bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical and physiological determinants of pulmonary venous flow: numerical analysis
Authors: Thomas J. D. , Zhou J. , Greenberg N. , Bibawy G. , McCarthy P. M. , Vandervoort P. M.
Published: December 2017

To study the physical and physiological determinants of transmitral and pulmonary venous flow, a lumped-parameter model of the cardiovascular system has been created, modeling the instantaneous pressure, volume, and influx/efflux of the pulmonary veins, left atrium and ventricle, systemic arteries and veins. right atrium and ventricle, and pulmonary arteries. Initial validation has been obtained by direct comparison with transesophageal echocardiographic recordings of mitral and pulmonary venous velocity for the following clinical situations: normal diastolic function, delayed ventricular relaxation, restrictive filling due to severe systolic dysfunction, severe mitral regurgitation before and after valve repair surgery, and premature atrial contraction occurring during ventricular systole. Sensitivity analysis has been performed with a Jacobian matrix, representing the proportional change in a group of output indexes (yi) in response to isolated changes in input parameters (xj), [(delta yi/yi)/ ([delta xj/xj)], demonstrating the complementary nature of mitral and pulmonary venous A-wave velocity for predicting ventricular stiffness and atrial systolic function. This unified numerical-experimental programming environment should facilitate model refinement and physiological data exploration, in particular guiding more accurate interpretations of Doppler echocardiographic data.
Pial arteriolar constriction to alpha 2-adrenergic agonist dexmedetomidine in the rat
Authors: Asano Y. , Koehler R. C. , Kawaguchi T. , McPherson R. W.
Published: December 2017

Dexmedetomidine (Dex) is an alpha 2-adrenergic agonist that decreases cerebral blood flow (CBF) when administered systemically. It is unclear whether cerebral vasoconstriction is mediated by a local effect on cerebral vessels or by a remote neural mechanism. In the present study, we compared the pial arteriole responses to locally and systemically administered Dex with and without local application of the specific alpha 2-adrenergic antagonist atipamezole. Six groups of male rats (n = 7 each) were anesthetized with isoflurane and prepared for measurements of small (20-39 microns), medium (40-59 microns), and large (60-79 microns) pial arteriole diameter by intravital microscopy or for regional CBF measurement by the radiolabeled-microsphere method. Local application of Dex caused dose-dependent constriction that was significant starting at 10(-8) M for small and medium-sized arterioles and at 10(-7) M for large arterioles. Constriction to 10(-5) M in small [21 +/- 2% (SE)], medium (21 +/- 2%), and large (15 +/- 1%) arterioles was almost completely blocked by local application of 10(-4) M atipamezole. Intravenous administration of Dex at 1 microgram/kg decreased CBF and caused modest arteriolar constriction that began to resolve 8 min after administration. A dose of 10 micrograms/kg constricted arterioles of all sizes with constriction beginning to resolve after approximately 10 min. Local application of atipamezole (10(-4) M) slightly blunted the response to 1 micrograms/kg of intravenous Dex but did not substantially limit constriction after 10 micrograms/kg. These data demonstrate that pial arterioles are capable of substantial constriction to Dex by a local alpha 2-adrenergic mechanism. However, the inability of locally applied atipamezole to substantially inhibit the vasoconstrictor response to systemically administered Dex suggests that Dex might also cause vasoconstriction indirectly through actions at other sites in the central nervous system.
Hypoxia and the cardiovascular response to dynamic knee-extensor exercise
Authors: Koskolou M. D. , Calbet J. A. , Radegran G. , Roach R. C.
Published: December 2017

Hypoxia affects O2 transport and aerobic exercise capacity. In two previous studies, conflicting results have been reported regarding whether O2 delivery to the muscle is increased with hypoxia or whether there is a more efficient O2 extraction to allow for compensation of the decreased O2 availability at submaximal and maximal exercise. To reconcile this discrepancy, we measured limb blood flow (LBF), cardiac output, and O2 uptake during two-legged knee-extensor exercise in eight healthy young men. They completed studies at rest, at two submaximal workloads, and at peak effort under normoxia (inspired O2 fraction 0.21) and two levels of hypoxia (inspired O2 fractions 0.16 and 0.11). During submaximal exercise, LBF increased in hypoxia and compensated for the decrement in arterial O2 content. At peak effort, however, our subjects did not achieve a higher cardiac output or LBF. Thus O2 delivery was not maintained and peak power output and leg O2 uptake were reduced proportionately. These data are consistent then with the findings of an increased LBF to compensate for hypoxemia at submaximal exercise, but no such increase occurs at peak effort despite substantial cardiac capacity for an elevation in LBF.
Direct coupling between blood flow and metabolism at the capillary level in striated muscle
Authors: Berg B. R. , Cohen K. D. , Sarelius I. H.
Published: December 2017

In hamster cremaster muscle, capillary networks consist of anatomically invariant subunits termed modules [Berg, B. R., and I. H. Sarelius, Am. J. Physiol. 268 (Heart Circ. Physiol. 37): H1215-H1222, 1995]. To explore local coupling between blood flow and metabolism, we used micropipettes to stimulate five to six muscle fibers running underneath specified capillary modules. Capillary erythrocyte flow increased significantly at all stimulation frequencies because of increased erythrocyte content at 2 Hz and increased erythrocyte velocity at 4 and 8 Hz. Erythrocyte flow did not increase when the fibers underlying the module were mechanically tugged but did not actively contract at these frequencies. Increased capillary flow was accommodated by dilation of three upstream arteriolar generations: the module inflow arteriole dilated significantly at all frequencies, and further upstream, dilations were significant at higher frequencies. Other module inflow arterioles in the same capillary network as the stimulated module did not dilate. Dilations in the module inflow arteriole were abolished by 600 mosM sucrose but were unaffected by 10(-6) M tetrodotoxin. These data suggest that local coupling between capillary flow and muscle contraction includes a conducted vasodilation that is responsible for the remote upstream dilations.
Estrogen relaxation of coronary artery smooth muscle is mediated by nitric oxide and cGMP
Authors: Darkow D. J. , Lu L. , White R. E.
Published: December 2017

