Energized by Circulation Research over 30 years.
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Animals↗
Biomedical subjects
Hiroyuki Suga
Publications and source records attributed to Hiroyuki Suga.
Pressor effect of electroacupuncture on hemorrhagic hypotension.
Neiguan (PC-6) is a traditional acupoint in each forearm and overlies the trunk of the median nerve. Previous studies show that electroacupuncture (EA) at the Neiguan acupoint could improve not only myocardial ischemic dysfunction by inducing a depressor response but also recover hemorrhagic hypotension by inducing a pressor response. However, their physiological mechanisms are not yet elucidated. We investigated the pressor effect of Neiguan EA and its mechanism by focusing on left ventricular (LV) performance in a canine hemorrhagic hypotension model. We hemorrhaged 36 anesthetized and thoracotomized mongrel dogs and decreased LV end-systolic pressure (ESP) to approximately 70 mmHg (35% decrease). We obtained LV pressure-volume (P-V) data with a micromanometer catheter and a conductance catheter. One-hour Neiguan EA significantly recovered the decreased ESP, end-diastolic volume, and stroke volume by 32 +/- 13%, 27 +/- 13%, and 39 +/- 17%, respectively (P < 0.05), without changing heart rate and the slope of the end-systolic P-V relation. Neiguan EA inhibited a hemorrhage-induced increase in plasma catecholamines. However, vecuronium (neuromuscular blocking agent) administration abolished the antihypotension effect of Neiguan EA. Furthermore, Neiguan EA was much more effective than a nonacupoint thigh EA. We conclude that Neiguan EA achieved the antihypotension effect by improving LV filling of the hemorrhage-depressed LV performance despite the inhibition of the hemorrhage-increased plasma catecholamines. This pressor effect seemed to accompany an increased venous return by Neiguan EA-increased vasomotor tone and muscle pump. This study demonstrated a scientific basis for the therapeutic efficacy of acupuncture in the treatment of hemorrhagic hypotension and shock.
Animals↗
Global cardiac function: mechano-energetico-informatics.
This review on the global cardiac function covers cardiac mechanics, energetics, and informatics that I have developed with my collaborators over the last 30 years in Japan and USA. We first established E(max) (end-systolic maximum elastance or pressure/volume ratio) as a new index of ventricular contractility using canine hearts. We then expanded the E(max) concept to PVA (systolic pressure-volume area consisting of external mechanical work and mechanical potential energy) as an innovative measure of total mechanical energy of ventricular contraction and discovered it to be a reliable determinant of ventricular energetics or O(2) consumption (V(O(2))). We have discovered that E(max) shifts the V(O(2))-PVA relation and the E(max) dependency (O(2) cost of E(max)) varies among different pathophysiological hearts. We also searched for the basis of E(max) in crossbridge behavior information contained in an X-ray diffraction of papillary muscle. Recently, we established a new integrative analysis to estimate total Ca(2+) recruited for excitation-contraction coupling in a beating heart using the E(max)-PVA-V(O(2)) information. These global, mechano-energetico-informatic approaches seem to facilitate better understanding of cardiac function, as required in the present post-genomic era when more physiomic knowledge is required not only in cardiac function but also in all other physiologic functions.
Animals↗
Cardiac energetics: from E(max) to pressure-volume area.
1. To celebrate this Festschrift for Professor Colin Gibbs, as an invited speaker, I would like to review briefly my 35 year research career in cardiac physiology. 2. My career started in the late 1960s in Tokyo with my serendipitous discovery of Emax (ventricular end-systolic maximum elastance) as a load-independent contractility index based on the time-varying elastance (E(t)) model of the ventricle. Professor K Sagawa at the Johns Hopkins University, USA, whom I joined in 1971, encouraged me to go further. 3. The next serendipitous event in my career was the discovery of ventricular pressure-volume area (PVA) as a measure of total mechanical energy of ventricular contraction in the late 1970s. The PVA concept was theoretically deducible from the E(t) and Emax concept and correlated surprisingly well with ventricular O2 consumption (Vo2). 4. Professor Gibbs' intuitive recognition of the significance of PVA in myocardial energetics in the 1980-1990s greatly encouraged me thereafter. The third serendipitous event in my career occurred in the mid 1990s and was my discovery of a novel integrative analysis method to assess the total amount of Ca2+ recruited in each excitation-contraction coupling from the decay rate of postextrasystolic potentiation, taking advantage of the Emax-PVA-Vo2 framework. 5. I am now hoping to experience one more serendipitous experience by developing an integrative analysis method of cross-bridge cycling in a beating heart using the Emax and PVA concepts.
Animals↗
Preparation of new nitrogen-bridged heterocycles. 53. Syntheses of 3-(benzylthio)thieno[3,4-b]indolizine derivatives and their intramolecular arene-arene interactions.
