bluuebunny/crossref_metadata_2025 huggingface dataset:
Muscle metaboreflex control of cardiac output and peripheral vasoconstriction exhibit different latencies
Authors: Augustyniak Robert A. , Ansorge Eric J. , O'Leary Donal S.
Published: December 2017

Experiments were designed to determine 1) the mechanisms mediating metaboreflex-induced increases in systemic arterial pressure (SAP) in response to total vascular occlusion of hindlimb blood flow [e.g., increases in cardiac output (CO) vs. peripheral vasoconstriction] and 2) whether the individual mechanisms display differential latencies for the onset of the responses. Responses were observed in seven dogs performing steady-state treadmill exercise of mild and moderate workloads (3.2 km/h at 0% grade and 6.4 km/h at 10% grade). Differential latencies were exhibited among CO, nonischemic vascular conductance (NIVC; conductance to all nonischemic vascular beds), and renal vascular conductance (RVC), with peripheral vasoconstriction significantly preceding metaboreflex-mediated increases in CO. In addition, the latencies for SAP were not different from those for NIVC or RVC at either workload. During the lower workload there were small increases and then subsequent decreases in CO before the metaboreflex-induced increase in CO, which did contribute somewhat to the initial increases in SAP. However, the increases in CO mediated by the metaboreflex occurred significantly later than the initial increases in SAP. Therefore, we conclude that the substantial metaboreflex-mediated pressor responses that occur during the initial phase of total vascular occlusion during mild and moderate exercise are primarily caused by peripheral vasoconstriction.
Stretch-activated whole cell currents in adult rat cardiac myocytes
Authors: Zeng Tao , Bett Glenna C. L. , Sachs Frederick
Published: December 2017

Mechanoelectric transduction can initiate cardiac arrhythmias. To examine the origins of this effect at the cellular level, we made whole cell voltage-clamp recordings from acutely isolated rat ventricular myocytes under controlled strain. Longitudinal stretch elicited noninactivating inward cationic currents that increased the action potential duration. These stretch-activated currents could be blocked by 100 μM Gd3+but not by octanol. The current-voltage relationship was nearly linear, with a reversal potential of approximately −6 mV in normal Tyrode solution. Current density varied with sarcomere length (SL) according to I (pA/pF) = 8.3 − 5.0SL (μm). Repeated attempts to record single channel currents from stretch-activated ion channels failed, in accord with the absence of such data from the literature. The inability to record single channel currents may be a result of channels being located on internal membranes such as the T tubules or, possibly, inactivation of the channels by the mechanics of patch formation.
Protective roles of endogenous carbon monoxide in neointimal development elicited by arterial injury
Authors: Togane Yuko , Morita Toshisuke , Suematsu Makoto , Ishimura Yuzuru , Yamazaki Jun-Ichi , Katayama Shigehiro
Published: December 2017

We reported that carbon monoxide (CO) generated through heme oxygenase (HO) inhibits mitogen-induced proliferation of vascular smooth muscle cells (VSMCs). We report that balloon injury induces HO-1, the stress-inducible isozyme of HO, in VSMCs and inhibits neointimal formation through the action of endogenous CO. Northern blot analysis and immunohistochemistry revealed that HO-1 is markedly induced in the media as early as 1 day after injury, whereas only a little expression was detected in the intact carotid artery. The neointimal proliferative changes were augmented or inhibited by the HO inhibitors or inducer, respectively, and effects of these interventions were not altered by suppression of endogenous nitric oxide (NO), if any. To elucidate the mechanisms by which HO controls the proliferative changes, effects of alterations in the HO reaction were examined by determining angiotensin II-elicited VSMC proliferation in vitro: the HO inducer attenuated and its inhibitor restored the proliferative response to angiotensin II (1 nM and 100 nM). Hemoglobin, a reagent trapping both NO and CO, but not met-hemoglobin, which can capture NO but not CO, augmented the proliferative response. These data suggest that endogenous CO serves as a protective factor that limits the excessive VSMC proliferation associated with vascular diseases.
Group III muscle afferents evoke reflex depressor responses to repetitive muscle contractions in rabbits
Authors: Legramante J. M. , Raimondi G. , Adreani C. M. , Sacco S. , Iellamo F. , Peruzzi G. , Kaufman M. P.
Published: December 2017

Repetitive-twitch contraction of the hindlimb muscles in anesthetized rabbits consistently evokes a reflex depressor response, whereas this type of contraction in anesthetized cats evokes a reflex pressor response in about one-half of the preparations tested. Rapidly conducting group III fibers appear to comprise the afferent arm of the reflex arc, evoking the depressor response to twitch contraction in rabbits because electrical stimulation of their axons reflexly decreases arterial pressure. In contrast, electrical stimulation of the axons of slowly conducting group III and group IV afferents reflexly increases arterial pressure in rabbits. In the present study, we examined the discharge properties of group III and IV muscle afferents and found that the former (i.e., 13 of 20), but not the latter (i.e., 0 of 10), were stimulated by 5 min of repetitive-twitch contraction (1 Hz) of the rabbit triceps surae muscles. Moreover, most of the group III afferents responding to contraction appeared to be mechanically sensitive, discharging in synchrony with the muscle twitch. On average, rapidly conducting group III afferents responded for the 5-min duration of 1-Hz repetitive-twitch contraction, whereas slowly conducting group III afferents responded only for the first 2 min of contraction. We conclude that rapidly conducting group III afferents, which are mechanically sensitive, are primarily responsible for evoking the reflex depressor response to repetitive-twitch contractions in anesthetized rabbits.
Interaction of glutamine and arginine on cerebrovascular reactivity to hypercapnia
Authors: Okada Toshiki , Watanabe Yukinaga , Brusilow Saul W. , Traystman Richard J. , Koehler Raymond C.
Published: December 2017

