bluuebunny/crossref_metadata_2025 huggingface dataset:
Ventricular fibrillation in preconditioned pig hearts: role of K ATP + channels
Authors: Rioufol Gilles , Ovize Michel , Loufoua Joseph , Pop Calin , André-Fouët Xavier , Minaire Yves
Published: December 2017

ATP-dependent potassium ([Formula: see text]) channels play a role in the infarct size-limiting effect of preconditioning in pigs. We previously demonstrated that preconditioning shortens monophasic action potential duration (MAPD) and accelerates the time to ventricular fibrillation (VF) during a prolonged ischemia in pigs. We sought to determine whether the mechanism of the reduced time to VF in preconditioned pigs is a consequence of[Formula: see text] channel activation. Pigs underwent 40 min of coronary occlusion and 2 h of reperfusion. Before this, animals received either no intervention (control), 10 min of ischemia and 10 min of reperfusion (preconditioned), or an intravenous infusion of nicorandil, a [Formula: see text] channel opener. Additional control, preconditioned, and nicorandil-treated pigs were pretreated by glibenclamide, an antagonist of[Formula: see text] channels. Because 1) the[Formula: see text] channel activator nicorandil did not produce shorter time to VF, 2) the[Formula: see text] channel inhibitor glibenclamide did not block the acceleration of VF by preconditioning, and 3) there was no relationship between time to VF and infarct size or MAPD, the major conclusion is that reduced time to VF in preconditioned animals is not a consequence of [Formula: see text] channel activation.
β-Adrenergic-mediated improvement in left ventricular function by exercise training in older men
Authors: Spina Robert J. , Turner Michael J. , Ehsani Ali A.
Published: December 2017

To test the hypothesis that the training-induced improvement in the age-related decline in left ventricular (LV) function is mediated by enhanced inotropic responses to β-adrenergic stimulation, 10 sedentary healthy men, 65 ± 1 yr (mean ± SE) of age, exercised for 9 mo, which resulted in a 28% increase in aerobic exercise capacity. Training induced a greater increase in LV systolic shortening, assessed with two-dimensional echocardiography, in response to isoproterenol with a steeper slope of the fractional shortening-end-systolic wall stress (ςes) relationship and an upward shift of the ςes-systolic diameter relationship without an acute increase in heart rate or preload. The increase in the early-to-late diastolic flow velocity ratio, normalized for heart rate and preload, in response to isoproterenol was larger after training. LV systolic reserve and cardiac output during peak exercise were higher after training. β-Adrenergic blockade with esmolol HCl abolished the adaptive increases in LV systolic reserve capacity and cardiac output during peak exercise in the trained state. The results suggest that one of the underlying mechanisms responsible for the adaptive increase in LV systolic function in response to exercise training is an enhanced inotropic sensitivity to catecholamines. Furthermore, the enhanced inotropic responses are associated with increased diastolic filling.
Effects of ischemic preconditioning on contractile and metabolic function during hypoperfusion in dogs
Authors: Minamino Tetsuo , Kitakaze Masafumi , Sato Hiroshi , Funaya Hiroharu , Ueda Yasunori , Asanuma Hiroshi , Kuzuya Tsunehiko , Hori Masatsugu
Published: December 2017

We examined the effects of ischemic preconditioning (IP) on metabolic and contractile function during coronary hypoperfusion in dogs. After the left anterior descending coronary artery (LAD) was occluded for 5 min (IP) and reperfused for 10 min, coronary blood flow (CBF) of the LAD was decreased to 33% of the control. IP increased ( P < 0.05) lactate extraction ratio and the pH of coronary venous blood and decreased ( P < 0.05) myocardial oxygen consumption and fractional shortening during hypoperfusion compared with those in the control group, although IP did not change the endocardial-to-epicardial blood flow ratio of the regional myocardium during hypoperfusion. IP increased ( P< 0.05) the adenosine levels in coronary venous blood during hypoperfusion. IP increased ( P< 0.05) myocardial ecto-5′-nucleotidase activity. Administration of 8-sulfophenyltheophylline or α,β-methyleneadenosine 5′-diphosphate blunted the IP-induced changes in metabolic and contractile parameters during hypoperfusion. These results suggest that IP reduced the severity of anaerobic myocardial metabolism of ischemic hearts by increasing the adenosine levels via an extracellular pathway.
Modeling the influence of body size and composition on M-mode echocardiographic dimensions
Authors: Batterham Alan M. , George Keith P.
Published: December 2017

The purpose of this study was to determine the optimal index for normalizing left ventricular (LV) echocardiographic dimensions for differences in body size. M-mode echocardiograms defined LV internal dimension at end diastole (LVIDD) and LV wall thickness (LVWT) in 107 adults (59 male, 48 female). Allometric relations were assessed between cardiac dimensions ( Y) and body size variables ( X) of fat-free mass (FFM), height (H), body surface area (BSA), and fat mass (FM). Further to confirmation of homogeneity of regression slopes, size exponents common to both genders were fitted by a log-linear model: ln Y = ln a + c ⋅ gender + b ⋅ ln X, where a is the proportionality coefficient, b is the size exponent, and c is the gender coefficient. For LVIDD, mean body size exponents (95% confidence interval) were FFM0.35(0.22–0.47), H0.68(0.32–1.03), and BSA0.44(0.26–0.62). For LVWT, the derived exponents were FFM0.43(0.20–0.65), H0.65(0–1.3), and BSA0.56(0.23–0.89). Body fatness (expressed by FM) had no influence on LV dimensions, with exponents not different from zero ( P > 0.05). The root-mean-squares error from the separate regression models indicated that the FFM index was the optimal solution. Indexation of LV dimensions by H was associated with the greatest error. Because the 95% confidence interval for the FFM exponents included 0.33, we recommend that linear LV dimensions be indexed by the cube root of FFM. In the absence of FFM data, the root of BSA was found to be the best surrogate index.
17β-Estradiol reduces vasoconstriction in endothelium-denuded rat aortas through inducible NOS
Authors: Binko J. , Majewski H.
Published: December 2017

