Biomedical subjects

Miyako Takaki

Publications and source records attributed to Miyako Takaki.

At least 19 recordsLinked to original sources

PubMed2006

Heart slice NMR.

Nuclear magnetic resonance (NMR) spectroscopy of the heart is normally carried out using whole heart preparations under coronary perfusion. In such preparations, either radical changes in ionic composition of the perfusate or applications of numerous drugs would affect coronary microcirculation. This report communicates the first (31)P NMR spectroscopy study using a heart slice preparation (left ventricular slices) superfused with extracellular medium. The ratio of phosphocreatine concentration to ATP concentration was approximately 2.1. Also, intracellular pH and Mg(2+) concentration ([Mg(2+)](i)), estimated from the chemical shifts of inorganic phosphate and ATP, were comparable with those under retrograde perfusion. [Mg(2+)](i) was significantly increased by the removal of extracellular Na(+), supporting the essential role of Na(+)-coupled Mg(2+) transport in Mg(2+) homeostasis of the heart. Heart slice preparation could also be used to evaluate the potency of cardiac drugs, regardless of their possible effects on coronary microcirculation.

Adenosine Triphosphate↗

PubMed2006

Transcoronary gene transfer of SERCA2a increases coronary blood flow and decreases cardiomyocyte size in a type 2 diabetic rat model.

The Otsuka Long-Evans Tokushima fatty rat is an animal model of Type 2 diabetes mellitus (DM), which is characterized by diastolic dysfunction associated with decreased sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a). The aim of this study was to examine whether gene transfer of SERCA2a can influence coronary blood flow and cardiomyocyte diameter in this model. DM rats were injected with adenovirus carrying SERCA2a (DM+SERCA) or beta-galactosidase gene (DM+betaGal). Coronary blood flow was measured in cross-circulated excised hearts 3 days after infection. Although in all groups coronary blood flow remained unchanged even if left ventricular (LV) volume or intracoronary Ca(2+) infusion was increased, the DM+SERCA group showed a sustained increase in coronary blood flow compared with the other groups. This result suggests that the sustained high coronary blood flow is a specific response in SERCA2a-overexpressed hearts. Although the LV weight-to-body weight ratio (LV/BW) and cardiomyocyte diameter were higher in the DM and DM+betaGal groups than in the non-DM group, in the DM+SERCA group, these measurements were restored to non-DM size. The percentages of collagen area in the three DM groups was significantly higher than results shown in non-DM rats, and there were no significant differences in collagen area percentage among the three DM groups. These results suggest that a lowered LV/BW by SERCA2a overexpression is due mainly to reduced size of cardiomyocytes without any changes in collagen area percentage. In conclusion, in DM failing hearts, SERCA2a gene transfer can increase coronary blood flow and reduce cardiomyocyte size without reduction in collagen production.

Adenoviridae↗

PubMed2006

Inverse relationship between serum erythropoietin and blood lead concentrations in Kathmandu tricycle taxi drivers.

OBJECTIVE: Kathmandu tricycle taxi drivers, whose environmental lead (Pb) exposure is ascribable mainly to vehicular exhaust, were studied to examine a dose-response relationship between blood Pb (Pb-B) and serum erythropoietin (sEPO) concentrations. METHODS: Subjects were 27 drivers and 9 non-drivers. They were non-anemic healthy men with normal renal function. Pb-B was measured by an atomic absorption spectrometer with a graphite furnace, and sEPO was determined with a sandwich-type enzyme-linked immunosorbent assay. RESULTS: sEPO levels in drivers were lower than those of non-drivers, while Pb-B levels in drivers were higher than those of non-drivers. There was an inverse relationship between Pb-B and sEPO. CONCLUSIONS: The data suggest that Pb inhibits renal EPO production in a dose-dependent manner in persons with subclinical Pb toxicity. sEPO may serve as an early biochemical marker of subclinical Pb toxicity.