Glutamine is purported to inhibit recycling of citrulline to arginine and to limit nitric oxide release in vitro. However, vasoactive effects of glutamine have not been clearly demonstrated in vivo. During hyperammonemia, impaired cerebrovascular reactivity to CO2 is related to glutamine accumulation. We tested the hypotheses that 1) glutamine infusion in the absence of hyperammonemia impairs cerebrovascular CO2 reactivity and 2) arginine infusion preserves CO2 reactivity during glutamine infusion and during hyperammonemia. Pentobarbital sodium-anesthetized rats were equipped with a closed cranial window for measuring pial arteriolar diameter. Intravenous infusion of 3 mmol ⋅ kg− 1 ⋅ h− 1of l-glutamine for 6 h produced threefold increases in plasma and cerebrospinal fluid concentrations. Dilation to hypercapnia was reduced by 45% compared with that of a time control group at 6 h but not at 3 h of glutamine infusion. Coinfusion of 2 mmol ⋅ kg− 1 ⋅ h− 1of l-arginine with glutamine maintained the hypercapnic vasodilation at the control value. Infusion of ammonium acetate at a rate known to produce threefold increases in cortical tissue glutamine concentration resulted in no significant hypercapnic vasodilation. Coinfusion of arginine with ammonium acetate maintained hypercapnic vasodilation at 60% of the control value. Arginine infusion did not augment hypercapnic vasodilation in a control group. We conclude that glutamine modulates cerebrovascular CO2 reactivity in vivo. Glutamine probably acts by limiting arginine availability because the vascular inhibitory effect required >3 h to develop and because arginine infusion counteracted the vascular effect of both endogenously and exogenously produced increases in glutamine.
Myocardial ischemia-reperfusion injury in estrogen receptor-α knockout and wild-type mice
Authors: Zhai Peiyong , Eurell Thomas E. , Cooke Paul S. , Lubahn Dennis B. , Gross David R.
Published: December 2017

We investigated the function of estrogen receptor-α in global myocardial ischemia and reperfusion injury in male estrogen receptor-α knockout (ERKO) and wild-type mice. Mouse hearts were subjected to 45 min of global ischemia followed by 180 min of reperfusion. The hearts were excised, cannulated, and maintained in a chilled (4°C) cardioplegia solution until warm (37°C) oxygenated Krebs-Henseleit bicarbonate buffer was perfused through the coronary arteries. ERKO hearts started beating later and had a higher incidence of ventricular fibrillation and/or tachycardia than control hearts. Coronary flow rate was significantly lower in ERKO hearts during the 90- and 120-min periods of reperfusion. Ca2+ accumulation was significantly greater following 30, 90, 120, 150, and 180 min of reperfusion in ERKO hearts. Nitrite production was significantly less in ERKO hearts following 90, 120, and 150 min of reperfusion. Myocardial reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was significantly lower in experimental ERKO hearts. Marked interstitial edema and contraction bands were seen in hematoxylin-eosin-stained sections of ischemia-reperfused ERKO hearts but not in control tissues. Hematoxylin-basic fuchsin-picric acid-stained sections from experimental ERKO hearts had fewer viable myocytes compared with controls. Transmission electron microscopy revealed swollen and fragmented mitochondria with amorphous and granular bodies, loss of matrix, and rupture of cristae in experimental ERKO hearts. This is the first demonstration that estrogen receptor-α plays a cardioprotective role in ischemia-reperfusion injury in males.
Cardioprotective effect of chronic hyperglycemia: effect on hypoxia-induced apoptosis and necrosis
Authors: Schaffer Stephen W. , Croft Cherry Ballard , Solodushko Viktoriya
Published: December 2017

It is generally accepted that mild forms of diabetes render the heart resistant to an ischemic insult. Because myocytes incubated chronically in medium containing high concentrations of glucose (25 mM) develop into a diabetes-like phenotype, we tested the hypothesis that high-glucose treatment diminishes hypoxia-induced injury. In support of this hypothesis, we found that cardiomyocytes incubated for 3 days with medium containing 25 mM glucose showed less hypoxia-induced apoptosis and necrosis than cells exposed to medium containing 5 mM glucose (control). Indeed, whereas 27% of control cells became necrotic after 1 h of chemical hypoxia with 10 mM deoxyglucose and 5 mM amobarbital (Amytal), only 11% of the glucose-treated cells became necrotic. Similarly, glucose treatment reduced the extent of apoptosis from 32% to 12%. This beneficial effect of glucose treatment was associated with a 40% reduction in the Ca2+content of the hypoxic cell. Glucose treatment also mediated an upregulation of the cardioprotective factor Bcl-2 but did not affect the cellular content of the proapoptotic factors Bax and Bad. Nonetheless, the phosphorylation state of Bad was shifted in favor of its inactive, phosphorylated form after high-glucose treatment. These data suggest that glucose treatment renders the cardiomyocyte resistant to hypoxia-induced apoptosis and necrosis by preventing the accumulation of Ca2+during hypoxia, promoting the upregulation of Bcl-2, and enhancing the inactivation of Bad.
Nonanticoagulant heparin inhibits NF-κB activation and attenuates myocardial reperfusion injury
Authors: Thourani Vinod H. , Brar Sukhdev S. , Kennedy Thomas P. , Thornton Lisa R. , Watts John A. , Ronson Russell S. , Zhao Zhi-Qing , Sturrock Anne L. , Hoidal John R. , Vinten-Johansen Jakob
Published: December 2017

