bluuebunny/crossref_metadata_2025 huggingface dataset:
Pressure wave propagation in a multibranched model of the human upper limb
Authors: Karamanoglu M. , Gallagher D. E. , Avolio A. P. , O'Rourke M. F.
Published: December 2017

The influence of the large arteries and the peripheral load on pressure wave propagation in the human upper limb was investigated in an anatomically realistic multibranched model based on linear transmission theory. To mimic vascular changes seen in life, the viscoelastic properties of large arteries and the peripheral load properties (represented as modified windkessels) were altered as follows: Young's modulus (from 10.9 x 10(6) to 15.3 x 10(6) dyn/cm2) and phase (from 0 to 15 degrees) of the complex elastance, windkessel time constant (from 0 to 0.6 s), and peripheral reflection coefficient (from 0 to 0.95). The relationship between the central aortic and peripheral radial pressure waveforms was analyzed in the time and the frequency domain. Results indicate that the large arterial properties have less influence (peak systolic pressure changed by 3% and peak of transfer function changed by 29%) than the properties of the peripheral load (systolic pressure changed by 14% and peak of transfer function changed by 74%) on the pressure wave propagation in the upper limb.
Role of NO mechanism in cardiovascular effects of diaspirin cross-linked hemoglobin in anesthetized rats
Authors: Sharma A. C. , Singh G. , Gulati A.
Published: December 2017

The role of nitric oxide (NO) in the cardiovascular actions of diaspirin cross-linked hemoglobin (DCLHb) was studied in anesthetized rats. The regional circulatory and systemic hemodynamic effects of DCLHb (400 mg/kg iv) were studied using a radioactive microsphere technique in control (untreated) and L-arginine (a NO precursor) pretreated rats. DCLHb produced a significant increase in blood pressure (75%), cardiac output (42%), stroke volume (36%), and total peripheral resistance (45%), without affecting heart rate, when administered to control rats. L-Arginine pretreatment significantly attenuated DCLHb-induced systemic hemodynamic effects. DCLHb-induced increase in blood flow to the skin and spleen was completely blocked, and that to the heart was partially blocked, by L-arginine pretreatment, suggesting that cardiovascular actions induced by DCLHb could be antagonized by the NO precursor L-arginine. The NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) produced significant increases in regional vascular resistance, leading to a decrease in blood flow to all the organs except the heart, where an increase in blood flow and a decrease in vascular resistance was observed. DCLHb, when administered in L-NAME-pretreated rats, accentuated the decrease in blood flow to the gastrointestinal system, spleen, mesentery and pancreas, skin, and musculoskeletal system. These studies provide evidence that the NO precursor L-arginine can attenuate the effects of DCLHb and that DCLHb can potentiate the effect of the NOS inhibitor L-NAME. The role of NO in the mechanism of action of DCLHb was further studied by estimating plasma guanosine 3',5'-cyclic monophosphate (cGMP) in control, DCLHb-treated, L-NAME-treated, and L-NAME followed by DCLHb-treated rats. DCLHb and L-NAME significantly decreased the concentration of circulating cGMP in blood plasma. L-NAME pretreatment potentiated DCLHb-induced decrease in cGMP levels. Because the formation of cGMP is stimulated by NO, these studies provide additional evidence for the involvement of NO in the mechanism of action of DCLHb. It is concluded that NO plays an important role in the cardiovascular effects of DCLHb.
Cellular pathways of the conducted electrical response in arterioles of hamster cheek pouch in vitro
Authors: Xia J. , Little T. L. , Duling B. R.
Published: December 2017

We have previously shown that conducted vasomotor responses follow patterns that are consistent with a passive spread of electrical current along the length of the arterioles [(Xia and Duling, Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H2022-H2030, 1995]. In this study, we define the cells through which the current flows. Isolated arterioles of hamster cheek pouch were used. The mean resting membrane potential (RMP) for randomly sampled arteriolar cells was -67 mV. When cell types were identified by dye injection, the RMPs were -68 and -67 mV for smooth muscle (SM) and endothelium (EC), respectively. Pulses of KCl induced transient, monophasic depolarizations at the site of stimulation (local), which were conducted decrementally along the length of the arteriole over several millimeters. During electrical conduction, three patterns of responses could be observed, but identical patterns of the conducted electrical responses were always observed in SM and EC. Phenylephrine stimulation also caused transient local and conducted depolarizations in both SM and EC. As with KCl stimuli, shapes of conducted electrical responses were identical in records made in both cell types. The results suggest that SM and EC are electrically coupled both homocellularly and heterocellularly.
A diffusion wake model for tracer ultrastructure-permeability studies in microvessels
Authors: Fu B. M. , Curry F. E. , Weinbaum S.
Published: December 2017