Estrogen produces vasodilatation through the induction of nitric oxide synthase (NOS) in the endothelium, but there are many reports of endothelium-independent effects. In the present study, these processes were investigated in rat aortas isolated from ovariectomized rats. Long-term in vitro treatment with 17β-estradiol (10 nM for 24 h) in an organ culture system slightly reduced acetylcholine-mediated vasorelaxation in endothelium-intact aortic rings. 17β-Estradiol (1 and 10 nM for 24 h) also attenuated the phenylephrine-induced constriction in endothelium-denuded aortas, and this effect was inhibited by the NOS inhibitorl- N5-(1-iminoethyl)ornithine hydrochloride, as well as the estrogen receptor antagonist ICI-182,780. Furthermore, 17β-estradiol treatment (1 and 10 nM for 24 h) increased nitric oxide production as assessed by the conversion of [3H]arginine to [3H]citrulline in endothelium-denuded rat aortas. These effects were prevented by the protein synthesis inhibitor cycloheximide. 17β-Estradiol (10 nM for 24 h) treatment also induced the formation of inducible NOS (iNOS) protein in aortas. The results indicate that 17β-estradiol can attenuate the vasoconstrictor effect of phenylephrine by a process that involves induction of iNOS in nonendothelial cells of the aorta. We suggest that long-term estrogen therapy may induce a partial hyporesponsiveness in vascular smooth muscle via a small but sustained nitric oxide production.
High-dose lidocaine does not affect defibrillation efficacy: implications for defibrillation mechanisms
Authors: Ujhelyi Michael R. , Sims J. Jason , Miller Allison Winecoff
Published: December 2017

This study assessed the effect of low (10 mg ⋅ kg−1 ⋅ h−1) and very high (18 mg ⋅ kg−1 ⋅ h−1) doses of lidocaine on defibrillation energy requirements (DER) to relate changes in indexes of sodium-channel blockade with changes in DER values using a dose-response study design. In group 1 (control; n = 6 pigs), DER values were determined at baseline and during treatment with 5% dextrose in water (D5W) and with D5W added to D5W. In group 2 ( n = 7), DER values were determined at baseline and during treatment with low-dose lidocaine followed by high-dose lidocaine. In group 3 ( n = 3), DER values were determined at baseline and high-dose lidocaine. Group 3 controlled for the order of lidocaine treatment with the addition of high-dose lidocaine after baseline. DER values in group 1 did not change during D5W. In group 2, low-dose lidocaine increased DER values by 51% ( P = 0.01), whereas high-dose lidocaine added to low-dose lidocaine reduced DER values back to within 6% of baseline values ( P = 0.02, low dose vs. high dose). DER values during high-dose lidocaine in group 3 also remained near baseline values (16.2 ± 2.7 to 12.9 ± 2.7 J), demonstrating that treatment order had no impact on group 2. Progressive sodium-channel blockade was evident as incremental reduction in ventricular conduction velocity as the lidocaine dose increased. Lidocaine also significantly increased ventricular fibrillation cycle length as the lidocaine dose increased. However, the greatest increase in DER occurred when ventricular fibrillation cycle length was minimally affected, demonstrating a negative correlation ( P = 0.04). In summary, lidocaine has an inverted U-shaped DER dose-response curve. At very high lidocaine doses, DER values are similar to baseline and tend to decrease rather than increase. Increased refractoriness during ventricular fibrillation may be the electrophysiological mechanism by which high-dose lidocaine limits the adverse effects that low-dose lidocaine has on DER values. However, there is a possibility that an unidentified action of lidocaine is responsible for these effects.
Effects of left ventricular hypertrophy on force and Ca2+handling in isolated rat myocardium
Authors: Maier Lars S. , Brandes Rolf , Pieske Burkert , Bers Donald M.
Published: December 2017

To study the effect of left ventricular (LV) hypertrophy on force and Ca2+handling in isolated rat myocardium, LV hypertrophy was induced in rats by banding of the abdominal aorta. After 16 wk, arterial pressure was assessed by catheterization. LV trabeculae were isolated and loaded with indo 1 salt by iontophoretic injection. Isometric force and intracellular free Ca2+concentration ([Ca2+]i) were measured at stimulation frequencies between 0.25 and 3 Hz and rest intervals between 2 and 240 s. Sarcoplasmic reticulum (SR) Ca2+content was also investigated using rapid cooling contractures (RCC). Systolic and diastolic pressure as well as heart weight-to-body weight ratios were significantly elevated in banded compared with control animals (167 vs. 117 mmHg, 108 vs. 83 mmHg, and 4.6 vs. 4.0 mg/g, respectively). At high frequencies, twitch relaxation and [Ca2+]idecline rates were significantly slower in banded compared with control rats, and diastolic [Ca2+]iwas higher in the banded rat muscles (at 3 Hz, force half-time = 83 vs. 68 ms; time constant of [Ca2+]idecline = 208 vs. 118 ms; and diastolic [Ca2+]i= 505 vs. 353 nM). These differences could not be ascribed to altered Na+/Ca2+exchange, since twitch relaxation and Ca2+handling were not different between groups in the presence of caffeine (or cyclopiazonic acid plus ryanodine), where relaxation depends primarily on Na+/Ca2+exchange. After long rest intervals (≥120 s), control rats showed a significant rest potentiation of force and Ca2+transients, whereas banded rats did not. In addition, RCC amplitudes increased with rest in control but were unaltered in banded rats. In summary, pressure-overload hypertrophy was associated with slower twitch relaxation and [Ca2+]idecline but also with blunted rest potentiation of twitches and SR Ca2+content of LV trabeculae. The decrease in SR Ca2+-ATPase function in banded rats may contribute to the observed diastolic dysfunction associated with pressure-overload hypertrophy.
Magnetic resonance myocardial fiber-orientation mapping with direct histological correlation
Authors: Hsu E. W. , Muzikant A. L. , Matulevicius S. A. , Penland R. C. , Henriquez C. S.
Published: December 2017

