bluuebunny/crossref_metadata_2025 huggingface dataset:
Downregulation of cardiac myocyte Na+-K+-ATPase by adenovirus-mediated expression of an α-subunit fragment
Authors: Kometiani Peter , Askari Amir , Liu Jiang , Xie Zijian , Askari Frederick K.
Published: December 2017

Cultured rat cardiac myocytes and A7r5 cells were transfected with an adenoviral vector used earlier for in vivo expression of functional α2-isoform of the catalytic subunit of rat Na+-K+-ATPase. Expressions of truncated forms of α2, but little or no intact α2, were detected, suggesting the rapid degradation of α2in these cultured cells. In neonatal myocytes normally containing the α1- and the α3-isoforms, expression of the α2-fragment led to 1) a significant decrease in the level of endogenous α1-protein and a modest decrease in α3-protein, 2) decreases in mRNAs of α1and α3, 3) decrease in Na+-K+-ATPase function measured as ouabain-sensitive Rb+uptake, 4) increase in intracellular Ca2+concentration similar to that induced by ouabain, and 5) eventual loss of cell viability. These findings indicate that the α2-fragment downregulates endogenous Na+-K+- ATPase most likely by dominant negative interference either with folding and/or assembly of the predominant housekeeping α1-isoform or with signal transducing function of the enzyme. Demonstration of rise in intracellular Ca2+resulting from α1-downregulation 1) does not support the previously suggested special roles of less abundant α2- and α3-isoforms in the regulation of cardiac Ca2+, 2) lends indirect support to proposals that observed decrease in total Na+-K+-ATPase of the failing heart may be a mechanism to compensate for impaired cardiac contractility, and 3) suggests the potential therapeutic utility of dominant negative inhibition of Na+-K+-ATPase.
Dynamic sympathetic control of atrioventricular conduction time and heart period
Authors: Kawada Toru , Chen Shi-Liang , Inagaki Masashi , Shishido Toshiaki , Sato Takayuki , Tatewaki Teiji , Sugimachi Masaru , Sunagawa Kenji
Published: December 2017

Although power spectra of R-R and P-R intervals in response to random respiration show similar frequency distributions, the way in which dynamic sympathetic regulation contributes to such similarity remains unknown. We estimated the transfer function from sympathetic stimulation to the atrioventricular interval (AV conduction time; T AV) with and without constant atrial pacing in seven anesthetized cats. The transfer function from sympathetic stimulation to T AV, except for absolute gain values, approximated a low-pass filter similar to that from sympathetic stimulation to the A-A interval (heart period; T AA). The 90%-rise times did not differ between the T AA and T AV step responses (32.3 ± 1.8 vs. 29.6 ± 3.2 s). Constant pacing augmented the T AV step response (−0.58 ± 0.10 vs. −0.86 ± 0.12 ms/Hz, P< 0.05) without affecting the 90%-rise time. These findings suggest that the dynamic characteristics of sympathetic control are similar between T AA and T AVdespite the different electrophysiological mechanisms determining T AA and T AV. A numerical simulation indicated that if the dynamic characteristics of the sympathetic control do not match between T AA and T AV, a critical condition for initiation of reentrant tachycardia would be encountered.
Neural blockade during exercise augments central command's contribution to carotid baroreflex resetting
Authors: Querry R. G. , Smith S. A. , Strømstad M. , Ide K. , Raven P. B. , Secher N. H.
Published: December 2017

This investigation was designed to determine central command's role on carotid baroreflex (CBR) resetting during exercise. Nine volunteer subjects performed static and rhythmic handgrip exercise at 30 and 40% maximal voluntary contraction (MVC), respectively, before and after partial axillary neural blockade. Stimulus-response curves were developed using the neck pressure-neck suction technique and a rapid pulse train protocol (+40 to −80 Torr). Regional anesthesia resulted in a significant reduction in MVC. Heart rate (HR) and ratings of perceived exertion (RPE) were used as indexes of central command and were elevated during exercise at control force intensity after induced muscle weakness. The CBR function curves were reset vertically with a minimal lateral shift during control exercise and exhibited a further parallel resetting during exercise with neural blockade. The operating point was progressively reset to coincide with the centering point of the CBR curve. These data suggest that central command was a primary mechanism in the resetting of the CBR during exercise. However, it appeared that central command modulated the carotid-cardiac reflex proportionately more than the carotid-vasomotor reflex.
Severe exercise alters the strength and mechanisms of the muscle metaboreflex
Authors: Augustyniak Robert A. , Collins Heidi L. , Ansorge Eric J. , Rossi Noreen F. , O'Leary Donal S.
Published: December 2017

Previous studies have shown that in dogs performing mild to moderate treadmill exercise, partial graded reductions in hindlimb blood flow cause active skeletal muscle to become ischemic and metabolites to accumulate thus evoking the muscle metaboreflex. This leads to a substantial reflex increase in mean arterial pressure (MAP) mediated almost solely via a rise in cardiac output (CO). However, during severe exercise CO is likely near maximal and thus metaboreflex-mediated increases in MAP may be attenuated. We therefore evoked the metaboreflex via partial graded reductions in hindlimb blood flow in seven dogs during mild, moderate, and severe treadmill exercise. During mild and moderate exercise there was a large rise in CO (1.5 ± 0.2 and 2.2 ± 0.3 l/min, respectively), whereas during severe exercise no significant increase in CO occurred. The rise in CO caused a marked pressor response that was significantly attenuated during severe exercise (26.3 ± 7.0, 33.2 ± 5.6, and 12.2 ± 4.8 mmHg, respectively). We conclude that during severe exercise the metaboreflex pressor response mechanisms are altered such that the ability of this reflex to increase CO is abolished, and reduced pressor response occurs only via peripheral vasoconstriction. This shift in mechanisms likely limits the effectiveness of the metaboreflex to increase blood flow to ischemic active skeletal muscle. Furthermore, because the metaboreflex is a flow-raising reflex and not a pressure-raising reflex, it may be most appropriate to describe the metaboreflex magnitude based on its ability to evoke a rise in CO and not a rise in MAP.
Cytochrome P-450 ω-hydroxylase: a potential O2 sensor in rat arterioles and skeletal muscle cells
Authors: Kunert Mary Pat , Roman Richard J. , Alonso-Galicia Magdalena , Falck John R. , Lombard Julian H.
Published: December 2017