Adolescent↗

PubMed2006

High mechanical efficiency of left ventricular arrhythmic contractions during atrial fibrillation.

We analyzed the frequency distribution of the left ventricular (LV) mechanical efficiency of individual arrhythmic beats during electrically induced atrial fibrillation (AF) in normal canine hearts. This efficiency is the fraction of the external mechanical work (EW) in the total mechanical energy measured by the systolic pressure-volume area (PVA). The mean, median, and mode of this efficiency (EW/PVA) were as high as 78%, 80%, and 81%, respectively, on average in six hearts. These high efficiencies were comparable to that of the regular beats in these hearts. The frequency distribution of the EW/PVA during AF tended to skew to the higher side in all the hearts. Since the EW/PVA is directly related to both the ventriculo-arterial (or afterload) coupling ratio (E(a)/E(max); E(a) = effective arterial elastance, E(max) = end-systolic ventricular elastance) and the ejection fraction on a per-beat basis, we also analyzed their frequency distributions. We found them to skew enough to account for the rightward skewed frequency distribution of the EW/PVA during AF with the unexpectedly high mean EW/PVA. These results indicate that the LV arrhythmia during AF per se does not directly suppress the mean level of LV mechanical efficiency in normal canine hearts.

Animals↗

PubMed2006

In vitro formation of enteric neural network structure in a gut-like organ differentiated from mouse embryonic stem cells.

Using an embryoid body (EB) culture system, we developed a functional organ-like cluster--a "gut"--from mouse embryonic stem (ES) cells (ES gut). Each ES gut exhibited spontaneous contractions but did not exhibit distinct peristalsis-like movements. In these spontaneously contracting ES guts, dense distributions of interstitial cells of Cajal (c-kit [a transmembrane receptor that has tyrosine kinase activity]-positive cells; gut pacemaker cells) and smooth muscle cells were discernibly identified; however, enteric neural ganglia were absent in the spontaneously differentiated ES gut. By adding brain-derived neurotrophic factor (BDNF) only during EB formation, we for the first time succeeded in in vitro formation of enteric neural ganglia with connecting nerve fiber tracts (enteric nervous system [ENS]) in the ES gut. The ES gut with ENS exhibited strong peristalsis-like movements. During EB culture in BDNF(+) medium, we detected each immunoreactivity associated with the trk proto-oncogenes (trkB; BDNF receptors) and neural crest marker, proto-oncogene tyrosine-protein kinase receptor ret precursor (c-ret), p75, or sox9. These results indicated that the present ENS is differentiated from enteric neural crest-derived cells. Moreover, focal stimulation of ES guts with ENS elicited propagated increases in intracellular Ca(2+) concentration ([Ca(2+)](i)) at single or multiple sites that were attenuated by atropine or abolished by tetrodotoxin. These results suggest in vitro formation of physiologically functioning enteric cholinergic excitatory neurons. We for the first time succeeded in the differentiation of functional neurons in ENS by exogenously adding BDNF in the ES gut, resulting in generation of distinct peristalsis-like movements.

Animals↗

PubMed2006

Mechanical and metabolic rescue in a type II diabetes model of cardiomyopathy by targeted gene transfer.