Estrogens are proposed to exert protection against cardiovascular disease, and evidence now suggests that this protection involves a direct vasodilatory effect. We have shown previously that estrogen relaxes endothelium-denuded porcine coronary arteries by opening the large-conductance calcium- and voltage-activated potassium (BKCa) channel of myocytes through guanosine 3',5'-cyclic monophosphate (cGMP)-dependent phosphorylation (35). The present study confirms these results and now demonstrates that this mechanism involves production of nitric oxide (NO). S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, or 8-bromo-cGMP mimicked the effect of estrogen on BKCa channels. Furthermore, inhibition of NO synthase (NOS) attenuated estrogen- or tamoxifen-induced BKCa-channel activity, and this effect was disinhibited by L-arginine. Inhibition of guanylyl cyclase activity blocked the stimulatory effect of estrogen, SNAP, or L-arginine on BKCa channels. Furthermore, 17 beta-estradiol stimulated accumulation of nitrite and cGMP in coronary myocytes. Therefore, we propose that the vasodilatory effect of estrogen on the coronary circulation is mediated by NO. A portion of the beneficial cardiovascular effects of estrogen may be attributed to relaxation of vascular smooth muscle by a process that involves NO- and cGMP-dependent stimulation of BKCa channels.
Effects of ventrolateral medullary AMPA-receptor antagonism on pressor response during muscle contraction
Authors: Kobayashi T. , Caringi D. , Mokler D. J. , Ally A.
Published: December 2017

Effects of administering 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) at a concentration that preferentially blocks alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors into rostral ventrolateral medulla (rVLM) or caudal ventrolateral medulla (cVLM) on cardiovascular responses elicited during static muscle contraction were investigated using anesthetized rats. Two microdialysis probes were inserted bilaterally into either the rVLM or the cVLM using stereotaxic guides. A tibial nerve stimulation-evoked static muscle contraction for 30 s increased mean arterial pressure (MAP) and heart rate (HR) by 27 +/- 3 mmHg and 28 +/- 4 beats/min, respectively. Microdialysis of CNQX into the rVLM for 30 min attenuated the contraction-evoked increases in MAP and HR (10 +/- 2 mmHg and 12 +/- 2 beats/min). Developed tensions were similar during the contractions before and after microdialyzing CNQX. In contrast, administration of CNQX into the cVLM potentiated the muscle contraction-evoked cardiovascular responses (MAP, 25 +/- 4 vs. 39 +/- 6 mmHg; HR, 27 +/- 3 vs. 42 +/- 3 beats/min), with no change in developed tensions. Results demonstrate that AMPA receptors within the rVLM and the cVLM appear to play opposite modulatory roles in the central integration of cardiovascular responses elicited during static muscle contraction.
Variation in effects of Cs+, UL-FS-49, and ZD-7288 within sinoatrial node
Authors: Nikmaram M. R. , Boyett M. R. , Kodama I. , Suzuki R. , Honjo H.
Published: December 2017

The effects of Cs+, UL-FS-49, and ZD-7288 on action potentials recorded from central, transitional, and peripheral sites in the rabbit sinoatrial (SA) node have been investigated. In isolated right atrial preparations, including the whole SA node, Cs+ (2 mM), UL-FS-49 (1 microM), and ZD-7288 (3 microM), decreased the spontaneous rate by 12 +/- 2% (n = 21), 16 +/- 3% (n = 10), and 13 +/- 3% (n = 10). They decreased the slope of the pacemaker potential without affecting action potential characteristics. The decrease of pacemaker slope was maximal (69-120%) in the periphery and minimal (22-25%) in the center. In experiments on small ball-like tissue specimens (approximately 0.3 mm diam), a decrease in spontaneous rate and pacemaker slope by Cs+ (2 mM) was largest (approximately 19 and approximately 47%) in tissue from the periphery and least (approximately 7 and approximately 17%) in tissue from the center. Because the hyperpolarization-activated inward current (If) is reduced by each of these agents, the results suggest that this current might play a relatively minor role in the center but a more important role in the periphery of the SA node.
Left-to-right systolic and diastolic ventricular interactions are dependent on right ventricular volume
Authors: Dickstein M. L. , Todaka K. , Burkhoff D.
Published: December 2017

Three-compartment elastance modeling predicts that the magnitude of gain is solely dependent on the ratio of free wall and septal elastances. However, when nonlinearities in pressure-volume relationships are considered, the same model predicts that gain is load dependent. We therefore studied left-to-right ventricular interactions in the isolated cross-perfused canine heart preparation to determine whether, in fact, right ventricular volume modulates left-to-right ventricular interaction. We found that left-to-right systolic gain increased from 0.035 +/- 0.022 to 0.073 +/- 0.017 (P = 0.003) and left-to-right diastolic gain increased from 0.067 +/- 0.050 to 0.186 +/- 0.097 (P = 0.03) in response to increased right ventricular volume. This degree of volume dependency of gain is predicted by the three-compartment model when measured nonlinearities in time-varying elastance are taken into account. Future studies will need to account for changes in loading conditions when interpreting changes in systolic and diastolic interactions.
Endothelial ATP-sensitive potassium channels mediate coronary microvascular dilation to hyperosmolarity
Authors: Ishizaka H. , Kuo L.
Published: December 2017