Heparin reduces ischemia-reperfusion injury to myocardium. This effect has been attributed to complement inhibition, but heparin also has other activities that might diminish ischemia-reperfusion. To further probe these mechanisms, we compared heparin or an o-desulfated nonanticoagulant heparin with greatly reduced anticomplement activity. When given at the time of coronary artery reperfusion in a canine model of myocardial infarction, heparin or o-desulfated heparin equally reduced neutrophil adherence to ischemic-reperfused coronary artery endothelium, influx of neutrophils into ischemic-reperfused myocardium, myocardial necrosis, and release of creatine kinase into plasma. Heparin or o-desulfated heparin also prevented dysfunction of endothelial-dependent coronary relaxation following ischemic injury. In addition, heparin and o-desulfated heparin inhibited translocation of the transcription nuclear factor-κB (NF-κB) from the cytoplasm to the nucleus in human endothelial cells and decreased NF-κB DNA binding in human endothelium and ischemic-reperfused rat myocardium. Thus heparin and nonanticoagulant heparin decrease ischemia-reperfusion injury by disrupting multiple levels of the inflammatory cascade, including the novel observation that heparins inhibit activation of the proinflammatory transcription factor NF-κB.
Cumulative plot of heart rate variability spectrum assesses kinetics of action of cholinergic drugs in rats
Authors: Perlstein I. , Hoffman A.
Published: December 2017

A new approach to assess autonomic nervous system (ANS) activity and its response to drug action is presented. Our approach is based on the use of a cumulative plot of data obtained by power spectral analysis of heart rate variability, in defined frequency bands, during short time epochs (e.g., 2 min in rats). The substantial temporal variability in power evolving from the constant balancing nature of the ANS activity is minimized by this approach and produces a measurable index of ANS activity vs. time. The cumulative plot emphasizes the temporal response pattern of different components of the ANS and thereby facilitates the investigation of the kinetics of action of drugs affecting the ANS. We used this method to measure the activity of cholinergic drugs in freely moving Sabra rats. Bolus atropine doses between 0.5 and 2 mg/kg produced a similar magnitude of effect, reduction of the ascending slope by 0.003 power units/h, whereas the duration of this effect was dose dependent. A lower atropine dose (0.1 mg/kg) or 0.5 mg/kg scopolamine elevated the slope (0.074 and 0.054 power units/h for 206 and 216 min, respectively). The method was used similarly to assess the interaction between cholinergic drugs. Pretreatment with pyridostigmine produced temporal blockage of the anticholinergic activity of atropine.
Short-term variability of pulse pressure and systolic and diastolic time in heart transplant recipients
Authors: Chemla Denis , Aptecar Eduardo , Hébert Jean-Louis , Coirault Catherine , Loisance Daniel , Lecarpentier Yves , Nitenberg Alain
Published: December 2017

In heart transplant recipients (HTR), short-term systolic blood pressure variability is preserved, whereas heart rate variability is almost abolished. Heart period is the sum of left ventricular ejection time (LVET) and diastolic time (DT). In the present time-domain prospective study, we tested the hypothesis that short-term fluctuations in aortic pulse pressure (PP) in HTR were related to fluctuations in LVET. Seventeen male HTR (age 48 ± 6 yr) were studied 16 ± 11 mo after transplantation. Aortic root pressure was obtained over a 15-s period using a micromanometer both at rest ( n = 17) and following the cold pressor test (CPT, n = 14). There was a strong positive linear relationship between beat-to-beat LVET and beat-to-beat PP in all patients at rest and in 13 of 14 patients following CPT (each P < 0.01). The slope of this relationship showed little scatter both at rest (0.34 ± 0.07 mmHg/ms) and following CPT (0.35 ± 0.09 mmHg/ms, P = not significant). Given the essentially fixed heart period, DT varied inversely with LVET. As a result, in 13 of 17 HTR at rest and in 12 of 14 HTR following CPT, there was a negative linear relationship between beat-to-beat PP and DT. In conclusion, our short-term time-domain study demonstrated a strong positive linear relationship between LVET and blood pressure variability in male HTR. We also identified a subgroup of HTR in whom there was a mismatch between PP and DT.
Maturation of end-systolic stress-strain relations in chick embryonic myocardium
Authors: Tobita Kimimasa , Keller Bradley B.
Published: December 2017

The embryonic myocardium increases functional performance geometrically during cardiac morphogenesis. We investigated developmental changes in the in vivo end-systolic stress-strain relations of embryonic chick myocardium in stage 17, 21, and 24 white Leghorn chick embryos ( n = 10 for each stage). End-systolic stress-strain relations were linear in all developmental stages. End-systolic strain decreased from 0.50 ± 0.02 to 0.31 ± 0.01 (mean ± SE, P < 0.05), while average end-systolic wall stress was similar at 3.29 ± 0.34 to 4.19 ± 0.43 mmHg ( P = 0.14) from stage 17 to 24. Normalized end-systolic myocardial stiffness, a load-independent index of ventricular contractility, increased from 2.98 ± 0.19 to 6.03 ± 0.39 mmHg from stage 17 to 24 ( P < 0.05). Zero-stress midwall volume increased from 0.024 ± 0.002 to 0.124 ± 0.004 μl from stage 17 to 24 ( P < 0.05). These results suggest that the embryonic ventricle increases normalized ventricular “contractility” while maintaining average end-systolic wall stress over a relatively narrow range during cardiovascular morphogenesis.
Reinforcement of arteriolar myogenic activity by endogenous ANG II: susceptibility to dietary salt
Authors: Nurkiewicz Timothy R. , Boegehold Matthew A.
Published: December 2017

