bluuebunny/crossref_metadata_2025 huggingface dataset:
Lumped constant for deoxyglucose is decreased when myocardial glucose uptake is enhanced
Authors: Hashimoto Katsuji , Nishimura Tsunehiko , Imahashi Ken-Ichi , Yamaguchi Hitoshi , Hori Masatsugu , Kusuoka Hideo
Published: December 2017

Quantification of myocardial glucose uptake by positron emission tomography with [18F]fluorodeoxyglucose (FDG) requires the “lumped constant” (LC), which corrects the difference of affinity between glucose and FDG to glucose transporters and phosphorylating system. Since LC was introduced, it has been considered to be constant. However, this has recently been questioned. To elucidate the constancy of LC by other than radioisotope techniques, the accumulation rate of sugar phosphates (d[SP]/d t) was measured in isolated, perfused rat hearts by31P NMR spectroscopy with 2-deoxyglucose (DG). We postulate α as the affinity of DG to transporters and the phosphorylating system relative to that of glucose. Theoretically, α is equivalent to LC. We determined α by measuring d[SP]/d t at DG concentration ([DG]) = 10, 7, 5, and 3 mmol/l, keeping the total of glucose concentration ([glucose]) and [DG] to 10 mmol/l. When the glucose uptake was enhanced by insulin (10 mU/ml) or stunning, calculated α was reduced (insulin stimulated, 0.15; stunning, 0.19) compared with the control (0.59). These results indicate that LC can be evaluated by methods without radiolabeled tracers and is smaller when glucose uptake is augmented.
Suppression of β-adrenergic responsiveness of L-type Ca2+ current by IL-1β in rat ventricular myocytes
Authors: Liu Shi J. , Zhou Weiguo , Kennedy Richard H.
Published: December 2017

The possible mechanism by which interleukin-1β (IL-1β) affects β-adrenergic responsiveness of L-type Ca2+ current ( I Ca,L) was examined in adult rat ventricular myocytes by use of whole cell patch-clamp techniques. In the presence of isoproterenol (Iso), exposure for 3 min to IL-1β suppressed the Iso-activated I Ca,L. In the presence of IL-1β, the response of I Ca,L to Iso was decreased, and the EC50 for Iso stimulation was increased. However, IL-1β had no effect on [3H]CGP-12177 binding, displacement of [3H]CGP-12177 binding by Iso, or on basal and Iso-enhanced cAMP content. When I Ca,L was activated by extracellular application of forskolin or 8-(4-chlorophenylthio)-cAMP, a membrane-permeable cAMP analog, or by intracellular dialysis with cAMP, IL-1β had little effect on I Ca,L. In contrast, in the presence of cAMP, IL-1β still suppressed the Iso-enhanced I Ca,L. These results show that the IL-1β-induced decrease in β-adrenergic responsiveness of I Ca,L does not result from inhibition of β-adrenoceptor binding, adenylyl cyclase activity, or cAMP-mediated pathways, suggesting a cAMP-independent mechanism.
PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+activation of PDH
Authors: Pepe Salvatore , Tsuchiya Naotaka , Lakatta Edward G. , Hansford Richard G.
Published: December 2017

Aberrations in cell Ca2+homeostasis have been known to parallel both changes in membrane lipid composition and aging. Previous work has shown that the lowered efficiency of work performance, which occurs in isolated hearts from rats fed a diet rich in n–6 polyunsaturated fatty acids (PUFA), relative to those fed n–3 PUFA, could be raised by mitochondrial (Mito) Ca2+transport inhibition. We tested whether, after Ca2+-dependent stress, the Ca2+-dependent activation of pyruvate dehydrogenase (PDHA/PDHTotal) and Mito Ca2+cycling could be manipulated by varying the ratio of n–3 to n–6 PUFA in Mito membranes in young (6 mo) and aged (24 mo) isolated rat hearts treated to n–3 or n–6 PUFA-rich diet. Inotropic stimulation by 1 μM norepinephrine (NE) of 24-mo n–6 PUFA-rich hearts elevated total Mito Ca2+content 38% more than in 6-mo hearts ( P < 0.05). However, both the NE-induced rise in Mito Ca2+and the difference in response between 6- and 24-mo hearts were partially abolished by n–3 PUFA treatment. NE increased the fractional activation of PDH by 44% above control levels in the 6-mo group compared with 49% in the 24-mo group after n–6 PUFA diet. However, NE stimulation of PDHAwas attenuated by n–3 PUFA diet, attaining values only 29 and 23% above control levels in 6- and 24-mo mitochondria, respectively ( P < 0.05). Global ischemia and reperfusion (I/R) in n–6 PUFA hearts gave rise to higher levels of total Mito Ca2+concentration ( P < 0.0001) and PDHA( P < 0.0001) compared with n–3 PUFA. Ruthenium red (3.4 μM) abolished the effects of I/R in all groups. With aging, heart Mito membrane phosphatidylcholine was increased after n–6 PUFA-rich diet (by ∼15%, P < 0.05), whereas cardiolipin and n–3 PUFA content were diminished by 31% ( P < 0.05) and 73% ( P < 0.05), respectively. These effects were prevented by n–3 PUFA-rich diet. The present study, by directly manipulating the cardiac Mito membrane n–3-to-n–6 PUFA ratio, shows that the activation of Ca2+-dependent PDH can be augmented when the n–3-to-n–6 PUFA ratio is low (n–6 PUFA-rich diet; 24-mo hearts) or attenuated when this ratio is relatively high (n–3 PUFA-rich diet). We propose that one of the consequences of dietary-induced manipulation of membrane phospholipids and PUFAs may be the altered flux of Ca2+across the Mito membrane and thus altered intramitochondrial Ca2+-dependent processes.
GABAergic effects on the depressor responses elicited by stimulation of central nucleus of the amygdala
Authors: Ciriello John , Roder Stefanie
Published: December 2017

