authors: Seagard J L , van Brederode J F , Dean C , Hopp F A , Gallenberg L A , Kampine J P
Published: June 2012

This study examined firing patterns of single-fiber carotid baroreceptors in response to slow ramp increases in carotid sinus pressure (1-2 mm Hg/sec) in vascularly isolated carotid sinus preparations in thiopental-anesthetized dogs (25 mg/kg, plus 10 mg/kg/hr). Two general types of baroreceptor discharge patterns were obtained: 1) type I, a discontinuous, hyperbolic pattern characterized by a sudden onset of discharge at threshold pressure with a relatively high threshold frequency, which gradually increased to a higher saturation firing rate and 2) type II, a continuous, sigmoidal pattern characterized by a gradual increase in discharge above threshold pressure and a relatively low threshold frequency and saturation firing rate. Type II baroreceptor curves typically showed spontaneous discharge below threshold pressure and significantly lower sensitivities, threshold frequency, saturation firing rate, and threshold pressure than those of type I receptors. However, the saturation pressures and operating ranges of the type II receptors were greater than those of type I receptors, and the pressure at which type II receptors had their greatest sensitivity was greater than that for type I receptors. Type I baroreceptors generally had large myelinated afferent A fibers; type II baroreceptors generally had smaller A and unmyelinated C fibers, based on conduction velocities. The presence of spontaneous activity with type II baroreceptors, combined with significantly lower sensitivities and wider pressure operating ranges seen relative to type I baroreceptors, suggests that these receptors may primarily serve to provide information on tonic, or baseline, levels of arterial blood pressure to the central cardiovascular centers. The sudden onset of discharge, higher sensitivities, and narrower operating ranges of type I baroreceptors suggest that their primary role may be to provide information on dynamic, sudden changes in arterial pressure.
Regulation of myosin heavy chain expression in the hearts of hypertensive rats by testosterone.
Authors: Morano I , Gerstner J , Rüegg J C , Ganten U , Ganten D , Vosberg H P
Published: June 2012

Stroke-prone spontaneously hypertensive rats were used for our investigation of the influence of prepubertal gonadectomy and testosterone substitution on blood pressure, cardiac hypertrophy, and the expression of ventricular myosin heavy chain (MHC) isoenzymes at different developmental stages. Blood pressure and the degree of cardiac hypertrophy were decreased by castration and increased by testosterone substitution. We found the same relative distributions of MHC isoforms on the protein level (investigated by pyrophosphate electrophoresis) and on the messenger RNA level (investigated by the polymerase chain reaction). Castration favored the expression of the beta-MHC form, and testosterone substitution enhanced the expression of the alpha-MHC form. These effects were more pronounced in 8-week-old than in 14-16-week-old animals. We conclude that testosterone regulates cardiac MHC expression on a pretranslational level. This regulation is independent of hemodynamic load or cardiac hypertrophy.
Does endocardial endothelium mediate positive inotropic response to angiotensin I and angiotensin II?
Authors: Meulemans A L , Andries L J , Brutsaert D L
Published: June 2012

The positive inotropic response to angiotensin I and II in cardiac tissue of most mammalian species, as well as the exact site in the heart for conversion of local and systemic angiotensin I into angiotensin II, remains to be elucidated. In isolated cat papillary muscles, angiotensin I and angiotensin II (0.1 nM to 1 microM, 35 degrees C, 1.25 mM Ca2+) increased, in a dose-dependent manner, peak twitch tension with typical slight prolongation of twitch duration. This typical response did not necessitate the presence of an intact endocardial endothelium (EE), as a similar response was observed in muscles where the EE had been damaged by a 1-second exposure to 0.5% Triton X-100. After addition of captopril, an angiotensin converting enzyme inhibitor, the positive inotropic response to angiotensin I was completely abolished, both in the presence and the absence of an intact EE. Hence, the heart possesses angiotensin converting enzyme, which mediates the positive inotropic response to angiotensin I. An intact EE was not a prerequisite for this response; thus, myocytes as well as nonmyocytes may be possible locations (in addition to the EE) for angiotensin converting enzyme. In the presence of an intact EE, and after addition of captopril, the positive inotropic response to angiotensin II was significantly diminished (desensitization). By contrast, in the absence of an intact EE, but also after addition of captopril, the positive response to angiotensin II was potentiated (sensitization). Both desensitization and sensitization (in the presence or absence of an intact EE, respectively) of the response to angiotensin II induced by the addition of captopril were inhibited by indomethacin, a cyclooxygenase inhibitor, suggesting a role for prostaglandins.
Selective beta 1-adrenoceptor blockade enhances positive inotropic responses to endogenous catecholamines mediated through beta 2-adrenoceptors in human atrial myocardium.
Authors: Hall J A , Kaumann A J , Brown M J
Published: June 2012

