bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial remodeling after discrete radiofrequency injury: effects of tissue inhibitor of matrix metalloproteinase-1 gene deletion
Authors: Mukherjee Rupak , Parkhurst Andrea M. , Mingoia Joseph T. , Sweterlitsch Sarah E. , Leiser Jennifer S. , Escobar G. Patricia , Spinale Francis G. , Saul J. Philip
Published: March 2004

Discrete myocardial lesions created through the delivery of radiofrequency (RF) energy can expand; however, the mechanisms have not been established. Matrix metalloproteinases (MMPs) play an important role in myocardial remodeling, and MMP activity can be regulated by the tissue inhibitors of the metalloproteinases (TIMPs). This study examined the role of TIMP-1 in postinjury myocardial remodeling. Lesions were created on the left ventricular (LV) epicardium of wild-type (WT, 8–12 wk, 129SVE) and age-matched TIMP-1 gene-deficient ( timp-1–/–) mice through the delivery of RF current (80°C, 30 s). Heart mass, LV scar volumes, and collagen content were measured at 1 h and 3, 7, and 28 days postinjury ( n = 10 each). Age-matched, nonablated mice were used as reference controls ( n = 5). Heart mass indexed to tibial length increased in WT and timp-1–/–mice but was greater in the timp-1–/–mice by 7 days. Scar volumes increased in a time-dependent manner in both groups but were higher in the timp-1–/–mice than the WT mice at 7 days (1.48 ± 0.09 vs. 1.20 ± 0.11 mm3·mg–1·mm, P < 0.05) and remained higher at 28 days. In the remote myocardium, wall thickness was greater and relative collagen content was lower in the timp-1–/–mice at 28 days postinjury. Discrete myocardial RF lesions expand in a time-dependent manner associated with myocyte hypertrophy remote to the scar. Moreover, postinjury myocardial remodeling was more extensive with TIMP-1 gene deletion. Thus TIMP-1 either directly or through modulation of MMP activity may regulate myocardial remodeling following infliction of a discrete injury.
Relationships among Doppler-derived umbilical artery absolute velocities, cardiac function, and placental volume blood flow and resistance in fetal sheep
Authors: Acharya Ganesh , Erkinaro Tiina , Mäkikallio Kaarin , Lappalainen Tomi , Rasanen Juha
Published: March 2004

We hypothesized that umbilical artery (UA) absolute blood flow velocities measured by Doppler ultrasonography reflect placental volume blood flow (QUA) and placental vascular resistance ( RUA) in a late gestation fetal sheep model. In addition, we examined the relationships between umbilical artery absolute blood flow velocities and parameters of fetal cardiac function. Twenty-six sheep fetuses were instrumented at 112–132 days of gestation. After a 5-day recovery period, experiments were performed under general anesthesia in 16 normal fetuses, in 5 fetuses after maternal administration of phenylephrine, and in 5 fetuses after placental embolization. The QUA and arterial blood pressures were measured using a transit-time ultrasonic flow probe and a catheter placed into the descending aorta, respectively. UA peak systolic velocity (PSV), end-diastolic velocity (EDV), time-averaged maximum velocity (TAMXV), pulsatility index (PI), mean velocity ( Vmean), fetal cardiac output, ventricular ejection forces, and the proportion of isovolumetric relaxation time (IRT%) in the cardiac cycle were measured with the use of Doppler ultrasonography. Significant positive linear correlations were found between UA EDV, TAMXV, and Vmean versus QUA, whereas UA PI had a significant negative correlation with QUA. Significant negative correlations were shown between UA EDV, TAMXV, and Vmean versus RUA. A significant positive correlation was present between UA PI and RUA. Doppler-derived UA parameters did not correlate with fetal arterial blood pressures, cardiac output, ventricular ejection forces or IRT%. In fetal sheep, Doppler-derived UA PI and absolute velocities, except PSV, are closely related to directly measured QUA and RUA, validating the use of noninvasive Doppler velocimetry in the assessment of placental circulation.
α1-AR-mediated activation of NKCC in rat cardiomyocytes involves ERK-dependent phosphorylation of the cotransporter
Authors: Andersen Geir Øystein , Skomedal Tor , Enger Mette , Fidjeland Astrid , Brattelid Trond , Levy Finn Olav , Osnes Jan-Bjørn
Published: March 2004

We studied molecular and functional characteristics as well as hormonal regulation of the Na-K-2Cl cotransporter (NKCC) in the isolated rat heart and cardiomyocytes. NKCC activity was measured as bumetanide-sensitive86Rb+influx in isolated perfused rat hearts and isolated cardiomyocytes. Stimulation of α1-adrenoceptors (AR) by phenylephrine (30 μM) increased86Rb+influx. The NKCC inhibitor bumetanide (50 μM) reduced the response to phenylephrine by 45 ± 13% ( n = 12, P < 0.01). PD-98059 (10 μM), an inhibitor of the activation of the mitogen-activated protein kinases extracellular signal-regulated protein kinase 1 and 2 (ERK1/2), reduced the total response to phenylephrine by 51 ± 13% ( n = 10, P < 0.01) and eliminated the bumetanide-sensitive component, indicating that α1-AR mediated stimulation of NKCC is dependent on activation of ERK1/2. Inhibitors of protein kinase C or phosphatidylinositol 3-kinase had no effect. The presence of NKCC mRNA and protein was demonstrated in isolated rat cardiomyocytes. Phosphorylation of NKCC after α1-AR stimulation was shown by immunoprecipitation of the phosphoprotein from32Piprelabeled cardiomyocytes. Increased phosphorylation of the NKCC protein was also abolished by PD-98059. We conclude that the NKCC is present in rat cardiomyocytes and that ion transport by the cotransporter is regulated by α1-AR stimulation through phosphorylation of this protein involving the ERK pathway.
Effects of Na+ channel and cell coupling abnormalities on vulnerability to reentry: a simulation study
Authors: Qu Zhilin , Karagueuzian Hrayr S. , Garfinkel Alan , Weiss James N.
Published: March 2004