GABAergic inputs have been demonstrated in the central nucleus of the amygdala (ACe). However, the contribution of these inhibitory inputs to the cardiovascular responses elicited from the ACe is not known. Experiments were done in chloralose-anesthetized, paralyzed, and artificially ventilated male Wistar rats to investigate the effects of microinjections of GABA, the selective GABAA-receptor antagonist bicuculline, or the GABAB-receptor antagonist phaclofen, in the ACe on the mean arterial pressure (MAP) and heart rate (HR) responses elicited byl-glutamate (Glu) stimulation of the ACe. Microinjections of Glu in the ACe elicited decreases in MAP (−13.7 ± 1.6 mmHg) and HR (−5.3 ± 1.9 beats/min). The MAP and HR responses elicited by Glu stimulation of the ACe were significantly reduced (89%) by the prior microinjection of GABA in the same ACe site. In addition, at some sites in the ACe at which microinjection of Glu did not elicit depressor responses, Glu injections in the presence of phaclofen elicited decreases in MAP (−9.5 ± 1.0 mmHg) and variable changes in HR. On the other hand, the magnitude of the depressor responses elicited during stimulation of the ACe site in the presence of bicuculline was significantly attenuated (60%), whereas phaclofen had no effect on the magnitude of the depressor responses elicited by Glu stimulation of the ACe. These data suggest that GABAergic mechanisms in the ACe alter the excitability of ACe neurons involved in mediating changes in systemic arterial pressure and HR.
The heart extrasystole: an energetic approach
Authors: Marengo Fernando D. , Márquez María T. , Bonazzola Patricia , Ponce-Hornos Jorge E.
Published: December 2017

The consequences of an extrasystole (ES) on cardiac muscle’s energetics and Ca2+homeostasis were investigated in the beating heart. The fraction of heat release related to pressure development (pressure dependent) and pressure-independent heat release were measured during isovolumic contractions in arterially perfused rat ventricle. The heat release by a contraction showed two pressure-independent components (H1 and H2) of short evolution and a pressure-dependent component (H3). The additional heat released by ES was decomposed into one pressure-independent ([Formula: see text]) and one pressure-dependent ([Formula: see text]) component with time courses similar to those of control components H2 and H3. ES also induced the potentiation of pressure development (P) and heat release during the postextrasystolic (PES) beat. The slope of the linear relationship between pressure-dependent heat and pressure maintenance was similar in control, ES, and PES contractions (0.08 ± 0.01, 0.10 ± 0.02, and 0.08 ± 0.01 mJ ⋅ g−1⋅ mmHg−1⋅ s−1, respectively). The potentiation of H2 (heat component related with Ca2+removal processes) in PES was equal to [Formula: see text] at 0.3, 0.5, 1, and 2 mM Ca2+, suggesting that the extra amount of Ca2+mobilized during ES was recycled in PES. Pretreatment with 1 mM caffeine to deplete sarcoplasmic reticulum Ca2+content inhibited both the mechanical and energetic potentiation of PES. However, the heat released and the pressure developed during ES were not changed by sarcoplasmic reticulum depletion. The results suggest that 1) the source of Ca2+for ES would be entirely extracellular, 2) the Ca2+entered during ES is accumulated in the sarcoplasmic reticulum, and 3) the Ca2+stored by the sarcoplasmic reticulum during ES induces an increased contribution of this organelle during PES compared with the normal contraction.
Rostral dorsolateral pontine neurons with sympathetic nerve-related activity
Authors: Barman Susan M. , Gebber Gerard L. , Kitchens Heather
Published: December 2017

Spike-triggered averaging, arterial pulse-triggered analysis, and coherence analysis were used to classify rostral dorsolateral pontine (RDLP) neurons into groups whose naturally occurring discharges were correlated to only the 10-Hz rhythm ( n = 29), to only the cardiac-related rhythm ( n = 15), and to both rhythms ( n = 15) in inferior cardiac sympathetic nerve discharge (SND) of urethan-anesthetized cats. Most of the neurons with activity correlated to only the cardiac-related rhythm were located medial to the other two groups of neurons. The firing rates of most RDLP neurons with activity correlated to only the 10-Hz rhythm (9 of 12) or both rhythms (7 of 8) were decreased during baroreceptor reflex-induced inhibition of SND produced by aortic obstruction; thus, they are presumed to be sympathoexcitatory. The firing rates of four of seven RDLP neurons with activity correlated to only the cardiac-related rhythm increased during baroreceptor reflex activation; thus, they may be sympathoinhibitory. We conclude that the RDLP contains a functionally heterogeneous population of neurons with sympathetic nerve-related activity. These neurons could not be antidromically activated by stimulation of the thoracic spinal cord.
A method for collecting right coronary venous blood samples from conscious dogs
Authors: Bian Xiaoming , Hart Bradley J. , Williams Arthur G. , Downey H. Fred
Published: December 2017

This report describes for the first time a technique to collect right coronary venous blood samples from conscious dogs. Catheters, prepared from Micro-Renathane tubing, were surgically implanted in right ventricular superficial veins of three anesthetized dogs. Also implanted were an arterial catheter, a right coronary flow transducer, and a right coronary artery constrictor. The coronary catheter was introduced at a venous bifurcation so that its side holes were positioned above the bifurcation; both ends of the catheter were exteriorized. Heparinized saline was continuously infused through the venous catheter by a battery-powered pump. The dogs were maintained for 10–13 days after surgery, and all catheters remained patent. Multiple right coronary venous samples were collected from each dog. These samples were analyzed for venous oxygen tension ([Formula: see text]) under baseline conditions, with right coronary pressure reduced to 50 mmHg, and during the reactive hyperemia after release of the right coronary artery constriction.[Formula: see text] was 27.7 ± 1.0 mmHg at baseline, 23.4 ± 1.0 mmHg during coronary artery constriction, and 34.3 ± 1.5 mmHg during reactive hyperemia. These data and the position of the catheter at autopsy demonstrated that coronary venous blood had been sampled.
Nicotine-modified postinfarction left ventricular remodeling
Authors: Villarreal Francisco J. , Hong Derrick , Omens Jeffrey
Published: December 2017