Functional properties of the myocardium are mediated by the tissue structure. Consequently, proper physiological studies and modeling necessitate a precise knowledge of the fiber orientation. Magnetic resonance (MR) diffusion tensor imaging techniques have been used as a nondestructive means to characterize tissue fiber structure; however, the descriptions so far have been mostly qualitative. This study presents a direct, quantitative comparison of high-resolution MR fiber mapping and histology measurements in a block of excised canine myocardium. Results show an excellent correspondence of the measured fiber angles not only on a point-by-point basis (average difference of −2.30 ± 0.98°, n = 239) but also in the transmural rotation of the helix angles (average correlation coefficient of 0.942 ± 0.008 with average false-positive probability of 0.004 ± 0.001, n = 24). These data strongly support the hypothesis that the eigenvector of the largest MR diffusion tensor eigenvalue coincides with the orientation of the local myocardial fibers and underscore the potential of MR imaging as a noninvasive, three-dimensional modality to characterize tissue fiber architecture.
Interaction among autoregulation, CO2 reactivity, and intracranial pressure: a mathematical model
Authors: Ursino Mauro , Lodi Carlo Alberto
Published: December 2017

The relationships among cerebral blood flow, cerebral blood volume, intracranial pressure (ICP), and the action of cerebrovascular regulatory mechanisms (autoregulation and CO2 reactivity) were investigated by means of a mathematical model. The model incorporates the cerebrospinal fluid (CSF) circulation, the intracranial pressure-volume relationship, and cerebral hemodynamics. The latter is based on the following main assumptions: the middle cerebral arteries behave passively following transmural pressure changes; the pial arterial circulation includes two segments (large and small pial arteries) subject to different autoregulation mechanisms; and the venous cerebrovascular bed behaves as a Starling resistor. A new aspect of the model exists in the description of CO2 reactivity in the pial arterial circulation and in the analysis of its nonlinear interaction with autoregulation. Simulation results, obtained at constant ICP using various combinations of mean arterial pressure and CO2 pressure, substantially support data on cerebral blood flow and velocity reported in the physiological literature concerning both the separate effects of CO2 and autoregulation and their nonlinear interaction. Simulations performed in dynamic conditions with varying ICP underline the existence of a significant correlation between ICP dynamics and cerebral hemodynamics in response to CO2 changes. This correlation may significantly increase in pathological subjects with poor intracranial compliance and reduced CSF outflow. In perspective, the model can be used to study ICP and blood velocity time patterns in neurosurgical patients in order to gain a deeper insight into the pathophysiological mechanisms leading to intracranial hypertension and secondary brain damage.
Perinatal changes in myocardial supply and flux of fatty acids, carbohydrates, and ketone bodies in lambs
Authors: Bartelds Beatrijs , Gratama Jan-Willem C. , Knoester Hennie , Takens Janny , Smid Gioia B. , Aarnoudse Jan G. , Heymans Hugo S. A. , Kuipers Jaap R. G.
Published: December 2017

No information is available on perinatal changes in myocardial metabolism in vivo. We measured myocardial supply and flux of fatty acids, carbohydrates, and ketone bodies in chronically instrumented fetal, newborn (1–4 days), and juvenile (7 wk) lambs, by measuring aorta-coronary sinus concentration differences and blood flow. In the fetal lambs, myocardial supply and flux of fatty acids were zero. In the newborn lambs, the supply of fatty acids increased tenfold, but there was no flux of fatty acids. Carbohydrates were the major energy source in fetal and newborn lambs, accounting for 89 and 69% of myocardial oxygen consumption, respectively. In the juvenile lambs, the flux of fatty acids was increased threefold. The supply and flux of carbohydrates were decreased (by 31 and 82%, respectively). The supply and flux of ketone bodies gradually increased with age. We show that the myocardium of the lamb in vivo does not switch immediately after birth from carbohydrates to fatty acids. The mechanisms involved in the development of myocardial fatty acid oxidation remain to be elucidated.
Effect of lidocaine on left ventricular pressure-volume curves during demand ischemia in pigs
Authors: Tayama Masao , Solomon Steven B. , Glantz Stanton A.
Published: December 2017