We developed a time-dependent diffusion model for analyzing the concentration profiles of low-molecular-weight tracers in the interendothelial clefts of the capillary wall that takes into account the three-dimensional time-dependent filling of the surrounding tissue space. The model provides a connecting link between two methods to investigate transvascular exchange: electron-microscopic experiments to study the time-dependent wake formed by low-molecular-weight tracers (such as lanthanum nitrate) on the tissue side of the junction strand discontinuities in the interendothelial cleft of frog mesentery capillaries (R. H. Adamson and C. C. Michel. J. Physiol. Lond. 466: 303-327, 1993) and confocal-microscopic experiments to measure the spread of low-molecular-weight fluorescent tracers in the tissue space surrounding these microvessels (R. H. Adamson, J. F. Lenz, and F. E. Curry, Microcirculation 1: 251-265, 1994). We show that the interpretation of the presence of tracer as an all-or-none indication of a pathway across the junctional strand is likely to be incorrect for small solutes. Large-pore pathways, in which the local tracer flux densities are high, reach a threshold concentration for detection and are likely to be detected after relatively short perfusion times, whereas distributed small-pore pathways may not be detected until the tissue concentrations surrounding the entire vessel approach threshold concentrations. The analysis using this approach supports the hypothesis advanced by Fu et al. (J. Biomech. Eng. 116: 502-513, 1994) that the principal pathways for water and solutes of < 1.0 nm diameter across the interendothelial cleft may be different and suggests new experiments to test this hypothesis.
Explorations into development of a neurally regulated cardiac pacemaker
Authors: Ikeda Y. , Sugimachi M. , Yamasaki T. , Kawaguchi O. , Shishido T. , Kawada T. , Alexander J. , Sunagawa K.
Published: December 2017

Although the artificial cardiac pacemaker has contributed to the management of patients with serious arrhythmias, its rate-responsive function is not sufficient to provide physiological regulation of heart rate (HR). To achieve truly physiological rate response in any given patient, we propose a framework to develop a pacemaker directly regulated by sympathetic nerve activity (SNA). In eight anesthetized rabbits, we quantified the dynamic transduction characteristics from SNA to HR as a transfer function. We then characterized the decoding rule as an impulse response, that is the transfer characteristics in the time domain. The transfer function was approximated by a first-order, low-pass filter with lag time (corner frequency: 0.024 +/- 0.013 Hz, lag time: 0.98 +/- 0.09 s). Predicted HR correlated well with measured HR (r = 0.80-0.98). The standard error of the prediction relative to mean HR was only 1.2 +/- 0.7%, indicating that the prediction was reasonably accurate. Direct decoding of SNA to predict instantaneous HR is possible through this analysis. This framework should enable development of a neurally regulated artificial pacemaker.
Different alpha-adrenoceptor subtypes mediate constriction of arterioles and venules
Authors: Leech C. J. , Faber J. E.
Published: December 2017