Cigarette smoking has been noted to impair wound healing in tissues such as skin, bone, and gut. This study was designed to examine whether nicotine adversely affects postinfarction cardiac wound healing and remodeling in an experimental model of myocardial infarction. For this purpose, two groups of rats were studied. The control group received a simple bandage, and the nicotine group had a section (1.75 mg/day) of a nicotine patch attached on their backs. After a 7-day treatment period, an anterior wall infarction was induced. A bandage-free 7-day healing period followed, after which hearts were isolated for mechanical tests. Nicotine-treated rats developed significantly enlarged left ventricles with thin, infarcted walls and a rightward shift in the passive pressure-volume relationship. Pressure-strain analysis also indicated possible changes in the material properties of the wound for nicotine-treated rats. In conclusion, nicotine has significant adverse effects on postinfarction healing and left ventricular remodeling. These observations have important clinical implications because of the enhanced risk for development of heart failure.
Cyclosporin A treatment alters characteristics of Ca2+-release channel in cardiac sarcoplasmic reticulum
Authors: Park Kyoung Sik , Kim Tae Kon , Kim Do Han
Published: December 2017

Chronic treatment with cyclosporin A (CsA) has been reported (H. S. Banijamali, M. H. ter Keurs, L. C. Paul, and H. E. ter Keurs. Cardiovasc. Res. 27: 1845–1854, 1993; I. Kingma, E. Harmsen, H. E. ter Keurs, H. Benediktsson, and L. C. Paul. Int. J. Cardiol. 31: 15–22, 1991) to induce reversible alterations of contractile properties in rat hearts. To define the molecular mechanisms underlying the physiological alterations, the Ca2+-release channel (CRC) and Ca2+-ATPase from sarcoplasmic reticulum in rats were examined. Ryanodine binding to whole homogenates of rat hearts shows time- and dose-dependent alterations in CRC properties by CsA. On 3 wk of treatment with 15 mg CsA ⋅ kg body wt−1⋅ day−1, 1) maximal ryanodine binding (Bmax) decreased, 2) the dissociation constant of ryanodine ( Kd) increased, 3) caffeine sensitivity of CRC increased, and 4) ruthenium red sensitivity of CRC decreased. On the other hand, Bmaxand Kdof ryanodine binding in rat skeletal muscles were not changed. Ryanodine-sensitive oxalate-supported Ca2+uptake in whole homogenates was lower in CsA-treated rat hearts than in control hearts, whereas total Ca2+uptake in the presence of 500 M ryanodine was not changed. Functional experiments with rapamycin and Western blot analysis suggest that the CsA-induced alteration of ryanodine binding is due at least in part to an upregulation of calcineurin. The heart muscle-specific alterations of CRC could be responsible for the previously reported contractile changes of CsA-treated rat hearts.
Modulation of AV nodal and Hisian conduction by changes in extracellular space
Authors: Lurie Keith G. , Sugiyama Atsushi , McKnite Scott , Coffeen Paul , Hashimoto Keitaro , Motomura Shigeru
Published: December 2017

Previous studies have demonstrated that the extracellular space (ECS) component of the atrioventricular (AV) node and His bundle region is larger than the ECS in adjacent contractile myocardium. The potential physiological significance of this observation was examined in a canine blood-perfused AV nodal preparation. Mannitol, an ECS osmotic expander, was infused directly into either the AV node or His bundle region. This resulted in a significant dose-dependent increase in the AV nodal or His-ventricular conduction time and in the AV nodal effective refractory period. Mannitol infusion eventually resulted in Wenckebach block ( n = 6), which reversed with mannitol washout. The ratio of AV nodal to left ventricular ECS in tissue frozen immediately on the development of heart block ( n = 8) was significantly higher in the region of block (4.53 ± 0.61) compared with that in control preparations (2.23 ± 0.35, n = 6, P < 0.01) and donor dog hearts (2.45 ± 0.18, n = 11, P < 0.01) not exposed to mannitol. With lower mannitol rates (10% of total blood flow), AV nodal conduction times increased by 5–10% and the AV node became supersensitive to adenosine, acetylcholine, and carbachol, but not to norepinephrine. We conclude that mannitol-induced changes in AV node and His bundle ECS markedly alter conduction system electrophysiology and the sensitivity of conductive tissues to purinergic and cholinergic agonists.
Effect of NO on transmural distribution of blood flow in hypertrophied left ventricle during exercise
Authors: Duncker Dirk J. , Traverse Jay H. , Ishibashi Yutaka , Bache Robert J.
Published: December 2017

When exercise in the presence of a coronary artery stenosis results in subendocardial ischemia, administration of a nitric oxide (NO) donor increases subendocardial blood flow, whereas NO synthesis blockade worsens subendocardial hypoperfusion. Because left ventricular hypertrophy (LVH) is also associated with subendocardial hypoperfusion during exercise, this study tested the hypothesis that alterations of NO availability can similarly influence subendocardial blood flow in the hypertrophied heart. Studies were performed in seven dogs in which ascending aortic banding resulted in an 80% increase in LV weight. Myocardial blood flow was measured with microspheres during treadmill exercise that increased heart rates to 216 ± 8 beats/min. During control exercise, mean myocardial blood flow in animals with LVH was similar to that in historic controls, but the ratio of subendocardial to subepicardial blood flow was lower in animals with hypertrophy (0.88 ± 0.07) than in controls (1.36 ± 0.08; P < 0.05). Blockade of NO synthesis with NG-nitro-l-arginine (l-NNA; 1.5 mg/kg ic) caused no change in heart rate or LV systolic pressure during exercise. Furthermore, l-NNA did not worsen subendocardial hypoperfusion during exercise. Intracoronary infusion of nitroglycerin (0.4 μg ⋅ kg−1⋅ min−1) did not significantly alter either mean blood flow or the transmural distribution of perfusion during exercise in the hypertrophied hearts. Thus, unlike the subendocardial underperfusion that occurs when a stenosis limits coronary blood flow, alterations of NO availability did not alter subendocardial hypoperfusion in the hypertrophied hearts.
AV3V lesions attenuate the cardiovascular responses produced by blood-borne excitatory amino acid analogs
Authors: Whalen Erin J. , Beltz Terry G. , Lewis Stephen J. , Johnson Alan Kim
Published: December 2017