We determined the relative contribution of beta 1- and beta 2-adrenoceptor stimulation to the positive inotropic responses of human atrial myocardium to catecholamines. (-)Norepinephrine produced stimulation predominantly through beta 1-receptors and (-)epinephrine through both beta 1- and beta 2-receptors. However, there were marked differences in the responses of tissues from patients treated with the beta 1-selective antagonist atenolol compared with non-beta-blocker-treated patients; surprisingly, beta 2-mediated responses were enhanced, and beta 1-mediated responses were unaltered. There was an enhanced responsiveness to (-)epinephrine (atenolol treated: -log M EC50, 7.57 +/- 0.07; non-beta-blocker treated: -log M EC50, 6.77 +/- 0.17; p less than 0.001), and the relative importance of beta 2-adrenoceptor stimulation was increased for both (-)norepinephrine and (-)epinephrine. In tissues from atenolol-treated patients, salbutamol, a beta 2-selective partial agonist, had an enhanced potency and a greater intrinsic activity (atenolol treated: -log M EC50, 7.13 +/- 0.09; intrinsic activity, 0.86 +/- 0.04; non-beta-blocker treated: -log M EC50, 5.76 +/- 0.44; intrinsic activity, 0.39 +/- 0.13). We investigated possible mechanisms underlying the enhanced responsiveness to beta 2 stimulation. Determination of beta 2-adrenoceptor affinity for salbutamol showed no change of affinity in atenolol-treated patients. Responses of the tissues to the cyclic AMP analogue dibutyryl cyclic AMP were not different between atenolol-treated and non-beta-blocker-treated patients. The results suggest that chronic blockade of beta 1-adrenoceptors causes enhanced coupling of beta 2-adrenoceptors to adenylate cyclase or to other mechanisms leading to increased contractile force.
Effect of acidosis on contraction of microvascular smooth muscle by alpha 1- and alpha 2-adrenoceptors. Implications for neural and metabolic regulation.
Authors: McGillivray-Anderson K M , Faber J E
Published: June 2012

Our previous studies have identified that adrenergic regulation of large arterioles and venules in skeletal muscle uses both postjunctional alpha 1- and alpha 2-adrenoceptors, whereas terminal arterioles appear to be subserved primarily by alpha 2-receptors. Adrenergic constriction of terminal arterioles is known to be particularly susceptible to inhibition by increased tissue metabolic rate. The purpose of this study was to examine the influence of tissue acidosis on alpha 1- and alpha 2-adrenoceptor constriction of skeletal muscle microvessels to determine if this differential receptor distribution might have significance in neural-metabolic interactions. Intravital microscopy of rat cremaster skeletal muscle was used to obtain concentration-response curves (diameter changes) of large distributing arterioles (mean diameter, 100 microns), small precapillary arterioles (20 microns), and capacitance venules (150 microns) for addition to the tissue bath of alpha-adrenergic agonists during normal pH (7.4) and during tissue bath acidosis (pH 7.1) produced by increasing bath PCO2. The following alpha-agonists were used: phenylephrine (alpha 1), B-HT 933 (alpha 2), and norepinephrine (mixed alpha 1/alpha 2). Acidosis had no effect on baseline diameter of the three vessel types, indicating a lack of effect on "intrinsic tone." Acidosis also had no effect on large microvessel sensitivity to phenylephrine but markedly reduced responses to B-HT 933. Acidosis had no effect on large arteriolar and venular sensitivity to norepinephrine but markedly decreased (x300) small precapillary arteriolar sensitivity. These data suggest that 1) alpha 2- but not alpha 1-adrenoceptor-mediated constriction of microvessels may be selectively sensitive to modest reductions in tissue pH, and 2) the prevalence of alpha 2-receptors on terminal arterioles and the marked sensitivity of alpha 2 constriction to tissue acidosis may contribute to the particular susceptibility of neural constriction at this level of the microcirculation to metabolic inhibition.
Bistabilities and annihilation phenomena in electrophysiological cardiac models.
Authors: Landau M , Lorente P , Michaels D , Jalife J
Published: June 2012