Coronary arterial occlusion has been shown to increase osmolarity in the myocardial interstitium. Intracoronary injection of hyperosmolar solutions reduces coronary vascular resistance. However, the response of coronary microvessels to an abluminal increase in osmolarity is unclear, and the underlying mechanism for its vasomotor regulation has not been elucidated. In this regard, porcine coronary arterioles (81 +/- 2 microns) were isolated, cannulated, and pressurized for in vitro study. Hyperosmolarity (300-345 mosM) was produced by adding D-glucose or D-sucrose to the extravascular solution. After the arterioles developed a stable vascular tone, a graded vasodilation was observed when glucose or sucrose was incrementally administered. This hyperosmotic vasodilation was abolished after endothelial removal. Intraluminal administration of KCl (80 mM) or the ATP-sensitive potassium (KATP)-channel inhibitor glibenclamide (1 microM) to the intact vessels significantly attenuated the hyperosmotic vasodilation. Inhibition of inward rectifier potassium channels by a low concentration of BaCl2 (10 microM) did not affect vasodilation. However, a high concentration of BaCl2 (100 microM), which has been reported to inhibit KATP channels, attenuated the hyperosmotic vasodilation. Iberiotoxin (100 nM), a calcium-activated potassium (KCa)-channel inhibitor had no effect on hyperosmolarity-induced vasodilation. Inhibition of the synthesis of endothelial nitric oxide, prostaglandins, and arachidonic acid metabolites from cytochrome P-450 had no effect on hyperosmotic vasodilation. Furthermore, inhibition of vascular smooth muscle KATP channels and the large- and small-conductance KCa channels by extraluminal administration of glibenclamide, iberiotoxin, and apamin, respectively, did not alter vasodilation in response to hyperosmolarity. These results indicate that dilation of coronary arterioles in response to hyperosmotic stimulation requires an intact endothelium. However, the response is independent of the release of nitric oxide, prostaglandins, or cytochrome P-450-related endothelium-derived hyperpolarizing factor and is not a result of activation of KATP and KCa channels in vascular smooth muscle. It is suggested that the opening of KATP channels in vascular endothelium and subsequent hyperpolarization of that cell type mediate coronary microvascular dilation in response to hyperosmolarity.
Ca2+ permeation through Na+ channels in guinea pig ventricular myocytes
Authors: Cole W. C. , Chartier D. , Martin M. , Leblanc N.
Published: December 2017

This study was undertaken to test the hypothesis that, in the absence of extracellular Na+, Ca2+ can permeate tetrodotoxin (TTX)-sensitive Na+ channels in Cs(+)-loaded whole cell voltage-clamped guinea pig ventricular myocytes (22-24 degrees C). With 10 mM extracellular Ca2+, 50-ms step depolarizations (-50 to +25 mV) from holding potentials of -100 or -80 mV elicited fast and slow types of inward current: 1) a small (< 400 pA) dihydropyridine-insensitive inward current that exhibited similar voltage dependence to that of Na+ channels, with an activation threshold and peak near -45 mV and -30 mV, respectively; and 2) a larger and slower L-type Ca2+ current that activated and peaked at more positive potentials. Extracellular replacement of Ca2+ by Mg2+ abolished both currents. The lack of sensitivity of the low-threshold Ca(2+)-current amplitude to 50 or 200 microM Ni2+ suggests that this current is not produced by T-type Ca2+ current. In contrast, TTX dose dependently inhibited the low-threshold Ca2+ current, with a half-maximal inhibition concentration of 2.4 microM. Veratridine (10-50 microM), a plant alkaloid that alters the gating and permeability properties of Na+ current, induced an outward shift of time-dependent current during steps to -25 mV and typical slowly decaying inward tail currents after repolarization to -80 mV. Cell exposure to 10 and 50 microM extracellular Na+ inhibited the inward current by 21.2 +/- 3.9% (n = 23) and 14.0 +/- 3.0% (n = 14), respectively, whereas 1 microM Na+ (n = 14) was without effect. The application of 200 microM Na+ produced a small enhancement of the current (+6.2 +/- 4.1%; n = 14) which was just at the limit of significance. Our data support the notion that Ca2+ can permeate cardiac Na+ channels in the absence of an agonist and external Na+.
Calcium and mechanotransduction of the myogenic response
Authors: D'Angelo G. , Davis M. J. , Meininger G. A.
Published: December 2017

The purpose of this study was to measure vascular smooth muscle (VSM) cytosolic calcium ([Ca2+]i) during the myogenic response. We examined the temporal and steady-state relationships between lumen diameter and VSM [Ca2+]i in isolated arterioles exposed to step changes in intravascular pressure. We also studied the relationship between step sizes in intravascular pressure and changes in [Ca2+]i. First-order arterioles from the hamster cheek pouch were isolated, cannulated, and pressurized. [Ca2+]i was quantified using the ratio of emitted fluorescence intensity (R340/380) during alternate excitation of fura 2-loaded vessels at 340 and 380 nm. Stepwise increases in transmural pressure elicited corresponding increases in steady-state [Ca2+]i and myogenic constriction. From a common baseline pressure, the initial rise in [Ca2+]i after a step change in pressure was directly related to the magnitude of the step size and of the distension caused by that pressure step. This supports the theory that there is a relationship between the initial distension of the vessel and the initial [Ca2+]i change. Also, increasing the size of the step change in pressure resulted in a greater myogenic response, yet no difference in the steady-state [Ca2+]i was detected, which suggests that Ca2+ is not the principal or only determinant of steady-state constriction. Finally, larger increases in [Ca2+]i do not necessarily augment the myogenic response, which suggests that some minimal rise in [Ca2+]i is required to elicit myogenic vasoconstriction. Collectively, these data suggest the presence of a separate, Ca(2+)-independent regulatory system.
NO-containing factors mediate hindlimb vasodilation produced by superior laryngeal nerve stimulation
Authors: Possas O. S. , Lewis S. J.
Published: December 2017

