bluuebunny/crossref_metadata_2025 huggingface dataset:
Arteriolar wall thickening in hypertensive rats unrelated to pressure or sympathoadrenergic influences.
Authors: Plunkett W C , Overbeck H W
Published: June 2012

We have previously reported that experimental aortic coarctation in rats is accompanied by non-pressure-related increases in the wall-to-lumen ratio (W/L) of cremaster arterioles. To investigate the role of the sympathoadrenergic system in this arteriolar wall thickening, we partially constricted or sham-constricted the abdominal aorta in adrenal-demedullated, 6-week-old rats that had had guanethidine injections to produce peripheral sympathectomy (S rats, n = 17 coarcted, 16 sham-coarcted) and in sham-demedullated, sham-sympathectomized control rats (SS rats, n = 13 coarcted, 15 sham-coarcted). In both SS and S rats with coarctation, tail and femoral arterial and conscious abdominal aortic pressures were not increased but carotid pressures rose by greater than 30% (p less than 0.01), accompanied by 46-75% increases in cardiac ventricular weight/body weight. In coarcted rats, 4-6 weeks after aortic constriction, compared with sham-coarcted rats, whether S or SS, observation of the cremaster microcirculation revealed increased wall area, wall thickness, and W/L of third- to fifth-order arterioles, both in the resting state and after maximal relaxation with topical nitroprusside. For example, in coarcted S rats wall area after nitroprusside was elevated by 24%, 39%, and 37% in third-, fourth-, and fifth-order arterioles (p less than 0.01). These findings indicate that arteriolar wall thickening in hypertension may occur independently of intra-arterial pressure or sympathoadrenergic influences. Humoral growth factors may be involved.
Spontaneous sarcoplasmic reticulum calcium release in rat and rabbit cardiac muscle: relation to transient and rested-state twitch tension.
Authors: Kort A A , Lakatta E G
Published: June 2012

Scattered light intensity fluctuations (SLIF) (which monitor spontaneous Ca2+ release from the sarcoplasmic reticulum [SR]) and resting and twitch tension were measured during intervals after stimulation in rat and rabbit papillary muscles. For 1 to 5 seconds after stimulation of rat muscle bathed in 1.5 mM [Ca2+] (Cao), twitch and resting tension are depressed and SLIF are transiently abolished. SLIF and resting tension then recover simultaneously and monotonically but lag behind the restitution of twitch tension. In the absence of further stimulation, SLIF persist and the rested state twitch amplitude remains potentiated. When Cao is increased above 2.5 mM, the restitution of all parameters following stimulation is accelerated and becomes oscillatory; the lag of SLIF and resting tension restitution behind that of the twitch increases such that twitch amplitude increases, overshoots, and decreases to a nadir as SLIF and resting tension reach their initial maximum. In a given muscle, the maximum twitch amplitude occurs at approximately the same level of SLIF; when this level is exceeded, either transiently during monotonic or oscillatory recovery after stimulation in a given Cao or in the steady rested state by an increase in Cao, twitch tension decreases. Ryanodine (1 microM), caffeine (10 mM), or replacement of Cao with strontium abolishes SLIF and causes twitch amplitude to decay with rest. In contrast to rat, twitch amplitude in rabbit muscle bathed in physiological Cao decays with rest and SLIF are nonmeasurable at any interval following stimulation. When Cao is increased to 20 mM during rest, SLIF occur and the rest decay of the twitch is abolished. We interpret the parallel behavior of SLIF and rest potentiation to indicate that in the presence of SLIF, the average SR Ca2+ load within the tissue is high. Depolarization of a tissue exhibiting SLIF causes a large twitch but also a transient depletion of the average SR Ca2+ load. That the restitution of SLIF lags behind recovery of twitch amplitude suggests that the onset of spontaneous SR Ca2+ release requires a delay following SR Ca2+ replenishment. The simultaneous occurrence of spontaneous Ca2+ release in a sufficient number of cells places an upper limit on twitch amplitude either during recovery following stimulation or at rest.
Dependence of instantaneous transfer function on regional ischemic myocardial volume.
Authors: Hashiguchi R , Koiwa Y , Ohyama T , Takagi T , Kikuchi J , Butler J P , Takishima T
Published: June 2012

To obtain the instantaneous left ventricular transfer function curve (instantaneous TFC) under conditions of regional ischemia, sinusoidal accelerations ranging from 30 to 150 Hz were applied to a small area of the epicardium of cross-circulated isovolumic canine left ventricle, and the contralateral acceleration was measured under control and during regional coronary occlusion (n = 11). The TFC is the ratio of the output to input acceleration amplitudes. The instantaneous TFC was characterized as a single-peaked configuration under control coronary perfusion. However, TFCs progressively changed from a single-peaked to a double-peaked configuration during regional ischemia. To quantify this change in instantaneous TFC, we defined an index D as the mean squared difference of TFC during ischemia from TFC during control. Index D was linearly related to the percent mass of the ischemic region at 40 minutes after onset of ischemia. We conclude that 1) transfer function curves are sensitive measures of myocardial heterogeneity and 2) the fractional ischemic weight of the ventricle is a major factor in determination of the deformation in instantaneous TFC at the later stages of regional ischemia.
Regional volume distensibility of canine thoracic aorta during moderate treadmill exercise.
Authors: Gentile B J , Chuong C J , Ordway G A
Published: June 2012