We have investigated the oscillatory behavior of cardiac cellular elements simulated by two electrophysiological models: the van Capelle and Durrer (VCD) model and the sinoatrial node cell model of Yanagihara, Noma, and Irisawa (YNI). The VCD model behavior was examined systematically by using continuation-bifurcation analysis. Bifurcation diagrams were constructed as a function of Qit1, an intrinsic parameter of the model, which sets both maximum diastolic potential and depolarization threshold of the cell. The existence of stable high amplitude oscillations was evidenced between two Hopf bifurcation points (HB). Near each HB, a zone of bistability was detected. Close to the HB that corresponded to high values of Qit1, a high amplitude periodic stable state coexisted with a stable steady state. Close to the other HB, in a narrow range of lower Qit1 values, a relatively high amplitude periodic stable state coexisted with a low amplitude periodic stable state. There was no stable steady state in the latter bistability zone. Through the use of phase-plane representations and the determination of separatrices between the different attractor basins, we could deduce the conditions of timing, polarity, and strength needed for a pulse perturbation to send the system from one state to another and vice versa. The YNI model was analyzed by numerical simulation, and the oscillatory behavior of the sinoatrial node cell was explored while applying a depolarizing bias current of various strengths. Results were similar to those obtained from the VCD model in that there were two bistability regions for two different ranges of applied bias current. Depending on current intensity, annihilation of pacemaker activity could be achieved in both zones. However, the coexistence of two oscillatory stable states was never observed in the YNI model. From the behavioral similarities of these different models, we can conclude that bistabilities and annihilation phenomena can be found in transitional zones between quiescence and rhythmic activity.
Effect of transmural pressure on low density lipoprotein and albumin transport and distribution across the intact arterial wall.
Authors: Curmi P A , Juan L , Tedgui A
Published: June 2012

To investigate the effect of hyperpressure on the transport of low density lipoprotein (LDL) and albumin in the arterial wall, we measured in vitro the uptake of both iodine-131-labeled LDL and iodine-125-labeled albumin in intact rabbit thoracic aorta, held at in vivo length and pressurized to 70 or 160 mm Hg. Arteries were incubated for 2 hours (n = 8) at 70 mm Hg, and for 5 minutes (n = 4), 30 minutes (n = 4), 1 hour (n = 5), and 2 hours (n = 5) at 160 mm Hg. The transmural distribution of the relative concentrations of LDL (CLDL) and albumin (Calb) across the wall was determined by using a serial frozen sectioning technique. At 70 mm Hg, the mean medial CLDL and Calb values were 0.0018 +/- 0.0007 and 0.0039 +/- 0.0013, respectively. At 160 mm Hg, CLDL and Calb were markedly increased. The distribution of labeled albumin was almost uniform across the media and reached a steady state after 30 minutes, whereas labeled LDL accumulated in the first inner layers, a steady state being achieved after 1 hour. The 1-hour values of CLDL in the first and second luminal sections (0.24 +/- 0.03 and 0.13 +/- 0.05, respectively) were much higher than those of Calb, the CLDL/Calb ratios being 4.12 +/- 0.94 and 2.34 +/- 0.42 (p less than 0.01), respectively. In the subsequent sections, the CLDL decreased markedly and became much lower than the Calb, the CLDL/Calb ratio averaging 0.2 in the two-thirds outer media. To investigate whether LDL was trapped at high pressure in the inner layers, vessels were exposed to a tracer-free intraluminal solution for 30 minutes, after a 30-minute incubation with tracers. After washout, albumin was almost totally removed from the wall, while the CLDL were practically unchanged. Compaction of the media induced by high distending stresses applied to the vessel might have hindered the efflux of LDL, whereas albumin moved freely through the wall. Synergy between increased endothelial permeability and compaction of the media together with enhanced pressure-driven convection might account for the marked increase in LDL concentration observed in the inner wall at high pressure.
Effects of aging on mechanics and composition of cerebral arterioles in rats.
Authors: Hajdu M A , Heistad D D , Siems J E , Baumbach G L
Published: June 2012

The purpose of this study was to examine effects of aging on the mechanics and composition of cerebral arterioles. We measured pressure (servo-null) and diameter in pial arterioles in anesthetized adult (9-12 months old) and aged (24-27 months old) Fischer 344 rats. After deactivation of smooth muscle with EDTA, diameter of pial arterioles at 70 mm Hg pial arteriolar pressure was less in aged than in adult rats (67 +/- 4 vs. 81 +/- 4 microns [mean +/- SEM], p less than 0.05). The stress-strain relation and the slope of tangential elastic modulus versus stress (6.8 +/- 0.6 vs. 5.3 +/- 0.3, p less than 0.05) indicated that distensibility of pial arterioles was reduced in aged rats. Cross-sectional area of the vessel wall, measured histologically, was less in aged than adult rats (1,239 +/- 91 vs. 1,832 +/- 180 microns2, p less than 0.05). Point counting stereology was used to quantitate smooth muscle, elastin, collagen, and basement membrane in the arteriolar wall. Cross-sectional areas of smooth muscle and elastin were significantly less in aged than adult rats (744 +/- 57 vs. 1,291 +/- 119 microns2 for smooth muscle, 52 +/- 6 vs. 113 +/- 15 microns2 for elastin; p less than 0.05), whereas cross-sectional areas of collagen and basement membrane were not significantly different in aged and adult rats (4 +/- 1 vs. 3 +/- 1 microns2 for collagen, 236 +/- 17 vs. 258 +/- 31 microns2 for basement membrane). The ratio of nondistensible (collagen and basement membrane) to distensible (smooth muscle and elastin) components was greater in aged than adult rats (0.30 +/- 0.01 vs. 0.18 +/- 0.01, p less than 0.05). Thus, we conclude that, during aging, cerebral arterioles undergo atrophy, distensibility of cerebral arterioles is reduced, and the relative proportion of distensible elements, elastin and smooth muscle, is reduced in the arteriolar wall.
Detection of moving flow separation in pulsatile flow and the degree of stenosis by power of Doppler shift signals.
Authors: Tamura T , Fronek A
Published: June 2012