The Otsuka-Long-Evans Tokushima Fatty rat represents a model for spontaneous non-insulin-dependent type II diabetes mellitus (DM), characterized by diastolic dysfunction and associated with abnormal calcium handling and decrease in sarcoplasmic reticulum Ca2+ -ATPase (SERCA2a) expression. The aim of this study was to examine whether SERCA2a gene transfer can restore the energetic deficiency and left ventricular (LV) function in this model. DM rats were randomized to receive adenovirus carrying either the SERCA2a gene (DM + Ad.SERCA2a) or the beta-galactosidase gene (DM + Ad.betaGal) or saline (DM + saline). LV mechanoenergetic function was measured in cross-circulated heart preparations 3 days after infection. In DM, end-systolic pressure at 0.1 ml intraballoon water (ESP0.1) was low and end-diastolic pressure at 0.1 ml intraballoon water (EDP0.1) was high (22 mm Hg), compared with non-DM (EDP0.1 12 mm Hg). In DM + Ad.SERCA2a, however, ESP0.1 was increased over 200 mm Hg and EDP(0.1) was decreased to 7 mm Hg. LV relaxation rate was fast in DM + Ad.SERCA2a, but slow in the other DM groups. There was no difference in relation between cardiac oxygen consumption per beat and systolic pressure-volume area among all groups. Finally, the oxygen cost of LV contractility in DM was about three times as high as that of normal. In DM + Ad.SERCA2a, the oxygen cost decreased to control levels, but in DM + Ad.betaGal/DM + saline it remained high. In DM failing hearts, the high oxygen cost indicates energy wasting, which contributes to the contractile dysfunction observed in diabetic cardiomyopathy. SERCA2a gene transfer transforms this inefficient energy utilization into a more efficient state and restores systolic and diastolic function to normal.

Adenoviridae↗

PubMed2006

Enhancement of the intrinsic defecation reflex by mosapride, a 5-HT4 agonist, in chronically lumbosacral denervated guinea pigs.

The defecation reflex is composed of rectal distension-evoked rectal (R-R) reflex contractions and synchronous internal anal sphincter (R-IAS) reflex relaxations in guinea pigs. These R-R and R-IAS reflexes are controlled via extrinsic sacral excitatory nerve pathway (pelvic nerves), lumbar inhibitory nerve pathways (colonic nerves) and by intrinsic cholinergic excitatory and nitrergic inhibitory nerve pathways. The effect of mosapride (a prokinetic benzamide) on the intrinsic reflexes, mediated via enteric 5-HT(4) receptors, was evaluated by measuring the mechanical activity of the rectum and IAS in anesthetized guinea pigs using an intrinsic R-R and R-IAS reflex model resulting from chronic (two to nine days) lumbosacral denervation (PITH). In this model, the myenteric plexus remains undamaged and the distribution of myenteric and intramuscular interstitial cells of Cajal is unchanged. Although R-R and R-IAS reflex patterns markedly changed, the reflex indices (reflex pressure or force curve-time integral) of both the R-R contractions and the synchronous R-IAS relaxations were unchanged. The frequency of the spontaneous R and IAS motility was also unchanged. Mosapride (0.1-1.0 mg/kg) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indices (maximum: 2.76) from that of the control (1.0) 6-9 days following chronic PITH. The dose-response curve was similar to that in the intact guinea pig, and had shifted to the left from that in the guinea pig after acute PITH. A specific 5-HT(4) receptor antagonist, GR 113808 (1.0 mg/kg), decreased both reflex indices by approximately 50% and antagonized the effect of mosapride 1.0 mg/kg. This was quite different from the result in the intact guinea pig where GR 113808 (1.0 mg/kg) did not affect either of the reflex indices. The present results indicate that mosapride enhanced the intrinsic R-R and R-IAS reflexes and functionally compensated for the deprivation of extrinsic innervation. The actions of mosapride were mediated through endogenously active, intrinsic 5-HT(4) receptors which may be post-synaptically located in the myenteric plexus of the anorectum.

Anal Canal↗

PubMed2005

Variable Unstressed Volume Keeps Normal Distributions of Canine Left Ventricular Contractility and Total Mechanical Energy under Atrial Fibrillation.