The purposes of this study were to 1) further evaluate the possible role that vasoconstrictor metabolites of cytochrome P-450 (CYP) ω-hydroxylase plays in O2-induced constriction of arterioles in the rat skeletal muscle microcirculation, 2) determine whether ω-hydroxylases are expressed in rat cremaster muscle, and 3) determine whether the enzyme is located in the parenchyma or the arterioles. O2-induced constriction of third-order arterioles in the in situ cremaster muscle of Sprague-Dawley rats was significantly inhibited by the CYP inhibitors N-methyl-sulfonyl-12,12-dibromododec-11-enamide (DDMS; 50 μM) and 17-octadecynoic acid (ODYA; 10 μM). Immunoblot analysis with antibody raised against CYP4A protein indicated the presence of immunoreactive proteins in the cremaster muscle and in isolated arterioles and muscle fibers from this tissue. However, the molecular mass of the immunoreactive proteins was 85 kDa instead of the expected 50–52 kDa for CYP4A ω-hydroxylase isolated from rat liver or kidney. Treatment of the cremaster muscle with deglycosidases shifted the bands to the expected range which indicates that these proteins are likely glycosylated in skeletal muscle. Immunohistochemistry revealed intense staining of both muscle fibers and microvessels in the cremaster muscle. The results of this study indicate that O2 sensing in the skeletal muscle microcirculation may be mediated by CYP4A ω-hydroxylases in both arterioles and parenchymal cells.
Regulation of Na+pump expression by vascular smooth muscle cells
Authors: Aydemir-Koksoy Aslihan , Allen Julius C.
Published: December 2017

The Na+pump and its regulation is important for maintaining membrane potential and transmembrane Na+gradient in all mammalian cells and thus is essential for cell survival and function. Vascular smooth muscle cells (VSMC) have a relatively low number of pump sites on their membrane compared with other cells. We wished to determine the mechanisms for regulating the number of pump sites in these cells. We used canine saphenous vein VSMC cultured in 10% serum and passaged one time. These cells were subcultured in 5% serum media with low K+(1 mM vs. control of 5 mM), and their pump expression was assessed. These VSMC upregulated their pump sites as early as 4 h after treatment (measured by [3H]ouabain binding). At this early time point, there was no detectable increase in protein expression of either α1- or β1-subunits of the pump shown by Western blots. When the cells were treated with the phosphoinositide 3-kinase (PI-3-K) inhibitor LY-294002 (which is known to inhibit cytoplasmic transport processes) in low-K+media, the pump site upregulation was inhibited. These data suggest that the low-K+-induced upregulation of Na+pump number can occur by translocation of preformed pumps from intracellular stores.
Helium inhalation enhances vasodilator effect of inhaled nitric oxide on pulmonary vessels in hypoxic dogs
Authors: Nie Masaki , Kobayashi Hirosuke , Sugawara Motoaki , Tomita Tomoyuki , Ohara Kuniyoshi , Yoshimura Hirokuni
Published: December 2017

There are theoretical and experimental indications that the presence of He as a balance gas markedly increase the diffusion velocity of other gases contained in a gas mixture. We allowed dogs with pulmonary vasoconstriction induced by hypoxia to inhale a mixture of 5 parts per million (ppm) of nitric oxide (NO) and O2 balanced with He (NO in He) instead of N2 (NO in N2). The dilating effect of NO in He and NO in N2 on the pulmonary artery was evaluated by determining conventional pulmonary hemodynamic parameters, mean pulmonary artery (PA) pressure (MPAP), and pulmonary vascular resistance indexed to body surface area (PVRI), pulmonary impedance ( Z), and the recently developed hemodynamic index, time-corrected wave intensity (WI). The main findings in this study were as follows: 1) hypoxia increased MPAP, PVRI, Z at 0 Hz ( Z 0), Z at the first harmonics, characteristic impedance ( Z c), the reflection coefficient (Γ), and the first peak of WI; 2) NO in N2 reduced Z 0and Γ; and 3) NO in He reduced the first peak of WI and reduced Z 0 and Γ more than NO in N2. The enhanced vasodilatory effect of NO in He might be associated with facilitated diffusion of NO diluted in the gas mixture with He. In conclusion, increased efficacy of NO in He offers the possibility to reduce the inhaled NO concentration.
Leukocyte-type 12-lipoxygenase-deficient mice show impaired ischemic preconditioning-induced cardioprotection
Authors: Gabel Scott A. , London Robert E. , Funk Colin D. , Steenbergen Charles , Murphy Elizabeth
Published: December 2017