The diastolic pressure-volume curve shifts upward during demand ischemia, most likely because of changes in Ca2+dynamics within the sarcomere. It is possible that agents that affect Na+/Ca2+exchange, such as lidocaine, a class 1b-type Na+-channel blocker that decreases intracellular Na+, could affect the diastolic pressure-volume relationship because of indirect effects on intracellular Ca2+. Lidocaine is a drug widely used to treat arrhythmias in patients with myocardial ischemia. We studied the effects of lidocaine on diastolic dysfunction associated with demand ischemia. We compared diastolic (as represented by the shift in the diastolic pressure-volume relationship) and systolic function during demand ischemia before and after lidocaine injection. We created demand ischemia in pigs before and after administering lidocaine (5 mg/kg) in eight open-pericardium anesthetized pigs. Demand ischemia was induced by constricting the left anterior descending coronary artery and then pacing at 1.5–1.8 times the baseline heart rate for 1.5–3 min. Hemodynamics were recorded during baseline, demand ischemia, baseline after lidocaine injection, and demand ischemia after lidocaine. Lidocaine did not affect systolic function or the time constant of isovolumic relaxation, but it increased the upward shift of the diastolic pressure-volume curve during demand ischemia compared with the increase that occurred before lidocaine was administered. This result suggests that lidocaine could aggravate diastolic dysfunction in patients with ischemic heart disease.
Direct observation of radial intracellular P O 2 gradients in a single cardiomyocyte of the rat
Authors: Takahashi Eiji , Sato Keiko , Endoh Hiroshi , Xu Zhe-Long , Doi Katsuhiko
Published: December 2017

The purpose of the present study was to directly visualize radial gradients of intracellular [Formula: see text] in a single individual cardiomyocyte isolated from the rat ventricle. Microspectrophotometry with the use of cytosolic myoglobin as an oxygen probe was conducted at 410 nm. When the quiescent cell was incubated with 1 μM carbonyl cyanide m-chlorophenylhydrazone to increase oxygen consumption approximately eightfold, gradual decreases in myoglobin oxygen saturation (SMb) were demonstrated toward the core of the cell, whereas these decreases disappeared when the cell was treated with 2 mM NaCN. These results highlighted the importance of diffusional oxygen transport in determining intracellular oxygenation in cardiac cells. From the measured SMb, we assessed the profile of radial changes in intracellular [Formula: see text]at the mean SMbcomparable to that in vivo (∼0.5). Quite steep [Formula: see text]gradients were demonstrated in the vicinity of the sarcolemma that were rapidly attenuated toward the cell core. These radial profiles of intracellular [Formula: see text] demonstrate the significance of myoglobin-facilitated diffusion of oxygen. Furthermore, the shallow gradients of [Formula: see text] near the center of the cell might arise from partial depression of oxygen consumption near the cell core.
Cellular mechanisms of heparinase III protection in rat traumatic shock
Authors: Hayward Reid , Scalia Rosario , Hopper Bruce , Appel James Z. , Lefer Allan M.
Published: December 2017

Pentobarbital-anesthetized rats subjected to traumatic shock developed a shock state characterized by marked hypotension to 65–70 mmHg, a survival time of 88 ± 13 min, significant increases in ileal myeloperoxidase activity ( P < 0.01), and severe endothelial dysfunction as evidenced by a significant ( P < 0.01) decrease in vasorelaxation to endothelium-dependent dilators. Treatment with heparinase III (45 μg ⋅ kg−1⋅ min−1) 10 min posttrauma prolonged survival time to 223 ± 19 min ( P < 0.001), significantly attenuated ileal myeloperoxidase activity ( P < 0.01), and significantly preserved endothelial function ( P < 0.05). Intravital microscopy of the rat mesentery showed that infusion of heparinase III (45–67 μg ⋅ kg−1⋅ min−1) significantly ( P < 0.01) attenuated both leukocyte rolling and adherence in the rat mesenteric microvasculature in response to NG-nitro-l-arginine methyl ester stimulation. Immunohistochemical localization of surface-expressed P-selectin on mesenteric venules showed that heparinase III infusion at 45–67 μg ⋅ kg−1⋅ min−1significantly ( P < 0.05) attenuated the increase in surface P-selectin expression. The beneficial effects of heparinase III are mediated at least in part by attenuating leukocyte-endothelial cell interactions via a P-selectin-dependent mechanism.
Endothelial dysfunction in human hand veins is rapidly reversible after smoking cessation
Authors: Moreno Heitor , Chalon Stephan , Urae Akinori , Tangphao Oranee , Abiose Ademola K. , Hoffman Brian B. , Blaschke Terrence F.
Published: December 2017

Cigarette smoking has been shown to impair endothelium-dependent dilation in arteries. We tested the hypothesis that cigarette smoking also impairs endothelium-dependent venodilation and evaluated changes in this response after smoking cessation in a time-course study using the dorsal hand vein technique. Dose-response curves were constructed in smokers and nonsmokers by infusing bradykinin (1–278 ng/min), an endothelium-dependent vasodilator, and nitroglycerin (0.006–1,583 ng/min), an endothelium-independent vasodilator, into hand veins preconstricted with the selective α1-adrenergic agonist phenylephrine. The maximal venodilation induced by bradykinin was 89 ± 5% in controls ( n = 16) and 61 ± 7% in smokers ( n = 18; P = 0.02). No difference in nitroglycerin-induced venodilation was observed between the two groups. Coinfusion of l-arginine (0.33 mg/min) markedly improved the bradykinin-induced venodilation in smokers (52 ± 7 to 90 ± 9%; P < 0.01). After acute smoking cessation ( n = 7), restoration to normal bradykinin-induced venodilation was observed within 24 h, whereas no change in the response to a maximally effective dose of nitroglycerin (1,583 ng/min) was detected. In a human vein model appropriate for testing vascular functional alterations, this study demonstrates that smoking impairs endothelium-dependent venodilation in heavy smokers. Moreover, this endothelial dysfunction appears to be rapidly reversible after smoking cessation. This model may be useful in studies evaluating mechanisms of endothelial dysfunction and interventions to modify it.
Ablation of lung endothelial injury after pacing-induced heart failure is related to alterations in Ca2+signaling
Authors: Ivey Claire L. , Roy Beverly J. , Townsley Mary I.
Published: December 2017