Various ethyl 1-arylcarbonyl-3-[(un)substituted methylthio]thieno[3,4-b]indolizine-9-carboxylates were synthesized in good yields by a novel methodology in which the S-alkylation of 5-arylcarbonyl-4-ethoxycarbonylmethyl-3-(1-pyridinio)thiophene-2-thiolates with alkyl or benzyl halides, the 1,5-dipolar cyclization of the resulting pyridinium salts in the presence of a base, and the aromatization were performed. In the X-ray analyses of some 3-(benzylthio)thieno[3,4-b]indolizine-9-carboxylates, a gauche and two anti conformers in relation to the exocyclic sulfide linkage were found. Interestingly, all of the 3-(benzylthio)thieno[3,4-b]indolizine derivatives showed significant high-field shifts (delta up to 0.3 ppm) for the 5- and 6-proton signals compared with those of the 3-methylthio derivatives in the (1)H-NMR spectra and exhibited a definite absorption band near 425 nm in their UV spectra, indicating an intramolecular arene-arene interaction between the thieno[3,4-b]indolizine and the phenyl ring.
Drug Interactions↗
Exponential fitting of postextrasystolic potentiation may underestimate the cardiac Ca2+ recirculation fraction: a theoretical analysis.
The recirculation fraction of intramyocardial Ca(2+) (RF) has conventionally been obtained from the monotonic decay of postextrasystolic potentiation (PESP). The used assumption is that the decay is exponential. However, we have found that PESP usually decays in alternans even at spontaneous heart rates (>100 beats/min) in excised, cross-circulated canine heart preparations under normal coronary perfusion and normothermia. We have already devised a means of extracting the exponential decay component for RF calculation by subtracting the oscillatory component from the alternans PESP decay by a curve-fitting method. Using mathematics, we assessed the possible error in estimated RF when an exponential curve was naively fit to the alternans PESP decay. We obtained results showing that the exponential assumption may considerably underestimate RF even when the alternans is trivial with the oscillatory component of only 10% of the exponential component.
Algorithms↗
Highly enantioselective 1,3-dipolar cycloaddition reactions of 2-benzopyrylium-4-olate catalyzed by chiral Lewis acids.
We have found that significant levels of enantioselectivity are obtained in the 1,3-dipolar cycloadditions of 2-benzopyrylium-4-olate using chiral 2,6-bis(oxazolinyl)pyridine (Pybox)-rare earth metal triflate complexes as chiral Lewis acid catalysts. The reactions with benzyloxyacetaldehyde derivatives catalyzed by Sc(III)-Pybox-i-Pr (10 mol %) proceeded to give endo-adducts selectively with high enantioselectivity (up to 93% ee). The reaction with benzyl pyruvate under similar conditions gave an exo-adduct selectively with 87% ee. In the reaction with 3-acryloyl-2-oxazolidinone, Yb(III)-Pybox-Ph was found to be effective in providing an exo-adduct with extremely high enantioselectivity (98% ee).
Aldehydes↗
[History of cardiology in the last 100 years: Japanese contribution to studies on Emax].
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Cardiology↗
Inhibitory effects of alprostadil (prostaglandin E1) incorporated in lipid microspheres of soybean oil on intimal hyperplasia following balloon injury in rabbits.
The present study was performed to assess the inhibitory effects of alprostadil (CAS 745-65-3, prostaglandin E1, PGE1) incorporated in lipid microspheres (here-in-after referred to as lipo PGE1; Palux inj.) on intimal thickening following balloon injury in the carotid artery of normal rabbits. Lipo PGE1 was given intravenously to animals twice a day at doses of 20 or 40 micrograms/kg/day from ballooning (day 1) until day 3, and at half these doses from day 4 to day 20. The carotid artery was removed for histopathological staining on the next day (day 21) after the last administration. Lipo PGE1 significantly reduced both the intimal/medial are (I/M) ratio and stenosis ratio by about half in the 40 micrograms/kg/day on day 21 after ballooning, compared with the vehicle group. Infiltration of macrophage, expression of proliferating cell nuclear antigen (PCNA)-positive cells was inhibited by the administration of lipo PGE1 on day 3 after ballooning. Adhesion of platelets to injured arterial walls was also inhibited on day 3. Lipo PGE1 at 40 micrograms/kg/day exerted more potent inhibitory effects on I/M and stenosis ratios and histopathological changes such as infiltration of macrophage and expression of PCNA-positive cells than at 20 micrograms/kg/day. These findings suggest that lipo PGE1 inhibits the intimal hyperplasia after balloon injury in rabbit carotid artery, possibly by inhibiting platelet functions.
Alprostadil↗
Temperature-dependent postextrasystolic potentiation and Ca(2+) recirculation fraction in canine hearts.