The electrical stimulation (ES) of the superior laryngeal nerve (SLN) produces reflex vasodilation in the rat hindlimb. This study determined whether this vasodilation is mediated by the release of nitric oxide (NO)-containing factors (NOF) from NO synthase (NOS)-positive postganglionic lumbar sympathetic fibers that innervate the rat hindlimb vasculature. ES of the SLN (1-10 Hz for 15 s) produced frequency-dependent reductions in mean arterial blood pressure (MAP) and hindlimb and mesenteric (MR) vascular resistances. The hindlimb vasodilation was not observed in rats in which the lumbar sympathetic trunk was transected 7-10 days previously. The falls in hindquarter vascular resistance (HQR) produced by lower intensity ES of the SLN were virtually abolished by the specific inhibitor of neuronal NOS 7-nitroindazole (7-NI, 45 mg/kg i.v.). The fall in HQR produced by 10 Hz ES of the SLN was not affected by 7-NI. The falls in MR produced by 1-10 Hz ES of the SLN were unaffected by 7-NI. Four consecutive episodes of ES at 10 Hz produced pronounced and equivalent reductions in MAP, HQR, and MR. After administration of 7-NI, the first ES produced similar hemodynamic responses to those observed before injection. However, each subsequent ES produced progressively and markedly smaller falls in HQR, whereas each episode of ES produced similar falls in MR. These results suggest that the reflex vasodilation in the rat hindlimb produced by ES of the SLN involves the release of newly synthesized and performed stores of NOF from NOS-positive postganglionic lumbar sympathetic nerves.
Vector autoregressive modeling for analyzing feedback regulation between heart rate and blood pressure
Authors: Matsukawa S. , Wada T.
Published: December 2017

We present a noninvasive technique for analyzing the feedback relationship between short-term fluctuations in blood pressure (BP) and heart rate (HR) in humans. Beat-to-beat BP was monitored for several minutes with a noninvasive BP measuring device, i.e., arterial tonometry, in 16 healthy subjects and 15 patients on hemodialysis (HD), and the recorded systolic BP (SBP) and the pulse wave interval (R-R interval) were fitted to vector autoregressive models according to Akaike's method. The impulse-response function was then simulated to determine the contribution of changes in R-R interval or SBP to the fluctuation of SBP or R-R interval along a time scale. In healthy subjects, when a simulated 1-mmHg impulse was applied to SBP, the R-R interval increased to approximately 3.5 ms with a delay of several beats. In HD patients the same impulse caused essentially no response in the R-R interval. A 1-ms impulse applied to the R-R interval decreased SBP, and the response was not different in healthy subjects and HD patients. In the R-R interval-to-R-R interval response and the SBP-to-SBP response, the exponential-like decay after the initial jump was more rapid in the HD patients than in the healthy subjects. The results demonstrated that this technique can provide information on the feedback regulation between fluctuations in BP and HR in patients with or without autonomic nervous system dysfunction. This technique provides a simple and practical way to estimate autonomic function in clinical medicine.
Low power, type II errors, and other statistical problems in recent cardiovascular research
Authors: Williams J. L. , Hathaway C. A. , Kloster K. L. , Layne B. H.
Published: December 2017

Frequently in biomedical literature, measurements are considered “not statistically different” if a statistical test fails to achieve a P value that is < or = 0.05. This conclusion may be misleading because the size of each group is too small or the variability is large, and a type II error (false negative) is committed. In this study, we examined the probabilities of detecting a real difference (power) and type II errors in unpaired t-tests in Volumes 246 and 266 of the American Journal of Physiology: Heart and Circulatory Physiology. In addition, we examined all articles for other statistical errors. The median power of the t-tests was similar in these volumes (approximately 0.55 and approximately 0.92 to detect a 20% and a 50% change, respectively). In both volumes, approximately 80% of the studies with nonsignificant unpaired t-tests contained at least one t-test with a type II error probability > 0.30. Our findings suggest that low power and a high incidence of type II errors are common problems in this journal. In addition, the presentation of statistics was often vague, t-tests were misused frequently, and assumptions for inferential statistics usually were not mentioned or examined.
Noninvasive determination of pulse-wave velocity in mice
Authors: Hartley C. J. , Taffet G. E. , Michael L. H. , Pham T. T. , Entman M. L.
Published: December 2017