We have previously shown that ANG II increases microvascular permeability in normal dog lungs but not after pacing-induced heart failure. This study investigated how ANG II induces permeability in isolated blood-perfused canine lung lobes and what alterations occur during heart failure. In normal lobes, the protein kinase C (PKC) inhibitors staurosporine (500 nM) or chelerythrine (10 μM) did not modify ANG II-induced increases in the capillary filtration coefficient ( Kf,c, ml ⋅ min−1⋅ cmH2O−1⋅ 100 g−1; an index of microvascular permeability), suggesting that PKC is not involved. Thapsigargin (150 nM) was used to stimulate capacitative Ca2+entry in lobes from control dogs and dogs paced at 245 beats/min for 4 wk to induce heart failure. In control lobes, Kf,crose after thapsigargin, from 0.06 ± 0.01 to 0.17 ± 0.03 ml ⋅ min−1⋅ cmH2O−1⋅ 100 g−1(mean ± SE, P < 0.05) but did not change in the paced group. A Ca2+ionophore, A-23187, increased Kf,cin both control (10 μM; 0.05 ± 0.01 to 0.17 ± 0.05 ml ⋅ min−1⋅ cmH2O−1⋅ 100 g−1, P < 0.05) and pace (5 μM; 0.06 ± 0.01 to 0.21 ± 0.07 ml ⋅ min−1⋅ cmH2O−1⋅ 100 g−1, P < 0.05) lobes, indicating that increasing intracellular Ca2+is sufficient to induce pulmonary microvascular permeability after pacing. We conclude that during heart failure, Ca2+signaling within the pulmonary microvascular endothelium is altered.
ET-receptor antagonism, myocardial gene expression, and ventricular remodeling during CHF in rats
Authors: Øie Erik , Bjønerheim Reidar , Grøgaard Haakon K. , Kongshaug Heidi , Smiseth Otto A. , Attramadal Håvard
Published: December 2017

Both myocardial and plasma endothelin-1 (ET-1) are elevated in congestive heart failure (CHF). However, the role played by endogenous ET-1 in the progression of CHF remains unknown. The aim of the present study was to investigate and correlate myocardial gene expression programs and left ventricular (LV) remodeling during chronic ET-receptor antagonism in CHF rats. After ligation of the left coronary artery, rats were randomized to oral treatment with a nonselective ET-receptor antagonist (bosentan, 100 mg ⋅ kg−1⋅ day−1, n = 11) or vehicle (saline, n = 13) for 15 days, starting 24 h after induction of myocardial infarction. Bosentan substantially attenuated LV dilatation during postinfarction failure as evaluated by echocardiography. Furthermore, bosentan decreased LV systolic and end-diastolic pressures and increased fractional shortening. Myocardial expression of preproET-1 mRNA and a fetal gene program characteristic of myocardial hypertrophy were increased in the CHF rats and were not affected by bosentan. Consistently, right ventricular-to-body weight ratios, diameters of cardiomyocytes, and echocardiographic analysis demonstrated a sustained hypertrophic response and a normalized relative wall thickness after intervention with bosentan. Thus the modest reduction of preload and afterload provided by bosentan substantially attenuates LV dilatation, causing improved pressure-volume relationships. However, the compensatory hypertrophic response was not altered by ET-receptor antagonism. Therefore, ET-1 does not appear to play a crucial role in the mechanisms of myocardial hypertrophy during the early phase of postinfarction failure.
Reduced venous compliance in lower limbs of aging humans and its importance for capacitance function
Authors: Olsen Henrik , Länne Toste
Published: December 2017

Venous compliance in the calf of humans and its importance for capacitance function in relation to age were studied with the aid of 22, 44, and 59 mmHg lower body negative pressure (LBNP). Negative pressure transmission to the calf as well as changes in calf volume were studied, and venous compliance was calculated [change in volume with pressure change (dV/dP)]. The change in capacitance response of the calf with age (20–70 yr) was evaluated during LBNP 44 mmHg. Transmission of negative pressure to the subcutaneous tissue was almost full without any changes with age (92%). However, it was reduced to 80% in the underlying muscle tissue, irrespective of depth. Venous compliance in the young was 0.051 ml ⋅ 100 ml−1⋅ mmHg−1and was reduced by 45% to 0.029 ml ⋅ 100 ml−1⋅ mmHg−1in the old ( P < 0.05). Accordingly, the capacitance response was reduced by 0.015 ml ⋅ 100 ml−1⋅ yr−1( P < 0.005). Furthermore, the hemodynamic response to hypovolemic circulatory stress was attenuated with age. The reduced pressure transmission in muscle tissue is probably due to restriction of the muscle fascia envelope. The reduced venous compliance with age and the concomitant reduction in capacitance response during LBNP have implications for both the sympathetic reflex responses as well as the capacitance response during acute hypovolemic circulatory stress, which might be defected in aging humans.
Induction and cDNA sequence of inducible nitric oxide synthase from canine aortic smooth muscle cells
Authors: Wang Xiaofang , McGregor Christopher G. A. , Miller Virginia M.
Published: December 2017