Systemic injections of the excitatory amino acid (EAA) analogs, kainic acid (KA) and N-methyl-d-aspartate (NMDA), produce a pressor response in conscious rats that is caused by a centrally mediated activation of sympathetic drive and the release of arginine vasopressin (AVP). This study tested the hypothesis that the tissue surrounding the anteroventral part of the third ventricle (AV3V) plays a role in the expression of the pressor responses produced by systemically injected EAA analogs. Specifically, we examined whether prior electrolytic ablation of the AV3V region would affect the pressor responses to KA and NMDA (1 mg/kg iv) in conscious rats. The KA-induced pressor response was smaller in AV3V-lesioned than in sham-lesioned rats (11 ± 2 vs. 29 ± 2 mmHg; P < 0.05). After ganglion blockade, KA produced a pressor response in sham-lesioned but not AV3V-lesioned rats (+27 ± 3 vs. +1 ± 2 mmHg; P < 0.05). The KA-induced pressor response in ganglion-blocked sham-lesioned rats was abolished by a vasopressin V1-receptor antagonist. Similar results were obtained with NMDA. The pressor response to AVP (10 ng/kg iv) was slightly smaller in AV3V-lesioned than in sham-lesioned ganglion-blocked rats (45 ± 3 vs. 57 ± 4 mmHg; P < 0.05). This study demonstrates that the pressor responses to systemically injected EAA analogs are smaller in AV3V-lesioned rats. The EAA analogs may produce pressor responses by stimulation of EAA receptors in the AV3V region, or the AV3V region may play an important role in the expression of these responses.
Cross bridge-dependent activation of contraction in cardiac myofibrils at low pH
Authors: Swartz D. R. , Zhang D. , Yancey K. W.
Published: December 2017

Striated muscle contracts in the absence of calcium at low concentrations of MgATP ([MgATP]), and this has been termed rigor activation because rigor cross bridges attach and activate adjacent actin sites. This process is well characterized in skeletal muscle but not in cardiac muscle. Rigor cross bridges are also thought to increase calcium binding to troponin C and play a synergistic role in activation. We tested the hypothesis that cross bridge-dependent activation results in an increase in contractile activity at normal and low pH values. Myofibrillar ATPase activity was measured as a function of pCa and [MgATP] at pH 7.0, and the data showed that, at pCa values of ≥5.5, there was a biphasic relationship between activity and [MgATP]. Peak activity occurred at 10–50 μM MgATP, and [MgATP] for peak activity was lower with increased pCa. The ATPase activity of rat cardiac myofibrils as a function of [MgATP] at a pCa of 9.0 was measured at several pH levels (pH 5.4–7.0). The ATPase activity as a function of [MgATP] was biphasic with a maximum at 8–10 μM MgATP. Lower pH did not result in a substantial decrease in myofibrillar ATPase activity even at pH 5.4. The extent of shortening, as measured by Z-line spacing, was greatest at 8 μM MgATP and less at both lower and higher [MgATP], and this response was observed at all pH levels. These studies suggest that the peak ATPase activity associated with low [MgATP] was coupled to sarcomere shortening. These results support the hypothesis that cross bridge-dependent activation of contraction may be responsible for contracture in the ischemic heart.
Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction
Authors: Zhang Weiguo , Huang Bing S. , Leenen Frans H. H.
Published: December 2017

Blockade of brain “ouabain” prevents the sympathetic hyperactivity and impairment of baroreflex function in rats with congestive heart failure (CHF). Because brain “ouabain” may act by activating the brain renin-angiotensin system (RAS), the aim of the present study was to assess whether chronic treatment with the AT1-receptor blocker losartan given centrally normalizes the sympathetic hyperactivity and impairment of baroreflex function in Wistar rats with CHF postmyocardial infarction (MI). After left coronary artery ligation (2 or 6 wk), rats received either intracerebroventricular losartan (1 mg ⋅ kg−1 ⋅ day−1, CHF-Los) or vehicle (CHF-Veh) by osmotic minipumps. To assess possible peripheral effects of intracerebroventricular losartan, one set of CHF rats received the same rate of losartan subcutaneously. Sham-operated rats served as control. After 2 wk of treatment, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) at rest and in response to air-jet stress and intracerebroventricular injection of the α2-adrenoceptor-agonist guanabenz were measured in conscious animals. Arterial baroreflex function was evaluated by ramp changes in MAP. Compared with sham groups, CHF-Veh groups showed impaired arterial baroreflex control of HR and RSNA, increased sympathoexcitatory and pressor responses to air-jet stress, and increased sympathoinhibitory and hypotensive responses to guanabenz. The latter is consistent with decreased activity in sympathoinhibitory pathways. Chronic intracerebroventricular infusion of losartan largely normalized these abnormalities. In CHF rats, the same rate of infusion of losartan subcutaneously was ineffective. In sham-operated rats, losartan intracerebroventricularly or subcutaneously did not affect sympathetic activity. We conclude that the chronic increase in sympathoexcitation, decrease in sympathoinhibition, and desensitized baroreflex function in CHF all appear to depend on the brain RAS, since this whole pattern of changes can be normalized by chronic central AT1-receptor blockade with losartan.
Carbon monoxide and cerebral microvascular tone in newborn pigs
Authors: Leffler Charles W. , Nasjletti Alberto , Yu Changhua , Johnson Robert A. , Fedinec Alexander L. , Walker Nicole
Published: December 2017