Some transgenic mice have abnormal vascular function, but arterial geometry and dynamics are difficult to evaluate. To examine whether ultrasonic velocimetry could be used to determine arterial pulse-wave velocity (PWV) in mice, a custom-made 20-MHz pulsed Doppler instrument was used to obtain blood flow velocity signals from the aortic arch and the abdominal aorta 4 cm downstream. The upstroke (foot) of the velocity wave was timed at each site with respect to the R wave of the electrocardiogram, and PWV was calculated by dividing the separation distance by the difference in R-foot times. Doppler determinations were compared with invasive tonometry, and PWV was altered pharmacologically. It was found that the upstrokes of pressure (by tonometry) and velocity were coincident (+/-1 ms) and that PWV could be calculated by either method on exposed vessels. With the use of Doppler methods, pulse transit time was determined noninvasively with +/-1-ms resolution in 140 of 142 attempts in 82 mice. The calculated PWV in mice ranged from 220 to 850 cm/s with vasodilating anesthetics producing the low values and vasoconstricting agents producing the higher values. Thus PWV can be determined noninvasively in mice, is similar to that in other mammals, and responds as expected to vasoactive agents.
Nitrovasodilators relax mesenteric microvessels by cGMP-induced stimulation of Ca-activated K channels
Authors: Carrier G. O. , Fuchs L. C. , Winecoff A. P. , Giulumian A. D. , White R. E.
Published: December 2017

Nitric oxide (NO) released from endothelial cells or exogenous nitrates is a potent dilator of arterial smooth muscle; however, the molecular mechanisms mediating relaxation to NO in the microcirculation have not been characterized. The present study investigated the relaxant effect of nitrovasodilators on microvessels obtained from the rat mesentery and also employed whole cell and single-channel patch-clamp techniques to identify the molecular target of NO action in myocytes from these vessels. Both sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) relaxed phenylephrine-induced contractions by approximately 80% but were significantly less effective in relaxing contractions induced by 40 mM KCl. Relaxation to SNP was also inhibited by the K(+)-channel blocker tetraethylammonium or by inhibition of the activity of the guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (PKG). These results suggest that SNP stimulated K+ efflux by opening K+ channels via PKG-mediated phosphorylation. Perforated-patch experiments revealed that both SNP and SNAP increased outward currents in microvascular myocytes, and single-channel studies identified the high-conductance Ca(2+)- and voltage-activated K+ (BKCa) channel as the target of nitrovasodilator action. The effects of nitrovasodilators on BKCa channels were mimicked by cGMP and inhibited by blocking the activity of PKG. We conclude that stimulation of BKCa-channel activity via cGMP-dependent phosphorylation contributes to the vasodilatory effect of NO on microvessels and that a direct effect of NO on BKCa channels does not play a major role in this process. We propose that this mechanism is important for the therapeutic effect of nitrovasodilators on peripheral resistance and arterial blood pressure.
Arterial compliance increases after moderate-intensity cycling
Authors: Kingwell Bronwyn A. , Berry Karen L. , Cameron James D. , Jennings Garry L. , Dart Anthony M.
Published: December 2017

Exercise training elevates arterial compliance at rest, but the effects of acute exercise in this regard are unknown. This study investigated the effects of a single, 30-min bout of cycling exercise at 65% of maximal oxygen consumption on indexes of arterial compliance. Whole body arterial compliance determined noninvasively from simultaneous measurements of aortic flow and carotid pressure was elevated (66 ± 26%) at 0.5 h postexercise ( P = 0.04), followed by a decline to baseline 1 h after exercise. Aortic pulse-wave velocity, which is inversely related to compliance, was reduced (4 ± 2%; P = 0.04) at 0.5 h postexercise. Pulse-wave velocity in the leg decreased by 10 ± 4% at this time ( P = 0.01). Mean arterial pressure was unchanged; however, central systolic blood pressure was reduced postexercise ( P = 0.03). Cardiac output was elevated after exercise ( P = 0.007) via heart rate elevation ( P = 0.001), whereas stroke volume was unchanged. Total peripheral resistance was therefore reduced ( P = 0.01) and would be expected to contribute to an elevation in arterial compliance. In conclusion, a single bout of cycling exercise increased whole body arterial compliance by mechanisms that may relate to vasodilation.
α2-Adrenergic autoreceptors in A5 and A6 neurons of neonate rats
Authors: Huangfu Donghai , Guyenet Patrice G.
Published: December 2017

A5 noradrenergic neurons control sympathetic outflow, nociception, and respiration. The presence of α2-adrenergic receptors (α2-ARs) in A5 cells has been suggested by immunohistochemistry. In the present experiments, we analyze the response of spinally projecting A5 cells to α2-AR agonists, and we compare it with that of locus ceruleus (A6) neurons. Whole cell recordings were obtained from 52 spinally projecting neurons in the ventrolateral pons of neonate rats. Immunohistochemistry showed that 60% of the recorded cells were A5 cells. In A5 cells clamped at −55 mV, norepinephrine (NE) in the presence of the α1-AR antagonist prazosin produced a Ba2+-sensitive outward current (20.4 ± 2.6 pA; n = 28). The α2-AR-induced current reversed at the K+ equilibrium potential ( E K) at three different extracellular K+ concentrations. Replacement of 82% of the extracellular Na concentration with N-methyl-d-glucamine did not change the reversal potential. The 19 presumably noncatecholaminergic neurons responded weakly or not at all to NE (2.5 ± 0.6 pA outward current). Pontospinal A6 neurons ( n = 11) were also recorded. Six A6 cells displayed large tetrodotoxin (TTX)-resistant membrane oscillations. In these cells, the current induced by α2-AR stimulation did not reverse over the voltages tested (−50 to −130 mV) or reversed at potentials more negative than E K (less than −114 mV). In A6 neurons that did not display large oscillations ( n = 5), the α2-AR-induced current reversed at or close to the E K (−90 ± 1.6 mV). In conclusion, A5 cells, like locus ceruleus neurons, have α2-ARs that may function as autoreceptors. In both cases, α2-AR activation increases an inwardly rectifying K+conductance. In A5 cells, we found no evidence that α2-AR activation decreases a resting Na+ conductance. The inhibition of A5 cells by clonidine and other agents with α2-AR agonist activity is likely to contribute to the ability of these drugs to decrease sympathetic tone and arterial pressure.
Interaction of PKC and NOS in signal transduction of microvascular hyperpermeability
Authors: Huang Qiaobing , Yuan Yuan
Published: December 2017