To investigate the role of 12-lipoxygenase in preconditioning, we examined whether hearts lacking the “leukocyte-type” 12-lipoxygenase (12-LOKO) would be protected by preconditioning. In hearts from wild-type (WT) and 12-LOKO mice, left ventricular developed pressure (LVDP) and31P NMR were monitored during treatment (±preconditioning) and during global ischemia and reperfusion. Postischemic function (rate-pressure product, percentage of initial value) measured after 20 min of ischemia and 40 min of reperfusion was significantly improved by preconditioning in WT hearts (78 ± 12% in preconditioned vs. 44 ± 7% in nonpreconditioned hearts) but not in 12-LOKO hearts (47 ± 7% in preconditioned vs. 33 ± 10% in nonpreconditioned hearts). Postischemic recovery of phosphocreatine was significantly better in WT preconditioned hearts than in 12-LOKO preconditioned hearts. Preconditioning significantly reduced the fall in intracellular pH during sustained ischemia in both WT and 12-LOKO hearts, suggesting that attenuation of the fall in pH during ischemia can be dissociated from preconditioning-induced protection. Necrosis was assessed after 25 min of ischemia and 2 h of reperfusion using 2,3,5-triphenyltetrazolium chloride. In WT hearts, preconditioning significantly reduced the area of necrosis (26 ± 4%) compared with nonpreconditioned hearts (62 ± 10%) but not in 12-LOKO hearts (85 ± 3% in preconditioned vs. 63 ± 11% in nonpreconditioned hearts). Preconditioning resulted in a significant increase in 12( S)-hydroxyeicosatetraenoic acid in WT but not in 12-LOKO hearts. These data demonstrate that 12-lipoxygenase is important in preconditioning.
AKAP proteins anchor cAMP-dependent protein kinase to KvLQT1/IsK channel complex
Authors: Potet Franck , Scott John D. , Mohammad-Panah Raha , Escande Denis , Baró Isabelle
Published: December 2017

In cardiac myocytes, the slow component of the delayed rectifier K+current ( IKs) is regulated by cAMP. Elevated cAMP increases IKsamplitude, slows its deactivation kinetics, and shifts its activation curve. At the molecular level, IKschannels are composed of KvLQT1/IsK complexes. In a variety of mammalian heterologous expression systems maintained at physiological temperature, we explored cAMP regulation of recombinant KvLQT1/IsK complexes. In these systems, KvLQT1/IsK complexes were totally insensitive to cAMP regulation. cAMP regulation was not restored by coexpression with the dominant negative isoform of KvLQT1 or with the cystic fibrosis transmembrane regulator. In contrast, coexpression of the neuronal A kinase anchoring protein (AKAP)79, a fragment of a cardiac AKAP (mAKAP), or cardiac AKAP15/18 restored cAMP regulation of KvLQT1/IsK complexes inasmuch as cAMP stimulation increased the IKsamplitude, increased its deactivation time constant, and negatively shifted its activation curve. However, in cells expressing an AKAP, the effects of cAMP stimulation on the IKsamplitude remained modest compared with those previously reported in cardiac myocytes. The effects of cAMP stimulation were fully prevented by including the Ht31 peptide (a global disruptor of protein kinase A anchoring) in the intracellular medium. We concluded that cAMP regulation of IKsrequires protein kinase A anchoring by AKAPs, which therefore participate with the channel protein complex underlying IKs.
Thyroid status influences baroreflex function and autonomic contributions to arterial pressure and heart rate
Authors: Foley C. Michael , McAllister Richard M. , Hasser Eileen M.
Published: December 2017

The effect of thyroid status on arterial baroreflex function and autonomic contributions to resting blood pressure and heart rate (HR) were evaluated in conscious rats. Rats were rendered hyperthyroid (Hyper) or hypothyroid (Hypo) with triiodothyronine and propylthiouracil treatments, respectively. Euthyroid (Eut), Hyper, and Hypo rats were chronically instrumented to measure mean arterial pressure (MAP), HR, and lumbar sympathetic nerve activity (LSNA). Baroreflex function was evaluated with the use of a logistic function that relates LSNA or HR to MAP during infusion of phenylephrine and sodium nitroprusside. Contributions of the autonomic nervous system to resting MAP and HR were assessed by blocking autonomic outflow with trimethaphan. In Hypo rats, the arterial baroreflex curve for both LSNA and HR was shifted downward. Hypo animals exhibited blunted sympathoexcitatory and tachycardic responses to decreases in MAP. Furthermore, the data suggest that in Hypo rats, the sympathetic influence on HR was predominant and the autonomic contribution to resting MAP was greater than in Eut rats. In Hyper rats, arterial baroreflex function generally was similar to that in Eut rats. The autonomic contribution to resting MAP was not different between Hyper and Eut rats, but predominant parasympathetic influence on HR was exhibited in Hyper rats. The results demonstrate baroreflex control of LSNA and HR is attenuated in Hypo but not Hyper rats. Thyroid status alters the balance of sympathetic to parasympathetic tone in the heart, and the Hypo state increases the autonomic contributions to resting blood pressure.
Heart rate modulates the slow enhancement of contraction due to sudden left ventricular dilation
Authors: Tucci Paulo José Ferreira , Murad Neif , Rossi Clever Land , Nogueira Roberto Janzon , Santana Orlando
Published: December 2017

In isovolumic blood-perfused dog hearts, left ventricular developed pressure (DP) was recorded while a sudden ventricular dilation was promoted at three heart rate (HR) levels: low (L: 52 ± 1.7 beats/min), intermediate (M: 82 ± 2.2 beats/min), and high (H: 117 ± 3.5 beats/min). DP increased instantaneously with chamber expansion (Δ1DP), and another continuous increase occurred for several minutes (Δ2DP). HR elevation did not alter Δ1DP (32.8 ± 1.6, 33.6 ± 1.5, and 34.3 ± 1.2 mmHg for L, M, and H, respectively), even though it intensified Δ2DP (17.3 ± 0.9, 20.7 ± 1.0, and 26.8 ± 1.2 mmHg for L, M, and H, respectively), meaning that the treppe phenomenon enhances the length dependence of the contraction component related to changes in intracellular Ca2+ concentration. Frequency increments reduced the half time of the slow response (82 ± 3.6, 67 ± 2.6, and 53 ± 2.0 s for L, M, and H, respectively), while the number of beats included in half time increased (72 ± 2.9, 95 ± 2.9, and 111 ± 3.2 beats for L, M, and H, respectively). HR modulation of the slow response suggests that L-type Ca2+ channel currents and/or the Na+/Ca2+ exchanger plays a relevant role in the stretch-triggered Ca2+ gain when HR increases in the canine heart.
Gadolinium attenuates exercise pressor reflex in cats
Authors: Hayes Shawn G. , Kaufman Marc P.
Published: December 2017