The present study addresses the hypothesis that CO produced from endogenous heme oxygenase (HO) can dilate newborn cerebral arterioles. HO-2 protein was highly expressed in large and small blood vessels, as well as parenchyma, of newborn pig cerebrum. Topically applied CO dose-dependently dilated piglet pial arterioles in vivo over the range 10−11—10−9M (maximal response). CO-induced cerebrovascular dilation was abolished by treatment with the Ca2+-activated K+ channel inhibitors tetraethylammonium chloride and iberiotoxin. The HO substrate heme-l-lysinate also produced tetraethylammonium-inhibitable, dose-dependent dilation from 5 × 10−8 to 5 × 10−7 M (maximal). The HO inhibitor chromium mesoporphyrin blocked dilation of pial arterioles in response to heme-l-lysinate. In addition to inhibiting dilation to heme-l-lysinate, chromium mesoporphyrin also blocked pial arteriolar dilations in response to hypoxia but did not alter responses to hypercapnia or isoproterenol. We conclude that CO dilates pial arterioles via activation of Ca2+-activated K+ channels and that endogenous HO-2 potentially can produce sufficient CO to produce the dilation.
Catecholamines and preconditioning: studies of contraction and function in isolated rat hearts
Authors: Hearse David J. , Sutherland Fiona J.
Published: December 2017

The aims of this study were to determine whether 1) like ischemic preconditioning, transient exposure to norepinephrine before ischemia exacerbates contracture during ischemia and 2) protection afforded by norepinephrine is stereospecific (receptor mediated). Isolated perfused rat hearts were randomized into five groups ( n = 6/group): 1) ischemic preconditioning (3 min of ischemia + 3 min of reperfusion + 5 min of ischemia + 5 min of reperfusion), 2) untreated control, 3) vehicle control (ascorbic acid), 4) substitution of preconditioning ischemia by perfusion with d-norepinephrine, and 5) substitution of preconditioning ischemia by perfusion with l-norepinephrine. This was followed by 40 min of zero-flow ischemia and 50 min of reperfusion. Ischemic preconditioning and l-norepinephrine exacerbated contracture (time to 50% contracture = 9.2 ± 1.1 and 9.0 ± 1.1 vs. 13.3 ± 0.3, 12.4 ± 0.5, and 13.2 ± 0.4 min for untreated control, vehicle control, and d-norepinephrine, respectively, P < 0.05). Postischemic left ventricular developed pressure was poor in untreated control (23.0 ± 2.2%), vehicle control (26.9 ± 2.3%), and d-norepinephrine (19.8 ± 2.8%) groups but good in preconditioned (52.4 ± 5.1%) and l-norepinephrine (52.5 ± 1.1%) groups ( P < 0.05). Thus norepinephrine preconditioning, like ischemic preconditioning, causes a paradoxical exacerbation of contracture coupled with enhanced postischemic recovery; both effects are stereospecific.
Modified hemoglobins produce venular interendothelial gaps and albumin leakage in the rat mesentery
Authors: Baldwin Ann L.
Published: December 2017

Cross-linked hemoglobin (αα-Hb) and polyethylene glycol (PEG)-conjugated Hb have both been considered as possible “blood substitutes.” Previously, we showed that PEG-Hb extravasates rapidly in the intestinal mucosa and causes transient epithelial sloughing, resulting in temporary opening of the intestinal epithelial barrier. In the present study, the rat mesenteric preparation was used to quantify the effects of the two Hbs on microvascular leakage to albumin and to investigate possible changes in the integrity of the interendothelial cell junctions and the endothelial actin cytoskeleton. In anesthetized Sprague-Dawley rats, the microvasculature of a mesenteric window was perfused with HEPES-buffered saline (HBS) containing 0.5 mg/ml BSA and 2 mg/ml αα-Hb ( n = 16) or PEG-Hb ( n = 5) for 2 or 10 min. Controls ( n = 4) just received HBS-BSA. In some experiments ( n = 9 for αα-Hb ; n = 5 for PEG-Hb), the perfusate was then replaced by FITC-albumin in HBS-BSA for the next 3 min. The vasculature was then perfusion fixed, stained for filamentous actin and for mast cells, and viewed microscopically. In the remaining experiments, the mesenteric microvasculature was stained with silver nitrate to determine the number of endothelial junctional gaps per length of venules. Both Hbs increased the number and area of leaks per micrometer of venular length compared with control, but αα-Hb increased to a greater extent than PEG-Hb. Formation of leaks was accompanied by changes in the endothelial actin cytoskeleton and by an increased number of endothelial gaps. Mast cell degranulation was significantly greater ( P < 0.05) in Hb-treated preparations compared with controls, but there was no direct correlation between sites of degranulation and albumin leakage. These Hbs appear to induce venular leakage in the mesentery by mechanisms similar to those previously observed after treatment with histamine or nitric oxide synthase inhibitors.
Gene transfer of endothelial nitric oxide synthase (eNOS) in eNOS-deficient mice
Authors: Lake-Bruse Kristy D. , Faraci Frank M. , Shesely Edward G. , Maeda Nobuyo , Sigmund Curt D. , Heistad Donald D. ,   (With the Technical Assistance of Kara L. Brown)
Published: December 2017