We have reported that the contractility index (E(max)) and the total mechanical energy (PVA) of arrhythmic beats of the left ventricle (LV) distribute normally in canine hearts under electrically induced atrial fibrillation (AF). Here, E(max) is the ventricular elastance as the slope of the end-systolic (ES) pressure-volume (P-V) relation (ESPVR), and PVA is the systolic P-V area as the sum of the external mechanical work within the P-V loop and the elastic potential energy under the ESPVR. To obtain E(max) and PVA, we had to assume the systolic unstressed volume (V(o)) as the V-axis intercept of the ESPVR to be constant despite the varying E(max), since there was no method to obtain V(o) directly in each arrhythmic beat. However, we know that in regular stable beats V(o) decreases by approximately 7 ml/100 g LV with approximately 100 times the increases in E(max) from ~0.2 mmHg/(ml/100 g LV) of almost arresting weak beats to approximately 20 mmHg/(ml/100 g LV) of strong beats with a highly enhanced contractility. In the present study, we investigated whether E(max) and PVA under AF could still distribute normally, despite such E(max)-dependent V(o) changes. The present analyses showed that the E(max) changes were only approximately 3 times at most from the weakest to the strongest arrhythmic beat under AF. These changes were not large enough to affect V(o) enough to distort the frequency distributions of E(max) and PVA from normality. We conclude that one could practically ignore the slight E(max) and PVA changes with the Emax-dependent V(o) changes under AF.

Animals↗

PubMed2005

Detrimental effects after dobutamine infusion on rat left ventricular function: mechanical work and energetics.

We have previously reported that continuous infusion of dobutamine into the coronary artery induces positive inotropic effects but induces no detrimental effects in cross-circulated, excised normal rat hearts and even in Ca2+ overload-induced contractile failing rat hearts. However, we hypothesized that some detrimental effects on left ventricular (LV) function are induced after continuous dobutamine infusion and the following clearance of blood dobutamine, as is the case after beta-adrenergic receptor stimulation. To test this hypothesis, we investigated LV mechanical work and energetics in the same type of preparations that underwent continuous dobutamine infusion and clearance of blood dobutamine. We found that both mean end-systolic pressure and systolic pressure-volume area (PVA; a measure of total mechanical energy per beat) at midrange LV volume were significantly (P < 0.01) decreased. The mean myocardial oxygen consumption per beat intercept, which is composed of for the total Ca2+ handling in excitation-contraction coupling and basal metabolism, of the and PVA linear relation was also significantly (P < 0.05) decreased (n=8). The mean slope of the linear relation was unchanged in such hearts. Post-dobutamine basal metabolism was unchanged (n = 5 of the 8 hearts). The moderate proteolysis of a cytoskeleton protein, alpha-fodrin was identified (n = 7 of the 8 hearts with the decreased intercept), after clearance of blood dobutamine. In agreement with our hypothesis, the detrimental effect of the post-beta-adrenergic receptor stimulation was induced by a moderate concentration of dobutamine; we found systolic dysfunction due to the impairment of Ca2+ handling in excitation-contraction coupling in the rat LV and proteolysis of a cytoskeleton protein, alpha-fodrin.

Adrenergic beta-Agonists↗

PubMed2005

A 5-HT4 agonist, mosapride, enhances intrinsic rectorectal and rectoanal reflexes after removal of extrinsic nerves in guinea pigs.

Distension-evoked reflex of rectorectal (R-R) contractions and rectointernal anal sphincter (R-IAS) relaxations can be generated in guinea pigs through an extrinsic sacral excitatory neural pathway (pelvic nerves) as well as intrinsic cholinergic excitatory and nitrergic inhibitory pathways. The aim of the present study was to create intrinsic R-R and R-IAS reflex models by pithing (destruction of the lumbar and sacral cords; PITH) and to evaluate whether the prokinetic benzamide mosapride, a 5-HT(4) receptor agonist, enhances these reflexes. The mechanical activities of the R-R and R-IAS were recorded in the anesthetized guinea pig on days 2-9 after PITH. Although the basal rectal pressure at distension after PITH was significantly lower than control, the reflex indexes of R-R contractions and synchronous R-IAS relaxations were unchanged between days 4 and 9 after PITH. The frequency of spontaneous rectal and IAS motility were also unchanged. Immunohistochemical studies revealed that the distribution of myenteric and intramuscular interstitial cells of Cajal (ICC) were not altered after PITH. Mosapride (0.1-1.0 mg/kg iv) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indexes (maximum: 2.76) from control (1.0) 6-9 days after PITH. The 5-HT(4) receptor antagonist, GR-113808 (1.0 mg/kg iv) decreased the R-R and R-IAS reflex indexes by approximately 50% and antagonized the effect of mosapride (1.0 mg/kg iv). The present results indicate that mosapride moderately enhanced intrinsic R-R and R-IAS reflexes functionally compensated after deprivation of extrinsic nerves, mediated through endogenously active intrinsic 5-HT(4) receptors.