The role of dynamic instabilities in the initiation of reentry in diseased (remodeled) hearts remains poorly explored. Using computer simulations, we studied the effects of altered Na+ channel and cell coupling properties on the vulnerable window (VW) for reentry in simulated two-dimensional cardiac tissue with and without dynamic instabilities. We related the VW for reentry to effects on conduction velocity, action potential duration (APD), effective refractory period dispersion and restitution, and concordant and discordant APD alternans. We found the following: 1) reduced Na+ current density and slowed recovery promoted postrepolarization refractoriness and enhanced concordant and discordant APD alternans, which increased the VW for reentry; 2) uniformly reduced cell coupling had little effect on cellular electrophysiological properties and the VW for reentry. However, randomly reduced cell coupling combined with decoupling promoted APD dispersion and alternans, which also increased the VW for reentry; 3) the combination of decreased Na+ channel conductance, slowed Na+ channel recovery, and cellular uncoupling synergistically increased the VW for reentry; and 4) the VW for reentry was greater when APD restitution slope was steep than when it was flat. In summary, altered Na+ channel and cellular coupling properties increase vulnerability to reentrant arrhythmias. In remodeled hearts with altered Na+ channel properties and cellular uncoupling, dynamic instabilities arising from electrical restitution exert important influences on the VW for reentry.
Impaired function of α2-adrenergic autoreceptors on sympathetic nerves associated with mesenteric arteries and veins in DOCA-salt hypertension
Authors: Luo Min , Fink Gregory D. , Lookingland Keith J. , Morris John A. , Galligan James J.
Published: March 2004

The present study tested the hypothesis that there is impaired function of α2-adrenergic autoreceptors and increased transmitter release from sympathetic nerves associated with mesenteric arteries and veins from DOCA-salt rats. High-performance liquid chromatography was used to measure the overflow of ATP and norepinephrine (NE) from electrically stimulated mesenteric artery and vein preparations in vitro. In sham arteries, nerve stimulation evoked a 1.5-fold increase in NE release, whereas in DOCA-salt arteries there was a 3.9-fold increase in NE release over basal levels ( P < 0.05). In contrast, stimulated ATP release was not different in DOCA-salt arteries compared with sham arteries. In sham veins, nerve stimulation evoked a 2.9-fold increase in NE release, whereas in DOCA-salt veins there was a 8.4-fold increase in NE release over basal levels ( P < 0.05). In sham rats NE release, normalized to basal levels, was greater in veins than in arteries ( P < 0.05). The α2-adrenergic receptor antagonist yohimbine (1 μM) increased ATP and NE release in sham but not DOCA-salt arteries. The α2-adrenergic receptor agonist UK-14,304 (10 μM) decreased ATP release in sham but not DOCA-salt arteries. In sham veins, UK-14,304 decreased, but yohimbine increased, NE release; effects that were not observed in DOCA-salt veins. These data show that nerve stimulation causes a greater increase in NE release from nerves associated with veins compared with arteries. In addition, impairment of α2-adrenergic autoreceptor function in sympathetic nerves associated with arteries and veins from DOCA-salt rats results in increased NE release.
Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function
Authors: Zolk Oliver , Münzel Felix , Eschenhagen Thomas
Published: March 2004

Endothelin-1 (ET-1) has acute positive inotropic effects, but consequences of chronically increased ET-1 on contractile function of cardiac myocytes are largely unknown. In the present study, effects of long-term treatment with ET-1 (10 nM) for 5 days on both force development [force of contraction (FOC)] and kinetics of contraction were determined in heart tissue reconstituted from rat cardiac cells. Isometric force was measured in response to cumulative concentrations of Ca2+and isoprenaline. ET-1 augmented basal FOC by 64 ± 11% ( P < 0.05), which was associated with a significantly blunted contractile response to Ca2+and isoprenaline. Moreover, ET-1 significantly prolonged relaxation (62 ± 3 vs. 53 ± 2 ms). Selective ETA(BQ-123) and ETBreceptor blockade (BQ-788) demonstrated that effects of ET-1 on contractile function were mediated through the ETAreceptor subtype. Effects of ET-1 were prevented by cotreatment with either Ro31-8425, a PKC inhibitor, or dimethylamiloride, an inhibitor of the Na+/H+exchanger. In contrast to long-term ET-1 treatment, no changes in contractile parameters were observed after ET-1 treatment for 3 h before force measurement. These data suggest that chronic ET-1 stimulation has dual effects on contractility: improvement of basal force but impairment of twitch kinetics and inotropic responsiveness to β-adrenoceptor stimulation. The signaling pathways involved include ETAreceptors, PKC, and the Na+/H+exchanger. The present in vitro findings raise the possibility that ET-1 may exert both adaptive and maladaptive effects in the failing myocardium in which local accumulation of ET-1 is present.
Right ventricular adaptation to pulmonary hypertension: an interspecies comparison
Authors: Wauthy Pierre , Pagnamenta Alberto , Vassalli Fabio , Naeije Robert , Brimioulle Serge
Published: March 2004