The exercise pressor reflex, which arises from the contraction-induced stimulation of group III and IV muscle afferents, is widely believed to be evoked by metabolic stimuli signaling a mismatch between blood/oxygen demand and supply in the working muscles. Nevertheless, mechanical stimuli may also play a role in evoking the exercise pressor reflex. To determine this role, we examined the effect of gadolinium, which blocks mechanosensitive channels, on the exercise pressor reflex in both decerebrate and α-chloralose-anesthetized cats. We found that gadolinium (10 mM; 1 ml) injected into the femoral artery significantly attenuated the reflex pressor responses to static contraction of the triceps surae muscles and to stretch of the calcaneal (Achilles) tendon. In contrast, gadolinium had no effect on the reflex pressor response to femoral arterial injection of capsaicin (5 μg). In addition, gadolinium significantly attenuated the responses of group III muscle afferents, many of which are mechanically sensitive, to both static contraction and to tendon stretch. Gadolinium, however, had no effect on the responses of group IV muscle afferents, many of which are metabolically sensitive, to either static contraction or to capsaicin injection. We conclude that mechanical stimuli arising in contracting skeletal muscles contribute to the elicitation of the exercise pressor reflex.
Systolic axial artery length reduction: an overlooked phenomenon in vivo
Authors: Tozzi P. , Hayoz D. , Oedman C. , Mallabiabarrena I. , Von Segesser L. K.
Published: December 2017

To demonstrate axial artery motion during the cardiac cycle, the common carotid arteries (CCA) of 10 pigs were exposed and equipped with piezoelectric crystals sutured onto the artery as axial position detectors. An echo-tracking system was used to simultaneously measure the CCA diameter. For each animal, data for pressure, length, and diameter were collected at a frequency of 457 Hz. At a mean pulse pressure of 33 ± 8 mmHg, the mean systolodiastolic length difference was 0.3 ± 0.01 mm for a mean arterial segment of 11.35 ± 1.25 mm. Systolic and diastolic diameters were 4.1 ± 0.3 and 3.9 ± 0.2 mm, respectively. The examined CCA segment displayed a mean axial systolic shortening of 2.7%. This study clearly demonstrates, for the first time, that the length of a segment of the CCA changes during the cardiac cycle and that this movement is inversely correlated with pulse pressure. It is also apparent that the segmental axial strain is significantly smaller than the diameter variation during the cardiac cycle and that the impact of the axial strain for compliance computation should be further evaluated.
Regression by ACE inhibition of arteriosclerotic changes induced by chronic blockade of NO synthesis in rats
Authors: Katoh Makoto , Egashira Kensuke , Kataoka Chu , Usui Makoto , Koyanagi Masamichi , Kitamoto Shiro , Ohmachi Yasushi , Takeshita Akira , Narita Hiroshi
Published: December 2017

We previously reported that chronic inhibition of nitric oxide (NO) synthesis with N ω-nitro-l-arginine methyl ester (l-NAME) induces vascular inflammation at week 1and produces subsequent arteriosclerosis at week 4 and that cotreatment with an angiotensin-converting enzyme (ACE) inhibitor prevents such changes. In the present study, we tested the hypothesis that treatment with an ACE inhibitor after development of vascular inflammation could inhibit arteriosclerosis in rats. Wistar-Kyoto rats were randomized to four groups: the control group received no drugs, the 4wl-NAME group received l-NAME (100 mg · kg−1 · day−1) for 4 wk, the 1wL + 3wNT group received l-NAME for 1 wk and no treatment for the subsequent 3 wk, and the 1wL + 3wACEI group received l-NAME for 1 wk and the ACE inhibitor imidapril (20 mg · kg−1 · day−1) for the subsequent 3 wk. After 4 wk, we observed significant arteriosclerosis of the coronary artery (medial thickening and fibrosis) and increased cardiac ACE activity in the 1wL + 3wNT group as well as in the 4wl-NAME group, but not in the 1wL + 3wACEI group. In a separate study, we examined apoptosis formation and found that posttreatment with imidapril (20 mg · kg−1 · day−1) or an ANG II AT1-receptor antagonist, CS-866 (5 mg · kg−1 · day−1), induced apoptosis (TdT-mediated nick end-labeling) in monocytes and myofibroblasts appearing in the inflammatory lesions associated with a clear degradation in the heart (DNA electrophoresis). In conclusion, treatment with the ACE inhibitor after 1 wk of l-NAME administration inhibited arteriosclerosis by inducing apoptosis in the cells with inflammatory lesions in this study, suggesting that increased ANG II activity inhibited apoptosis of the cells with inflammatory lesions and thus contributed to the development of arteriosclerosis.
Nitric oxide reduces energy supply by direct action on the respiratory chain in isolated cardiomyocytes
Authors: Stumpe Thomas , Decking Ulrich K. M. , Schrader Jürgen
Published: December 2017