We characterized the in vivo mechanical properties of segments of upper descending thoracic aorta (UDTA) in terms of volume distensibility, which was derived from measurements of pulsatile intravascular pressure, inner wall radius, and length changes. Data for this analysis were obtained from six dogs at rest and during moderate treadmill exercise (8% grade, 4.5 miles/hr). Volume distensibility reflects the regional rheological properties of the UDTA at in vivo states. It was shown to be the sum of circumferential extensibility, longitudinal extensibility, and higher-order extensibilities. Circumferential extensibility and longitudinal extensibility are linear expressions of vessel kinematic changes which represent percent volume changes per pulse pressure and are due to circumferential and longitudinal dimensional changes alone. The higher-order extensibilities (second and third order), however, account for the coupling effect, which is the percentage volume change per millimeter mercury pulse pressure due to the interactions among radial, circumferential, and axial dimensional changes. The volume distensibility of the UDTA during exercise was significantly less than that at rest (0.67 +/- 0.12 vs. 0.91 +/- 0.11% V/mm Hg pressure). This was the result of a significant decrease in circumferential extensibility and higher-order extensibility in response to exercise with no change in longitudinal extensibility. The higher order extensibilities were also important since the volume distensibility of the UDTA was underestimated by 10% for both rest and exercise when they were ignored. We also evaluated radial extensibility by using pressure and wall thickness data and showed that this variable did not change in response to exercise.
Gonadectomy and hormonal replacement changes systolic blood pressure and ventricular myosin isoenzyme pattern of spontaneously hypertensive rats.
Authors: Lengsfeld M , Morano I , Ganten U , Ganten D , Rüegg J C
Published: June 2012

We investigated the influence of testosterone on systolic blood pressure, heart weight, body weight, and ventricular myosin isoenzyme pattern of male spontaneously hypertensive stroke-prone rats (SHRSP). In two different study series (study 1, postpubertal; study 2, prepubertal), SHRSP were gonadectomized (HG), gonadectomized and replaced with dihydrotestosterone (HG-T), and sham-operated (H). Blood pressure was significantly higher in HG-T animals in both study series. Only prepubertal gonadectomy (study 2, HG group) led to a significantly decreased blood pressure. Heart weight and body weight were significantly diminished in the HG group when compared to the H group in study 2. Dihydrotestosterone (HG-T group) reversed this effect. In both study series gonadectomy shifted the myosin isoenzyme pattern to the V3 form while testosterone replacement led to a myosin isoenzyme pattern in favor of the V1 form. We conclude that the ventricular myosin isoenzyme pattern is under the dominant control of androgens and dissociates the expression of myosin isoenzyme from both blood pressure and cardiac hypertrophy in spontaneously hypertensive rats.
Inotropic responses to isoproterenol and phosphodiesterase inhibitors in intact guinea pig hearts: comparison of cyclic AMP levels and phosphorylation of sarcoplasmic reticulum and myofibrillar proteins.
Authors: Rapundalo S T , Solaro R J , Kranias E G
Published: June 2012

The influence of selective (milrinone: 10, 50, 100 microM) and nonselective phosphodiesterase (isobutylmethylxanthine: 0.1, 10, 100 microM) inhibitors and beta-adrenergic stimulation (isoproterenol: 0.01, 0.1 microM) on phospholamban and myofibrillar protein phosphorylation was studied in guinea pig hearts perfused with [32P]orthophosphate. Changes in protein phosphorylation were compared to alterations in tissue cyclic AMP (cAMP) levels and positive inotropic effects induced by these agents. Isoproterenol (0.01 microM), milrinone (50 microM), and isobutylmethylxanthine (100 microM) all produced similar, twofold increases in dP/dt and -dP/dt but only stimulation with isobutylmethylxanthine and isoproterenol was associated with significant increases in phospholamban phosphorylation. At these equipotent doses, the effects of isobutylmethylxanthine were associated with higher increases (3.1-fold) in cAMP than those observed with isoproterenol (twofold). Milrinone (50 microM) produced a 2.5-fold increase in cAMP levels but failed to change phospholamban phosphorylation. Higher doses of milrinone (100 microM) resulted in relatively high (4.1-fold) cAMP levels, and this was associated with increased (1.5-fold) phosphorylation of phospholamban. Phosphorylation of troponin I was significantly increased at 0.01 microM and 0.1 microM isoproterenol, while phosphorylation of C protein was observed only at 0.1 microM isoproterenol. Isobutylmethylxanthine and milrinone did not significantly increase phosphorylation of either troponin I or C protein at any of the doses studied. These findings indicate that cardiotonic agents acting via the cAMP pathway may produce similar inotropic responses at different levels of cAMP and phosphorylation of sarcoplasmic reticulum and myofibrillar proteins.
Regional differences in the in vivo synthesis and degradation of myosin subunits in rabbit ventricular myocardium.
Authors: Samarel A M
Published: June 2012

To test for regional differences in the rates of synthesis and degradation of contractile proteins during normal physiological growth of the heart in vivo, fractional rates of protein accumulation and synthesis were assessed for total protein, myosin heavy chain, myosin light chain, phosphorylatable myosin light chain, and actin in the right and left ventricular free walls of growing, New Zealand White rabbits. Fractional rates of protein accumulation were determined from regional protein content growth curves of total and individual myofibrillar proteins measured in 82 animals ranging from 1 day to 9 weeks of age. In vivo right and left ventricular fractional rates of protein synthesis were determined by the [3H]leucine constant infusion method in 9-week-old rabbits. At this age, right and left ventricular fractional accumulation rates for total protein, myosin subunits, and actin were found to be identical, thus allowing for the comparison of the effect of regional hemodynamic load on protein degradation independent of its effect on growth. Total protein and individual myofibrillar protein fractional degradative rates were then derived as the difference between fractional rates of synthesis and accumulation. The results indicate increased fractional synthesis and degradation of myosin heavy chain and light chains, but not actin, in the left compared to the right ventricular free wall. Accelerated left ventricular replacement of myosin subunits may be related to regional differences in hemodynamic load. These results help explain the apparent increase in the in vivo rate of myocardial protein degradation observed in several experimental models of ventricular hypertrophy.
Electrophysiological properties of cultured dog myocytes obtained by endomyocardial biopsy.
Authors: Sakai S , Tokimasa T , Nohara M , Koga Y , Akasu T , Toshima H
Published: June 2012