Right ventricular (RV) adaptation is an important prognostic factor in acute and chronic pulmonary hypertension. Pulmonary vascular basal tone and hypoxic reactivity are known to vary widely between species. We investigated how RV adaptation to acute pulmonary hypertension is preserved in species with low, intermediate, and high pulmonary vascular resistance and reactivity. Acute pulmonary hypertension was induced by hypoxia, distal embolism, and proximal constriction in anesthetized dogs ( n = 10), goats ( n = 8), and pigs ( n = 8). Pulmonary vessels were assessed by flow-pressure curves and by impedance to quantify distal resistance, proximal elastance, and wave reflections. RV function was assessed by pressure-volume curves to quantify afterload, contractility, and ventricular-arterial coupling efficiency. First, hypoxia was associated with a progressive increase of resistance, elastance, and wave reflection from dogs to goats and from goats to pigs. RV contractility increased proportionally to RV afterload, and optimal coupling was preserved in all species. Second, embolism increased resistance and wave reflection but not elastance. The increase in RV contractility matched the increase in RV afterload and optimal coupling was preserved. Finally, proximal pulmonary artery constriction increased resistance, increased and accelerated wave reflection, and markedly increased elastance. RV contractility increased markedly and coupling showed a nonsignificant trend to decrease. We conclude that optimal or near-optimal ventricular-arterial coupling is maintained in acute pulmonary hypertension, whether in absence or presence of chronic species-induced pulmonary hypertension.
Remodeling of excitation-contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal KATP channels
Authors: Flagg Thomas P. , Charpentier Flavien , Manning-Fox Jocelyn , Remedi Maria Sara , Enkvetchakul Decha , Lopatin Anatoli , Koster Joseph , Nichols Colin
Published: March 2004

Reducing the ATP sensitivity of the sarcolemmal ATP-sensitive K+ (KATP) channel is predicted to lead to active channels in normal metabolic conditions and hence cause shortened ventricular action potentials and reduced myocardial inotropy. We generated transgenic (TG) mice that express an ATP-insensitive KATP channel mutant [Kir6.2(ΔN2–30,K185Q)] under transcriptional control of the α-myosin heavy chain promoter. Strikingly, myocyte contraction amplitude was increased in TG myocytes (15.68 ± 1.15% vs. 10.96 ± 1.49%), even though KATP channels in TG myocytes are very insensitive to inhibitory ATP. Under normal metabolic conditions, steady-state outward K+ currents measured under whole cell voltage clamp were elevated in TG myocytes, consistent with threshold KATP activation, but neither the monophasic action potential measured in isolated hearts nor transmembrane action potential measured in right ventricular muscle preparations were shortened at physiological pacing cycles. Taken together, these results suggest that there is a compensatory remodeling of excitation-contraction coupling in TG myocytes. Whereas there were no obvious differences in other K+ conductances, peak L-type Ca2+ current ( ICa) density (–16.42 ± 2.37 pA/pF) in the TG was increased compared with the wild type (–8.43 ± 1.01 pA/pF). Isoproterenol approximately doubled both ICa and contraction amplitude in wild-type myocytes but failed to induce a significant increase in TG myocytes. Baseline and isoproterenol-stimulated cAMP concentrations were not different in wild-type and TG hearts, suggesting that the enhancement of ICa in the latter does not result from elevated cAMP. Collectively, the data demonstrate that a compensatory increase in ICa counteracts a mild activation of ATP-insensitive KATP channels to maintain the action potential duration and elevate the inotropic state of TG hearts.
Myocardial electrical alteration in canine preparations with combined chronic rapid pacing and progressive coronary artery occlusion
Authors: Cardinal René , Rousseau Guy , Bouchard Caroline , Vermeulen Michel , Latour Jean-Gilles , Pagé Pierre L.
Published: March 2004

Our objective was to create an animal preparation displaying long-term electrical alterations after chronic regional energetic stress without myocardial scarring. An Ameroid (AM) constrictor was implanted around the left circumflex coronary artery (LCx) 2 wk before chronic rapid ventricular pacing (CRP) was initiated at 240 beats/min for 4 wk (CRP-AM). Comparisons were made with healthy canines and canines with either AM or CRP. Unipolar electrograms were recorded from 191 sites in the LCx territory in open-chest, anesthetized animals during sinus rhythm and while pacing at 120–150 beats/min, with bouts of transient rapid pacing (TRP; 240/min). In CRP-AM and AM, ST segment elevation was identified at central sites and ST depression at peripheral sites, both increasing with TRP. In CRP-AM and CRP, the maximum negative slope of unipolar activation complexes was significantly depressed and activation-recovery intervals prolonged. Areas of inexcitability as well as irregular isocontour patterns displaying localized activation-recovery intervals shortening and gradients >20 ms between neighboring sites were identified in one-third of CRP-AM at slow rate, with increasing incidence and magnitude in response to TRP. In CRP-AM, programmed stimulation-induced marked conduction delay and block as well as polymorphic ventricular tachycardias, which stabilized into monomorphic tachycardias with the use of lidocaine or procainamide. Whole cell Na+ current and channel protein expression were reduced in CRP-AM and CRP. Despite complete constrictor closure, small areas of necrosis were detected in a minority of CRP-AM. Long-term electrical alterations and their exacerbation by TRP contribute to arrhythmia formation in collateral-dependent myocardium subjected to chronic tachycardic stress.
Blood pressure regulates the activity and function of the Na-K-2Cl cotransporter in vascular smooth muscle
Authors: Jiang Gengru , Akar Fatma , Cobbs Scott L. , Lomashvilli Koba , Lakkis Randala , Gordon Frank J. , Sutliff Roy L. , O'Neill W. Charles
Published: March 2004