Acute Disease↗

PubMed2005

Different modulation of spontaneous activities by nitrergic inhibitory nerves between ileum and jejunum in W/Wv mutant mice.

We compared the spontaneous electrical and mechanical activities between the jejunum and ileum in the W/Wv mutant mouse, where ICC in the myenteric region (ICC-MY) are deficient. Electrical slow waves (SWs) superimposed with spike potentials, and synchronous circular and longitudinal muscle mechanical activities at a regular rhythm under approximately 1 cm H2O were recorded in the jejunum and ileum of wild-type mice. However, in the jejunum and ileum of W/Wv mice, irregular electrical and mechanical activities without discernable SWs were recorded. N-nitro-L-arginine methyl ester (L-NAME) significantly decreased the mean interval of longitudinal muscle contractions from 4.43+/-3.39 to 2.50+/-1.23 s in the ileum of W/W(V) mice. L-NAME also significantly decreased mean coefficient of variance (decreased irregularity) in the intervals from 2.59+/-0.84 to 0.48+/-0.46 in the ileum. Tetrodotoxin also significantly decreased mean interval and coefficient of variance in the ileum. Neither L-NAME nor tetrodotoxin affected contractile activity in the jejunum. These results suggest that enteric nitrergic nerves in the ileum, but not the jejunum, mediate a steady-state inhibition of myogenic activity in W/Wv mice.

Action Potentials↗

PubMed2005

Positive inotropic effect of nicorandil in adult rats in situ.

PURPOSE: Although the cardiac protective and negative inotropic effects of nicorandil via opening the sarcolemmal or mitochondrial K(ATP) channel and NO-like action are well known, positive inotropic effects of nicorandil in normal hearts have not been reported. The aim of the current study was to investigate how nicorandil affects left ventricular (LV) function of in situ adult rat hearts through the entire cardiovascular system. METHODS: We performed simultaneous and continuous measurements of LV pressure (P) by a catheter-tip micromanometer and LV volume (V) using a conductance catheter. We obtained steady-state LV P-V loops and intermittent curvilinear LV end-systolic pressure-volume relations (ESPVRs), LV end-systolic pressure (ESP(mLVV)), and systolic pressure-volume area (PVA(mLVV)) at midrange LVV (mLVV). We evaluated the effects of nicorandil on LV function by these mechanical indexes sensitively reflecting changes in LV contractility and work capability, preload (end-diastolic volume, EDV), and afterload (effective arterial elastance, Ea). RESULTS: Nicorandil (10 and 20 microg.kg(-1).min(-1)) (blood concentration: 0.53 +/- 0.14 and 1.48 +/- 0.21 microg/ml) largely shifted ESPVR upward and thus significantly increased ESP(0.06), PVA(0.06), stroke volume due to increase in EDV, and ejection fraction without significant changes in Ea and heart rate. In contrast, an NO donor, nitroglycerin (1 microg.kg(-1) . min(-1)), significantly decreased Ea but did not change ESP(0.06), PVA(0.06), and EDV. Furthermore, either a nonselective K(ATP) channel blocker, glybenclamide, or a mitochondrial K(ATP) channel blocker, 5-hydroxydecanoate, abolished these nicorandil-induced positive inotropic actions. CONCLUSION: These results suggest that nicorandil exhibited positive inotropic actions on LV function of in situ hearts in adult rats with resultant increased preload (EDV).