To investigate the effect of nitric oxide (NO) on cardiac energy metabolism, isolated cardiomyocytes of Wistar rats were incubated in an Oxystat system at a constant ambient Po2(25 mmHg) and oxygen consumption (V˙o2); free intracellular Ca2+(fura 2), free cytosolic adenosine [ S-adenosylhomocysteine (SAH) method], and mitochondrial NADH (autofluorescence) were measured after application of the NO donor morpholinosydnonimine (SIN-1). In Na+-free medium (contracting cardiomyocytes), V˙o2increased from 7.9 ± 1.2 to 26.4 ± 3.1 nmol · min−1· mg protein−1. SIN-1 (100 μmol/l) decreased V˙o2in contracting (−21 ± 3%) and in quiescent cells (−24 ± 7%) by the same extent. Inhibition ofV˙o2was dose dependent (EC50: 10−7mol/l). S-nitroso- N-acetyl-penicillamine, another NO donor, also inhibited V˙o2, whereas SIN-1C (100 μmol/l), the degradation product of SIN-1, displayed no inhibitory effect. Intracellular Ca2+remained unchanged, and inhibition of protein kinases G, A, or C did not antagonize the effect of NO. Mitochondrial NADH increased with NO, indicating a reduced flux through the respiratory chain. In quiescent but not in contracting cardiomyocytes, NO significantly increased adenosine, indicating a reduced energy status. These data suggest the following. 1) NO decreases cardiac respiration, most likely via direct inhibition of the respiratory chain. 2) Whereas in quiescent cardiomyocytes the inhibition of aerobic ATP formation by NO causes reduction in energy status, contracting cells are able to compensate for the NO-induced inhibition of oxidative phosphorylation, maintaining energy status constant.
Anatomical and functional characteristics of carotid sinus stimulation in humans
Authors: Querry R. G. , Smith S. A. , Strømstad M. , Ide K. , Secher N. H. , Raven P. B.
Published: December 2017

Transmission characteristics of pneumatic pressure to the carotid sinus were evaluated in 19 subjects at rest and during exercise. Either a percutaneous fluid-filled ( n = 12) or balloon-tipped catheter ( n = 7) was placed at the carotid bifurcation to record internal transmission of external neck pressure/neck suction (NP/NS). Sustained, 5-s pulses, and rapid ramping pulse protocols (+40 to −80 Torr) were recorded. Transmission of pressure stimuli was less with the fluid-filled catheter compared with that of the balloon-tipped catheter (65% vs. 82% negative pressure, 83% vs. 89% positive pressure; P < 0.05). Anatomical location of the carotid sinus averaged 3.2 cm (left) and 3.6 cm (right) from the gonion of the mandible with a range of 0–7.5 cm. Transmission was not altered by exercise or Valsalva maneuver, but did vary depending on the position of the carotid sinus locus beneath the sealed chamber. These data indicate that transmission of external NP/NS was higher than previously recorded in humans, and anatomical variation of carotid sinus location and equipment design can affect transmission results.
Arterial baroreflex control of sympathetic nerve activity during acute hypotension: effect of fitness
Authors: Fadel P. J. , Stromstad M. , Hansen J. , Sander M. , Horn K. , Ogoh S. , Smith M. L. , Secher N. H. , Raven P. B.
Published: December 2017

We examined arterial baroreflex control of muscle sympathetic nerve activity (MSNA) during abrupt decreases in mean arterial pressure (MAP) and evaluated whether endurance training alters baroreflex function. Acute hypotension was induced nonpharmacologically in 14 healthy subjects, of which 7 were of high fitness (HF) and 7 were of average fitness (AF), by releasing a unilateral arterial thigh cuff after 9 min of resting ischemia under two conditions: control, which used aortic and carotid baroreflex (ABR and CBR, respectively) deactivation; and suction, which used ABR deactivation alone. The application of neck suction to counteract changes in carotid sinus transmural pressure during cuff release significantly attenuated the MSNA response (which increased 134 ± 32 U/14 s) compared with control (which increased 195 ± 43 U/14 s) and caused a greater decrease in MAP (19 ± 2 vs. 15 ± 2 mmHg; P < 0.05). Furthermore, during both trials, the HF subjects exhibited a greater decrease in MAP compared with AF subjects despite an augmented baroreflex control of MSNA. These data indicate that the CBR contributes importantly to the MSNA response during acute systemic hypotension. Additionally, we suggest that an impaired control of vascular reactivity hinders blood pressure regulation in HF subjects.
Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents
Authors: Braun Rod D. , Lanzen Jennifer L. , Snyder Stacey A. , Dewhirst Mark W.
Published: December 2017

In this study we compare oxygen tension (Po 2) histograms measured with O2 microelectrodes and a new optical Po 2 measurement device, the OxyLite, in normal tissues (mouse spleen and thymus) and in tumors (R3230Ac in rats) ( n = 5–6). The transient response to glucose infusion or 100% O2 breathing (hyperoxia) was also measured in tumors. Po 2 histograms of spleen and thymus with the two devices were not different. The OxyLite tumor Po 2 histogram, however, was left-shifted compared with the microelectrode (median Po 21.0 vs. 4.0 mmHg, P = 0.016). Both probes responded to acute hyperglycemia with a mean increase of 3–6 mmHg, but the microelectrode change was not significant. The OxyLite consistently recorded large Po 2 increases (∼28 mmHg) with hyperoxia, whereas the microelectrode response was variable. The OxyLite averages Po 2 over an area that contains interstitial and vascular components, whereas the microelectrode measures a more local Po 2. This study demonstrates the importance of considering the features of the measurement device when studying tissues with heterogeneous Po 2 distributions (e.g., tumors).
Compression of interventricular septum during right ventricular pressure loading
Authors: Nelson Gregory S. , Sayed-Ahmed Ezzeldin Y. , Kroeker Carol A. Gibbons , Sun Yi-Hui , Keurs Henk E. D. J. Ter , Shrive Nigel G. , Tyberg John V.
Published: December 2017

The interventricular septum, which flattens and inverts in conditions such as pulmonary hypertension, is considered by many to be an unstressed membrane, in that its position is assumed to be determined solely by the transseptal pressure gradient. A two-dimensional finite element model was developed to investigate whether compression and bending moments (behavior incompatible with a membrane) exist in the septum during diastole under abnormal loading, i.e., pulmonary artery (PA) constriction. Hemodynamic and echocardiographic data were obtained in six open-chest anesthetized dogs. For both control and PA constriction, the measured left ventricular and right ventricular pressures were applied to a residually stressed mesh. Adjustments were made to the stiffness and end-bending moments until the deformed and loaded residually stressed mesh matched the observed configuration of the septum. During PA constriction, end-bending moments were required to obtain satisfactory matches but not during control. Furthermore, substantial circumferential compressive stresses developed during PA constriction. Such stresses might impede septal blood flow and provoke the unexplained ischemia observed in some conditions characterized by abnormal septal motion.
Right atrial pressure as measure of ventricular constraint in newborn lambs
Authors: Fauchère Jean-Claude , Walker Adrian M. , Skuza Elizabeth M. , Grant Daniel A.
Published: December 2017