The Na-K-2Cl cotransporter (NKCC1) is one of several transporters that have been linked to hypertension, and its inhibition reduces vascular smooth muscle tone and blood pressure. NKCC1 in the rat aorta is stimulated by vasoconstrictors and inhibited by nitrovasodilators, and this is linked to the contractile state of the smooth muscle. To determine whether blood pressure also regulates NKCC1, we examined the acute effect of hypertension on NKCC1 in rats after aortic coarctation. In the hypertensive aorta (28-mmHg rise in mean blood pressure), an increase in NKCC1 activity (measured as bumetanide-sensitive86Rb efflux) was apparent by 16 h and reached a plateau of 62% greater than control at 48 h. In contrast, there was a slight decrease in NKCC1 activity in the hypotensive aorta (21% decrease in mean blood pressure). Measurement of NKCC1 mRNA by real-time PCR revealed a fivefold increase in the hypertensive aorta compared with the hypotensive aorta or sham aorta. The inhibition by bumetanide of isometric force response to phenylephrine was significantly greater in the hypertensive aorta than in the control aorta or hypotensive aorta. We conclude that NKCC1 in rat aortic smooth muscle is regulated by blood pressure, most likely through changes in transporter abundance. This upregulation of NKCC1 is associated with a greater contribution to force generation in the hypertensive aorta. This is the first demonstration that NKCC1 in vascular smooth muscle is regulated by blood pressure and indicates that this transporter is important in the acute response of vascular smooth muscle to hypertension.
Mechanisms of postspaceflight orthostatic hypotension: low α1-adrenergic receptor responses before flight and central autonomic dysregulation postflight
Authors: Meck Janice V. , Waters Wendy W. , Ziegler Michael G. , deBlock Heidi F. , Mills Paul J. , Robertson David , Huang Paul L.
Published: March 2004

Although all astronauts experience symptoms of orthostatic intolerance after short-duration spaceflight, only ∼20% actually experience presyncope during upright posture on landing day. The presyncopal group is characterized by low vascular resistance before and after flight and low norepinephrine release during orthostatic stress on landing day. Our purpose was to determine the mechanisms of the differences between presyncopal and nonpresyncopal groups. We studied 23 astronauts 10 days before launch, on landing day, and 3 days after landing. We measured pressor responses to phenylephrine injections; norepinephrine release with tyramine injections; plasma volumes; resting plasma levels of chromogranin A (a marker of sympathetic nerve terminal release), endothelin, dihydroxyphenylglycol (DHPG, an intracellular metabolite of norepinephrine); and lymphocyte β2-adrenergic receptors. We then measured hemodynamic and neurohumoral responses to upright tilt. Astronauts were separated into two groups according to their ability to complete 10 min of upright tilt on landing day. Compared with astronauts who were not presyncopal on landing day, presyncopal astronauts had 1) significantly smaller pressor responses to phenylephrine both before and after flight; 2) significantly smaller baseline norepinephrine, but significantly greater DHPG levels, on landing day; 3) significantly greater norepinephrine release with tyramine on landing day; and 4) significantly smaller norepinephrine release, but significantly greater epinephrine and arginine vasopressin release, with upright tilt on landing day. These data suggest that the etiology of orthostatic hypotension and presyncope after spaceflight includes low α1-adrenergic receptor responsiveness before flight and a remodeling of the central nervous system during spaceflight such that sympathetic responses to baroreceptor input become impaired.
Transmural heterogeneity of calcium activity and mechanical function in the canine left ventricle
Authors: Cordeiro Jonathan M. , Greene Lindsey , Heilmann Cory , Antzelevitch Daniel , Antzelevitch Charles
Published: March 2004

Although electrical heterogeneity within the ventricular myocardium has been the focus of numerous studies, little attention has been directed to the mechanical correlates. This study examines unloaded cell shortening, Ca2+ transients, and inward L-type Ca2+ current ( ICa,L) characteristics of epicardial, endocardial, and midmyocardial cells isolated from the canine left ventricle. Unloaded cell shortening was recorded using a video edge detector, Ca2+ transients were measured in cells loaded with 15 μM fluo-3 AM and voltage and current-clamp recordings were obtained using patch-clamp techniques. Time to peak and latency to onset of contraction were shortest in epicardial and longest in endocardial cells; midmyocardial cells displayed an intermediate time to peak. When contraction was elicited using uniform voltage-clamp square waves, epicardial versus endocardial distinctions persisted and midmyocardial cells displayed a time to peak comparable to that of epicardium. The current-voltage relationship for ICa,L and fluorescence-voltage relationship were similar in the three cell types when quantitated using square pulses. However, peak ICa,L and total charge were significantly larger when an epicardial versus endocardial action potential waveform was used to elicit the current under voltage-clamp conditions. Sarcoplasmic reticulum Ca2+ content, assessed by rapid application of caffeine, was largest in epicardial cells and contributed to a faster time to peak. Our data point to important differences in calcium homeostasis and mechanical function among the three ventricular cell types. These differences serve to synchronize contraction across the ventricular wall. Although these distinctions are conferred in part by differences in electrical characteristics of the three cell types, intrinsic differences in excitation-contraction coupling are evident.
Central angiotensin II-induced pressor responses and neural activity in utero and hypothalamic angiotensin receptors in preterm ovine fetus
Authors: Xu Zhice , Shi Lijun , Yao Jiaming
Published: March 2004