Our previous studies have shown that inflammatory mediators increase microvascular permeability through a phospholipase C-nitric oxide synthase (NOS)-guanylate cyclase cascade. The aim of this study is to delineate in more detail the signaling pathway leading to microvascular hyperpermeability. Endothelial cytosolic calcium and the apparent permeability coefficient of albumin ( Pa) were measured in isolated and perfused coronary venules. Histamine stimulated a rapid increase in cytosolic calcium followed by a transient elevation in Pa. The NOS inhibitor NG-monomethyl-l-arginine (l-NMMA) and the guanosine 3′,5′-cyclic monophosphate-dependent protein kinase G (PKG) inhibitor KT-5823 abolished the hyperpermeability but did not affect the calcium response to histamine. Similarly, the calcium ionophore ionomycin produced a calcium spike preceding venular hyperpermeability. Blockage of the NOS-PKG cascade inhibited the increase in Pa, whereas the endothelial calcium was still elevated on administration of ionomycin. Furthermore, the relationship between protein kinase C (PKC) and the calcium-NOS-PKG pathway in modulation of venular permeability was investigated. Stimulation of PKC with phorbol 12-myristate 13-acetate (PMA) dramatically increased basal Pawithout significantly changing the cytosolic calcium level. The selective PKC inhibitor bisindolylmaleimide abolished the effect of PMA but did not alter the effect of histamines on Pa. In contrast, both l-NMMA and KT-5823 were able to greatly attenuate the increase in Pacaused by PMA. These results suggest that 1) elevation of endothelial cytosolic calcium is an early signaling event preceding nitric oxide (NO) synthesis in the transduction of endothelial hyperpermeability, and 2) activation of PKC may alter the endothelial barrier function partially through the modulation of NO production.
Myocardial, skeletal muscle, and renal blood flow during exercise in conscious dogs with heart failure
Authors: Neumann Till , Heusch Gerd
Published: December 2017

The present study characterizes the hemodynamic and neurohumoral responses to moderate treadmill exercise in conscious dogs with pacing-induced heart failure. Seven dogs were instrumented with a left ventricular micromanometer, ultrasonic crystals for the measurement of systolic wall thickening, left atrial and aortic catheters for the injection of colored microspheres and reference withdrawal, respectively, and ventricular pacing leads with a subcutaneous pacemaker. Dogs were run on a treadmill at a speed of 5 km/h. After control studies, heart failure was induced by rapid left ventricular pacing at 250 beats/min for (mean ± SD) 23 ± 6 days. In the control state, cardiac output was increased from 4.5 ± 1.5 to 7.9 ± 1.4 l/min ( P < 0.05 vs. rest). With heart failure, cardiac output was decreased to 2.5 ± 0.5 l/min at rest ( P < 0.05 vs. control state) and was only 3.0 ± 0.3 l/min during exercise ( P < 0.05 vs. control state; not significant vs. rest). Myocardial and, more so, skeletal muscle blood flows at rest were reduced in heart failure; their increases with exercise were attenuated. An increase in renal blood flow during exercise in the control state was no longer seen in heart failure. Increases in plasma catecholamines and lactate during exercise were more pronounced in heart failure. In conclusion, in heart failure, the increase in cardiac output during exercise was largely attenuated. Increased catecholamine levels may have contributed to splanchnic vasoconstriction and preferential distribution of cardiac output into the working skeletal muscle.
β-Adrenoceptor-coupled Gsprotein facilitates the activation of cAMP-dependent cardiac Cl− current
Authors: Pelzer Siegried , You Yongdong , Shuba Yaroslav M. , Pelzer Dieter J.
Published: December 2017

Here a comparison is made between adenosine 3′,5′-cyclic monophosphate (cAMP)-activated Cl− current ( I Cl) density and activation time course in response to β-adrenoceptor stimulation with isoproterenol and adenylyl cyclase activation with forskolin. Saturating concentrations of isoproterenol and forskolin failed to activate an I Cl in guinea pig atrial as well as in rat and frog ventricular cardiomyocytes. In guinea pig ventricular cardiomyocytes, step application of 1 μM isoproterenol induced an I Clof −0.89 ± 0.32 pA/pF (holding potential −40 mV, temperature 22 ± 1°C). I Cl activation started after 3 ± 1 s, was complete within 44 ± 9 s, and was abolished after cell dialysis with the Rp diastereomer of adenosine 3′,5′-cyclic monophosphothioate. Stimulation with increasing concentrations of forskolin (0.01–10 μM) increased I Cl density and accelerated I Clactivation. With 1 μM forskolin, I Cl density was maximal (−0.57 ± 0.30 pA/pF) but significantly smaller than that achieved with 1 μM isoproterenol. Although I Cl density could not be further augmented by forskolin >1 μM, current activation (latency 28 ± 8 s, full activation after 112 ± 8 s with 1 μM forskolin) was further accelerated by 3 and 10 μM forskolin. However, I Cl activation with 10 μM forskolin was still slower than that with 1 μM isoproterenol. A low isoproterenol concentration (1 nM), which did not activate I Cl by itself, accelerated the 1 μM forskolin-induced activation of I Cl by 35%; this speeding up was abolished after cell dialysis with guanosine 5′- O-(2-thiodiphosphate). I Cl deactivation after the washout of 1 μM forskolin or 1 μM isoproterenol followed a similar time course. After stimulation with 10 μM forskolin or 1 μM forskolin + 1 μM isoproterenol, but not with 1 μM forskolin + 1 nM isoproterenol, the decay of I Cl was significantly delayed. These results indicate that both cAMP-dependent and cAMP-independent G protein pathways contribute to the regulation of guinea pig ventricular I Cl.
Endothelin reactivity and receptor profile of pulmonary vessels in postobstructive pulmonary vasculopathy
Authors: Shi Weibin , Cernacek Peter , Hu Fu , Michel René P.
Published: December 2017