Right ventricular cardiac tissue (10-20 mg wet weight) was obtained from anesthetized adult dogs by endomyocardial biopsy. The biopsy could be repeated in one dog every 2 weeks for up to 3 months. Fifty to 200 cardiomyocytes, dispersed with collagenase and trypsin, were collected by centrifugation of the cells with 50% polysucrose-sodium diatrizoate solution (Ficoll-Paque). Single cardiomyocytes were suspended in a minimum essential medium containing 20% fetal bovine serum and 8-bromoadenosine 3': 5'-cyclic monophosphate (0.1 mM) for up to 3 weeks. Approximately 70-80% of the cultured cardiomyocytes were rod shaped after 24 hours (10-20% after 7 days). Cytoplasmic organelles of the cultured cells, examined with a transmission electron microscope, were within the normal range of canine heart morphology in vivo. Resting membrane potential of the cells was about -80 mV when superfused with a Krebs' solution containing 4.7 mM potassium ions. The action potential lasted for 300 msec and had a peak amplitude of about 120 mV. Voltage-clamp experiments demonstrated the presence of an inward calcium current (congruent to 0.9 nA at +9 mV), which was facilitated by isoproterenol (0.1-1 microMs). The background potassium current showed typical inward rectification at potentials more negative than -80 mV. The results indicate that morphological, electrophysiological, and pharmacological properties of the cultured cardiomyocytes were intact. We propose that the culture techniques we have developed can be useful for repeated investigation on functional aspects of cardiac muscles in myocardial disease.
Role of renal nerves in the potentiation of atriopeptin-induced natriuresis by vasopressin.
Authors: Hartupee D A , Trapani A J , Koepke J P , Blaine E H
Published: June 2012

Previous studies have shown that vasopressin potentiates the natriuresis produced by atriopeptin. In five anesthetized dogs of this study, we found that the potentiation was proportional to the dose of vasopressin infused. Sodium excretion was 46 +/- 16 mueq/min with atriopeptin (103-126) (AP24) alone (0.36 nmol/kg.min), was increased to 127 +/- 29 by concomitant intravenous infusion of 0.4 mU/kg.min vasopressin, was further increased to 301 +/- 75 by 1.2 mU/kg.min vasopressin and leveled off at 328 +/- 37 with 3.6 mU/kg.min vasopressin. To investigate whether the potentiation by vasopressin was due to an intrarenal action, we infused three doses of vasopressin (0.04, 0.12, and 0.36 mU/kg.min) into the renal artery during intravenous AP24 infusion in a second group of five dogs. The natriuresis, 128 +/- 18 mueq/min, was unaffected by any intrarenal dose of vasopressin. In a third group, we determined whether the potentiation produced by vasopressin was mediated by a mechanism involving the renal nerves by denervating the left kidney before AP24 infusion. In the denervated kidneys, sodium excretion was increased from a control value of 33 +/- 5 mueq/min to 303 +/- 38 with AP24 alone and was unresponsive to subsequent intravenous vasopressin administration. The exaggerated natriuresis with AP24 alone was of the same magnitude as that produced by AP24 plus the highest doses of intravenous vasopressin in the innervated kidneys of the first group. From these results we conclude that the potentiation of AP-induced natriuresis by vasopressin is mediated by a mechanism involving the renal nerves and probably results from the known effect of vasopressin to inhibit renal nerve activity.
Collagen-stimulated human platelet aggregation is mediated by endogenous calcium-activated neutral protease.
Authors: Toyo-oka T , Shin W S , Okai Y , Dan Y , Morita M , Iizuka M , Sugimoto T
Published: June 2012

To clarify the physiological role of calcium-activated neutral protease (CANP) in human platelets, we loaded the platelets with a Ca2+ -sensitive fluorescent dye, fura-2, and measured the degree of aggregation, cytosolic calcium ion concentration [( Ca2+]i), and proteolysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). At physiological concentration of Ca2+ (1 mM) in the incubation medium, [Ca2+]i was below 0.5 microM and platelet aggregation was not shown. Ionomycin (0.15 microM) or collagen (50 micrograms/ml), but not ADP (10 microM), sharply enhanced the [Ca2+]i to near 1 microM and caused the aggregation. A calcium entry blocker, verapamil, completely abolished both the [Ca2+]i rise and the aggregation. NCO-700, a membrane permeable inhibitor against cysteine proteases (including CANP), dose-dependently blocked the aggregation but did not change the [Ca2+]i transient. SDS-PAGE revealed that filamin, talin, and 70 kDa protein were specifically degraded when platelets were aggregated by ionomycin or collagen and that the proteolysis was not observed when the aggregation was blocked by verapamil or NCO-700. These data provided evidence that Ca2+ entry exceeding 0.5 microM is essential, but not sufficient per se, and that activation of cysteine protease, most likely CANP, is involved in the platelet aggregation by collagen or calcium ionophore.
Effects of melittin on endothelium-dependent relaxation and cyclic GMP levels in rat aorta.
Authors: Rapoport R M , Ashraf M , Murad F
Published: June 2012