The central renin-angiotensin system is important in the control of blood pressure in the adult. However, few data exist about the in utero development of central angiotensin-mediated pressor responses. Our recent studies have shown that the application of ANG II into the fetal brain can increase blood pressure at near term. The present study determined fetal blood pressure and heart rate in response to a central application of ANG II in the chronically prepared preterm ovine fetus, determined the action sites marked by c-Fos expression in the fetal central pathways after intracerebroventricular injection of ANG II in utero, and determined angiotensin subtype 1 receptors in the fetal hypothalamus. Central injection of ANG II significantly increased fetal mean arterial pressure (MAP). Adjusted fetal MAP against amniotic pressure was also increased by ANG II. Fetal heart rate was subsequently decreased after the central administration of ANG II and/or the increase of blood pressure. ANG II induced c-Fos expression in the central putative cardiovascular area, the paraventricular nuclei in the brain sympathetic pathway. Application of ANG II also caused intense Fos immunoreactivity in the tractus solitarius nuclei in the hindbrain. In addition, intense angiotensin subtype 1 receptors were expressed in the hypothalamus at preterm. These data demonstrate that central ANG II-related pressor centers start to function as early as at preterm and suggest that the central angiotensin-related sympathetic pathway is likely intact in the control of blood pressure in utero.
Myocardial hypertrophy of normotensive Wistar-Kyoto rats
Authors: Aiello Ernesto A. , Villa-Abrille María C. , Escudero Eduardo M. , Portiansky Enrique L. , Pérez Néstor G. , Camilión de Hurtado María C. , Cingolani Horacio E.
Published: March 2004

In our studies with spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Wistar rats, we observed normotensive WKY rats with cardiac hypertrophy determined by a greater left ventricular (LV) mass (LVM)-to-body weight (BW) ratio (LVM/BW) than that of normotensive Wistar rats. Thus we compared the following parameters in SHR, WKY, and Wistar rats: LVM/BW, cell capacitance as index of total surface area of the myocytes, length, width, and cross-sectional area of cardiac myocytes, LV collagen volume fraction, and myocardial stiffness. The LVM/BW of WKY (2.41 ± 0.03 mg/g, n = 41) was intermediate between SHR (2.82 ± 0.04 mg/g, n = 47) and Wistar rats (1.98 ± 0.04 mg/g, n = 28). A positive correlation between blood pressure and LVM was found in SHR, whereas no such relationship was observed in WKY or Wistar rats. Cell capacitance and cross-sectional area were not significantly different in SHR and WKY rats; these values were significantly higher than those of Wistar rats. The cell length was smaller but the width was similar in WKY compared with SHR. Papillary muscles isolated from the LV of WKY and SHR were stiffer than those from Wistar rats. Consistently, a greater level of myocardial fibrosis was detected in WKY and SHR compared with Wistar rats. These findings demonstrate blood pressure-independent cardiac hypertrophy in normotensive WKY rats.
ACE inhibitors and statins acutely improve endothelial dysfunction of human coronary arterioles
Authors: Tiefenbacher Christiane P. , Friedrich Stefanie , Bleeke Tina , Vahl Christian , Chen Xiaobo , Niroomand Feraydoon
Published: March 2004

Long-term treatment with angiotensin-converting enzyme (ACE) inhibitors as well as angiotensin II type 1 (AT1) receptor antagonists and statins reduces cardiovascular mortality in patients with coronary artery disease as well as chronic heart failure. Little is known about the acute effects of these compounds on vascular reactivity of coronary resistance vessels. Coronary arterioles were obtained from patients undergoing coronary bypass operation (atherosclerosis group) or valve replacement (control group). Responses to endothelium-dependent agonists (histamine, serotonin, and acetylcholine) as well as to the endothelium-independent agonist sodium nitroprusside (SNP) were investigated under baseline conditions and after incubation (15 min) with lisinopril (ACE inhibitor), candesartan (AT1 receptor antagonist), or fluvastatin. In atherosclerotic vessels, vasorelaxation was significantly reduced to all endothelium-dependent agonists but not, however, to SNP (77 ± 8, –24 ± 16, –46 ± 24, and 98 ± 8% relaxation for histamine, serotonin, acetylcholine, and SNP, respectively). Lisinopril and fluvastatin but not candesartan significantly improved the responses to the endothelium-dependent agonists (lisinopril: 94 ± 4, 17 ± 22, and –20 ± 13%; fluvastatin: 96 ± 8, 23 ± 21, and –25 ± 18% relaxation for histamine, serotonin, and acetylcholine, repectively). The effect of lisinopril was prevented by pretreatment with a bradykinin antagonist (HOE-130) and dichloroisocoumarine, an inhibitor of kinine-forming enzymes. Pretreatment with a nitric oxide (NO) synthase inhibitor abolished the improvement of endothelial function by lisinopril and fluvastatin. Vascular reactivity in the control group was not influenced by any of the pharmacological interventions. The data demonstrate that in atherosclerosis, endothelium-dependent relaxation of coronary resistance arteries is severely compromised. The impairment can acutely be reversed by ACE inhibitors and statins via increasing the availability of NO.
NO and endogenous angiotensin II interact in the generation of renal sympathetic nerve activity in conscious rats
Authors: McKeogh Donogh F. , O'Donaughy Theresa L. , Brooks Virginia L.
Published: March 2004