Relaxation to acetylcholine (ACh) and calcium ionophore (A-23187) is absent in aortas from endothelial nitric oxide synthase (eNOS)-deficient (eNOS -/-) mice. We hypothesized that gene transfer of eNOS would restore relaxation to ACh and A-23187 in eNOS -/- mice. Aortic rings from eNOS -/- and eNOS +/+ mice were exposed in vitro to vehicle or adenoviral vectors encoding β-galactosidase (lacZ) or eNOS. Histochemical staining for β-galactosidase and eNOS demonstrated transduction of endothelial cells and adventitia. Vehicle-treated vessels from eNOS -/- mice did not relax to ACh or A-23187 compared with eNOS +/+ mice. In contrast, relaxation to nitroprusside (NP) was significantly greater in eNOS -/- mice than in eNOS +/+ mice. Gene transfer of eNOS, but not lacZ, to vascular rings of eNOS -/- mice restored relaxation to ACh and A-23187. In vessels from eNOS -/- mice that were transduced with eNOS, N ω-nitro-l-arginine (10−4 M) inhibited relaxation to ACh and A-23187 but not NP. Thus vascular function can be significantly improved by gene transfer in vessels where a major relaxation mechanism is genetically absent.
Pentoxifylline prevents the transition from the hyperdynamic to hypodynamic response during sepsis
Authors: Yang Shaolong , Zhou Mian , Koo Douglas J. , Chaudry Irshad H. , Wang Ping
Published: December 2017

The cardiovascular response to sepsis includes an early, hyperdynamic phase followed by a late, hypodynamic phase. Although administration of pentoxifylline (PTX) produces beneficial effects in sepsis, it remains unknown whether this agent prevents the transition from the hyperdynamic to the hypodynamic response during the progression of sepsis. To study this, male adult rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). At 1 h after CLP, PTX (50 mg/kg body wt) or vehicle was infused intravenously over 30 min. At 20 h after CLP (i.e., the late stage of sepsis), cardiac output and organ blood flow were measured by radioactive microspheres. Systemic and regional (i.e., hepatic, intestinal, and renal) oxygen delivery (Do 2) and oxygen consumption (V˙o 2) were determined. Moreover, plasma levels of lactate and alanine aminotransferase (ALT) were measured, and histological examinations were performed. In additional animals, the necrotic cecum was excised at 20 h after CLP, and mortality was monitored for 10 days thereafter. The results indicate that cardiac output, organ blood flow, and systemic and regional Do 2decreased by 36–65% ( P < 0.05) at 20 h after CLP. Administration of PTX early after the onset of sepsis, however, prevented reduction in measured hemodynamic parameters and increased systemic and regional Do 2 andV˙o 2 by 50–264% ( P < 0.05). The elevated levels of lactate (by 173%, P < 0.05) and ALT (by 718%, P < 0.05), as well as the morphological alterations in the liver, small intestine, and kidneys during sepsis were attenuated by PTX treatment. In addition, PTX treatment decreased the mortality rate from 50 to 0% ( P < 0.05) after CLP and cecal excision. Because PTX prevents the occurrence of hypodynamic sepsis, this agent appears to be a useful adjunct for maintaining hemodynamic stability and preventing lethality from sepsis.
Linear and nonlinear analysis of human dynamic cerebral autoregulation
Authors: Panerai Ronney B. , Dawson Suzanne L. , Potter John F.
Published: December 2017

The linear dynamic relationship between systemic arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV) was studied by time- and frequency-domain analysis methods. A nonlinear moving-average approach was also implemented using Volterra-Wiener kernels. In 47 normal subjects, ABP was measured with Finapres and CBFV was recorded with Doppler ultrasound in both middle cerebral arteries at rest in the supine position and also during ABP drops induced by the sudden deflation of thigh cuffs. Impulse response functions estimated by Fourier transfer function analysis, a second-order mathematical model proposed by Tiecks, and the linear kernel of the Volterra-Wiener moving-average representation provided reconstructed velocity model responses, for the same segment of data, with significant correlations to CBFV recordings corresponding to r = 0.52 ± 0.19, 0.53 ± 0.16, and 0.67 ± 0.12 (mean ± SD), respectively. The correlation coefficient for the linear plus quadratic kernels was 0.82 ± 0.08, significantly superior to that for the linear models ( P < 10−6). The supine linear impulse responses were also used to predict the velocity transient of a different baseline segment of data and of the thigh cuff velocity response with significant correlations. In both cases, the three linear methods provided equivalent model performances, but the correlation coefficient for the nonlinear model dropped to 0.26 ± 0.25 for the baseline test set of data and to 0.21 ± 0.42 for the thigh cuff data. Whereas it is possible to model dynamic cerebral autoregulation in humans with different linear methods, in the supine position a second-order nonlinear component contributes significantly to improve model accuracy for the same segment of data used to estimate model parameters, but it cannot be automatically extended to represent the nonlinear component of velocity responses of different segments of data or transient changes induced by the thigh cuff test.
Alteration of gene expression for glycolytic enzymes in aerobic and ischemic myocardium
Authors: Liedtke A. James , Lynch Matthew L.
Published: December 2017

The purpose of this report was to describe mRNA abundance for the glycolytic enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase, and pyruvate dehydrogenase in ischemic and adjacent aerobic myocardium. Mechanical, metabolic, and mRNA data were acquired in a pig model of regulated coronary flow using extracorporeal perfusion. Trials of coronary hypoperfusion included sustained and intermittent exposures of acute ischemia with or without reperfusion. These were compared with a chronic 4-day model of partial coronary stenosis. In ischemic tissues, levels of mRNA, normalized by mRNA for β-actin, were increased over control values for GAPDH (range 2.7- to 4.6-fold), pyruvate kinase (2.9-fold), and pyruvate dehydrogenase (2.1-fold). It is of interest that increases in mRNA levels over control values were also observed in adjacent aerobic heart muscle from intervention hearts, including 3.6- to 4.5-fold elevations in message for GAPDH and a 2.1-fold increase in signal for pyruvate dehydrogenase. Augmentation in mRNA abundance occurred in as short a time as 40 min of ischemia and was maintained for as long as 4 days in partial coronary stenosis. Whether the former time was of an interval sufficient to affect protein production is problematic, but the latter time was ample to influence enzyme concentration, which may in turn have regulated glycolysis in this condition.
Reflex cardiovascular response to brief abdominal visceral ischemia is mediated in part by prostaglandins
Authors: Chahal Premjit S. , Rendig Stephen V. , Longhurst John C.
Published: December 2017