Power ratios were derived from the principle of ultrasonic Doppler velocimetry to determine a ratio of the volume of vortices to the total vessel volume under the ultrasonic beam. This ratio also equals the ratio of the cross-sectional area of vortices to the vessel lumen. In vitro pulsatile flow experiments were performed in a Reynolds number range of 1,230-4,320 with axisymmetric constrictions with area reductions of 55%, 65%, 70%, and 85% to model carotid stenosis. Flow separation downstream from the model stenoses was detected, and the power ratio fluctuated when vortices with the forward- and reverse-flow velocity components passed by the measurement position. The power ratio estimated the degree of stenosis within 10% of error. Ensemble average of the power ratio was computed to obtain the statistically averaged separated flow region. The moving flow reattachment point was revealed downstream from the 85% stenosis at a Reynolds number of 900.
Integrin receptors on aortic smooth muscle cells mediate adhesion to fibronectin, laminin, and collagen.
Authors: Clyman R I , McDonald K A , Kramer R H
Published: June 2012

Extracellular matrix receptors on vascular smooth muscle cells help in anchoring the cells during contraction and in promoting cellular migration after vessel injury. We found that rat aortic smooth muscle cells attach to surfaces coated with fibronectin, laminin, and collagen types I and IV. Cell attachment to these substrates appears to be mediated by members of the beta 1 integrin family of extracellular matrix receptors. Antibodies to the beta 1 subunit not only demonstrated the presence of integrin complexes in focal adhesion plaques but also blocked cell adhesion to the different substrates. Ligand-affinity chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis isolated a series of receptor complexes that were recognized by antisera to beta 1 integrin receptors. Each of the receptors appeared to be a heterodimer in which one of several alpha subunits shared a common 120-kDa (nonreduced) beta 1 subunit protein. The rat aortic smooth muscle cells had one alpha subunit (150 kDa nonreduced, 140 kDa reduced) that bound exclusively to fibronectin. There was a second alpha subunit (150 kDa nonreduced, 160 kDa reduced) that bound exclusively to collagen type I. In addition, there was a third alpha subunit (185 kDa nonreduced, 200 kDa reduced) that was promiscuous and bound to collagen types I and IV as well as to laminin; the 185-kDa alpha subunit appeared to bind to collagen more efficiently than it did to laminin. Thus, smooth muscle cells express multiple integrin receptors with different ligand specificities that appear to mediate cell interactions with the extracellular matrix.
Attenuation of long-lasting effects of sympathetic stimulation after repeated stimulation.
Authors: Hall G T , Gardner T D , Potter E K
Published: June 2012

Neuropeptide Y (NPY) is stored with norepinephrine in sympathetic nerves throughout the cardiovascular system and is released during activation of the sympathetic nervous system in humans and other animals. After stimulation of the cardiac sympathetic nerves in anesthetized dogs, the action of the vagus nerve on heart rate is attenuated for a prolonged period. This attenuation of cardiac vagal action is also seen after injection of NPY. Both sympathetic stimulation and exogenous NPY inhibit cardiac vagal effects by acting on postganglionic vagal nerves. Because the supply of neuropeptides to nerve terminals is by axonal transport, it might be expected that repeated stimulation of cardiac sympathetic nerves would deplete the sympathetic neural factor, proposed to be NPY. In all 11 dogs of this study, repeated episodes of stimulating the cardiac sympathetic nerve (16 Hz for 1 minute each) had a diminishing effect in attenuating cardiac vagal action. However, the episodes of sympathetic stimulation did not show diminishing effectiveness in increasing heart rate. Exogenous NPY had similar inhibitory effects on vagal action whether given at the beginning or the end of the episodes of sympathetic stimulation. Transmural stimulation of sympathetic nerves around rabbit ear arteries produced effects that are also mimicked by NPY. These are prolonged potentiation of contractions evoked by injection of norepinephrine or by brief bursts of transmural stimulation. Repeated stimulations in this case also had diminishing abilities to evoke such potentiations. Both sets of observations are consistent with repeated stimulation of sympathetic nerves causing depletion of a nonadrenergic transmitter, possibly NPY.
Digestion of cardiac and skeletal muscle junctional sarcoplasmic reticulum vesicles with calpain II. Effects on the Ca2+ release channel.
Authors: Rardon D P , Cefali D C , Mitchell R D , Seiler S M , Hathaway D R , Jones L R
Published: June 2012