An inducible isoform of nitric oxide synthase (type II, iNOS) is expressed in cardiac and vascular smooth muscle in response to inflammatory cytokines. The dog is an important large animal used for cardiovascular research including effects of exercise, heart failure, and allograft rejection. However, molecular probes for iNOS developed in other mammals have not been reliable for the study of iNOS induction in canine vascular smooth muscle. Experiments were designed to develop a molecular probe for canine iNOS. Smooth muscle cells were isolated from canine aortas. The cells ( passages 3–10) were incubated for 1, 3, 6, 12, 24, 48, or 72 h in the absence and presence of Escherichia coli lipopolysaccharide (LPS) to induce iNOS. Total RNA was isolated from the cells using standard techniques. RT-PCR with primers against conserved regions of all known iNOS enzyme was used to clone the iNOS cDNA. RT-PCR showed a single band only from cells treated with LPS. Cloned cDNA from cultured canine aortic smooth muscle cells has 84% homology to human, 81% to rat, and 81% to mouse iNOS gene. Identification of the cDNA for canine iNOS will be useful in the study of differential, transcriptional regulation of inducible (type II) compared with constitutive endothelial (type III) NOS in canine studies of allograft rejection and cardiovascular disease.
Effect of treadmill exercise on transmural distribution of blood flow in hypertrophied left ventricle
Authors: Duncker Dirk J. , Ishibashi Yutaka , Bache Robert J.
Published: December 2017

Pressure-overload left ventricular (LV) hypertrophy (LVH) is associated with increased vulnerability to subendocardial hypoperfusion during exercise. Abnormal perfusion could be the result of failure of the coronary vessels to grow in proportion to the degree of myocyte hypertrophy or could be due to increased extravascular forces acting on the intramural coronary vasculature. This study assessed the contribution of extravascular forces by examining the effect of exercise on the distribution of myocardial blood flow when coronary vasomotor tone was abolished with a maximal vasodilating dose of intracoronary adenosine. One year after ascending aortic banding in six dogs, the LV-to-body weight ratio was 7.80 ± 0.38 g/kg compared with 4.57 ± 0.20 g/kg in nine normal dogs ( P < 0.01). Under awake resting conditions blood flow in LVH hearts increased from 1.17 ± 0.27 ml ⋅ min−1⋅ g−1during basal conditions to 5.78 ± 1.06 ml ⋅ min−1⋅ g−1during adenosine (at a coronary pressure of 100 ± 6 mmHg), whereas in normal dogs blood flow increased from 1.22 ± 0.17 to 5.26 ± 0.71 ml ⋅ min−1⋅ g−1(at a coronary pressure of 62 ± 4 mmHg). At rest the transmural distribution of blood flow during adenosine was not different between hypertrophied and normal hearts, with subendocardial-to-subepicardial (Endo-to-Epi) blood flow ratios of 1.01 ± 0.09 and 1.14 ± 0.13, respectively ( P = not significant). During adenosine infusion, treadmill exercise to produce heart rates of 200–220 beats/min caused redistribution of blood flow away from the subendocardium that was much more marked in LVH (Endo-to-Epi blood flow ratio = 0.35 ± 0.04) than in normal hearts (Endo-to-Epi blood flow ratio = 0.76 ± 0.09, P < 0.05 vs. LVH). In comparison with normal, the exaggerated decrease in subendocardial blood flow produced by exercise in LVH hearts resulted from abnormally increased extravascular compressive forces, including a greater decrease in diastolic duration and an increase in LV end-diastolic pressure.
Effect of cross-linked hemoglobin transfusion on endothelial-dependent dilation in cat pial arterioles
Authors: Asano Yoshio , Koehler Raymond C. , Ulatowski John A. , Traystman Richard J. , Bucci Enrico
Published: December 2017

We determined whether addition of hemoglobin to the plasma would inhibit endothelial-dependent dilation in brain where tight endothelial junctions limit hemoglobin extravasation. Pial arteriolar diameter was measured by intravital microscopy through closed cranial windows in anesthetized cats either without transfusion (hematocrit = 32%) or after exchange transfusion with an albumin or sebacyl-cross-linked human hemoglobin solution (hematocrit = 18%). Dilation of small, medium, and large arterioles to acetylcholine and ADP was not significantly altered by hemoglobin transfusion. The dilatory responses were inhibited by the nitric oxide synthase inhibitor N G-nitro-l-arginine, although significant dilation to 30 μM acetylcholine persisted in small arterioles in the control and albumin-transfused group but not in the hemoglobin-transfused group. The dilatory response to the nitric oxide donor 3-morpholinosydnonimine was unaffected by albumin or hemoglobin transfusion, but the response to nitroprusside was reduced by one-third after hemoglobin transfusion. When cross-linked hemoglobin was superfused through the cranial window, the acetylcholine response became inhibited at a hemoglobin concentration of 0.1 μM and was completely blocked at 10 μM. Because this concentration is substantially less than the 500 μM hemoglobin concentration in plasma after transfusion when there was no inhibition of the acetylcholine response, hemoglobin permeation of the blood-brain barrier was considered negligible. We conclude that exchange of red cell-based hemoglobin with plasma-based hemoglobin does not produce a more effective sink for endothelial-derived nitric oxide evoked by agonist receptor-mediated activation. Furthermore, decreased hematocrit does not affect agonist-evoked endothelial-dependent dilation.
A nonlinear explanation of aging-induced changes in heartbeat dynamics
Authors: Giuliani A. , Piccirillo G. , Marigliano V. , Colosimo A.
Published: December 2017

The possibility of computing a cardiac age on the basis of spectral analysis of healthy individual tachograms was confirmed and facilitated by the use of a nonlinear technique: recurrence quantification analysis. The age of 112 subjects was predicted by this technique in terms of a progressive increase in the deterministic character of the heartbeat. This result confirms the “random-walk” character of the heartbeat as predicted by the terminal dynamics paradigm, thus allowing for a simple and comprehensive model of the effect of aging on cardiac dynamics: as age progresses, heart rate dynamics become increasingly predictable (constrained) on a beat-to-beat basis. This implies a basically stochastic nature of heart rate dynamics, probably reflecting the continuous adjustments to an unpredictable internal environment.
Arterial baroreceptor denervation impairs long-term regulation of arterial pressure during dietary salt loading
Authors: Osborn John W. , Hornfeldt Barbara J.
Published: December 2017