Chronic ligation of one pulmonary artery results in pulmonary vascular remodeling and bronchial angiogenesis, collectively known as postobstructive pulmonary vasculopathy (POPV). To determine whether the reactivity of pulmonary vessels to endothelins (ET) was altered in POPV and to explore potential mechanisms, we ligated the left main pulmonary artery of 18 rats. Four weeks later, using a lung explant technique, we compared POPV lungs with controls for contractile responses of intrapulmonary vessels to ET-1 and ET-3 and for relaxant responses to ET-1 and sodium nitroprusside (SNP) after precontraction with U-46619. Morphometric measurements were made on vessels studied pharmacologically. Competition receptor binding studies with125I-labeled ET-1 and unlabeled ET-1 and BQ-123 were performed using membrane proteins of pulmonary vessels. We found, in arteries, that contractile responses to ET-1 and ET-3 were significantly increased and that relaxant responses to ET-1 but not to SNP were reduced; in veins, only relaxation to SNP was increased. Morphometry showed that arteries and veins in POPV had reduced diameters without altered muscle thickness. Receptor binding studies showed that the proportion of ETA receptors in arteries was significantly increased in POPV (66%) vs. controls (54%). We conclude that, in POPV, the increase in reactivity to ET-1 and ET-3 is primarily related to an augmented proportion of ETA receptors.
Induction of nitric oxide synthase mRNA in coronary resistance arteries isolated from exercise-trained pigs
Authors: Woodman Christopher R. , Muller Judy M. , Laughlin M. Harold , Price Elmer M.
Published: December 2017

The purpose of this study was to develop a method by which endothelial cell nitric oxide synthase (ecNOS) mRNA expression could be measured in single coronary resistance arteries and to test the hypothesis that ecNOS gene expression is upregulated by exercise training. Yucatan miniature swine were randomly assigned to exercise-trained (ET; n = 5) or sedentary (Sed; n = 4) groups for 16 wk. Individual coronary resistance arteries (50–100 μm) were dissected, frozen in liquid nitrogen, and homogenized in a LiCl buffer. mRNA was isolated from each vessel, and ecNOS gene expression was assessed using reverse transcriptase (RT)-polymerase chain reaction (PCR) standardized by coamplifying ecNOS with glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The ecNOS-to-GAPDH amplicon ratio was significantly greater in coronary resistance arteries isolated from ET pigs than in Sed controls. On the basis of these data, it is concluded that RT-PCR can be used on single coronary resistance arteries to assess cell-specific mRNA expression and that ecNOS gene expression is upregulated by exercise training in porcine coronary resistance arteries.
Sarcoplasmic reticulum and Na+/Ca2+exchanger function during early and late relaxation in ventricular myocytes
Authors: Yao Atsushi , Matsui Hiroshi , Spitzer Kenneth W. , Bridge John H. B. , Barry William H.
Published: December 2017

The relative importance of the Na+/Ca2+exchanger in the initial and terminal phases of relaxation and the decline in the [Ca2+]itransient was investigated in adult rabbit ventricular myocytes loaded with the Ca2+indicator fluo 3. For electrically stimulated contractions, the peak intracellular Ca2+concentration ([Ca2+]i) was 700 ± 87 nM and end-diastolic [Ca2+]iwas 239 ± 30 nM (0.25 Hz, 37°C, 1.08 mM extracellular Ca2+concentration; n = 14). Abrupt inhibition of Na+/Ca2+exchange was produced by removal of extracellular Na+(KCl substitution) and Ca2+[2 mM Ca2+-free ethylene glycol-bis(β-aminoethyl ether)- N, N, N′, N′-tetraacetic acid] by means of a rapid switcher device (SW). Abrupt exposure to high K+induced an action potential, although sufficient Ca2+remained adjacent to the sarcolemma to induce a contraction (SW beat) and [Ca2+]itransient that were identical in amplitude to those induced by electrical stimulation (ES beat). The initial relaxation and decline in the [Ca2+]itransient was not significantly prolonged by abrupt elimination of the Na+/Ca2+exchanger, but the rate and extent of the terminal phase of the decline in the [Ca2+]itransient were significantly reduced. The first derivative of [Ca2+]iwith respect to time versus [Ca2+]iduring the decline of the [Ca2+]itransient attributable to sarcoplasmic reticulum (SR) function was estimated from the average SW transients, and that attributable to Na+/Ca2+exchange was estimated from the difference between SW and ES transients. By this analysis, the Na+/Ca2+exchanger produces 13% of the first half of the decline in [Ca2+]iand 45% of the second half of the decline. We conclude that abrupt inhibition of forward Na+/Ca2+exchange does not significantly affect the amplitude or the initial rate of decline of the [Ca2+]itransient and relaxation. However, its contribution to the reduction of [Ca2+]ibecomes apparent late during the [Ca2+]itransient, when cytosolic [Ca2+]ihas been reduced.
High extracellular glucose impairs cardiac E-C coupling in a glycosylation-dependent manner
Authors: Ren Jun , Gintant Gary A. , Miller Richard E. , Davidoff Amy J.
Published: December 2017