The purpose of this study was to determine whether endogenous ANG II augments arteriolar myogenic behavior in striated muscle. Because circulating ANG II is decreased during high salt intake, we also investigated whether dietary salt could alter any influence of ANG II on myogenic behavior. Normotensive rats fed low-salt (0.45%, LS) or high-salt (7%, HS) diets were enclosed in a ventilated box with the spinotrapezius muscle exteriorized for intravital microscopy. Dietary salt did not affect resting arteriolar diameters. Microvascular pressure elevation by box pressurization caused greater arteriolar constriction in LS rats (up to 12 μm) than in HS rats (up to 4 μm). The ANG II-receptor antagonists saralasin and losartan attenuated myogenic responsiveness in LS rats but not HS rats. The bradykinin-receptor antagonist HOE-140 had no effect on myogenic responsiveness in LS rats but augmented myogenic responsiveness in HS rats. HOE-140 with the angiotensin-converting enzyme inhibitor captopril attenuated myogenic responsiveness to a greater extent in LS rats than in HS rats. We conclude that endogenous ANG II normally reinforces arteriolar myogenic behavior in striated muscle and that attenuated myogenic behavior associated with high salt intake is due to decreased circulating ANG II and increased local kinin levels.
Effect of selective ETA receptor blockade on natriuretic peptide gene expression in DOCA-salt hypertension
Authors: Bianciotti Liliana G. , De Bold Adolfo J.
Published: December 2017

To determine the role of endothelin-1 (ET-1) in the upregulation of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) observed in deoxycorticosterone acetate (DOCA)-salt hypertension, the selective ET-1 type-A receptor (ETA) antagonist ABT-627 was chronically administered to normal controls and hypertensive rats. Chronic ETA blockade in DOCA-salt-treated rats prevented the increase in blood pressure and circulating natriuretic protein (NP) levels and partially prevented left ventricular hypertrophy. The changes observed in NP gene expression in the atria were not affected by ABT-627. In the ventricles, ABT-627 reduced NP gene expression. Rats receiving the ETA antagonist alone showed reduced left ventricular NP gene expression. ABT-627 did not affect ventricular collagen III gene expression but enhanced left ventricular α-myosin heavy chain expression. These findings suggest that in vivo, ventricular but not atrial NP production is regulated by ET-1. This difference in response between atrial and ventricular NP gene expression to ETA receptor blockade is similar to that observed by us after applying angiotensin-converting enzyme inhibitors in other hypertensive models. In general therefore, atrial NP gene expression may not be as sensitive to the endocrine environment as is ventricular NP gene expression.
Depressed modulation of oxygen consumption by endogenous nitric oxide in cardiac muscle from diabetic dogs
Authors: Zhao Gong , Zhang Xiaoping , Xu Xiaobin , Wolin Michael S. , Hintze Thomas H.
Published: December 2017

Our previous study indicated that nitric oxide (NO)-dependent coronary vasodilation was impaired in conscious dogs with diabetes. Our goal was to determine whether modulation of O2consumption by NO is depressed in canine cardiac muscle after diabetes. Diabetes was induced by injection of alloxan (40–60 mg/kg iv), dogs were killed after diabetes was induced (4–5 wk), and the cardiac muscle from the left ventricle was cut into 15- to 30-mg slices. O2uptake by the muscle slices was measured polarographically with a Clark-type O2electrode. S-nitroso- N-acetylpenicillamine decreased O2consumption in normal and diabetic tissues (10−4M, 61 ± 7 vs. 61 ± 8%, P > 0.05). Bradykinin (10−4M)- or carbachol (CCh, 10−4M)-induced inhibition of O2consumption was impaired in diabetic tissues (51 ± 6 vs. 17 ± 4% or 48 ± 4 vs. 19 ± 3%, respectively, both P < 0.05 compared with normal). The inhibition of O2consumption by kininogen or kallikrein was depressed in diabetic tissues as well. In coronary microvessels from diabetic dogs, bradykinin or ACh (10−5M) caused smaller increases in NO production than those from normal dogs. Our results indicate that the modulation of O2consumption by endogenous, but not exogenous, NO is depressed in cardiac muscle from diabetic dogs, most likely because of decreased release of NO from the vascular endothelium.
Role of superoxide in hemorrhagic shock-induced P-selectin expression
Authors: Akgür Feza M. , Brown Mark F. , Zibari Gazi B. , McDonald John C. , Epstein Charles J. , Ross Christopher R. , Granger D. Neil
Published: December 2017

Superoxide has been implicated in the regulation of endothelial cell adhesion molecule expression and the subsequent initiation of leukocyte-endothelial cell adhesion in different experimental models of inflammation. The objective of this study was to assess the contribution of oxygen radicals to P-selectin expression in a murine model of whole body ischemia-reperfusion, i.e., hemorrhage-resuscitation (H/R), with the use of different strategies that interfere with either the production (allopurinol, CD11/CD18-deficient or p47phox−/− mice) or accumulation [intravenous superoxide dismutase (SOD), mutant mice that overexpress SOD] of oxygen radicals. P-selectin expression was quantified in different regional vascular beds by use of the dual-radiolabeled monoclonal antibody technique. H/R elicited a significant increase in P-selectin expression in all vascular beds. This response was blunted in SOD transgenic mice and in wild-type mice receiving either intravenous SOD or the xanthine oxidase inhibitor allopurinol. Mice genetically deficient in either a subunit of NADPH oxidase or the leukocyte adhesion molecule CD11/CD18 also exhibited a reduced P-selectin expression. These results implicate superoxide, derived from both xanthine oxidase and NADPH oxidase, as mediators of the increased P-selectin expression observed in different regional vascular beds exposed to hemorrhage and retransfusion.
Lack of hypoxic stimulation of VEGF secretion from neutrophils and platelets
Authors: Koehne Petra , Willam Carsten , Strauss Evelyn , Schindler Ralf , Eckardt Kai-Uwe , Bührer Christoph
Published: December 2017