The present study investigates the mechanism of endothelium-dependent relaxation of vascular smooth muscle. Melittin, a polypeptide found in honeybee venom and a known activator of phospholipase A2, induced transient, endothelium-dependent relaxations of rat thoracic aortae contracted with norepinephrine. Higher concentrations of melittin induced relaxations followed by contractions. Prior incubation of melittin with trypsin abolished the changes in relaxation and contraction due to melittin. Melittin (10 micrograms/ml)-induced relaxations were associated with transiently elevated levels of cyclic GMP with a peak increase of 30-fold, which occurred 30 seconds after melittin exposure. Melittin (10 micrograms/ml) elevated cyclic AMP levels less than twofold and this effect was variable. A lower concentration of melittin (1 microgram/ml) elevated cyclic GMP levels approximately twofold, while exposure to 1 microgram/ml melittin in the presence of the cyclic GMP phosphodiesterase inhibitor, M&B 22948 (1 mM), increased cyclic GMP levels fivefold. Removal of the endothelium prevented the increased levels of cyclic GMP and cyclic AMP due to melittin. Exposure to the guanylate cyclase inhibitor, methylene blue, prevented the increased levels of cyclic GMP. Methylene blue, nordihydroguaiaretic acid, and the phospholipase A2 inhibitor, parabromophenacyl bromide, inhibited melittin-induced relaxations, while the cyclo-oxygenase inhibitor, indomethacin, was without effect. Arachidonic acid increased cyclic AMP levels but had no effect on cyclic GMP levels in the presence or absence of indomethacin. Relaxations to melittin, and to the endothelium-dependent vasodilators acetylcholine, trypsin, histamine, and the Ca2+ ionophore A23187, and/or the associated increased cyclic GMP levels, were reduced following exposure to melittin. Prior exposure to polyarginine (10 micrograms/ml), which induced endothelium-dependent relaxations that were prevented by methylene blue, also inhibited relaxations to the endothelium-dependent vasodilators. In contrast, relaxations to sodium nitroprusside were potentiated in tissues previously exposed to melittin. Removal of the endothelium by rubbing the intimal surface also potentiated relaxations to sodium nitroprusside. Scanning electron micrographs of the intimal surface demonstrated that melittin and polyarginine greatly damaged the endothelial cells. The present results suggest that polycation containing peptides induce endothelium-dependent relaxation through elevation of cyclic GMP levels within the smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)
Cardiac gap junctions and gap junction-associated vesicles: ultrastructural comparison of in situ negative staining with conventional positive staining.
Authors: Chen L , Goings G E , Upshaw-Earley J , Page E
Published: June 2012

By comparing in situ negative staining of mammalian heart muscle using La(NO3)3 with conventional positive staining by uranium and lead salts, we showed that 1) the membrane area of rat cardiac gap junctions (GJs) at the intercalated disks is threefold to fourfold greater than previously thought; 2) connexon arrays of cardiac GJ are subdivided into microdomains by connexon-free aisles; 3) profiles of GJ-associated vesicles (GJAVs) of plasmalemmal origin (which are present extracellularly and sharply localized at three extracellular sites) are paired to form GJs with each other and with myocyte plasmalemma; 4) some GJAVs contain arrays of assembled connexons; and 5) myocytes contain intracytoplasmic complexes lying within cylindrical or cigar-shaped membranes and consisting of GJs and multiple vesicles apparently dissociating from these GJs.
High-salt diet elevates baroreceptor pressure thresholds in normal and Dahl rats.
Authors: Andresen M C
Published: June 2012

Dahl Salt Sensitive (DS) rats rapidly develop high blood pressure when exposed to a high-salt diet. Recent studies suggest that DS rats have poorly functioning baroreceptor afferents and baroreflexes even when salt intake is restricted. This study examines baroreceptor pressure- and mechano-transduction in DS, Dahl Resistant (DR), and Sprague-Dawley (SD) rats during low- and high-salt conditions. Single unit, regularly discharging baroreceptors were studied using an in vitro aortic arch-aortic nerve preparation. Pressure thresholds and suprathreshold pressure sensitivities were determined from responses to slow ramps of pressure. Pressure-diameter relations measured in each rat were used to transform pressure threshold and pressure sensitivity values to their mechanical equivalents in terms of aortic wall strain. A total of 407 unit baroreceptors were studied from 49 rats. Tail systolic blood pressures were significantly higher only in DS during high salt. Pressure threshold was similar for all groups on low salt. Exposure to a high-salt diet increased the mean pressure threshold for all three groups. Pressure threshold for high-salt diet was highest in DS and lowest in DR. Pressure sensitivities were lowest in DS and highest in DR on low salt. High salt had no significant effect on pressure sensitivity. The differences in threshold apparent when expressed in terms of pressure were eliminated by conversion to their mechanical equivalents (strain threshold and strain sensitivity). The results suggest that baroreceptors in the two Dahl rat strains represent two extremes from normal baroreceptor function. DS tend to be less pressure responsive than normal (SD), and DR tend to be somewhat more responsive to pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypoxia-induced acute changes in capillary and fiber density and capillary red cell distribution in the rat heart.
Authors: Vetterlein F , Hemeling H , Sammler J , Pethö A , Schmidt G
Published: June 2012