Experiments were performed to examine the contribution of arterial baroreceptors to long-term regulation of mean arterial pressure (MAP) during changes in dietary salt intake. Normotensive Sprague-Dawley rats were subjected to either sinoaortic denervation (SAD; n= 8) or Sham surgery ( n = 6) and instrumented 1 wk later with radiotelemetry transmitters for continuous minute-to-minute monitoring of MAP and heart rate (HR) over the 8-wk protocol. Rats consumed three levels of dietary NaCl: 0.4% NaCl ( week 1), 4.0% NaCl ( weeks 2–4), and 8.0% NaCl ( weeks 5–7). Rats returned to a 0.4% NaCl diet during the eighth week of the experiment. During week 1 (0.4% NaCl), there were no differences between Sham and SAD groups for 24-h averages of MAP or HR. However, by the third week of 4.0% NaCl, 24-h MAP was elevated significantly from baseline in SAD (10 ± 2 mmHg) but not Sham (1 ± 1 mmHg) rats. By the end of the third week of 8.0% NaCl diet, 24-h MAP was elevated 15 ± 2 mmHg above control in SAD rats compared with a 4 ± 1 mmHg increase in Sham rats ( P < 0.05). Hourly analysis of the final 72 h of each level of dietary salt revealed a marked effect of dietary NaCl on MAP in SAD rats, particularly during the dark cycle. MAP increased ∼20 and 30 mmHg in SAD rats over the 12-h dark cycle for 4.0 and 8.0% NaCl diets, respectively. In contrast, increased dietary NaCl had no effect on MAP during any phase of the light or dark period in Sham rats. These data support the hypothesis that arterial baroreceptors play a critical role in long-term regulation of MAP under conditions of altered dietary salt intake. Finally, hourly analysis of MAP revealed that the majority of the hypertensive response to increased NaCl occurs during the dark cycle in SAD rats. Hence, previous investigations may have underestimated the magnitude of the hypertensive response to increased dietary NaCl in animals with baroreceptor dysfunction.
ACh- and caffeine-induced Ca2+mobilization and current activation in rabbit arterial endothelial cells
Authors: Fransen P. , Katnik C. , Adams D. J.
Published: December 2017

Fura 2 microfluorometry and perforated-patch whole cell recording were carried out simultaneously to investigate the relationship between intracellular free Ca2+concentration ([Ca2+]i) and membrane current activation in response to ACh and caffeine in freshly dissociated arterial endothelial cells. ACh and caffeine evoked transient increases in [Ca2+]i. The initial increase in [Ca2+]iwas accompanied by a transient outward current, which caused membrane hyperpolarization. The amplitudes of the [Ca2+]itransient and outward current were dependent on caffeine concentration (EC50∼ 1 mM). Cyclopiazonic acid raised resting [Ca2+]ilevels by ≥50 nM and failed to completely block caffeine- or ACh-induced [Ca2+]itransients but slowed [Ca2+]irecovery fourfold. The reversal potential of caffeine-induced currents was dependent on external K+and Cl−concentrations. Caffeine-induced current amplitudes, but not [Ca2+]iresponses, were attenuated by external tetraethylammonium, Zn2+, and La3+. A consistent temporal relationship between agonist-activated membrane current and [Ca2+]iincreases was not observed, and, in some cases, time differences were greater than expected for simple diffusion of Ca2+throughout the cell. These results suggest that Ca2+-dependent current activation monitors local [Ca2+]ichanges adjacent to the plasmalemma, whereas single-cell photometry provides a measure of global changes in [Ca2+]i.
Estimation of regional left ventricular wall stresses in intact canine hearts
Authors: DeAnda Abe , Komeda Masashi , Moon Marc R. , Green G. Randall , Bolger Ann F. , Nikolic Srdjan D. , Daughters George T. , Miller D. Craig
Published: December 2017

Left ventricular (LV) wall stress is an important element in the assessment of LV systolic function; however, a reproducible technique to determine instantaneous local or regional wall stress has not been developed. Fourteen dogs underwent placement of twenty-six myocardial markers into the ventricle and septum. One week later, marker images were obtained using high-speed biplane videofluoroscopy under awake, sedated, atrially paced baseline conditions and after inotropic stimulation (calcium). With a model taking into account LV pressure, regional wall thickness, and meridional and circumferential regional radii of curvature, we computed average midwall stress for each of nine LV sites. Regional end-systolic and maximal LV wall stress were heterogeneous and dependent on latitude (increasing from apex to base, P < 0.001) and specific wall (anterior > lateral and posterior wall stresses; P = 0.002). Multivariate ANOVA demonstrated only a trend ( P = 0.056) toward increased LV stress after calcium infusion; subsequent univariate analysis isolated significant increases in end-systolic LV wall stress with increased inotropic state at all sites except the equatorial regions. The model used in this analysis incorporates local geometric factors and provides a reasonable estimate of regional LV wall stress compared with previous studies. LV wall stress is heterogeneous and dependent on the particular LV site of interest. Variation in wall stress may be caused by anatomic differences and/or extrinsic interactions between LV sites, i.e., influences of the papillary muscles and the interventricular septum.
Effects of aging on sarcoplasmic reticulum Ca2+-cycling proteins and their phosphorylation in rat myocardium
Authors: Xu A. , Narayanan N.
Published: December 2017