The Ca2+ release channel and ryanodine receptor are activities copurifying with the 400,000-450,000 Da high molecular weight protein of cardiac and skeletal junctional sarcoplasmic reticulum. Calpain II, an endogenous cytosolic protease, was used to selectively degrade the high molecular weight protein in cardiac and skeletal muscle sarcoplasmic reticulum vesicles, and its effects on the activity of the Ca2+ release channel and [3H]ryanodine binding sites were analyzed. Degradation of the high molecular weight protein was associated with appearance of 315,000 and 150,000 Da proteolytic fragments and with a change in the ultrastructure of the "feet," extravesicular projections that protrude from the junctional sarcoplasmic reticulum membrane. The maximal number of [3H]ryanodine binding sites and the affinities of the sites for ryanodine were not remarkably affected by calpain II. Ca2+ release channels recorded from nondegraded cardiac and skeletal membrane vesicle preparations had slope conductances of 85 and 110 pS, respectively, measured with 1 microM cis-Ca2+ and 50 mM trans-Ba2+. Proteolysis did not alter the unitary channel conductances but did increase the percentage of channel open times from 36% to more than 90%. After proteolysis, channel opening remained dependent on micromolar cis-Ca2+, and high concentrations of ryanodine (300 microM) still blocked the channel. Our results suggest that proteolysis of the Ca2+ release channel with calpain II selectively impairs its inactivation, leaving its unitary conductance and the requirement for micromolar Ca2+ intact.
Effect of thyroid status on thin-filament Ca2+ regulation and expression of troponin I in perinatal and adult rat hearts.
Authors: Dieckman L J , Solaro R J
Published: June 2012

There is evidence for the existence of developmental changes in expression of troponin I (TNI) in cardiac thin filaments; however, regulation of TNI expression has not been described. We tested whether thyroid state affects expression of TNI using neonatal and adult rats made hypothyroid by treatment with 6-n-propyl-2-thiouracil. Polyacrylamide gels of myofibrils from hearts of 7-, 14-, 21-, and 28-day-old animals indicated that both euthyroid and hypothyroid rats display a developmental shift toward the adult form of TNI. However, hypothyroid rats displayed a lower percentage of adult TNI at each age studied. When adult rats were made hypothyroid, the proportion of adult TNI decreased slightly. Thin-filament activity was determined from measurements of the effect of acidic pH on calcium activation of myofibrillar ATPase activity. Sensitivity to acidic pH was measured by the magnitude of shift in pCa50 (-log of half-maximally activating molar Ca2+) between pH 7.0 and 6.5. Euthyroid rats displayed developmental increases in pH sensitivity. At 7, 14, and 28 days of development, shifts in pCa50 were 0.11, 0.38, and 0.43 units, respectively. Hypothyroid rats displayed less pH sensitivity with pCa50 shifts of 0.07, 0.21, and 0.15 units at 7, 14, and 28 days of development. Adult hypothyroid rats displayed a 0.38-unit shift in pCa50, whereas euthyroid adults displayed a 0.44-unit shift. Our results indicate that pH sensitivity and expression of cardiac TNI are influenced by developmental stage and hormonal status.
Increasing fibrillation duration enhances relative asymmetrical biphasic versus monophasic defibrillator waveform efficacy.
Authors: Jones J L , Swartz J F , Jones R E , Fletcher R
Published: June 2012

Biphasic waveforms reduce defibrillation threshold compared with corresponding monophasic waveforms. However, effects of fibrillation duration on relative efficacy of monophasic and biphasic waveforms are unknown. This study used a newly developed defibrillation model, the isolated right- and left-sided working rabbit heart, with epicardial defibrillation electrodes, to compare threshold for a monophasic waveform (5 msec rectangular) and an asymmetrical biphasic waveform (5 msec each pulse, V2 = 50% V1). Mean voltage defibrillation threshold (V50) was determined from sigmoidal probability of successful defibrillation versus shock intensity curves after 5, 15, and 30 seconds of fibrillation in a paired study with 10 hearts. Results showed that biphasic waveforms had significantly lower voltage and energy thresholds at all fibrillation durations and that their relative efficacy improved with increasing fibrillation duration. Biphasic voltage threshold was 38.2 +/- 2.2, 44.7 +/- 4.8, and 46.6 +/- 3.2 V after 5, 15, and 30 seconds of fibrillation compared with monophasic thresholds of 51.7 +/- 4.4 (p less than 0.002), 63.0 +/- 7.6 (p less than 0.05), and 72.1 +/- 3.9 V (p less than 0.005). Biphasic waveform energy threshold was 0.67 that for the monophasic waveform after 5 seconds of fibrillation (0.12 +/- 0.01 versus 0.18 +/- 0.03 J, p less than 0.05). The ratio between biphasic waveform threshold and monophasic waveform threshold (B/M) decreased to 0.62 at 15 seconds. At 30 seconds, B/M was 0.52 (0.17 +/- 0.02 versus 0.33 +/- 0.04 J, p less than 0.02). This study also showed that biphasic waveform threshold was a nonlinear function of monophasic waveform threshold so that improved biphasic defibrillator waveform efficacy was greatest for hearts having higher monophasic thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of protein intake on regional vascular resistance and reactivity to angiotensin II in the rat.
Authors: Murray B M
Published: June 2012