ATP-Binding Cassette Transporters↗

PubMed2005

Absence of peristalsis in the ileum of W/W(V) mutant mice that are selectively deficient in myenteric interstitial cells of Cajal.

It is well known that the enteric nervous system plays a key role in the generation of gastrointestinal peristaltic movements. Recently, the networks of interstitial cells of Cajal (ICC) have been found to be essential in the generation of spontaneous gastrointestinal movements. However, the role of ICC in the mechanisms involved in the generation of peristaltic movements is still controversial. The aim of the present study was to reveal how pacemaker myenteric ICC (ICC-MY) and the enteric nervous system contribute to the mechanisms involved in the generation of intestinal peristalsis. We compared spontaneous peristaltic movements of the ileum in wild type (WT) mice with those in W/W(V) mutant mice which are selectively deficient in ICC-MY. Simultaneous recordings were made from both the circular and longitudinal muscle of a 4-cm long segment of ileum under hydrostatic pressure of 0--0.5 cm H(2)O. Mechanical activity and continuous video-images of the ileum were compared between WT and W/W(V) mutant mice under control conditions, in the presence of N-nitro-L-arginine methyl ester (L-NAME) and after tetrodotoxin (TTX). In the WT mouse ileum, peristaltic waves to propagate from the oral to the anal end were frequently observed. The frequency of these peristaltic waves and their associated synchronous longitudinal and circular muscle contractions was increased by L-NAME. The peristaltic waves were abolished by TTX. In the W/W(V) mutant mouse ileum, no peristaltic waves to propagate from the oral to the anal end were observed in control and even after L-NAME, although the local spontaneously generated longitudinal and circular muscle contractions were enhanced by L-NAME. These local contractions were not abolished by TTX. The results presented here suggested that ICC-MY are essential for the generation of spontaneous intestinal peristaltic movements. It is conceivable that ICC-MY may determine the polarity of the excitation of the intestine such that longitudinal and circular muscle contractions propagate from the oral to the anal end of the intestinal segments, although the question of why ICC-MY are necessary for the neural pathways remains unresolved.

Anesthetics, Local↗

PubMed2004

Na+/Ca2+ exchange inhibition protects the rat heart from ischemia-reperfusion injury by blocking energy-wasting processes.

We have recently reported that exposure of rat hearts to high Ca(2+) produces a Ca(2+) overload-induced contractile failure in rat hearts, which was associated with proteolysis of alpha-fodrin. We hypothesized that contractile failure after ischemia-reperfusion (I/R) is similar to that after high Ca(2+) infusion. To test this hypothesis, we investigated left ventricular (LV) mechanical work and energetics in the cross-circulated rat hearts, which were subjected to 15 min global ischemia and 60 min reperfusion. Sixty minutes after I/R, mean systolic pressure-volume area (PVA; a total mechanical energy per beat) at midrange LV volume (mLVV) (PVA(mLVV)) was significantly decreased from 5.89 +/- 1.55 to 3.83 +/- 1.16 mmHg.ml.beat(-1).g(-1) (n = 6). Mean myocardial oxygen consumption per beat (Vo(2)) intercept of (Vo(2)-PVA linear relation was significantly decreased from 0.21 +/- 0.05 to 0.15 +/- 0.03 microl O(2).beat(-1).g(-1) without change in its slope. Initial 30-min reperfusion with a Na(+)/Ca(2+) exchanger (NCX) inhibitor KB-R7943 (KBR; 10 micromol/l) significantly reduced the decrease in mean PVA(mLVV) and Vo(2) intercept (n = 6). Although Vo(2) for the Ca(2+) handling was finally decreased, it transiently but significantly increased from the control for 10-15 min after I/R. This increase in Vo(2) for the Ca(2+) handling was completely blocked by KBR, suggesting an inhibition of reverse-mode NCX by KBR. alpha-Fodrin proteolysis, which was significantly increased after I/R, was also significantly reduced by KBR. Our study shows that the contractile failure after I/R is similar to that after high Ca(2+) infusion, although the contribution of reverse-mode NCX to the contractile failure is different. An inhibition of reverse-mode NCX during initial reperfusion protects the heart against reperfusion injury.