The influence of acute hypoxia (respiration gas 12%, 10%, and 8% O2 and asphyxia, respectively) on 1) the density of perfused capillaries and muscle fibers, and 2) the capillary red cell distribution was investigated in the left heart of anesthetized rats. To observe capillaries and fibers, fluorescein isothiocyanate-labeled (FITC)-gamma-globulin and lissamine-rhodamine-B200-labeled (RB200) myoglobin were injected intravenously as labels of the perfused intravasal and the extracellular space, respectively. The hypoxic conditions were induced subsequently and maintained for 3 minutes. After this period the heart was rapidly frozen for histological demonstration of the dyes. Ventilation with 12% or 10% O2 did not induce any changes in the density of perfused capillaries; however, 8% O2 in respiration gas did lead to a significant increase (capillaries/mm2: subepicardium, 4,180, controls, 3,620; subendocardium, 3,930, controls, 3,240). A similar increase was found in the asphyxia group (capillaries/mm2: subepicardium, 4,170; subendocardium, 3,700). The increases in the density of perfused capillaries were paralleled by rises in fiber density. This leads to the conclusion that the changes in capillary counts were caused by fiber elongation with a resultant decrease in intercapillary distances. This assumption was supported by observations that there were no signs of changes in ventricular segment length during respiration of 12% or 10% O2 but that an increase did occur with 8% oxygen and with asphyxia. Densities of perfused capillaries exactly coincided with anatomical densities (demonstrated by additional labeling of capillary basement membranes with isolectin B4) in normoxic and asphyctic hearts. The distribution of red cells in the capillaries, determined in histological sections, did not differ appreciably under hypoxia due to reduced O2 in respiration air (12%) or asphyxia. The results obtained indicate that 1) extreme hypoxic states cause the capillaries to move closer to each other due to elongation of myocardial fibers and 2) red cell distribution is not altered during these conditions.
Calcium current is increased in isolated adult myocytes from hypertrophied rat myocardium.
Authors: Keung E C
Published: June 2012

To study the effects of myocardial hypertrophy resulting from chronic pressure overload on excitation-contraction coupling, the cardiac transmembrane L-type calcium current (ICa) was investigated in the Goldblatt renovascular hypertensive (HBP) rat. ICa was measured in single myocytes enzymatically isolated from control (CTRL) and HBP rat hearts using the whole-cell, patch-clamp method. The peak ICa and ICa density (obtained by normalizing ICa to the average cell capacitative surface area) were larger in HBP cells (n = 15) than in CTRL cells (n = 10) at membrane potentials of -20 to 50 mV (p less than 0.01). The maximal peak ICa increased from 0.9 +/- 0.5 nA (mean +/- SD) in CTRL cells to 2.8 +/- 1.0 nA in HBP cells (p less than 0.001). The corresponding ICa density increased from 5.3 +/- 2.7 to 16.2 +/- 6.0 microA/cm2 (p less than 0.001). There was no shift in the current-voltage relation between CTRL and HBP cells. The time course of decay of HBP ICa in response to clamp steps to the plateau range of the action potential (membrane potential, Vm = -10 to 30 mV) was delayed when compared with that of CTRL ICa. The inactivation time constants (biexponential) for the maximal ICa were 6.9 +/- 1.9 and 36.0 +/- 9.3 msec for CTRL cells and 6.7 +/- 1.4 and 49.5 +/- 12.9 msec for HBP cells (p less than 0.05 for the slower component of the maximal ICa). There was no difference in the steady-state inactivation of ICa (f infinity) for the CTRL and HBP cells. From the maximal peak ICa, cytoplasmic free Ca2+ was estimated to reach a pCa of 6.95 +/- 0.07 for CTRL cells and 6.64 +/- 0.13 for HBP cells. It is concluded that ICa is increased with myocardial hypertrophy. The lengthening of the action potential in hypertrophied rat myocardium is due to an increase in peak current density and to the slower inactivation of the maximal ICa. The increased transmembrane flux of Ca2+ via ICa in HBP cells is inadequate to achieve a myoplasmic free Ca2+ level sufficient for direct partial activation of the contractile myofilaments. However, in the scheme of the calcium-triggered calcium release hypothesis such an increase could provide an increased amount of activator calcium and/or serve to amplify the release of Ca2+ from sarcoplasmic reticulum, thereby contributing to preserved peak developed tension in hypertrophied rat myocardium.
Neuropeptide Y as a putative modulator of the vagal effects on heart rate.
Authors: Warner M R , Levy M N
Published: June 2012

Neuropeptide Y is stored in sympathetic nerve terminals throughout the heart and has direct and indirect effects on cardiac function. Although neuropeptide Y has been shown to be released upon intense (16-30 Hz) cardiac sympathetic stimulation, we sought to determine whether effective quantities of neuropeptide Y were released from cardiac sympathetic neurons under more natural conditions. We recorded arterial pressure and cardiac cycle length in 29 anesthetized dogs. We assessed neuropeptide Y release by measuring the attenuation of vagally induced increases in cardiac cycle length (10 seconds every 2 minutes) after trains of sympathetic stimulation. We examined the effect of constant-frequency sympathetic stimulation (frequencies of 2, 5, 10, and 15 Hz, applied for train durations of 1, 3, and 5 minutes) on vagally induced chronotropic responses. We also determined the effect of varying the pattern of sympathetic stimulation. Both the magnitude and duration of the inhibition of the vagal effects on cardiac cycle length were augmented significantly by increases in the frequency or duration of sympathetic stimulation. In contrast, the inhibition of the vagally induced chronotropic responses was not significantly affected by changes in the pattern of sympathetic stimulation. We also characterized the role of adrenergic receptors. Phentolamine significantly increased the sympathetically mediated inhibition of the vagal effects on cardiac cycle length, but propranolol had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Role of LDL receptors in the in vitro uptake and degradation of LDL in the media of rabbit thoracic aorta.
Authors: Curmi P A , Renaud G , Juan L , Chiron B , Tedgui A
Published: June 2012