Nitric oxide (NO) appears to inhibit sympathetic tone in anesthetized rats. However, whether NO tonically inhibits sympathetic outflow, or whether endogenous angiotensin II (ANG II) promotes NO-mediated sympathoinhibition in conscious rats is unknown. To address these questions, we determined the effects of NO synthase (NOS) inhibition on renal sympathetic nerve activity (RSNA) and heart rate (HR) in conscious, unrestrained rats on normal (NS), high-(HS), and low-sodium (LS) diets, in the presence and absence of an ANG II receptor antagonist (AIIRA). When arterial pressure was kept at baseline with intravenous hydralazine, NOS inhibition with l-NAME (10 mg/kg iv) resulted in a profound decline in RSNA, to 42 ± 11% of control ( P < 0.01), in NS animals. This effect was not sustained, and RSNA returned to control levels by 45 min postinfusion. l-NAME also caused bradycardia, from 432 ± 23 to 372 ± 11 beats/min postinfusion ( P < 0.01), an effect, which, in contrast, was sustained 60 min postdrug. The effects of NOS inhibition on RSNA and HR did not differ between NS, HS, and LS rats. However, when LS and HS rats were pretreated with AIIRA, the initial decrease in RSNA after l-NAME infusion was absent in the LS rats, while the response in the HS group was unchanged by AIIRA. These findings indicate that, in contrast to our hypotheses, NOS activity provides a stimulatory input to RSNA in conscious rats, and that in LS animals, but not HS animals, this sympathoexcitatory effect of NO is dependent on the action of endogenous ANG II.
A model for human ventricular tissue
Authors: ten Tusscher K. H. W. J. , Noble D. , Noble P. J. , Panfilov A. V.
Published: March 2004

The experimental and clinical possibilities for studying cardiac arrhythmias in human ventricular myocardium are very limited. Therefore, the use of alternative methods such as computer simulations is of great importance. In this article we introduce a mathematical model of the action potential of human ventricular cells that, while including a high level of electrophysiological detail, is computationally cost-effective enough to be applied in large-scale spatial simulations for the study of reentrant arrhythmias. The model is based on recent experimental data on most of the major ionic currents: the fast sodium, L-type calcium, transient outward, rapid and slow delayed rectifier, and inward rectifier currents. The model includes a basic calcium dynamics, allowing for the realistic modeling of calcium transients, calcium current inactivation, and the contraction staircase. We are able to reproduce human epicardial, endocardial, and M cell action potentials and show that differences can be explained by differences in the transient outward and slow delayed rectifier currents. Our model reproduces the experimentally observed data on action potential duration restitution, which is an important characteristic for reentrant arrhythmias. The conduction velocity restitution of our model is broader than in other models and agrees better with available data. Finally, we model the dynamics of spiral wave rotation in a two-dimensional sheet of human ventricular tissue and show that the spiral wave follows a complex meandering pattern and has a period of 265 ms. We conclude that the proposed model reproduces a variety of electrophysiological behaviors and provides a basis for studies of reentrant arrhythmias in human ventricular tissue.
Muscle mechanoreflex induces the pressor response by resetting the arterial baroreflex neural arc
Authors: Yamamoto Kenta , Kawada Toru , Kamiya Atsunori , Takaki Hiroshi , Miyamoto Tadayoshi , Sugimachi Masaru , Sunagawa Kenji
Published: March 2004

The effects of the muscle mechanoreflex on the arterial baroreflex neural control have not previously been analyzed over the entire operating range of the arterial baroreflex. In anesthetized, vagotomized, and aortic-denervated rabbits ( n = 8), we isolated carotid sinuses and changed intracarotid sinus pressure (CSP) from 40 to 160 mmHg in increments of 20 mmHg every minute while recording renal sympathetic nerve activity (SNA) and arterial pressure (AP). Muscle mechanoreflex was induced by passive muscle stretch (5 kg of tension) of the hindlimb. Muscle stretch shifted the CSP-SNA relationship (neural arc) to a higher SNA, whereas it did not affect the SNA-AP relationship (peripheral arc). SNA was almost doubled [from 63 ± 15 to 118 ± 14 arbitrary units (au), P < 0.05] at the CSP level of 93 ± 8 mmHg, and AP was increased ∼50% by muscle stretch. When the baroreflex negative feedback loop was closed, muscle stretch increased SNA from 63 ± 15 to 81 ± 21 au ( P < 0.05) and AP from 93 ± 8 to 109 ± 12 mmHg ( P < 0.05). In conclusion, the muscle mechanoreflex resets the neural arc to a higher SNA, which moves the operating point towards a higher SNA and AP under baroreflex closed-loop conditions. Analysis of the baroreflex equilibrium diagram indicated that changes in the neural arc induced by the muscle mechanoreflex might compensate for pressure falls resulting from exercise-induced vasodilatation.
Genesis of the monophasic action potential: role of interstitial resistance and boundary gradients
Authors: Tranquillo Joseph V. , Franz Michael R. , Knollmann Björn C. , Henriquez Alexandra P. , Taylor Doris A. , Henriquez Craig S.
Published: March 2004

The extracellular potential at the site of a mechanical deformation has been shown to resemble the underlying transmembrane action potential, providing a minimally invasive way to access membrane dynamics. The biophysical factors underlying the genesis of this signal, however, are still poorly understood. With the use of data from a recent experimental study in a murine heart, a three-dimensional anisotropic bidomain model of the mouse ventricular free wall was developed to study the currents and potentials resulting from the application of a point mechanical load on cardiac tissue. The applied pressure is assumed to open nonspecific pressure-sensitive channels depolarizing the membrane, leading to monophasic currents at the electrode edge that give rise to the monophasic action potential (MAP). The results show that the magnitude and the time course of the MAP are reproduced only for certain combinations of local or global intracellular and interstitial resistances that form a resting tissue length constant that, if applied over the entire domain, is smaller than that required to match the wave speed. The results suggest that the application of pressure not only causes local depolarization but also changes local tissue properties, both of which appear to play a critical role in the genesis of the MAP.
Hypothermia augments reactive oxygen species detected in the guinea pig isolated perfused heart
Authors: Camara Amadou K. S. , Riess Matthias L. , Kevin Leo G. , Novalija Enis , Stowe David F.
Published: March 2004