Animals↗

PubMed2004

Combined determination with functional and morphological studies of origin of nerve fibers expressing transient receptor potential vanilloid 1 in the myenteric plexus of the rat jejunum.

The aim of this study was to determine the action of capsaicin in isolated rat intestine and the origin of nerve fibers expressing transient receptor potential vanilloid 1 (TRPV1: capsaicin receptor) in the rat jejunum by combination of functional and immunohistochemical experiments. Capsaicin (1 microM) produced a prolonged relaxation response (52. +/-15.3% of the relaxation response to papaverine, mean +/- S.D., n=27) of the isolated jejunum in the presence of atropine and guanethidine. Pretreatment with the TRPV1 antagonist, capsazepine (10 microM) and ruthenium red (3 microM) significantly reduced the relaxation response to capsaicin by 78% (P<0.01) and 38% (P<0.05), respectively. Tetrodotoxin and calcitonin gene-related peptide (CGRP)-desensitization significantly reduced the response to capsaicin by 72% (P<0.01) and 42% (P<0.01), respectively. Therefore, we investigated the distribution of TRPV1-immunoreactivity (IR) in the myenteric plexus of the rat jejunum. Using antisera raised against either the N-terminal or C-terminal domains of rat TRPV1, TRPV1-IR was present in the nerve fibers, but not in the cell bodies of myenteric neurons. These TRPV1-immunoreactive nerve fibers were running in myenteric ganglia and their interconnecting strands. Most TRPV1-immunoreactive nerve fibers showed CGRP-IR, whereas few VR1-immunoreactive nerve fibers showed substance P-IR. After chronic denervation of the extrinsic nerve supply to the jejunum, both the relaxation response to capsaicin and TRPV1-immunoreactive nerve fibers completely disappeared. These findings indicate that these TRPV1-immunoreactive nerve fibers in the rat jejunum derive from extrinsic neurons and that activation of TRPV1 produces the relaxation response in the rat jejunum, at least in part, through the release of CGRP from nerve fibers expressing TRPV1.

Action Potentials↗

PubMed2004

Calpain inhibitor-1 protects the rat heart from ischemia-reperfusion injury: analysis by mechanical work and energetics.

We hypothesized that calpain inhibitor-1 protected left ventricular (LV) function from ischemia-reperfusion injury by inhibiting the proteolysis of alpha-fodrin. To test this hypothesis, we investigated the effect of calpain inhibitor-1 on LV mechanical work and energetics in the cross-circulated rat hearts that underwent 15-min global ischemia and 60-min reperfusion (n = 9). After ischemia-reperfusion with calpain inhibitor-1, mean end-systolic pressure at midrange LV volume and systolic pressure-volume area (PVA) at midrange LV volume (total mechanical energy per beat) were hardly changed, although they were significantly (P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. Mean myocardial oxygen consumption per beat (Vo(2)) intercepts (PVA-independent Vo(2); Vo(2) for the total Ca(2+) handling in excitation-contraction coupling and basal metabolism) of Vo(2)-PVA linear relations were also unchanged after ischemia-reperfusion with calpain inhibitor-1, although they were significantly (P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. There were no significant differences in O(2) costs of LV PVA and contractility among the hearts in control (or normal) postischemia-reperfusion and postischemia-reperfusion with calpain inhibitor-1. Western blot analysis of alpha-fodrin and the immunostaining of 150-kDa products of alpha-fodrin confirmed that calpain inhibitor-1 almost completely protected the proteolysis of alpha-fodrin. Our results indicate that calpain inhibitor-1 prevents the heart from ischemia-reperfusion injury associated with the impairment of total Ca(2+) handling by directly inhibiting the proteolysis of alpha-fodrin.