Prostaglandin concentrations are elevated in intestinal lymph during brief abdominal visceral ischemia, and exogenously applied prostaglandins can directly stimulate or sensitize ischemically sensitive visceral sympathetic nerve fibers. However, it is not known if prostaglandin production during abdominal ischemia is sufficient to contribute to the reflex cardiovascular response (e.g., hypertension). Accordingly, in anesthetized cats, the femoral artery was cannulated for measurement of arterial blood pressure, and the superior mesenteric and celiac arteries were isolated and fitted with snare occluders. After dual occlusion of these arteries (≤20 min), the cyclooxygenase inhibitors indomethacin (10–20 mg/kg iv, n = 5, group 1) or acetylsalicylic acid [50 mg/kg iv ( n = 6) and ia ( n = 2); group 2] were administered and ischemia was repeated. In group 1, indomethacin lowered the reflex arterial blood pressure increment by 39% from 31 ± 7 to 19 ± 5 mmHg ( P > 0.05). In group 2, acetylsalicylic acid significantly ( P < 0.05) reduced the reflex rise in blood pressure by 46% (28 ± 3 to 15 ± 4 mmHg). A second, more invasive preparation ( group 3) was utilized to 1) minimize the confounding, transient, nonreflex rise in blood pressure associated with arterial ligation, and 2) further assess the inhibitory effect of indomethacin. In group 3, the ischemia-induced blood pressure rise of 28 ± 6 mmHg was reduced by 43% to 16 ± 4 mmHg after indomethacin ( n = 4, P < 0.05). Thus blockade of the cyclooxygenase pathway by two structurally dissimilar inhibitors attenuated the visceral-cardiovascular reflex response to brief ischemia, suggesting that prostaglandins released during visceral ischemia contribute significantly to the activation of the reflex cardiovascular response.
Autonomic control of skeletal muscle blood flow at the onset of exercise
Authors: Buckwalter John B. , Clifford Philip S.
Published: December 2017

The purpose of this study was to determine whether the autonomic nervous system is involved in skeletal muscle vasodilation at the onset of exercise. Mongrel dogs ( n = 7) were instrumented with flow probes on both external iliac arteries. Before treadmill exercise at 3 miles/h, 0% grade, hexamethonium (10 mg/kg) and atropine (0.2 mg/kg) or saline was infused intravenously. Ganglionic blockade increased resting heart rate from 87 ± 5 to 145 ± 8 beats/min ( P < 0.01) and reduced mean arterial pressure from 100 ± 4 to 88 ± 5 mmHg ( P < 0.01). During steady-state exercise, heart rate was unaffected by ganglionic blockade (from 145 ± 8 to 152 ± 5 beats/min), whereas mean arterial pressure was reduced (from 115 ± 4 to 72 ± 4 mmHg; P < 0.01). Immediate and rapid increases in iliac blood flow and conductance occurred with initiation of exercise with or without ganglionic blockade. Statistical analyses of hindlimb conductance at 5-s intervals over the first 30 s of exercise revealed a statistically significant difference between the control and ganglionic blockade conditions at 20, 25, and 30 s ( P < 0.01) but not at 5, 10, and 15 s of exercise. Hindlimb conductance at 1 min of exercise was 9.21 ± 0.68 and 11.82 ± 1.32 ml ⋅ min−1 ⋅ mmHg−1for the control and ganglionic blockade conditions, respectively. Because ganglionic blockade did not affect the initial rise in iliac conductance, we concluded that the autonomic nervous system is not essential for the rapid vasodilation in active skeletal muscle at the onset of exercise in dogs. Autonomic control of skeletal muscle blood flow during exercise is manifested through vasoconstriction and not vasodilation.
NRG-1-induced cardiomyocyte hypertrophy. Role of PI-3-kinase, p70S6K, and MEK-MAPK-RSK
Authors: Baliga Ragavendra R. , Pimental David R. , Zhao You-Yang , Simmons William W. , Marchionni Mark A. , Sawyer Douglas B. , Kelly Ralph A.
Published: December 2017

Neuregulins are a family of growth-promoting peptides known to be important in neural and mesenchymal tissue development. Targeted disruption of neuregulin (NRG)-1 or one of two of its cognate receptors, ErbB2 or ErbB4, results in embryonic lethality because of failure of the heart to develop. Although expression of NRGs and their receptors declines after midembryogenesis, both ErbB2 and ErbB4 are present in cardiac myocytes, and NRG-1 expression remains inducible in primary cultures of coronary microvascular endothelial cells from adult rat ventricular muscle. In neonatal rat ventricular myocytes, a soluble NRG-1, recombinant human glial growth factor-2, increased [3H]phenylalanine uptake and induced expression of atrial natriuretic factor (ANF) and sarcomeric F-actin polymerization. The effect of NRG-1 on [3H]phenylalanine uptake and sarcomeric F-actin polymerization was maximal at 20 ng/ml but declined at higher concentrations. NRG-1 activated p42/p44 mitogen-activated protein kinase (MAPK) [extracellular signal-regulated kinase (ERK)-2/ERK1] and ribosomal S6 kinase (RSK)-2 (90-kDa ribosomal S6 kinase), both of which could be inhibited by the MAPK/ERK kinase-1 antagonist PD-098059. NRG-1 also activated 70-kDa ribosomal S6 kinase, which was inhibited by either rapamycin or wortmannin. Activation of these pathways exhibited the same “biphasic” response to increasing NRG-1 concentrations. Wortmannin and LY-294002 blocked sarcomeric F-actin polymerization but not [3H]phenylalanine uptake or ANF expression, whereas PD-098059 consistently blocked both [3H]phenylalanine uptake and ANF expression but not actin polymerization. In contrast, rapamycin inhibited [3H]phenylalanine uptake and F-actin polymerization but not ANF expression. Thus NRG-ErbB signaling triggers multiple nonredundant pathways in postnatal ventricular myocytes.
Calf blood flow during prolonged tilt in idiopathic dilated cardiomyopathy and after cardiac transplantation
Authors: Galatius Søren , Wroblewski Henrik , Sørensen Vibeke B. , Bie Peter , Arendrup Henrik , Kastrup Jens
Published: December 2017