Hypothermic perfusion of the heart decreases oxidative phosphorylation and increases NADH. Because O2 and substrates remain available and respiration (electron transport system, ETS) may become impaired, we examined whether reactive oxygen species (ROS) exist in excess during hypothermic perfusion. A fiberoptic probe was placed on the left ventricular free wall of isolated guinea pig hearts to record intracellular ROS, principally superoxide ([Formula: see text]), and an extracellular reactive nitrogen reactant, principally peroxynitrite (ONOO–), a product of nitric oxide (NO·) + [Formula: see text]. Hearts were loaded with dihydroethidium (DHE), which is oxidized by [Formula: see text] to ethidium, or were perfused with l-tyrosine, which is oxidized by ONOO– to dityrosine (diTyr). Shifts in fluorescence were measured online; diTyr fluorescence was also measured in the coronary effluent. To validate our methods and to examine the source and identity of ROS during cold perfusion, we examined the effects of a superoxide dismutase mimetic Mn(III) tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME), and several agents that impair electron flux through the ETS: menadione, sodium azide (NaN3), and 2,3-butanedione monoxime (BDM). Drugs were given before or during cold perfusion. ROS measured by DHE was inversely proportional to the temperature between 37°C and 3°C. We found that perfusion at 17°C increased DHE threefold versus perfusion at 37°C; this was reversed by MnTBAP, but not by l-NAME or BDM, and was markedly augmented by menadione and NaN3. Perfusion at 17°C also increased myocardial and effluent diTyr (ONOO–) by twofold. l-NAME, MnTBAP, or BDM perfused at 37°C before cooling or during 17°C perfusion abrogated, whereas menadione and NaN3 again enhanced the cold-induced increase in ROS. Our results suggest that hypothermia moderately enhances [Formula: see text] generation by mitochondria, whereas [Formula: see text] dismutation is markedly slowed. Also, the increase in [Formula: see text] during hypothermia reacts with available NO· to produce ONOO–, and drug-induced [Formula: see text] dismutation eliminates the hypothermia-induced increase in [Formula: see text].
Coronary artery diameter can be assessed reliably with transthoracic echocardiography
Authors: Kiviniemi Tuomas O. , Saraste Markku , Koskenvuo Juha W. , Airaksinen K. E. Juhani , Toikka Jyri O. , Saraste Antti , Pärkkä Jussi P. , Hartiala Jaakko J.
Published: March 2004

We studied whether diameters of coronary arteries can be measured accurately with the use of transthoracic echocardiography (TTE). By knowing the anatomic diameter of the coronary artery together with coronary flow velocity it is possible to measure coronary flow volume more precisely by TTE. However, the suitability of TTE for measurement of diameters of all main epicardial coronary arteries has not been systematically validated. We measured the diameters of the left main (LM), left anterior descending (LAD), left circumflex (LCX), and right coronary arteries (RCA) with the use of TTE [manual two-dimensional (2D), color-Doppler, and automated 2D analysis] in 30 patients who had normal coronary anatomy. We compared these diameters to those measured with quantitative coronary angiography (QCA). We could measure diameters of LM, LAD, LCX, and RCA by TTE in up to 37%, 63%, 7%, and 60% of patients, respectively. The overall correlation coefficients between TTE and QCA measurements were 0.83 ( P < 0.01) with manual 2D analysis, 0.82 ( P < 0.01) with automated 2D analysis, and 0.94 ( P < 0.01) with a color-Doppler-based analysis. Interobserver variability of TTE measurements was low (coefficient of variation 5.4 ± 4.6–7.5 ± 8.8%). TTE is an accurate method to evaluate coronary artery diameter in patients with healthy coronary arteries.
Senescence alters blood flow responses to acute heat stress
Authors: Kenney Michael J. , Musch Timothy I.
Published: March 2004

Renal and splanchnic sympathetic nerve discharge (SND) responses to heating are significantly reduced in senescent compared with young Fischer-344 (F344) rats (Kenney MJ and Fels RJ. Am J Physiol Regul Integr Comp Physiol 283: R513–R520, 2002). However, the functional significance of this finding is not known. We tested the hypothesis that blood flow distribution profiles to heating are altered in senescent (24 mo old) compared with mature (12 mo old) and young (3 mo old) F344 rats. Visceral organ, skeletal muscle, and tail blood flows were determined with the radionuclide-tagged microsphere technique before (control, 38°C) and during heating that increased body temperature to 41°C in anesthetized F344 rats. Vascular conductance in the kidney, stomach, large intestine, pancreas, spleen, and tail was significantly reduced during control before heating in senescent compared with young F344 rats. Heating significantly decreased kidney, stomach, small and large intestine, and pancreas vascular conductance in young and mature but not senescent F344 rats. Vascular conductance at 41°C in the kidney and small intestine was significantly lower and in the stomach tended to be lower in young compared with senescent rats. Splenic conductance increased during heating in young and senescent rats but was highest in young rats. Tail conductance during heating was significantly increased in young rats but remained unchanged in mature and senescent rats. These results demonstrate a marked attenuation in heating-induced vascular conductance changes in senescent rats, suggesting an important functional consequence for the attenuated SND responses to heating in aged rats.
Rapid exchange of actin-bound nucleotide in perfused rat heart
Authors: Bárány Michael , de Tombe Pieter P.
Published: March 2004