Low oxygen (O2) is the key stimulus for expression of vascular endothelial growth factor (VEGF) in several adherent cells. Whether hypoxia also directs the release of VEGF protein from neutrophils (polymorphonuclear neutrophils; PMN) and platelets has not been investigated. We therefore compared VEGF release of platelets, PMN, and human vascular smooth muscle cells (HSMC) in response to hypoxia with that to activators of cellular degranulation. In contrast to HSMC, VEGF release from PMN and platelets or VEGF mRNA expression in PMN was not stimulated under hypoxic conditions (1% O2). Hypo- or hyperthermia and acidosis, other conditions potentially associated with ischemic and inflammatory tissue injury, also did not stimulate VEGF secretion from PMN. However, stimulation of platelets with thrombin and of PMN with phorbol 12-myristate 13-acetate induced a time-dependent release of VEGF, peaking after 30 and 60 min, respectively. This was blocked by the degranulation inhibitor pentoxifylline but not by the protein-synthesis inhibitor cycloheximide. We conclude that rapid release of VEGF from platelets and PMN may occur independently of oxygenation during inflammation and hemostasis.
High-calcium diet enhances vasorelaxation in nitric oxide-deficient hypertension
Authors: Jolma Pasi , Kalliovalkama Jarkko , Tolvanen Jari-Petteri , Kööbi Peeter , Kähönen Mika , Hutri-Kähönen Nina , Wu Xiumin , Pörsti Ilkka
Published: December 2017

Because the effects of calcium supplementation on arterial tone in nitric oxide-deficient hypertension are unknown, we investigated the influence of elevating dietary calcium from 1.1 to 3.0% in Wistar rats treated with N G-nitro-l-arginine methyl ester (l-NAME; 20 mg · kg−1 · day−1) for 8 wk. A high-calcium diet attenuated the development of hypertension induced by l-NAME and abrogated the associated impairments of endothelium-independent mesenteric arterial relaxations to nitroprusside, isoproterenol, and cromakalim. Endothelium-dependent relaxations to acetylcholine during nitric oxide synthase inhibition in vitro were decreased in l-NAME rats and improved by calcium supplementation. The inhibition of cyclooxygenase by diclofenac augmented the responses to acetylcholine in l-NAME rats but not in calcium + l-NAME rats. When hyperpolarization of smooth muscle was prevented by KCl precontraction, the responses to acetylcholine during combined nitric oxide synthase and cyclooxygenase inhibition were similar in all groups. Furthermore, superoxide dismutase enhanced the acetylcholine-induced relaxations in l-NAME rats but not in calcium + l-NAME rats. In conclusion, calcium supplementation reduced blood pressure during chronic nitric oxide synthase inhibition and abrogated the associated impairments in endothelium-dependent and -independent arterial relaxation. The augmented vasorelaxation after increased calcium intake inl-NAME hypertension may be explained by enhanced hyperpolarization and increased sensitivity to nitric oxide in arterial smooth muscle and decreased vascular production of superoxide and vasoconstrictor prostanoids.
Left ventricular wall stress normalization in chronic pressure-overloaded heart: a mathematical model study
Authors: Segers Patrick , Stergiopulos Nikos , Schreuder Jan J. , Westerhof Berend E. , Westerhof Nico
Published: December 2017

It is generally accepted that the left ventricle (LV) hypertrophies (LVH) to normalize systolic wall stress (ςs) in chronic pressure overload. However, LV filling pressure (Pv) may be elevated as well, supporting the alternative hypothesis of end-diastolic wall stress (ςd) normalization in LVH. We used an LV time-varying elastance model coupled to an arterial four-element lumped-parameter model to study ventricular-arterial interaction in hypertension-induced LVH. We assessed model parameters for normotensive controls and applied arterial changes as observed in hypertensive patients with LVH (resistance +40%, compliance −25%) and assumed 1) no cardiac adaptation, 2) normalization of ςs by LVH, and 3) normalization of ςs by LVH and increase in Pv, such that ςd is normalized as well. In patients, systolic and diastolic blood pressures increase by ∼40%, cardiac output (CO) is constant, and wall thickness increases by 30–55%. In scenarios 1 and 2, blood pressure increased by only 10% while CO dropped by 20%. In scenario 2, LV wall thickness increased by only 10%. The predictions of scenario 3 were in qualitative and quantitative agreement with in vivo human data. LVH thus contributes to the elevated blood pressure in hypertension, and cardiac adaptations include an increase in Pv, normalization of ςs, and preservation of CO in the presence of an impaired diastolic function.
Role of ductus venosus in distribution of umbilical blood flow in human fetuses during second half of pregnancy
Authors: Bellotti Maria , Pennati Giancarlo , De Gasperi Camilla , Battaglia Frederick C. , Ferrazzi Enrico
Published: December 2017

Color Doppler sonography was used to study umbilical and ductus venosus (DV) flow in 137 normal fetuses between 20 and 38 wk of gestation. Hepatic flows were also evaluated. In all parts of the venous circulation examined, blood flow increased significantly with advancing gestational age. The weight-specific amniotic umbilical flow did not change significantly during gestation (120 ± 44 ml · min−1· kg−1), whereas DV flow decreased significantly (from 60 to 17 ml · min−1· kg−1). The percentage of umbilical blood flow shunted through the DV decreased significantly (from 40% to 15%); consequently, the percentage of flow to the liver increased. The right lobe flow changed from 20 to 45%, whereas the left lobe flow was approximately constant (40%). These changes are related to different patterns of growth of the umbilical veins and DV diameters. The present data support the hypothesis that the DV plays a less important role in shunting well-oxygenated blood to the brain and myocardium in late normal pregnancy than in early gestation, which leads to increased fetal liver perfusion.
Efficiency of energy transfer, but not external work, is maximized in stunned myocardium
Authors: Trines Serge A. I. P. , Slager Cornelis J. , Van der Moer Joost , Verdouw Pieter D. , Krams Rob
Published: December 2017