The possible role of plasma low-density protein (LDL) receptors in the uptake and degradation of LDL in the whole arterial wall was investigated by comparison of the in vitro uptake of 125I-native LDL (nLDL) and 131I-methylated LDL (mLDL) by the media of deendothelialized rabbit thoracic aorta excised at in vivo length and pressurized to 70 mm Hg, taking the advantage that mLDL is not recognized by the LDL receptor. The distribution of the relative concentrations of nLDL (Cn) and mLDL (Cm) across the wall was obtained using a serial frozen sectioning technique. The aorta was incubated under three different conditions for varying periods of incubation in order to analyze separately the processes of binding, binding-internalization, and degradation. At 39 degrees C, in which binding-internalization and degradation occurred, Cn was significantly higher than Cm at each position across the media. The mean medial Cn/Cm ratio was 1.36 +/- 0.15 (n = 5) after 1 hour of incubation, and decreased to 1.23 +/- 0.22 (n = 7) after 2 hours of incubation and to 1.13 +/- 0.11 (n = 5) after 4 hours of incubation. At 4 degrees C, in which internalization and degradation were blocked, the Cn/Cm ratio reflected the surface nLDL binding alone; the Cn/Cm ratio was 1.47 +/- 0.20 (n = 5) after 4 hours of incubation, higher than the value obtained at 39 degrees C. To investigate whether degradation of nLDL occurred after receptor binding, the interstitial LDL was washed out by an LDL-free solution after 2-hour incubation at 39 degrees C. After 30 minutes of washout, the Cn/Cm ratio decreased to 1.06 +/- 0.20 (n = 5) in the inner media and was unchanged in the outer media. After 1 hour of washout, the ratio declined to 0.57 +/- 0.18 (n = 7) in the inner part of the media and increased progressively to 1 at the media-adventitia boundary. The Cn/Cm ratio, at 0.67 +/- 0.12 (n = 5), was practically constant throughout the media after 2 hours of washout. The nLDL degradation rate across the media was obtained from the comparison of nLDL and mLDL before and after the washout. A steep decreasing gradient in nLDL degradation rate was observed from the luminal to the external surface. The mean medial nLDL degradation rate value was 9.6 +/- 4.5 microliters/cm3 wet tissue/hr. We concluded that functional LDL receptors participate in the uptake and degradation of LDL in the whole aorta.
Beneficial effect of chronic bradycardial pacing on capillary growth and heart performance in volume overload heart hypertrophy.
Authors: Wright A J , Hudlicka O , Brown M D
Published: June 2012

We have previously reported that chronic bradycardial pacing increases both capillary density/mm2 (CD) and maximal work output in normal rabbit hearts. This technique has now been applied to rabbits with volume-overload hypertrophy due to lesion of the aortic valve. Four groups of animals were studied: controls (C), paced (P), valve-lesioned (VL), and paced valve-lesioned (PVL). The aortic valve was lesioned 8 weeks before the acute experiments; pacing was started 4 weeks before the acute experiments, and thus, the PVL group had developed hypertrophy before pacing was started. The degree of hypertrophy was similar in VL hearts whether paced or not: heart wt/body wt ratio increased by 33.5 +/- 8.9% (mean +/- SEM) in VL and 25.2 +/- 8.2% in PVL versus control animals of similar body weight (p less than 0.001). The hearts of the PVL animals showed a higher CD (2,277 +/- 107) than VL hearts (1,383 +/- 43), CD in C hearts of similar weights being 1,595 +/- 103, and in P hearts 2,350 +/- 194. Thus, CD was lower by 14% in VL and higher by 43% in PVL than in C hearts. Valve-lesioning had a significant effect in reducing maximal cardiac minute work (p less than 0.001), whereas pacing significantly improved maximal cardiac minute work (p less than 0.001) to 2.467 +/- 0.206 J/g x 10(-4) in the P group versus 1.609 +/- 0.105 in the C group.(ABSTRACT TRUNCATED AT 250 WORDS)
Origin, domain, and dynamics of rate-induced variations of functional refractory period in rabbit atrioventricular node.
Authors: Billette J , Métayer R
Published: June 2012

Different aspects of the intrinsic regulation of rate-induced variations of functional refractory period of atrioventricular node (FRPN) were studied in isolated rabbit heart preparations. First, the hypothesis that these variations originate from the net interaction between facilitation and fatigue was tested. For a constant fast rate, selective effects of faciliation and of steady-stage fatigue were independently shown to shorten and prolong, respectively, FRPN while their combined effects were shown to result in intermediate changes corresponding to the sum of their individual effects. Second, selective and combined effects on FRPN were shown to start for rates corresponding to the upper half of the 1:1 nodal conduction range and to reach their maximums at the fastest rate tested. Third, the time-courses of fatigue-induced prolongations in nodal conduction time and FRPN were shown to be closely linked. Facilitation effects on conduction time and FRPN were confirmed, as previously shown for in situ dog hearts, to be linked, but time-independent. Fourth, FRPN was shown not to correspond to particular limits in its subintervals, but to be, nevertheless, related to nodal refractoriness. Fifth, it was demonstrated that, in conditions of combined facilitation and transient fatigue such as those prevailing in current endocavitary investigations of nodal function, FRPN could be shortened, left unchanged or prolonged by a constant fast rate depending on its duration. In conclusion, the present study demonstrates the dual origin of rate-induced FRPN variations, their rate and time dependence, their relation to changes in nodal refractoriness, and their involvements in various nodal responses.
Pharmacological evidence for A1 and A2 adenosine receptors in the skin microcirculation.
Authors: Stojanov I , Proctor K G
Published: June 2012