Male Sprague-Dawley rats (200-250 g) were fed low protein (6%) diets (LP rats), high protein (50%) diets (HP rats), or regular rat chow (approximately 16% protein) (control rats) and studied under anesthesia after 2 weeks. Dietary protein intake did not affect mean arterial pressure, but renal blood flow was increased in the HP rats and decreased in the LP rats compared with the control rats. Mesenteric blood flow was not significantly different in the three diet groups. Captopril (10 mg.kg-1 i.v.) had no effect on renal vascular resistance in the HP rat but did reduce the elevated renal vascular resistance seen in the LP rat. Meclofenamate (5 mg.kg-1 i.v.) did not significantly affect renal hemodynamics in either HP or LP rats. Finally, the HP rat exhibited resistance to the systemic pressor, renal, and mesenteric vasoconstrictor effects of angiotensin II. Captopril restored the systemic pressor and the mesenteric vasoconstrictor response but not the renal vasoconstrictor response to angiotensin II. Meclofenamate, on the other hand, restored both the systemic pressor response and the renal vasoconstrictor response. Thus, in the LP rat, the vascular response to angiotensin II remains intact, and renal vasoconstriction appears to be mediated by angiotensin II. In contrast, in the HP rat, the renovascular response to angiotensin II is blunted apparently because of enhanced renal prostaglandin production. However, neither increased renal prostaglandin synthesis nor blunting of the renovascular response to angiotensin II appears to account for the chronic vasodilation seen in the HP rat.
An in vitro study of the onset of turbulence in the sinus of Valsalva.
Authors: Peacock J A
Published: June 2012

During systole a small portion of the mainstream aortic flow is intercepted by the sinus ridge, or downstream corner of the sinus of Valsalva. This fluid curls back toward the ventricle to form a large eddy, or vortex, that spins within the sinus cavity. The fluid motion within similar recirculating flows is known to be unstable with an early transition to turbulence. The stability of the aortic sinus vortex was examined in the current study in an in vitro pulsatile flow rig. The geometry of the experimental test section was the same as the geometry of the natural aortic root. Different model valves, including a natural valve, were placed in the test section, and different flow conditions were studied. Point velocities were measured by hot film probes placed at two locations within the sinus vortex. The velocity waveforms and their power spectra were used to determine the stability of the sinus flow. The experimental results revealed that the aortic sinus vortex becomes turbulent under simulated exercise conditions. Turbulent intensities were highest near the sinus ridge, which is the location of the coronary ostia. Despite the transition to turbulence within the vortex, the mainstream aortic flow upstream from the valve remained laminar. The turbulence within the vortex was also associated with vibration of the valve leaflets under exercise conditions. These vibrations may be related to the systolic ejection murmurs that are heard clinically. Furthermore, the localized turbulence may explain the location of atherosclerotic lesions and dissecting aneurysms, as well as the distribution of the lesions of bacterial endocarditis.
High-dose atrial natriuretic factor enhances albumin escape from the systemic but not the pulmonary circulation.
Authors: Zimmerman R S , Trippodo N C , MacPhee A A , Martinez A J , Barbee R W
Published: June 2012