Diminished Ca2+-sequestering activity of the sarcoplasmic reticulum (SR) is implicated in the age-associated slowing of cardiac muscle relaxation. In attempting to further define the underlying mechanisms, the present study investigated the impact of aging on the contents of major SR Ca2+-cycling proteins and SR protein phosphorylation by endogenous Ca2+/calmodulin-dependent protein kinase (CaM kinase). The studies were performed using homogenates and SR vesicles derived from the ventricular myocardium of adult (6–8 mo old) and aged (26–28 mo old) Fischer 344 rats. Western immunoblotting analysis showed no significant age-related difference in the relative amounts of ryanodine receptor-Ca2+-release channel (RyR-CRC), the Ca2+-storage protein calsequestrin, Ca2+-pumping ATPase (Ca2+-ATPase), and Ca2+-ATPase-regulatory protein phospholamban (PLB) in SR or homogenate. On the other hand, the relative amount of immunoreactive CaM kinase II (δ-isoform) was ∼50% lower in the aged heart. CaM kinase-mediated phosphorylation of RyR-CRC, Ca2+-ATPase, and PLB was reduced significantly (∼25–40%) in the aged compared with adult rat. ATP-dependent Ca2+-uptake activity of SR and the stimulatory effect of calmodulin on Ca2+uptake were also reduced significantly with aging. Treatment of SR vesicles with anti-PLB antibody (PLBab) invoked relatively less stimulation of Ca2+uptake in the aged (≤26%) compared with the adult (≤65%) rat. Ca2+-ATPase but not PLB underwent phosphorylation by CaM kinase in PLBab-treated SR with resultant stimulation of Ca2+uptake. The rates of Ca2+uptake by PLBab-treated SR were significantly lower (45–55%) in the aged compared with adult rat in the absence and presence of calmodulin. These findings imply that changes in the intrinsic functional properties of SR Ca2+-cycling proteins and/or their phosphorylation-dependent regulation contribute to impaired SR function in the aging heart.
Pattern of neuronal activation in rats with CHF after myocardial infarction
Authors: Vahid-Ansari Faranak , Leenen Frans H. H.
Published: December 2017

To identify neuronal populations possibly contributing to the sympathetic hyperactivity in rats with congestive heart failure (CHF) after myocardial infarction (MI), immunohistochemical detection of Fra-like immunoreactivity (Fra-LI) was used as a marker of long-term neuronal activation. In adult Wistar rats, 2 and 4 wk after left coronary artery ligation, left ventricular (LV) peak systolic pressure and LV end-diastolic pressure were measured, immediately followed by transcardial perfusion and removal of the heart and brain. The brains were processed using an antibody that recognizes Fos, FosB, Fra-1, and Fra-2 for the detection of Fra-LI and using an antibody that only recognizes Fos-like immunoreactivity (Fos-LI). At both 2 and 4 wk after large MI, LV peak systolic pressure was significantly decreased and LV end-diastolic pressure increased. At 2 wk post-MI or sham surgery, Fra-LI was observed in several areas of either group but was significantly higher in the MI versus the sham group in the magnocellular division of the paraventricular nucleus (PVN), supraoptic nucleus (SON), subfornical organ, and caudal part of the nucleus of the solitary tract. At 4 wk after large MI, Fra-LI was clearly detected in the parvocellular and magnocellular divisions of the PVN, SON, and locus ceruleus. Modest expression was noted in these nuclei in rats with small MI, whereas Fra-like positive immunoreactive neurons were barely detectable in the sham group 4 wk postsurgery. In these nuclei, the extent of expression of Fra-LI correlated significantly with the LV end-diastolic pressure. Fos-LI was only noted in the cerebral cortex. These results indicate clear activation of neurons as identified by Fra-LI in specific cardiovascular control centers in rats with CHF 2 and 4 wk post-MI.
Predictions of capillary oxygen transport in the presence of fluorocarbon additives
Authors: Eggleton Charles D. , Roy Tuhin K. , Popel Aleksander S.
Published: December 2017

A mathematical model of capillary oxygen transport was formulated to determine the effect of increasing plasma solubility, e.g., by the addition of an intravascular fluorocarbon emulsion. The effect of increased plasma solubility is studied for two distributions of fluorocarbon, when the fluorocarbon droplets are uniformly distributed throughout the plasma and when the fluorocarbon droplets are concentrated in a layer adjacent to the endothelium. The model was applied to working hamster retractor muscle at normal and lowered hematocrit. The intracapillary mass transfer coefficient was found to increase by 18% as the solubility was increased by a factor of 1.7 at a hematocrit of 43%. An additional increase of 6% was predicted when the solubility increase was concentrated in the layer adjacent to the endothelium. At a hematocrit of 25%, the intracapillary mass transfer coefficient increased 14% when the solubility was increased by a factor of 1.7.
Influence of arteriovenular pairing on PAF-induced capillary filtration
Authors: Harris Norman R. , First Georgia A. Morgan , Specian Robert D.
Published: December 2017

The purpose of this study was to determine the basic mechanism by which leukocyte-endothelial cell adhesion mediates platelet-activating factor (PAF)-induced increases in capillary fluid filtration rate. A modified Landis technique was used to observe fluid filtration from capillaries in the rat mesentery. Hypothetical mechanisms of increased filtration that were tested included 1) a direct action of leukocytes on endothelial cells during transit through the capillaries; 2) an upstream propagated response (via gap junction communication by adjacent endothelial cells) originating at sites of venular leukocyte adhesion; and 3) venule-to-arteriole communication, where mediators produced at the site of venular leukocyte adhesion reach a nearby paired arteriole that delivers the mediators to branching capillaries. Evidence was obtained in opposition to the first two hypotheses. However, in support of the third hypothesis, a significant correlation was found between the extent of arteriolar pairing to venules and the PAF-induced increase in capillary fluid filtration rate. These findings suggest that venule-to-arteriole communication might modify capillary filtration rate during acute inflammation.