In severe congestive heart failure (CHF), abnormal reflex control of calf blood flow during brief head-up tilt that appears to normalize after transplantation (HTX) may be present during prolonged observation also. Therefore, we studied the effect of prolonged (30 min) 50° head-up tilt on calf skeletal muscle blood flow measured by the local133Xe washout method in CHF and after HTX and in patients with the presence vs. absence of native right atrium (+PNA and −PNA, respectively). During brief head-up tilt, skeletal muscle blood flow increased 13 ± 42% in 9 severe CHF patients in contrast to a −28 ± 22% decrease ( P < 0.01) in 11 control subjects, −24 ± 30% decrease in 15 moderate CHF patients ( P < 0.05), −25 ± 14% decrease in 12 patients with recent HTX ( P < 0.01), and −21 ± 24% decrease in 8 patients with distant HTX ( P = 0.06). However, during sustained tilt, blood flow declined to similar levels of that in the other groups in severe CHF. HTX −PNA vs. +PNA showed blunted skeletal muscle vasomotor control ( P < 0.05) and a higher systolic blood pressure (139 ± 14 vs. 125 ± 15 mmHg, P < 0.05) and heart rate (92 ± 10 vs. 83 ± 8 beats/min, P < 0.05). Thus paradox vasodilatation of calf skeletal muscle in severe CHF is present only during brief but not prolonged tilt. This may be one explanation of the rare presence of orthostatic intolerance in CHF and implies only a minor possible role for the abnormality in edema pathogenesis. Removal of all right atrium in HTX has an important hemodynamic impact that may possibly affect later clinical outcome.
Ischemic preconditioning in rats: role of mitochondrial KATPchannel in preservation of mitochondrial function
Authors: Fryer Ryan M. , Eells Janis T. , Hsu Anna K. , Henry Michele M. , Gross Garrett J.
Published: December 2017

We examined the role of the sarcolemmal and mitochondrial KATPchannels in a rat model of ischemic preconditioning (IPC). Infarct size was expressed as a percentage of the area at risk (IS/AAR). IPC significantly reduced infarct size (7 ± 1%) versus control (56 ± 1%). The sarcolemmal KATPchannel-selective antagonist HMR-1098 administered before IPC did not significantly attenuate cardioprotection. However, pretreatment with the mitochondrial KATPchannel-selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before IPC partially abolished cardioprotection (40 ± 1%). Diazoxide (10 mg/kg iv) also reduced IS/AAR (36.2 ± 4.8%), but this effect was abolished by 5-HD. As an index of mitochondrial bioenergetic function, the rate of ATP synthesis in the AAR was examined. Untreated animals synthesized ATP at 2.12 ± 0.30 μmol ⋅ min−1⋅ mg mitochondrial protein−1. Rats subjected to ischemia-reperfusion synthesized ATP at 0.67 ± 0.06 μmol ⋅ min−1⋅ mg mitochondrial protein−1. IPC significantly increased ATP synthesis to 1.86 ± 0.23 μmol ⋅ min−1⋅ mg mitochondrial protein−1. However, when 5-HD was administered before IPC, the preservation of ATP synthesis was attenuated (1.18 ± 0.15 μmol ⋅ min−1⋅ mg mitochondrial protein−1). These data are consistent with the notion that inhibition of mitochondrial KATPchannels attenuates IPC by reducing IPC-induced protection of mitochondrial function.
Role of endothelin receptor subtypes in volume-stimulated ANF secretion
Authors: Baertschi Alex J. , Pedrazzini Thierry , Aubert Jean-François , Roatti Angela , Pence Richard A.
Published: December 2017

The role of endothelin (ET) receptors was tested in volume-stimulated atrial natriuretic factor (ANF) secretion in conscious rats. Mean ANF responses to slow infusions (3 × 3.3 ml/8 min) were dose dependently reduced ( P < 0.05) by bosentan (nonselective ET-receptor antagonist) from 64.1 ± 18.1 (SE) pg/ml (control) to 52.6 ± 16.1 (0.033 mg bosentan/rat), 16.1 ± 7.6 (0.33 mg/rat), and 11.6 ± 6.5 pg/ml (3.3 mg/rat). The ET-A-receptor antagonist BQ-123 (1 mg/rat) had no effect relative to DMSO controls, whereas the putative ET-B antagonist IRL-1038 (0.1 mg/rat) abolished the response. In a second protocol, BQ-123 (≥0.5 mg/rat) nonsignificantly reduced the peak ANF response (106.1 ± 23.0 pg/ml) to 74.0 ± 20.5 pg/ml for slow infusions (3.5 ml/8.5 min) but reduced the peak response (425.3 ± 58.1 pg/ml) for fast infusions (6.6 ml/1 min) by 49.9% ( P < 0.001) and for 340 pmoles ET-1 (328.8 ± 69.5 pg/ml) by 83.5% ( P < 0.0001). BQ-123 abolished the ET-1-induced increase in arterial pressure (21.8 ± 5.2 mmHg at 1 min). Changes in central venous pressure were similar for DMSO and BQ-123 (slow: 0.91 and 1.14 mmHg; fast: 4.50 and 4.13 mmHg). The results suggest 1) ET-B receptors mainly mediate the ANF secretion to slow volume expansions of <1.6%/min; and 2) ET-A receptors mainly mediate the ANF response to acute volume overloads.