Atrial natriuretic factor (ANF) causes plasma fluid to shift out of the circulation and enhances the escape of radiolabeled albumin. Examination of the mechanisms by which ANF alters microcirculatory fluid and protein transfer will likely require studies in localized vascular regions. This study was aimed at determining the specific organs in which ANF increases the escape of albumin. Anesthetized, splenectomized rats that had both kidneys removed were infused with vehicle alone or rat ANF-(99-126) at 0.025, 0.05, 0.1, or 0.5 micrograms.min-1.kg-1 for 2 hours (n = 8 per group). Total red cell and plasma volumes were measured with chromium-51-labeled erythrocytes and iodine-125-labeled albumin, respectively. At the end of 2 hours, the rats were frozen in liquid nitrogen, and organ blood volumes and tissue 125I-albumin were determined. ANF decreased plasma volume at infusion rates of 0.1 and 0.5 micrograms.min-1.kg-1. ANF increased the rate at which 125I-albumin escaped from the overall circulation at infusion rates of 0.1 and 0.5 micrograms.min-1.kg-1. At an ANF infusion rate of 0.1 micrograms.min-1.kg-1, the albumin escape rate increased in the gastrointestinal tract, skeletal muscle, heart, and lungs. At an infusion rate of 0.5 micrograms.min-1.kg-1, the albumin escape rate increased in the gastrointestinal tract, muscle, and skin, but not the lungs. These findings suggest that at pathophysiological levels, ANF shifts protein out of the circulation in peripheral vascular beds and the lungs and may contribute to pulmonary edema in states such as congestive heart failure. At pharmacological levels, ANF may be protective of the lungs by preventing increased pulmonary albumin escape.
Actions of Ca2+ antagonists on two types of Ca2+ channels in rat aorta smooth muscle cells in primary culture.
Authors: Kuga T , Sadoshima J , Tomoike H , Kanaide H , Akaike N , Nakamura M
Published: June 2012

Mechanisms of blockade of two types of Ca2+ channels by the organic Ca2+ antagonists, nicardipine, diltiazem, verapamil, and flunarizine, were examined in rat aorta smooth muscle cells in primary culture by using the whole-cell voltage-clamp method. T-type Ca2+ current (T-type ICa) was isolated by an internal perfusion of 5 mM F-, which irreversibly suppressed the L-type ICa, without affecting T-type ICa. L-type ICa was isolated by setting a holding potential at -60 mV, at which most of the T-type Ca2+ channels were inactivated. L-type ICa is halved by 0.1 microM nicardipine, 3.0 microM diltiazem, 0.6 microM verapamil, and 0.1 microM flunarizine, whereas T-type ICa is halved by the same drugs at 0.6, 30, 30, and 0.1 microM, respectively. Diltiazem and verapamil accelerated the decay of L-type ICa and cumulatively blocked L-type ICa during repetitive step depolarizations elicited every 30 seconds ("use-dependent block"). Diltiazem and verapamil neither changed the decay of T-type ICa nor showed a use-dependent block of T-type ICa. Nicardipine and flunarizine blocked both L- and T-type ICa from the first depolarization step after drug treatment ("tonic block") and shifted their steady-state inactivation curves to the left. The estimated binding constants of nicardipine and flunarizine for the inactivated state of T-type Ca2+ channels (48 and 19 nM, respectively) were smaller than those for the resting state of L-type Ca2+ channels (160 and 90 nM, respectively). A low concentration (0.1 microM) of nicardipine initially potentiated T-type ICa and then reduced it. We conclude from these results that 1) nicardipine and flunarizine block not only the resting state but, more preferentially, the inactivated state of both the L- and T-type Ca2+ channels; 2) verapamil and diltiazem preferentially act on the open state of the L-type Ca2+ channel and on the resting and inactivated state of the T-type Ca2+ channel; and 3) the T-type Ca2+ channel of the rat aorta smooth muscle cells appears to be more sensitive to nicardipine and flunarizine than does the L-type Ca2+ channel at around the resting membrane potential.
Potentiation of reperfusion-associated ventricular fibrillation by left ventricular hypertrophy.
Authors: Taylor A L , Winter R , Thandroyen F , Murphree S , Buja L M , Eckels R , Pastor P , Kremers M
Published: June 2012

Important electrophysiological alterations that may predispose hearts to arrhythmias have been described for hypertrophied myocytes, and hypertrophy coupled with ischemia has been associated with an increased incidence of sudden death; however, an influence of hypertrophy on reperfusion arrhythmias has not been previously described. We hypothesized that reperfusion-associated arrhythmias would be potentiated by left ventricular hypertrophy. After induction of renovascular hypertension, 37 awake, unsedated dogs (17 with left ventricular hypertrophy and 20 without hypertrophy) underwent 15 minutes of coronary artery occlusion and reperfusion. All dogs were pretreated with lidocaine bolus injections and with lidocaine by continuous infusion during coronary occlusion and reperfusion. Reperfusion-associated ventricular fibrillation occurred in seven of 17 dogs with left ventricular hypertrophy versus one of 18 dogs without hypertrophy (p less than or equal to 0.05). The presence of hypertension was not significantly associated with an increased incidence of reflow ventricular arrhythmias. Neither QT interval nor area-at-risk was different between the dogs with and without reperfusion ventricular fibrillation; however, increased heart rate just before reperfusion did correlate with an increased incidence of ventricular fibrillation at reperfusion. Thus, 1) left ventricular hypertrophy was associated with a significantly increased incidence of reperfusion-induced ventricular fibrillation after 15 minutes of ischemia, 2) this increased incidence was independent of the presence of hypertension, and 3) lidocaine protected control and hypertrophied hearts against ventricular fibrillation during ischemia but was ineffective in protecting hypertrophied hearts against reperfusion-induced ventricular fibrillation.
Neurohormonal control of calcium sensitivity of myofilaments in rat single heart cells.
Authors: Puceat M , Clement O , Lechene P , Pelosin J M , Ventura-Clapier R , Vassort G
Published: June 2012