There is no evidence regarding the effect of stunning on maximization of regional myocardial external work (EW) or efficiency of energy transfer (EET) in relation to regional afterload (end-systolic stress, ςes). To that end, we studied these relationships in both the left anterior descending coronary artery (LADCA) and left circumflex coronary artery regions in anesthetized, open-chest pigs before and after LADCA stunning. In normal myocardium, EET vs. ςes was maximal at 75.4 (69.7–81.0)%, whereas EW vs. ςes was submaximal at 12.0 (6.61–17.3) × 102 J/m3. Increasing ςes increased EW by 18 (10–27)%. Regional myocardial stunning decreased EET (27%) and EW (36%) and caused the myocardium to operate both at maximal EW (EWmax) and at maximal EET (EETmax). EET and EW became also more sensitive to changes in ςes. In the nonstunned region the situation remained unchanged. Combining the data from before and after stunning, both EWmax and EETmax displayed a positive relationship with contractility. In conclusion, the normal regional myocardium operated at maximal EET rather than at maximal EW. Therefore, additional EW could be recruited by increasing regional afterload. After myocardial stunning, the myocardium operated at both maximal EW and maximal EET, at the cost of increased afterload sensitivity. Contractility was a major determinant of this shift.
Myocyte cytoskeletal disorganization and right heart failure in hypoxia-induced neonatal pulmonary hypertension
Authors: Lemler Matthew S. , Bies Roger D. , Frid Maria G. , Sastravaha Amornrate , Zisman Lawrence S. , Bohlmeyer Teresa , Gerdes A. Martin , Reeves John T. , Stenmark Kurt R.
Published: December 2017

Previous studies have demonstrated that environmentally or genetically induced changes in the intracellular proteins that compose the cytoskeleton can contribute to heart failure. Because neonatal right ventricular myocytes are immature and are in the process of significant cytoskeletal change, we hypothesized that they may be particularly susceptible to pressure stress. Newborn calves exposed to hypobaric hypoxia (barometric pressure = 430 mmHg) for 14 days developed severe pulmonary hypertension (pulmonary arterial pressure = 101 ± 6 vs. 27 ± 1 mmHg) and right heart failure compared with age-matched controls. Light microscopy showed partial loss of myocardial striations in the failing neonatal right but not left ventricles and in neither ventricle of adolescent cattle dying of altitude-induced right heart failure. In neonatal calves, immunohistochemical analysis of the cytoskeletal proteins (vinculin, metavinculin, desmin, vimentin, and cadherin) showed selectively, within the failing right ventricles, patchy areas characterized by loss and disorganization of costameres and intercalated discs. Within myocytes from the failing ventricles, vinculin and desmin were observed to redistribute diffusely within the cytosol, metavinculin appeared in disorganized clumps, and vimentin immunoreactivity was markedly decreased. Western blot analysis of the failing right ventricular myocardium showed, compared with control, vinculin and desmin to be little changed in total content but redistributed from insoluble (structural) to soluble (cytosolic) fractions; metavinculin total content was markedly decreased, tubulin content increased, particularly in the structural fraction, and cadherin total content and distribution were unchanged. We conclude that hypoxic pulmonary hypertensive-induced neonatal right ventricular failure is associated with disorganization of the cytoskeletal architecture.
Transmyocardial revascularization aggravates myocardial ischemia around the channels in the immediate phase
Authors: Hattan Naoichiro , Ban Kazunobu , Tanaka Etsuro , Abe Sumihisa , Sekka Takafumi , Sugio Yoshinori , Mohammed Minhaz U. , Sato Eriko , Shinozai Yoshiro , Onishi Yozo , Suma Hisayoshi , Handa Shunnosuke , Kawada Shiaki , Hori Shingo , Iida Atsuo , Nakazawa Hiroe , Mori Hidezo
Published: December 2017

We examined whether transmyocardial revascularization (TMR) relieves myocardial ischemia by increasing regional perfusion via the transmural channels in acute canine experiments. Regional blood flow during transient coronary ligation (2 min) was compared before and 30 min after TMR, and at the third transient ischemia the mid-left ventricle (LV) was cut and immediately frozen along the short axis for the analysis of NADH fluorescence in the regions around the TMR channels. In low-resolution analysis (2–4 g tissue or 2–3 cm2 area), regional perfusion was not significantly altered after TMR, and NADH fluorescence was observed throughout the ischemic region without significant spatial variation. High-resolution analysis (2.8 mg, 1 mm × 1 mm) revealed that the flow after TMR was lower, and NADH fluorescence was higher in the regions close to the channels (1–2 mm) than in the regions 3–4 mm away from them. Creating TMR channels did not improve the regional perfusion and rather aggravated the local ischemia in the vicinity of the channels in the immediate phase.
Influence of erythrocyte aggregation on leukocyte margination in postcapillary venules of rat mesentery
Authors: Pearson Mark J. , Lipowsky Herbert H.
Published: December 2017

The role of erythrocyte (red blood cell; RBC) aggregation in affecting leukocyte (white blood cell; WBC) margination in postcapillary venules of the mesentery (rat) was explored by direct intravital microscopy. Optical techniques were refined and applied to relate the light-scattering properties of RBCs to obtain a quantitative index of aggregate size ( G), which, under idealized conditions, represents the number of RBCs per aggregate. WBC margination, defined as the radial migration of WBCs to the venular wall and their subsequent rolling along the endothelium, was measured as the percentage of the potentially maximal WBC volumetric flux within the microvessel lumen ( F WBC ∗). In normal blood, F WBC ∗ increased exponentially fourfold, and G increased from 1 to 1.15 as wall shear rates (γ˙) were reduced from a steady-state value of ∼600 to <100 s−1 by proximal occlusion with a blunt microprobe. Enhancement of aggregation by infusion (iv) of dextran 500 (428 kDa), to attain a systemic concentration of 3 g/100 ml, resulted in a four- and sevenfold increase in G and F WBC ∗, respectively, as γ˙was reduced below 100 s−1. Inhibition of RBC aggregation by infusion of dextran 40 (37.5 kDa) caused F WBC ∗ to fall to one-half of its steady-state level for γ˙ < 100 s−1. Thus it appears that the well-known increase of WBC margination with reductions in γ˙ is strongly dependent on the occurrence of RBC aggregation. Increasing the extent of RBC aggregation during reductions in γ˙ also increased the firm adhesion of WBCs to the endothelium because of an enhanced probability of contact between leukocytes and the postcapillary venular wall.
Role of protein kinase C in α1-adrenergic regulation of aNaiin guinea pig ventricular myocytes
Authors: Jo Su-Hyun , Cho Chung-Hyun , Chae Soo Wan , Lee Chin O.
Published: December 2017