Although the lungs and pericardium constrain the heart and limit cardiac output, no method exists to assess this constraint in sick newborns. We hypothesize that a useful estimate of ventricular constraint may be obtained by measuring right atrial pressure (PRA) in the newborn. To test this hypothesis, we measured PRA, thoracic inferior vena caval pressure (PIVC; saline-filled catheters), and ventricular constraint (pericardial pressure, PPER; liquid-containing balloon) in 4-wk-old (neonatal, n = 12) and 3-day-old (newborn, n = 6) anesthetized lambs. The measurements were made while LV filling pressure was altered (0–20 mmHg) and while positive end-expiratory pressure (PEEP) was maintained at 2.5 or 15 cmH2O. In all of the lambs, a strong linear relationship ( r) existed between PRA and PPER(PRA = 1.19 PPER + 0.0, r = 0.99) and between PIVC and PPER (PIVC = 1.24 PPER + 0.1, r = 0.99; PEEP of 2.5 cmH2O). Similar relationships were also observed with increased PEEP (PRA = 1.29 PPER−1.2, r = 0.98 and PIVC = 1.32 PPER−1.2, r = 0.97). Because PRA provides an accurate measure of ventricular constraint in the normal lamb, it may be a useful measure of ventricular constraint in the sick newborn.
Myocardial ischemia selectively depletes cardiolipin in rabbit heart subsarcolemmal mitochondria
Authors: Lesnefsky Edward J. , Slabe Thomas J. , Stoll Maria S. K. , Minkler Paul E. , Hoppel Charles L.
Published: December 2017

Mitochondria contribute to myocyte injury during ischemia. After 30 and 45 min of ischemia in the isolated perfused rabbit heart, subsarcolemmal mitochondria (SSM), located beneath the plasma membrane, sustain a decrease in oxidative phosphorylation through cytochrome oxidase. In contrast, oxidation through cytochrome oxidase in interfibrillar mitochondria (IFM), located between the myofibrils, remains unaffected. Cytochrome oxidase activity in the intact membrane requires an inner mitochondrial membrane lipid environment enriched in cardiolipin. During ischemia, the content of cardiolipin decreased only in SSM, whereas the content of other phospholipids was preserved. Ischemia did not alter the composition of the cardiolipin that remained in SSM. Cardiolipin content was preserved in IFM during ischemia. Thus cardiolipin is a relatively early target of ischemic mitochondrial damage, leading to loss of oxidative phosphorylation through cytochrome oxidase in SSM.
TNF-α increases sensitivity to LPS in chronically catheterized rats
Authors: Goto Masakatsu , Deriy Lucy V. , Chen Yong J. , Beno David W. A. , Uhing Michael R. , Jiyamapa-Serna Vanida A. , Kimura Robert E.
Published: December 2017

Patients with severe trauma injury are transiently exposed to increased serum concentrations of tumor necrosis factor-α (TNF-α). These patients are susceptible to the development of multisystem organ failure (MSOF) triggered by subsequent exposure to bacterial toxins either via infection or increased intestinal permeability. We simulated the cytokine response of trauma by infusing 0.8 or 8.0 μg/kg of TNF-α (priming dose) into chronically catheterized rats. After 48 h, rats were challenged with endotoxin [lipopolysaccharide (LPS); 10 or 1,000 μg/kg]. Animals primed with either dose of TNF-α and then challenged with 1,000 μg/kg of LPS demonstrated significantly increased mortality, mean peak serum concentrations of interferon-γ (IFN-γ), and blood lactate concentrations ( P < 0.05) compared with nonprimed animals. Mean peak serum concentrations of IFN-γ and blood lactate concentrations were increased after challenge with 10 μg/kg of LPS only in animals primed with 8.0 μg/kg of TNF-α. Priming with TNF-α did not increase mortality after challenge with 10 μg/kg of LPS. These data suggest that both TNF-α release and the subsequent exposure to bacterial toxins mediate the pathophysiological progression from trauma to subsequent MSOF.
Nitric oxide synthase in porcine heart mitochondria: evidence for low physiological activity
Authors: French Stephanie , Giulivi Cecilia , Balaban R. S.
Published: December 2017

The capacity of isolated porcine heart mitochondria to produce nitric oxide (NO) via mitochondrial NO synthase (NOS) was evaluated. The mitochondrial NOS content and activity (0.2 nmol NO · mg mitochondrial protein−1· min−1) were ∼10 times lower than previously reported for the rat liver. No evidence for mitochondrial NOS-generated NO was found in mitochondrial suspensions based on the lack of NO production and the lack of effect of eitherl-arginine or NOS inhibitors on the rate of respiration. The reason that even the low mitochondrial NOS activity did not result in net NO production and metabolic effects is because the mitochondrial metabolic breakdown of NO (1–4 nmol NO · mg mitochondrial protein−1· min−1) was greater than the maximum rate of NO production measured in homogenates. These data suggest that NO production at the mitochondria via NOS is not a significant source of NO in the intact heart and does not regulate cardiac oxidative phosphorylation.
Descending pathways mediating cardiovascular response from dorsomedial hypothalamic nucleus
Authors: Fontes M. A. P. , Tagawa T. , Polson J. W. , Cavanagh S.-J. , Dampney R. A. L.
Published: December 2017