To investigate the changes in the properties of cardiac contractile proteins due to neurohormonal stimulation, different agonists were applied to single cells isolated from rat ventricle. Cells were then rapidly skinned by Triton X-100, and force was recorded after gluing the cells to a strain gauge. The skinned cells had mechanical properties very similar to those described for thin trabeculas. Tension-pCa relations were highly reproducible from one cell to another, with sarcomere length fixed at 2.1 microns. The application of alpha 1-adrenergic and muscarinic agonists, which increase the turnover of phosphatidylinositol, for 5 minutes before skinning the cells increased the sensitivity of the myofilaments to calcium, as indicated by a leftward shift of the tension-pCa relation, whereas beta-adrenergic stimulation induced a rightward shift. The increase in calcium sensitivity was also evoked by protein kinase C activators such as 1,2-dioctanoylglycerol and phorbol 12-myristate 13-acetate but not by protein kinase C itself or by purinergic agonists, although the latter also increased the turnover of phosphatidylinositol. Incubation of the skinned cells with phosphatase reversed the alterations in calcium sensitivity induced by previous agonist stimulation of the intact cells. In conclusion, this study demonstrates a potentially influential mechanism for the physiological regulation of cardiac muscle contractility.
Developmental changes in cardiac myocyte calcium regulation.
Authors: Chin T K , Friedman W F , Klitzner T S
Published: June 2012

Developmental changes in the contributions of transsarcolemmal Ca2+ influx and Ca2+ release from intracellular storage sites to myocardial contraction were evaluated in isolated ventricular myocytes from neonatal (aged 1-7 days) and adult (aged 8-10 weeks) New Zealand White rabbits. Contractions ceased in one beat when extracellular Ca2+ was decreased from 1mM to micromolar levels using a rapid perfusion technique. On reperfusion with 1 mM Ca2+, recovery of control contraction amplitude occurred after significantly fewer beats in neonatal myocytes compared with adult myocytes, and after 1 minute compared with 5 minutes of reduced Ca2+. After 15 minutes of perfusion with either 1 or 10 microM ryanodine, contraction amplitude decreased in both age groups, but the decrease was significantly greater in adults than in neonates. These experiments indicate that isolated ventricular myocytes may be used in the study of developmental changes in intracellular Ca2+ regulation. Results suggest that cardiac contraction in neonates is relatively more dependent on transsarcolemmal Ca2+ influx. Furthermore, although Ca2+ release from intracellular storage sites is present in both neonates and adults, its role in cardiac contraction is more significant in adults.
Repeated sympathetic stimuli elicit the decline and disappearance of prostaglandin modulation and an increase of vascular resistance in humans.
Authors: Neri Serneri G G , Castellani S , Scarti L , Trotta F , Chen J L , Carnovali M , Poggesi L , Masotti G
Published: June 2012

To investigate the role of prostaglandins I2 and E2 in modulating the vasoconstrictor response to sympathetic stimulation, repeated and proximate cold pressor tests were performed in 23 healthy young volunteers. Limb vascular resistance (blood flow measured by venous occlusion plethysmography), prostaglandin I2 (as 6-ketoprostaglandin F1 alpha) and prostaglandin E2 plasma levels (detected by radioimmunoassay), and plasma catecholamines (detected by high-performance liquid chromatography and electrochemical detection) were measured. A progressive increase in the duration of the vasoconstrictor response was observed with repetition of cold applications (p less than 0.001, by analysis of variance for trends). This increase was associated with a progressive decrease in cold-induced elevation of 6-ketoprostaglandin F1 alpha and prostaglandin E2 plasma levels until, after five stimulations, neither prostaglandin was detectable. The maximum detected concentration of norepinephrine did not significantly change, but its area under the curve in time showed a trend toward an increase. Epinephrine levels did not significantly change. The increase of vascular resistance was significantly correlated with the decrease of both prostaglandins (r = 0.93, p less than 0.05 for prostaglandin E2 and r = 0.89, p less than 0.05 for 6-ketoprostaglandin F1 alpha), whereas no significant correlations were found between variations of vascular resistance and catecholamines. Prostaglandin blockade induced by diclofenac sodium administration caused, from the first cold application, a pattern of the vasoconstrictor response and plasma prostaglandin and norepinephrine changes similar to that observed at the fifth cold application in untreated subjects, when prostaglandins are no longer detectable in plasma. We conclude that an increased vasoconstrictor response to sympathetic stimulation in humans may result from a diminished inhibitory influence of prostaglandins on adrenergic transmission.