Recent studies indicate that rat vascular smooth muscle can express mRNAs for the alpha 1A-(alpha 1c-), alpha 1B-, alpha 1D-, alpha 2B-, and alpha 2D-adrenoceptors (ARs). The present study sought to determine which subtypes mediate constriction of resistance and capacitance vessels in rat cremaster skeletal muscle using videomicroscopy. Arterioles (125 microns internal diameter) were isolated, cannulated, and pressurized in a tissue bath. Vascularly "isolated" first-order venules (211 microns) were studied in situ in the cremaster muscle maintained in a tissue bath. Concentration-response curves for stimulation of alpha 1-ARs (norepinephrine plus 1 microM rauwolscine) and alpha 2-ARs (UK-14,304 plus 10 microM 5-methyl-urapidil) were obtained in the presence or absence of alpha-AR subtype-selective antagonists. Chloroethylclonidine (35 and 70 microM), which is most potent against alpha 1B-ARs, had no effect on alpha 1-constriction of arterioles but decreased venule alpha 1-sensitivity (50% effective concentration) by 13-fold (P < 0.01). The alpha 1A- and alpha 1D-selective AR antagonists WB-4101 (50 nM) and 5-MU (350 nM) had no effect on venule alpha 1-sensitivity but reduced arteriole alpha 1-AR sensitivity by 35-fold (P < 0.001) and 6-fold (P < 0.01), respectively. The alpha 1D-antagonist BMY-7378 (350 nM) decreased arteriole sensitivity by fourfold (P < 0.01) but had no effect on venule sensitivity. The alpha 2D-antagonist BRL-44408 (1 microM) caused a ninefold (P < 0.01) decrease in arteriole sensitivity to UK-14,304, whereas the alpha 2B-antagonist ARC-239 (1 microM) had no effect. BRL-44408 also caused a fourfold decrease (P < 0.01) in arteriole sensitivity to oxymetazoline, an agonist selective for alpha 2D- over alpha 2B-ARs. Venule sensitivity to UK-14,304 was reduced fivefold by BRL-44408 (P < 0.05), whereas ARC-239 had no effect. alpha 2 Subtype-selective antagonists inhibited UK-14,304 constriction of venules, with 50% inhibitory concentration values for BRL-44408 (alpha 2D-selective) of 6.04 +/- 0.07, and for the alpha 2B-selective antagonists ARC-239 of 4.79 +/- 0.20, spiroxatrine of 4.91 +/- 0.07, and SK&F-104856 of 5.06 +/- 0.10. These results suggest that constriction of rat skeletal muscle arterioles is mediated predominantly by an alpha 1D-like receptor and the alpha 2D-AR, whereas constriction of venules is dominated by the alpha 1B- and alpha 2D-adrenergic receptor subtypes.
Relationship between nitric oxide and opioids in hypoxia-induced pial artery vasodilation
Authors: Wilderman M. J. , Armstead W. M.
Published: December 2017

It has previously been observed that nitric oxide (NO) and the opioids Met- and Leu-enkephalin contribute to hypoxia-induced pial artery dilation in the newborn pig. The present study was designed to investigate the relationship between NO and opioids in hypoxic pial dilation. Piglets equipped with closed cranial windows were used to measure pial artery diameter and collect cortical periarachnoid cerebrospinal fluid (CSF) for assay of opioids. Sodium nitroprusside (SNP; 10(-8) and 10(-6) M) elicited pial dilation that was blunted by the soluble guanylate cyclase inhibitor LY-83583 (10(-5) M; 10 +/- 1 and 23 +/- 1 vs. 3 +/- 1 and 7 +/- 1% for 10(-8) and 10(-6) M SNP before and after LY-83583, respectively). SNP-induced dilation was accompanied by increased CSF Met-enkephalin, and coadministration of LY-83583 with SNP blocked these increases in CSF opioid concentration (1,144 +/- 59, 2,215 +/- 165, and 3,413 +/- 168 vs. 1,023 +/- 16, 1,040 +/- 18, and 1,059 +/- 29 pg/ml for control and 10(-8) and 10(-6) M SNP before and after LY-83583, respectively). SNP-induced release of CSF Leuenkephalin was also blocked by LY-83583. Similar blunted vascular and biochemical effects of SNP were observed with coadministration of the purported guanosine 3', 5'-cyclic monophosphate (cGMP) antagonist, the phosphorothioate analogue of 8-bromo-cGMP (BrcGMP) [(R)-p-BrcGMP[S]; 10(-5) M]. The cGMP analogue, BrcGMP, elicited dilation that was also accompanied by increased CSF Met- and Leu-enkephalin. Vascular and biochemical effects of BrcGMP were blunted by (R)-p-cGMP[S] and unchanged by LY-83583. Hypoxia-induced pial artery dilation was attenuated by N omega-nitro-L-arginine (L-NNA; 10(-6) M), an NO synthase inhibitor (25 +/- 2 vs. 14 +/- 1%). Hypoxic pial dilation was accompanied by increased CSF Met-enkephalin, and these increases were attenuated by L-NNA (1,137 +/- 60 and 3,491 +/- 133 vs. 927 +/- 25 and 2,052 +/- 160 pg/ml for control and hypoxia before and after L-NNA, respectively). Hypoxia also increased CSF Leuenkephalin, and these CSF changes were similarly attenuated by L-NNA. These data show that cGMP increases CSF Met- and Leu-enkephalin. Furthermore, these data suggest that NO contributes to hypoxic dilation, at least in part, via formation of cGMP and the subsequent release of opioids.
Coronary artery resistance changes depend on how surrounding myocardial tissue is stretched
Authors: Sipkema P. , Yamada H. , Yin F. C.
Published: December 2017