Physiological and anatomic methods were used to determine whether neurons in the rostral ventrolateral medulla (RVLM), nucleus tractus solitarius (NTS), or hypothalamic paraventricular nucleus (PVN) mediate the cardiovascular response evoked from the dorsomedial hypothalamic nucleus (DMH), which is believed to play a key role in mediating responses to stress. In urethane-anesthetized rats, activation of neurons in the DMH by microinjection of bicuculline resulted in a large increase in arterial pressure, heart rate, and renal sympathetic nerve activity. The pressor and sympathoexcitatory responses, but not the tachycardic response, were greatly reduced after bilateral muscimol injections into the RVLM even when baseline arterial pressure was maintained at a constant level. These responses were not reduced by muscimol injections into the PVN or NTS. Retrograde tracing experiments identified many neurons in the DMH that projected directly to the RVLM. The results indicate that the vasomotor and cardiac components of the response evoked from the DMH are mediated by pathways that are dependent and independent, respectively, of neurons in the RVLM.
Intermittent hypoxia modulates nNOS expression and heart rate response to sympathetic nerve stimulation
Authors: Mohan R. M. , Golding S. , Paterson D. J.
Published: December 2017

Nitric oxide (NO) decreases norepinephrine (NE) release and the heart rate (HR) response to sympathetic nerve stimulation (SNS). We tested the hypothesis that the enhanced HR response to sympathetic activation following chronic intermittent hypoxia (IH) results from a peripheral modulation of pacemaking by NO. Isolated guinea pig double atrial/right stellate ganglion preparations were studied from animals that had been exposed to IH ( n = 20) and control animals ( n = 22). The HR response to SNS was significantly enhanced in the IH group compared with the controls. However, the increase in HR with cumulative doses (0.1–10 μM) of bath-applied NE was similar in both groups. Western blot analysis showed less neuronal NO synthase in the right atria from the IH group. In IH animals, the NO synthase inhibitor, N ω-nitro-l-arginine (l-NNA; 100 μM) did not alter the increased HR response to SNS, whereas in control animals l-NNA significantly increased the HR response to SNS; an effect that was reversed with excess l-arginine. In conclusion, the enhanced HR response to SNS after IH may be related to a decreased inhibitory action of NO on presynaptic NE release.
Estrogen restores postischemic pial microvascular dilation
Authors: Watanabe Y. , Littleton-Kearney M. T. , Traystman R. J. , Hurn P. D.
Published: December 2017

Estrogen protects the brain from experimental cerebral ischemia, likely through both vascular and neuronal cellular mechanisms. The purpose of this study was to determine whether chronic estrogen treatment in males and repletion in ovariectomized (Ovx) females reverses abnormalities in pial arteriolar reactivity during reperfusion from global forebrain ischemia (4-vessel occlusion, 15 min) and whether the site of protection is vascular endothelium. Male and Ovx female rats were implanted with either placebo or a 25-μg 17β-estradiol pellet 10 days before ischemia. With the use of intravital microscopy, pial vessel dilation to ACh (10 μM) and S-nitroso- N-acetyl-penicillamine (SNAP; 1 μM) and vasoconstriction to serotonin (10 μM) was examined in situ at 30–60 min of reperfusion. Postischemic changes in vessel diameter were compared with preischemic values for each agent. Postischemic response to both ACh and SNAP was lost in males and Ovx females, but not in estrogen pellet-implanted males and estrogen-implanted Ovx females, suggesting that estrogen protects both endothelial and smooth muscle-mediated vasodilation. Ischemia blunted vessel constriction to serotonin regardless of treatment. These data demonstrate that estrogen acts as a vasoprotective agent within the cerebral circulation and can improve microvascular function under conditions of an acutely evolving ischemic pathology.
Mechanism of temporal gradients in shear-induced ERK1/2 activation and proliferation in endothelial cells
Authors: Bao Xuping , Lu Chuanyi , Frangos John A.
Published: December 2017

The aim of the current study was to investigate the intracellular signaling cascade that leads to temporal gradients in shear (TGS)-induced endothelial cell proliferation, with a focus on the involvement of extracellular signal-regulated kinases 1 and 2 (ERK1/2). With the use of well-defined pulsatile, impulse, step, and ramp laminar flow profiles, we found that TGS (impulse flow and pulsatile flow) induced an enhanced and sustained (>30 min) phosphorylation of ERK1/2 relative to step flow (which contains a step increase in shear followed by steady shear), whereas steady shear (ramp flow) alone downregulated activated ERK1/2. Nitric oxide (NO) was found to mediate both the stimulatory effect of TGS and the inhibitory effect of steady shear on endothelial ERK1/2 phosphorylation. Reactive oxygen species (ROS) were also demonstrated to be associated with TGS-induced ERK1/2 phosphorylation. Both Gq/11and Gi3were necessary for the activation of ERK1/2 by TGS. Finally, the TGS-induced endothelial proliferative response was abolished by ERK1/2 inhibition. Our study demonstrated the essential role of G proteins, NO, and ROS in TGS-dependent ERK1/2 activation and proliferative response in vascular endothelial cells.
Relationship between capillary angiogenesis, fiber type, and fiber size in chronic systemic hypoxia
Authors: Deveci D. , Marshall Janice M. , Egginton S.
Published: December 2017