We investigated the role of protein kinase C (PKC) in α1-adrenergic regulation of intracellular Na+activity (aNai) in single guinea pig ventricular myocytes. aNaiand membrane potentials were measured with the Na+-sensitive indicator sodium-binding benzofuran isophthalate and conventional microelectrodes, respectively, at room temperature (24–26°C) while myocytes were stimulated at a rate of 0.25–0.3 Hz. The PKC activator 4β-phorbol 12-myristate 13-acetate (PMA) decreased aNaiin a concentration-dependent manner. PMA (100 nM) produced a maximal decrease in aNaiof 1.5 mM from 6.5 ± 0.4 to 5.0 ± 0.4 mM (means ± SE, n = 12, P< 0.01). The PMA concentration required for a half-maximal decrease in aNaiwas 0.46 ± 0.13 nM ( n = 3, P < 0.01). An inactive phorbol, 4α-phorbol 12-myristate 13-acetate, did not decrease aNai. The decrease caused by PMA could be blocked by the PKC inhibitors staurosporine and bisindolylmaleimide I (GF-109203X). Stimulation of the α1-adrenoceptor with 50 μM phenylephrine decreased aNaifrom 6.1 ± 0.3 to 4.6 ± 0.3 mM ( n = 11, P< 0.01). The decrease in aNaiproduced by phenylephrine was blocked by pretreatment with staurosporine, GF-109203X, or PMA. The decrease in aNaiproduced by PMA was not prevented by pretreatment with tetrodotoxin but was blocked by pretreatment with strophanthidin or high extracellular K+concentration. The results suggest that α1-adrenergic receptor activation results in a decrease in aNaivia PKC-induced stimulation of the Na+-K+pump in cardiac myocytes.
2,3-Butanedione monoxime unmasks Ca2+-induced NADH formation and inhibits electron transport in rat hearts
Authors: Scaduto Russell C. , Grotyohann Lee W.
Published: December 2017

We used 2,3-butanedione monoxime (BDM) to suppress work by the perfused rat heart and to investigate the effects of calcium on NADH production and tissue energetics. Hearts were perfused with buffer containing BDM and elevated perfusate calcium to maintain the rates of cardiac work and oxygen consumption at levels similar to those of control perfused hearts. BDM plus calcium hearts displayed higher levels of NADH surface fluorescence, indicating calcium activation of mitochondrial dehydrogenases. These hearts, however, displayed 20% lower phosphocreatine levels. BDM suppressed the rates of state 3 respiration of isolated mitochondria. Uncoupled respiration was suppressed to a lesser degree, and the state 4 respiration rates were not affected. Double-inhibitor experiments with liver mitochondria using BDM and carboxyatractyloside (CAT) were used to identify the site of inhibition. BDM at low levels (0–5 mM) suppressed respiration. In the presence of CAT at levels that inhibit respiration by 60%, low levels of BDM were without effect. Because these effects were not additive, BDM does not inhibit adenine nucleotide transport. This was supported by an assay of adenine nucleotide transport in liver mitochondria. BDM did not inhibit ATP hydrolysis by submitochondrial particles but strongly suppressed reversed electron transport from succinate to NAD+. Oxidation of NADH by submitochondrial particles was inhibited by BDM but oxidation of succinate was not. We conclude that BDM inhibits electron transport at site 1.
Cardiovascular and neuroendocrine responses to water immersion in compensated heart failure
Authors: Gabrielsen Anders , Sørensen Vibeke B. , Pump Bettina , Galatius Søren , Videbæk Regitze , Bie Peter , Warberg Jørgen , Christensen Niels Juel , Wroblewski Henrik , Kastrup Jens , Norsk Peter
Published: December 2017

The hypothesis was tested that cardiovascular and neuroendocrine (norepinephrine, renin, and vasopressin) responses to central blood volume expansion are blunted in compensated heart failure (HF). Nine HF patients [New York Heart Association class II–III, ejection fraction = 0.28 ± 0.02 (SE)] and 10 age-matched controls (ejection fraction = 0.68 ± 0.03) underwent 30 min of thermoneutral (34.7 ± 0.02°C) water immersion (WI) to the xiphoid process. WI increased ( P < 0.05) central venous pressure by 3.7 ± 0.6 and 3.2 ± 0.4 mmHg and stroke volume index by 12.2 ± 2.1 and 7.2 ± 2.1 ml · beat−1 · m−2 in controls and HF patients, respectively. During WI, systemic vascular resistance decreased ( P < 0.05) similarly by 365 ± 66 and 582 ± 227 dyn · s · cm−5 in controls and HF patients, respectively. Forearm subcutaneous vascular resistance decreased by 19 ± 7% ( P < 0.05) in controls but did not change in HF patients. Heart rate decreased less during WI in HF patients, whereas release of norepinephrine, renin, and vasopressin was suppressed similarly in the two groups. We suggest that reflex control of forearm vascular beds and heart rate is blunted in compensated HF but that baroreflex-mediated systemic vasodilatation and neuroendocrine responses to central blood volume expansion are preserved.
Echocardiographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude
Authors: Allemann Yves , Sartori Claudio , Lepori Mattia , Pierre Sébastien , Mélot Christian , Naeije Robert , Scherrer Urs , Maggiorini Marco
Published: December 2017