In the rat heart the actin-bound nucleotide contained both ATP and ADP. The ratio of bound ATP to bound ADP depended on the functional state of the heart; it was higher in hearts stopped reversibly in diastole (low Ca2+, high Mg2+, or high K+), than in stimulated (inotropic agents or pacing) hearts. Immunoblotting and gel electrophoresis showed the existence of G-actin (30% of total actin) in the cytoplasm of the heart. Pure actin was isolated from rat hearts: in G-actin the bound nucleotide readily exchanged with ATP or ADP, and in F-actin the bound nucleotide did not exchange with ATP or ADP. The free and bound nucleotides were separated in the intact heart by extraction with 75% methanol at –15°C. In rat hearts perfused with32P-labeled orthophosphate the actin-bound nucleotide rapidly exchanged with the cytoplasmic ATP. The full exchange of the bound ATP was immediate, whereas the full exchange of the bound ADP was slower. The full exchange of the bound ATP was independent of the heartbeat frequency, whereas the full exchange of the bound ADP was frequency dependent. The data suggest that the transformation of actin monomer-ATP to actin polymer-ADP is a part of the normal contraction-relaxation cycle of the rat heart.
Ascorbic acid does not affect large elastic artery compliance or central blood pressure in young and older men
Authors: Eskurza Iratxe , Monahan Kevin D. , Robinson Jed A. , Seals Douglas R.
Published: March 2004

Large elastic artery compliance is reduced and arterial blood pressure (BP) is increased in the central (cardiothoracic) circulation with aging. Reactive oxygen species may tonically modulate central arterial compliance and BP in humans, and oxidative stress may contribute to adverse changes with aging. If so, antioxidant administration may have beneficial effects. Young (Y; 26 ± 1 yr, mean ± SE) and older (O; 63 ± 2 yr, mean ± SE) healthy men were studied at baseline and during acute (intravenous infusion; Y: n = 13, O: n = 12) and chronic (500 mg/day for 30 days; Y: n = 10, O: n = 10) administration of ascorbic acid (vitamin C). At baseline, peripheral (brachial artery) BP did not differ in the two groups, but carotid artery compliance was 43% lower (1.2 ± 0.1 vs. 2.1 ± 0.1 mm2/mmHg × 10–1, P < 0.01) and central (carotid) BP (systolic: 116 ± 5 vs. 101 ± 3 mmHg, P < 0.05, and pulse pressure: 43 ± 4 vs. 36 ± 3 mmHg, P = 0.16), carotid augmentation index (AIx; 27.8 ± 7.8 vs. –20.0 ± 6.6%, P < 0.001), and aortic pulse wave velocity (PWV; 950 ± 88 vs. 640 ± 38 cm/s, P < 0.01) were higher in the older men. Plasma ascorbic acid concentrations did not differ at baseline (Y: 71 ± 5 vs. O: 61 ± 7 μmol/l, P = 0.23), increased ( P < 0.001) to supraphysiological levels during infusion (Y: 1,240 ± 57 and O: 1,056 ± 83 μmol/l), and were slightly elevated ( P < 0.001 vs. baseline) with supplementation (Y: 96 ± 5 μmol/l vs. O: 85 ± 6). Neither ascorbic acid infusion nor supplementation affected peripheral BP, heart rate, carotid artery compliance, central BP, carotid AIx, or aortic PWV (all P > 0.26). These results indicate that the adverse changes in large elastic artery compliance and central BP with aging in healthy men are not 1) mediated by ascorbic acid-sensitive oxidative stress (infusion experiments) and 2) affected by short-term, moderate daily ascorbic acid (vitamin C) supplementation.
Exogenous nitric oxide generates ROS and induces cardioprotection: involvement of PKG, mitochondrial KATP channels, and ERK
Authors: Xu Zhelong , Ji Xiang , Boysen Philip G.
Published: March 2004

We examined whether cGMP-dependent protein kinase (PKG) and mitochondrial ATP-sensitive potassium (KATP) channels are involved in S-nitroso- N-acetyl penicillamine (SNAP)-induced reactive oxygen species (ROS) generation. SNAP significantly increased ROS generation in cardiomyocytes. This increase was suppressed by both 5-hydroxydecanoate (5-HD) and glibenclamide. Direct opening of mitochondrial KATP channels with diazoxide led to ROS generation. The increased ROS generation was reversed by N-(2-mercaptopropionyl)glycine (MPG), a scavenger of ROS. Myxothiazol partially suppressed the ROS generation. KT-5823, an inhibitor of PKG, prevented ROS generation, indicating that PKG is required for ROS generation. In addition, 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP), an activator of PKG, induced ROS generation. The effect of 8-BrcGMP was reversed by either 5-HD or MPG. YC-1, an activator of guanylyl cyclase, also increased ROS production, which was reversed by 5-HD. Neither LY-294002 nor wortmannin, the inhibitors of phosphatidylinositol 3-kinase (PI3-kinase), affected SNAP's action. In a whole heart study, SNAP significantly reduced infarct size. The anti-infarct effect of SNAP was abrogated by either MPG or 5-HD. This effect was also blocked by PD-98059, an ERK inhibitor, but not by LY-294002. A Western blotting study showed that SNAP significantly enhanced phosphorylation of ERK, which was reversed by MPG. These results suggest that SNAP-induced ROS generation is mediated by activation of PKG and mitochondrial KATP channels and that opening of mitochondrial KATP channels is the downstream event of PKG activation. ROS and mitochondrial KATP channels participate in the anti-infarct effect of SNAP. Moreover, phosphorylation of ERK is the downstream signaling event of ROS and plays a role in the cardioprotection of SNAP.