We have found that cardiac temperature proportionally changes O(2) cost of contractility, defined as O(2) consumption for myocardial total Ca(2+) handling normalized to contractility in terms of the end-systolic pressure-volume ratio (maximal elastance, E(max)), in the canine left ventricle (temperature sensitivity, Q(10) = 2). We have separately found that a decrease in the recirculation fraction (RF) of Ca(2+) within myocardial cells underlies an increased O(2) cost of E(max) in stunned hearts. We therefore hypothesized that a similar change in RF would underlie the Q(10) of O(2) cost of E(max). We tested this hypothesis by analyzing RF calculated from an exponential decay component of the transiently alternating postextrasystolic potentiation in the canine left ventricle. RF decreased from 0.7 to 0.5 as cardiac temperature increased from 33 to 38 degrees C with Q(10) of 0.5, reciprocal to that of O(2) cost of E(max). We conclude that Q(10) of ATP-consuming reactions involved in Ca(2+) handling and E(max) response to it could reasonably account for the reciprocal Q(10) of RF and O(2) cost of E(max).
Adenosine Triphosphate↗
Heart size-independent analysis of myocardial function in murine pressure overload hypertrophy.
Pressure overload cardiac hypertrophy may be a compensatory mechanism to normalize systolic wall stress and preserve left ventricular (LV) function. To test this concept, we developed a novel in vivo method to measure myocardial stress (sigma)-strain (epsilon) relations in normal and hypertrophied mice. LV volume was measured using two pairs of miniature omnidirectional piezoelectric crystals implanted orthogonally in the endocardium and one crystal placed on the anterior free wall to measure instantaneous wall thickness. Highly linear sigma-epsilon relations were obtained in control (n = 7) and hypertrophied mice produced by 7 days of transverse aortic constriction (TAC; n = 13). Administration of dobutamine in control mice significantly increased the load-independent measure of LV contractility, systolic myocardial stiffness. In TAC mice, systolic myocardial stiffness was significantly greater than in control mice (3,156 +/- 1,433 vs. 1,435 +/- 467 g/cm(2), P < 0.01), indicating enhanced myocardial contractility with pressure overload. However, despite the increased systolic performance, both active (time constant of LV pressure decay) and passive (diastolic myocardial stiffness constant) diastolic properties were markedly abnormal in TAC mice compared with control mice. These data suggest that the development of cardiac hypertrophy is associated with a heightened contractile state, perhaps as an early compensatory response to pressure overload.
Animals↗
Left ventricular diastolic dysfunction in type 2 diabetes mellitus model rats.
To gain insight into the pathogenesis of diabetic cardiomyopathy, we investigated cardiac function in terms of the coupling of left ventricular mechanical work and the energetics in Otsuka Long-Evans Tokushima Fatty rats, which are well known as a model of type 2 diabetes mellitus (DM). Neither left ventricular systolic function and mean coronary flow nor coronary flow reserve differed even in late DM rats. The amount of oxygen required for mechanical work and contraction was unaltered, although myosin isozyme was finally transformed from V(1) to V(3). The maximum pacing rate was decreased from 300 to 240 beats/min, and the left ventricular relaxation rate was significantly (P < 0.05) slower only in late DM rats, resulting in decreased oxygen consumption per minute for total Ca(2+) handling in excitation-contraction coupling mainly consumed by sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) without significant changes in basal metabolism or in mitochondrial oxidative phosphorylation. The protein level of SERCA2 in membranes was significantly (P < 0.001) lower in severe DM rats. We conclude that the only lusitropic dysfunction due to the depressed expression of SERCA2 is related to generating diabetic cardiomyopathy even in the present type 2 diabetic rats.
Analysis of Variance↗
Frequency distribution, variance, and moving average of left ventricular rhythm and contractility during atrial fibrillation in dog.
Mean levels of left ventricular rhythm and contractility averaged over arrhythmic beats would characterize the average cardiac performance during atrial fibrillation (AF). However, no consensus exists on the minimal number of beats for their reliable mean values. We analyzed their basic statistics to find out such a minimal beat number in canine hearts. We produced AF by electrically stimulating the atrium and measured left ventricular arrhythmic beat interval (RR) and peak isovolumic pressure (LVP). From these, we calculated instantaneous heart rate (HR = 60,000/RR), contractility (E(max) = LVP/isovolumic volume above unstressed volume), and beat interval ratio (RR1/RR2). We found that all their frequency distributions during AF were variably nonnormal with skewness and kurtosis. Their means +/- standard deviations alone cannot represent their nonnormal distributions. A 90% reduction of variances of E(max) and RR1/RR2 required a moving average of 15 and 24, respectively, arrhythmic beats on the average, whereas that of RR and HR required 60 beats on the average. These results indicate that a statistical characterization of arrhythmic cardiodynamic variables facilitates better understanding of cardiac performance during AF.
Animals↗