Exaggerated hypoxia-induced pulmonary hypertension is a hallmark of high-altitude pulmonary edema (HAPE) and plays a major role in its pathogenesis. Many studies of HAPE have estimated systolic pulmonary arterial pressure (SPAP) with Doppler echocardiography. Whereas at low altitude, Doppler echocardiographic estimation of SPAP correlates closely with its invasive measurement, no such evidence exists for estimations obtained at high altitude, where alterations of blood viscosity may invalidate the simplified Bernoulli equation. We measured SPAP by Doppler echocardiography and invasively in 14 mountaineers prone to HAPE and in 14 mountaineers resistant to this condition at 4,559 m. Mountaineers prone to HAPE had more pronounced pulmonary hypertension (57 ± 12 and 58 ± 10 mmHg for noninvasive and invasive determination, respectively; means ± SD) than subjects resistant to HAPE (37 ± 8 and 37 ± 6 mmHg, respectively), and the values measured in the two groups as a whole covered a wide range of pulmonary arterial pressures (30–83 mmHg). Spearman test showed a highly significant correlation ( r = 0.89, P < 0.0001) between estimated and invasively measured SPAP values. The mean difference between invasively measured and Doppler-estimated SPAP was 0.5 ± 8 mmHg. At high altitude, estimation of SPAP by Doppler echocardiography is an accurate and reproducible method that correlates closely with its invasive measurement.
Genetic mapping of quantitative trait loci influencing left ventricular mass in rats
Authors: Tsujita Yasuyuki , Iwai Naoharu , Tamaki Shinji , Nakamura Yasuyuki , Nishimura Masato , Kinoshita Masahiko
Published: December 2017

High blood pressure is the leading cause of left ventricular hypertrophy (LVH); however, not all hypertensive patients develop LVH. Genetic factors are important in the development of LVH. With the use of F2 male rats from spontaneously hypertensive rats and Lewis rats, we performed a study to identify the quantitative trait loci (QTL) that influence left ventricular mass (LVM). Mean arterial pressure (MAP) was measured by the direct intra-arterial method in conscious animals, and LVM was determined at 24 wk of age. QTL analysis was done using 160 microsatellite markers for a genome-wide scan. Two loci that influenced body weight-adjusted LVM with logarithm of the odds scores >3.4 were found. One locus on chromosome 17 influenced LVM independently of MAP. Another locus on chromosome 7 influenced LVM and MAP. These findings indicate not only the existence of a gene on chromosome 7 that influences LVM in a manner dependent on blood pressure but also the existence of a gene on chromosome 17 that influences LVM independently of blood pressure.
Inhibition of adenosine kinase induces expression of VEGF mRNA and protein in myocardial myoblasts
Authors: Gu Jian-Wei , Ito Bruce R. , Sartin Amanda , Frascogna Nan , Moore Michael , Adair Thomas H.
Published: December 2017

We tested whether increased endogenous adenosine produced by the adenosine kinase inhibitor GP-515 (Metabasis Therapeutics) can induce vascular endothelial growth factor (VEGF) expression in cultured rat myocardial myoblasts (RMMs). RMMs were cultured for 18 h in the absence (control) and presence of GP-515, adenosine (Ado), adenosine deaminase (ADA), or GP-515 + ADA. GP-515 (0.2–200 μM) caused a dose-related increase in VEGF protein expression (1.99–2.84 ng/mg total cell protein); control VEGF was 1.84 ± 0.05 ng/mg. GP-515 at 2 and 20 μM also increased VEGF mRNA by 1.67- and 1.82-fold, respectively. ADA (10 U/ml) decreased baseline VEGF protein levels by 60% and completely blocked GP-515 induction of VEGF. Ado (20 μM) and GP-515 (20 μM) caused a 59 and 39% increase in VEGF protein expression and a 98 and 33% increase in human umbilical vein endothelial cell proliferation, respectively, after 24 h of exposure. GP-515 (20 μM) had no effect on VEGF protein expression during severe hypoxia (1% O2) but increased VEGF by an additional 27% during mild hypoxia (10% O2). These results indicate that raising endogenous levels of Ado through inhibition of adenosine kinase can increase the expression of VEGF and stimulate endothelial cell proliferation during normoxic and hypoxic conditions.
Mechanism of adenosine-induced vasodilation in rat diaphragm microcirculation
Authors: Chen Chang-Wen , Chang Han-Yu , Hsiue Tzuen-Ren
Published: December 2017

The mechanism of adenosine-induced vasodilation in rat diaphragm microcirculation was investigated using laser Doppler flowmetry. Adenosine (10−5, 3.2 × 10−5, and 10−4 M), the nonselective adenosine agonist 5′- N-ethylcarboxamido-adenosine (NECA) (10−8-10−7 M), the specific A2Aagonist 2- p-(2-carboxyethyl)phenyl-amino-5′- N-ethyl carboxamidoadenosine (CGS-21680) (10−8-10−7M), and the adenosine agonist with higher A1-receptor affinity, R- N 6-phenylisopropyladenosine ( R-PIA) (10−7, 3.2 × 10−7, and 10−6 M) elicited a similar degree of incremental increase of microcirculatory flow in a dose-dependent manner. The ATP-dependent potassium (KATP) channel blocker glibenclamide (3.2 × 10−6 M) significantly attenuated the vasodilation effects of these agonists. Adenosine-induced vasodilation could be significantly attenuated by the nonselective adenosine antagonist 8-( p-sulfophenyl)-theophylline (3 × 10−5M) or the selective A2A antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl) phenol (ZM-241385, 10−6 M), but not by the selective A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (5 × 10−8 M). Adenylate cyclase inhibitor N-( cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride (MDL-12330A, 10−5M) effectively suppressed the vasodilator response of adenosine and forskolin. These results suggest that adenosine-induced vasodilation in rat diaphragm microcirculation is mediated through the stimulation of A2A receptors, which are coupled to adenylate cyclase activation and opening of the KATP channel.