To characterize adenosine-mediated vascular responses, synthetic A1 and A2 receptor agonists (N-ethyl carboxamido adenosine [NECA], 2-chloro adenosine [2CA], or cyclohexyl adenosine [CHA]), the parent compound (adenosine [ADO]), an uptake inhibitor (dipyridamole [DIPYRID]) or a nonselective, competitive antagonist (8-phenyl theophylline [8pTHEO]) were topically applied to 20-60 microns arterioles in the subcutaneous microcirculation of the hamster. Blood flow was calculated from arteriolar diameter and red blood cell velocity using intravital microscopy. At greater than 10(-8) M, the potency order for vasodilation (maximum, 170-190% of control) was NECA greater than 2CA greater than ADO; these responses were attenuated by 10(-5) M 8pTHEO. From 10(-8) to 10(-6) M, 2CA evoked vasodilation whereas ADO, which has an identical affinity at A1 and A2 receptors, evoked lesser responses. ADO-induced vasodilation was potentiated by 10(-5) M DIPYRID; this response was similar to that evoked by 2CA alone or 2CA + DIPYRID. In contrast to ADO, 2CA is a poor substrate for cellular uptake, which suggests that uptake reduces the A2 effect of exogenous ADO. From 10(-10) to 10(-8) M, CHA and ADO were equipotent antagonized by 8pTHEO. Norepinephrine was a more potent vasoconstrictor and 8pTHEO did not alter these responses. Since ADO is a metabolic substrate and a nonselective receptor agonist, while CHA is A1-selective and a poor substrate for cellular uptake, neither A2 activation nor cellular uptake altered expression of the A1 effect of exogenous ADO. Furthermore, DIPYRID had no effect on the A1 response.(ABSTRACT TRUNCATED AT 250 WORDS)
fMet-Leu-Phe receptor expression by an interstitial cell in rabbit right atrium following left ventricular myocardial infarction.
Authors: Dunkel C G , Saffitz J E , Evers A S
Published: June 2012

Previous studies have shown that rabbit hearts subjected to in vivo left ventricular myocardial infarction and subsequent ex vivo perfusion respond to N-formylmethionyl-leucyl-phenylalanine (fMLP) with enhanced eicosanoid synthesis. This synthetic response occurs primarily in the right cardiac atrium, a site distant from the injury, and is not the result of increased enzymatic capacity for arachidonate metabolism. To further investigate the mechanism of this enhanced synthetic response, [3H]fMLP binding was characterized and binding sites were localized autoradiographically in intact tissue sections prepared from control hearts and hearts subjected to left ventricular myocardial infarction (1, 2, and 4 days postinfarction). Analysis of binding isotherms revealed a saturable high affinity (KD approximately 1 nM) fMLP binding site in the right cardiac atrium. After myocardial infarction specific binding in right atria (2 day) increased 12-fold (Bmax = 14.8 +/- 2.4 fmol/cm2) compared with normal controls (Bmax = 1.2 +/- 0.1 fmol/cm2). Specific binding of fMLP also increased in the infarcted zone of left ventricle, but Bmax was only 30-50% that of right atria. Light microscopic autoradiography studies revealed that atrial fMLP binding sites were highly concentrated in small morphologically undifferentiated cells located in interstitial and perivascular spaces. These results demonstrate the existence of a formylated peptide receptor on a nonleukocytic cell and illustrate its regulation following left ventricular injury.
Coronary pressure-flow relations in hypertensive left ventricular hypertrophy. Comparison of intact autoregulation with physiological and pharmacological vasodilation in the dog.
Authors: Jeremy R W , Fletcher P J , Thompson J
Published: June 2012

Coronary pressure-flow relations during autoregulated and vasodilated flow states were compared between eight dogs with renovascular hypertension and left ventricular hypertrophy and 12 normal dogs. Each relation was constructed from serial steady-state measurements of end-diastolic coronary pressure and flow during perfusion of the circumflex artery by an extracorporeal circuit at controlled diastolic pressures of 20-200 mm Hg. Autoregulated pressure-flow relations were compared at three levels of myocardial oxygen demand: resting, high (dobutamine 10 micrograms/kg/min), and low (propranolol 2.5 micrograms/kg/min). Autoregulatory capacity was assessed by calculation of closed-loop flow gain. At each level of myocardial oxygen demand, the lower limit of autoregulation occurred at higher perfusion pressures in the hypertrophy group (rest 65 +/- 3, high 92 +/- 4, low 66 +/- 4 mm Hg) than in the normal group (rest 53 +/- 2, p less than 0.05; high 75 +/- 5, p less than 0.05; low 51 +/- 3 mm Hg) (p less than 0.05). Maximum autoregulatory gain was similar in the normal and hypertrophy groups during resting and low myocardial oxygen demand but was reduced in the hypertrophy group during dobutamine studies. When coronary flow decreased below the lower limit of autoregulation, systolic shortening was reduced in both normal and hypertrophy groups. However, as the autoregulatory limits were at higher pressures in the hypertrophy group, shortening in this group deteriorated at perfusion pressures that did not affect the normal heart. Coronary pressure-flow relations during physiological (peak hyperemia after 15-second flow occlusion) and pharmacologica (intracoronary adenosine 400 micrograms/min) vasodilation was curvilinear and fitted by quadratic regression. During hyperemic vasodilation, maximal conductance per unit mass of myocardium was less in the hypertrophy group over a wide range of perfusion pressures. At a diastolic perfusion pressure of 80 mm Hg, maximum conductance was 4.6 +/- 0.5 ml/min/100 g/mm Hg in the normal group and 3.4 +/- 0.4 ml/min/100 g/mm Hg (p less than 0.05) in the hypertrophy group. Intracoronary adenosine elicited further vasodilation in both groups, but maximum conductance remained less in the hypertrophy group (8.5 +/- 1.7 ml/min/100 g/mm Hg at a perfusion pressure of 80 mm Hg) than in the normal group (13.5 +/- 2.0 ml/min/100 g/mm Hg) (p less than 0.05). Maximal coronary flow reserve is reduced in left ventricular hypertrophy, with a consequent shift of the lower limit of autoregulation to higher perfusion pressures. Thus, as coronary perfusion pressure is decreased, coronary flow and myocardial shortening become impaired at higher
Nonhomogeneous left ventricular regional shortening during acute right ventricular pressure overload.
Authors: Goto Y , Slinker B K , LeWinter M M
Published: June 2012