Animals↗

PubMed2004

Left ventricular mechanoenergetics after hyperpolarized cardioplegic arrest by nicorandil and after depolarized cardioplegic arrest by KCl.

We hypothesized that there are no differences in left ventricular (LV) mechanoenergetics between after hyperpolarized cardioplegic arrest by nicorandil (nicorandil arrest) and after depolarized one by high potassium chloride (KCl arrest). The aim of the present study was to test this hypothesis using LV curved end-systolic pressure-volume relation (ESPVR) and linear pressure-volume area (PVA)-myocardial oxygen consumption per beat (VO2) relation. All hearts underwent 30 min global ischemia (30 degrees C) after infusion of 5 ml of cardioplegia. Cardioplegia consisted of either 30 mmol/l KCl (7 hearts) or nicorandil (100 micromol/l) in Tyrode solution (6 hearts). After a 30-min blood reperfusion, ESPVR and VO2-PVA relation were assessed again. Mean end-systolic pressure (ESP(mLVV)) and mean PVA at midrange LV volume (PVA(mLVV)) significantly (P < 0.05) decreased to 79.1 +/- 13.4% and 85.4 +/- 17.1% of control after KCl arrest and to 85.3 +/- 14.8% and 86.4 +/- 16.9% of control after nicorandil arrest. There were no significant differences in both decreases of mean ESP(mLVV) and PVA(mLVV) between each arrest. The slopes of VO2-PVA relations were also unchanged after each arrest. There was a significant (P < 0.005) difference in the decreases of mean VO2 intercepts of VO2-PVA relations between post-KCl arrest (73.9 +/- 8.2% of control) and post-nicorandil arrest (99.2 +/- 10.1% of control), however. Proteolysis of alpha-fodrin due to Ca2+ overload was significantly marked after KCl arrest. The present results indicate that the total calcium handling in excitation-contraction coupling is transiently impaired after KCl arrest, whereas it is unchanged after nicorandil arrest. This suggests the possibility that nicorandil is a better cardioplegia than KCl.

Animals↗

PubMed2004

Reversible effects of isoproterenol-induced hypertrophy on in situ left ventricular function in rat hearts.

The aim of the present study was to evaluate specifically left ventricular (LV) function in rat hearts as they transition from the normal to hypertrophic state and back to normal. Either isoproterenol (1.2 and 2.4 mg.kg(-1).day(-1) for 3 days; Iso group) or vehicle (saline 24 microl.day(-1) for 3 days; Sa group) was infused by subcutaneous implantation of an osmotic minipump. After verifying the development of cardiac hypertrophy, we recorded continuous LV pressure-volume (P-V) loops of in situ ejecting hypertrophied rat hearts. The curved LV end-systolic P-V relation (ESPVR) and systolic P-V area (PVA) were obtained from a series of LV P-V loops in the Sa and Iso groups 1 h or 2 days after the removal of the osmotic minipump. PVA at midrange LV volume (PVA(mLVV)) was taken as a good index for LV work capability (13, 15, 20, 21). However, in rat hearts during remodeling, whether PVA(mLVV) is a good index for LV work capability has not been determined yet. In the present study, in contrast to unchanged end-systolic pressure at midrange LV volume, PVA(mLVV) was significantly decreased by isoproterenol treatment relative to saline; however, these measurements were the same 2 days after pump removal. Simultaneous treatment with a beta(1)-blocker, metoprolol (24 mg.kg(-1).day(-1)), blocked the formation of cardiac hypertrophy and thus PVA(mLVV) did not decrease. The reversible changes in PVA(mLVV) reflect precisely the changes in LV work capability in isoproterenol-induced hypertrophied rat hearts mediated by beta(1)-receptors. These results indicate that the present approach may be an appropriate strategy for evaluating the effects of antihypertrophic and antifibrotic modalities.

Adrenergic beta-Agonists↗