Whether chronic hypoxia causes angiogenesis in skeletal muscle is controversial. Male Wistar rats, 5–6 wk of age, were kept at constant 12% O2 for 3 wk, and frozen sections of their postural soleus (SOL), phasic extensor digitorum longus (EDL), and tibialis anterior (TA) muscles were compared with those of normoxic controls. Capillary supply increased in SOL muscles [capillary-to-fiber ratio (C/F) = 2.55 ± 0.09 hypoxia vs. 2.17 ± 0.06 normoxia; capillary density (CD) = 942 ± 14 hypoxia vs. 832 ± 20 mm−2 normoxia, P < 0.01] but not in EDL muscles (C/F = 1.44 ± 0.04 hypoxia vs. 1.42 ± 0.04 normoxia; CD = 876 ± 52 hypoxia vs. 896 ± 24 mm−2 normoxia). The predominantly glycolytic cortex of TA muscles showed higher C/F after hypoxia (1.79 ± 0.09 vs. 1.53 ± 0.05 normoxia, P < 0.05), whereas the mainly oxidative TA core with smaller fibers showed no change in capillarity. The region of the SOL muscle with large-sized (mean fiber area 2,843 ± 128 μm2) oxidative fibers (90% type I) had a higher C/F (by 30%) and CD (by 25%), whereas there was no angiogenesis in the region with sparse (76%) and smaller-sized (2,200 ± 85 μm2) type I fibers. Thus systemic hypoxia differentially induces angiogenesis between and within hindlimb skeletal muscles, with fiber size contributing either directly (via a metabolic stimulus) or indirectly (via a mechanical stimulus) to the process.
Bradykinin and des-Arg9-bradykinin metabolic pathways and kinetics of activation of human plasma
Authors: Cyr Mélanie , Lepage Yves , Blais Charles , Gervais Nicole , Cugno Massimo , Rouleau Jean-Lucien , Adam Albert
Published: December 2017

In the serum of 116 healthy individuals, exogenous bradykinin (BK) half-life (27 ± 10 s) was lower than that of des-Arg9-BK (643 ± 436 s) and was statistically different in men compared with women. The potentiating effect of an angiotensin-converting enzyme (ACE) inhibitor was, however, more extensive for BK (9.0-fold) than for des-Arg9-BK (2.2- fold). The activities of ACE, aminopeptidase P (APP), and kininase I were respectively 44 ± 12, 22 ± 9, and 62 ± 10 nmol · min−1· ml−1. A mathematical model ( y = ktαe−β t, t > 0), applied to the BK kinetically released from endogenous high-molecular-weight kininogen (HK) during plasma activation in the presence of an ACE inhibitor, revealed a significant difference in the rate of formation of BK between men and women. For des-Arg9-BK, the active metabolite of BK, the rate of degradation was higher in women compared with men, correlating significantly with serum APP activity ( r2= 0.6485, P < 0.001). In conclusion, these results constitute a basis for future pathophysiological studies of inflammatory processes where activation of the contact system of plasma and the kinins is involved.
Contribution of perfusion pressure to vascular resistance response during head-up tilt
Authors: Imadojemu Virginia A. , Lott Mary E. J. , Gleeson Kevin , Hogeman Cynthia S. , Ray Chester A. , Sinoway Lawrence I.
Published: December 2017

We measured brachial and femoral artery flow velocity in eight subjects and peroneal and median muscle sympathetic nerve activity (MSNA) in five subjects during tilt testing to 40°. Tilt caused similar increases in MSNA in the peroneal and median nerves. Tilt caused a fall in femoral artery flow velocity, whereas no changes in flow velocity were seen in the brachial artery. Moreover, with tilt, the increase in the vascular resistance employed (blood pressure/flow velocity) was greater and more sustained in the leg than in the arm. The ratio of the percent increase in vascular resistance in leg to arm was 2.5:1. We suggest that the greater vascular resistance effects in the leg were due to an interaction between sympathetic nerve activity and the myogenic response.
Metabolism of S-nitrosoglutathione by endothelial cells
Authors: Zeng Hong , Spencer Netanya Y. , Hogg Neil
Published: December 2017

S-nitrosoglutathione (GSNO) is an inhibitor of platelet aggregation and has also been shown to protect the ischemic heart from reperfusion-mediated injury. Although GSNO is often used in cell culture as a source of nitric oxide, the mechanisms of GSNO metabolism are not well established. We show here that GSNO decomposition by bovine aortic endothelial cells has an absolute dependence on the presence of cystine in the cell culture medium. In addition, GSNO decay is inhibited by diethyl maleate, an intracellular glutathione scavenger, but not by buthionine sulfoximine, a glutathione synthesis inhibitor. This indicates that thiols in general, rather than specifically glutathione, are the major factors that influence GSNO decay. Only 40% of the nitroso group of GSNO could be recovered as nitrite/nitrate, suggesting that the primary route of GSNO decay is reductive and that nitric oxide is only a minor product of GSNO decay. We conclude that the intracellular thiol pool causes the reduction of extracellular disulfides to thiols, which then directly reduce GSNO.
HMG-CoA reductase inhibitor stabilizes rabbit atheroma by increasing basal NO and decreasing superoxide
Authors: Thakur Navin Kumar , Hayashi Toshio , Sumi Daigo , Kano Hatsuyo , Tsunekawa Taku , Iguchi Akihisa
Published: December 2017

Male rabbits fed a 0.5% cholesterol diet for 8 wk were divided into three groups. Group 1 was hypercholesterolemic; group 2 was fed a regular diet for an additional 12 wk; and group 3 was fed a regular diet with simvastatin (5 mg · kg−1· day−1). Simvastatin treatment reduced the atherosclerotic area and total and esterified cholesterol concentrations in the thoracic aorta. Tone-related basal nitric oxide (NO) release was highest in group 3. Acetylcholine-induced, NO-dependent relaxation was improved in group 3 compared with group 2. Amount of endothelial nitric oxide synthase (eNOS) mRNA in vessels increased in group 1, compared with normal aorta, and decreased in group 2; however, it did not decrease in group 3. The amount of O[Formula: see text] released from vessels increased in group 1 and group 2 compared with normal rabbits; however, it decreased in group 3, especially in the endothelial cells. Peroxynitrite determined by nitrotyrosine staining decreased in group 3. Additionally, the arteries of rabbits fed a regular diet with or without simvastatin were investigated. The aorta from simvastatin-treated group showed increase of tone-related basal NO release and eNOS mRNA and decrease of O[Formula: see text]release. Taken together, upregulation of eNOS and decrease of O[Formula: see text] treatment were observed in vivo in the process of the sufficient stabilization of atheroma following simvastatin.