Acute right ventricular pressure overload shifts the interventricular septum leftward and decreases systolic shortening of the left ventricular (LV) septal-lateral diameter. These changes should alter regional shortening in the LV minor axis. To test this hypothesis, LV minor axis circumferential segment lengths of the septum and anterior, lateral, and posterior walls were measured during pulmonary artery or venae caval constriction in seven open-chest dogs with intact pericardia. Starting at an end-diastolic pressure of 10 mm Hg, venae caval constriction decreased LV end-systolic pressure by 19 +/- 6% and stroke volume by 40 +/- 15% and produced uniform decreases in systolic shortening and end-diastolic length around the minor axis. However, during pulmonary artery constriction resulting in similar decreases in end-systolic pressure (22 +/- 7%) and stroke volume (39 +/- 11%), decreases in systolic shortening were significantly larger in the anterior (-34 +/- 10%) and posterior (-33 +/- 21%) walls than in the septum (-10 +/- 9%) or lateral wall (-8 +/- 13%). The mechanisms of these large anterior and posterior shortening decreases differed: anterior end-diastolic length decreased more than posterior and lateral end-diastolic lengths, while posterior end-systolic length decreased less than anterior and lateral end-systolic lengths. Similar changes were seen at starting end-diastolic pressures of 5 and 15 mm Hg. Propranolol did not alter this nonuniform response, while pericardiectomy attenuated the regional variations. Thus, changes in LV geometry during acute right ventricular pressure overload are associated with nonuniform regional changes in systolic shortening in the LV minor axis that are enhanced by the pericardium.
Ventricles as a major site of atrial natriuretic factor synthesis and release in cardiomyopathic hamsters with heart failure.
Authors: Thibault G , Nemer M , Drouin J , Lavigne J P , Ding J , Charbonneau C , Garcia R , Genest J , Jasmin G , Sole M
Published: June 2012

The aim of the present study was to correlate in cardiomyopathic hamsters with congestive heart failure the levels of atrial and ventricular atrial natriuretic factor (ANF) messenger RNA (mRNA) with immunoreactive ANF (IR-ANF) plasma levels and the relative amount of IR-ANF released by the whole heart versus isolated ventricles in the Langendorff preparation. High-performance liquid chromatography analysis of the forms of ANF present in plasma and in the Langendorff effluent of whole heart versus isolated ventricles was also performed. As previously found for cardiac IR-ANF, the levels of ANF mRNA decreased gradually in atria and increased in an analogous fashion in ventricles with the severity of congestive heart failure. Plasma IR-ANF levels (C-terminal) were more elevated in moderate than in severe congestive heart failure, as were the IR-ANF levels in the Langendorff effluent of the whole heart. On the contrary, the effluent of isolated ventricles from animals in severe heart failure yielded more IR-ANF than that from hamsters in moderate heart failure. Thus, while the isolated ventricles from controls contributed 35.8% of IR-ANF released by the whole heart, ventricles from hamsters in moderate heart failure contributed 17.5%, and those from hamsters in severe heart failure contributed 73.9%. These results indicate that atrial cardiocytes contribute more IR-ANF than their ventricular counterpart in moderate heart failure and that ventricles are a major source of plasma IR-ANF in severe heart failure. Analysis of IR-ANF from plasma and the Langendorff effluent from whole hearts and isolated ventricles revealed that the ventricles are the major source of the propeptide (and of its cleaved products) found in the circulation of cardiomyopathic hamsters. These results suggest that ANF synthesis and secretion do not increase conjointly in atria but do increase in ventricles during congestive heart failure.
Continuous infusion of tracer norepinephrine may miscalculate unidirectional nerve uptake of norepinephrine in humans.
Authors: Henriksen J H , Christensen N J , Ring-Larsen H
Published: June 2012

In order to evaluate uptake kinetics of norepinephrine (NE) in different tissues, a catheterization study was performed in control subjects (n = 6) and patients with enhanced sympathetic nervous activity (cirrhosis, n = 12) during constant intravenous infusion of L[3H]norepinephrine ([3H]NE) for 75 minutes. In spite of a higher NE spillover from kidneys in patients compared with controls (82 vs. 49 ng/min, p less than 0.01), renal extraction ratios of [3H]NE were similar in the two groups (0.33 vs. 0.32, NS), and no significant change was observed during the time of infusion. In contrast, liver-intestine extraction ratios of [3H]NE decreased significantly and equally with infusion time in patients (from 0.57 to 0.44, p less than 0.01) and controls (from 0.59 to 0.46, p less than 0.01). This was observed despite the fact that spillover of NE from this vascular bed was observed only in patients with cirrhosis and not in controls (41 vs. -5 ng/min, p less than 0.02). In the lower limb, net release of NE was similar in patients and controls, and extraction ratios of [3H]NE decreased almost equally with infusion time (from 0.35 to 0.30, p less than 0.01 and from 0.40 to 0.24, p less than 0.1, respectively). Whole-body clearance of [3H]NE decreased over time in patients (-6%, p less than 0.01) and controls (-20%, p less than 0.01), but significant difference was not observed between the groups. We conclude that failure to attain a steady state with respect to [3H]NE removal was demonstrated in areas of large tissue volume relative to blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)