Hyperglycemia is a major manifestation of all forms of diabetes mellitus and is associated with increased risk of cardiovascular disease. It is well established that cardiac excitation-contraction (E-C) coupling is adversely affected in diabetic animals such that ventricular myocyte action potential duration is prolonged and intracellular Ca2+clearing and mechanical relaxation are slowed. We now report that ventricular myocytes incubated in a culture medium containing high extracellular glucose (25.5 mM) also exhibit these same changes in E-C coupling. These effects are not manifested for ∼24 h after exposure. Furthermore, in the presence of normal glucose (5.5 mM), relaxation is also prolonged by fructose (20 mM), yet is unaffected by equimolar concentrations of nonmetabolizable sugars such as l-glucose and mannitol, implying that the high glucose effects require glucose entry into the cell and metabolic processing. The prolonged relaxation can also be produced by 5 mM glucosamine (an intermediate of glycosylation) and is blocked by 0.5 μg/ml tunicamycin (an inhibitor of N-linked glycoprotein synthesis). Culturing myocytes with an inhibitor of glycation (10 mM aminoguanidine) does not prevent the high extracellular glucose concentration effects. Thus our data indicate that high extracellular glucose impairs cellular mechanisms contributing to myocardial relaxation and that this impairment may involve glycosylation of nascent proteins.
Perfusion-induced changes in cardiac contractility depend on capillary perfusion
Authors: Dijkman Marieke A. , Heslinga Johannes W. , Sipkema Pieter , Westerhof Nico
Published: December 2017

The perfusion-induced increase in cardiac contractility (Gregg phenomenon) is especially found in heart preparations that lack adequate coronary autoregulation and thus protection of changes in capillary pressure. We determined in the isolated perfused papillary muscle of the rat whether cardiac muscle contractility is related to capillary perfusion. Oxygen availability of this muscle is independent of internal perfusion, and perfusion may be varied or even stopped without loss of function. Muscles contracted isometrically at 27°C ( n = 7). During the control state stepwise increases in perfusion pressure resulted in all muscles in a significant increase in active tension. Muscle diameter always increased with increased perfusion pressure, but muscle segment length was unaffected. Capillary perfusion was then obstructed by plastic microspheres (15 μm). Flow, at a perfusion pressure of 66.6 ± 26.2 cmH2O, reduced from 17.6 ± 5.4 μl/min in the control state to 3.2 ± 1.3 μl/min after microspheres. Active tension developed by the muscle in the unperfused condition before microspheres and after microspheres did not differ significantly (−12.8 ± 29.4% change). After microspheres similar perfusion pressure steps as in control never resulted in an increase in active tension. Even at the two highest perfusion pressures (89.1 ± 28.4 and 106.5 ± 31.7 cmH2O) that were applied a significant decrease in active tension was found. We conclude that the Gregg phenomenon is related to capillary perfusion.
Capillary blood flow and tissue metabolism in skeletal muscle during sympathetic trunk stimulation
Authors: Pál Miklós , Tóth András , Ping Peipei , Johnson Paul C.
Published: December 2017

NADH fluorescence at tissue sites 15–20 μm in diameter and red blood cell velocity in adjacent capillaries were measured in resting sartorius muscle of the anesthetized cat during a 3-min period of sympathetic trunk stimulation. At stimulation frequencies of 2 and 4 Hz, red blood cell velocity fell briefly to 30–40% of control and then returned to ∼75% of control values (vascular escape). No change in NADH fluorescence was observed. With stimulus frequencies of 6–12 Hz, flow reduction was greater and led to an increase in fluorescence when the flow reduction was >50% and was sustained for >30 s. NADH changes were more pronounced at tissue sites near venous capillaries than at sites near arterial capillaries. Hyperemia ensued after the end of sympathetic stimulation only when NADH fluorescence rose during stimulation. Resting blood flow in this muscle appears to be well above the minimum required to support oxidative metabolism. A shift to anaerobic metabolism does not appear to cause vascular escape during sympathetic stimulation but appears to be required for poststimulation hyperemia. These observations suggest that two separate oxygen-dependent mechanisms elicit vasodilation during and after sympathetic trunk stimulation.
Nitric oxide production by cultured human aortic smooth muscle cells: stimulation by fluid flow
Authors: Papadaki Maria , Tilton Ronald G. , Eskin Suzanne G. , McIntire Larry V.
Published: December 2017

This study demonstrated that exposure of cultured human aortic smooth muscle cells (SMC) to fluid flow resulted in nitric oxide (NO) production, monitored by nitrite and guanosine 3′,5′-cyclic monophosphate production. A rapid burst in nitrite production rate was followed by a more gradual increase throughout the period of flow exposure. Neither the initial burst nor the prolonged nitrite production was dependent on the level of shear stress in the range of 1.1–25 dyn/cm2. Repeated exposure to shear stress after a 30-min static period restimulated nitrite production similar to the initial burst. Ca2+-calmodulin antagonists blocked the initial burst in nitrite release. An inhibitor of nitric oxide synthase (NOS) blocked nitrite production, indicating that changes in nitrite reflect NO production. Treatment with dexamethasone or cycloheximide had no effect on nitrite production. Monoclonal antibodies directed against the inducible and endothelial NOS isoforms showed no immunoreactivity on Western blots, whereas monoclonal antibodies directed against the neuronal NOS gave specific products. These findings suggest that human aortic SMC express a constitutive neuronal NOS isoform, the enzymatic activity of which is modulated by flow.