Deforming the tissue surrounding a coronary artery may change its hydraulic resistance. In excised blocks of dog left ventricular walls we examined how resistance (R) of a maximally dilated branch of a circumflex coronary artery was affected by 10% stretching of the tissue from its unloaded state, first parallel then perpendicular to the vessel axis (with the orthogonal dimension held constant) and finally biaxially. At 30 mmHg transmural pressure (Ptm) R per segment length (mmHg.min.ml-1.cm-1) increased significantly from the unloaded value of 0.0233 +/- 0.0031 (means +/- SE) to 0.0445 +/- 0.0073 and 0.0505 +/- 0.0090 during parallel and biaxial stretch, respectively. At Ptm of 80 mmHg unloaded R decreased to 0.0111 +/- 0.0016 mmHg.min.ml-1.cm-1 but did not change further with stretching. Stretching an isolated circular vessel 10% does not produce nearly this large an increase in R. A finite-element model simulating an epicardial vessel under our experimental conditions qualitatively predicted our results and demonstrated the combined roles of size and shape changes. Simulating a midwall arteriole surrounded by tissue predicted qualitatively similar results as for an epicardial vessel. Thus mechanical interaction between a coronary artery and surrounding tissue depends on both transmural pressure and the direction of stretching.
Relationship of renin-angiotensin system and ET-1 system activation in long-lasting response to postural changes
Authors: Modesti P. A. , Cecioni I. , Naldoni A. , Migliorini A. , Neri Serneri G. G.
Published: December 2017

The present study was performed in seven healthy subjects (aged 22-35 years) to investigate 1) whether plasma and urinary endothelin-1 (ET-1) are involved in the response to postural changes and 2) the relationship between ET-1 formation and the renin-angiotensin system (RAS). Six hours of standing caused a prompt but very short-lasting increase in plasma ET-1 concentration (59% after 5 min, 12% after 1 h) and a notable and sustained enhancement of urinary ET-1 excretion (from 0.59 +/- 0.10 to 1.43 +/- 0.28 pg/min, or 142%; P < 0.001). Plasma renin activity increased by 169% after 1 h of standing. A parallel contraction of urinary volume (-62%), sodium excretion (-55%), and free water reabsorption (-24%) occurred. The return to the supine position after 6 h of orthostasis caused a reduction to baseline values of the ET-1 urinary excretion and urinary volume within 2 h. Inhibition of angiotensin-converting enzyme blunted, but did not eliminate, the orthostasis-induced increase in ET-1 urinary excretion (100%, P < 0.002) and changes in the renal functions. The present results indicate that renal ET-1 is involved in the hemodynamic long-lasting responses to postural changes and that its increase is partially controlled by RAS and suggest that ET-1 might play a role in the regulation of renal function in humans.
Ca(2+)-activated Cl- currents in pulmonary arterial myocytes
Authors: Clapp L. H. , Turner J. L. , Kozlowski R. Z.
Published: December 2017

Currents from smooth muscle cells isolated from the pulmonary arterial tree of the rat were recorded under voltage clamp using the whole cell configuration of the patch-clamp technique. Rapid increases in cytosolic free calcium evoked by flash photolysis of Nitr-5 activated a current that, following ion substitution and pharmacological experiments, proved to be carried by Cl-. This current [ICl(Ca)] was evoked independently of photolytic by-products and, although smaller, was still activated in the absence of pipette ATP. Experiments revealed that ICl(Ca) was evoked in 80% in the cells isolated from the main pulmonary artery but only in 43% of the cells isolated from small vessels (200-400 microns ID). Application of caffeine also resulted in activation of ICl(ca), although the response current magnitude was larger in the main pulmonary artery. Photolysis of Nitr-5 still activated ICl(ca) in the presence of caffeine, suggesting that Ca2-release is not a prerequisite for activation of ICl(ca). These results represents in the first electrophysiological recordings of Cl- currents from small pulmonary arterial vessels and indicate that their Ca2+ regulation and/or distribution may be different throughout the pulmonary circulation.
Cardiovascular, renal, and endocrine responses to graded volume expansion in lambs during maturation
Authors: Smith F. G. , McWeeny O. J. , Robillard J. E.
Published: December 2017

To further investigate the maturation of the cardiopulmonary baroreflex, we measured the effects of a 45-min blood volume expansion to an increase in right atrial pressure of approximately 4 mmHg in chronically instrumented newborn (n = 17) and older lambs (n = 14). Measurements included various parameters of endocrine, cardiovascular, and renal function and concomitant recording of renal sympathetic nerve activity (RSNA). During blood volume expansion, RSNA was inhibited to a similar extent in newborns and older lambs when atrial pressures were increased by approximately 4 mmHg. A sympathoinhibition persisted in newborns but was only transient in older lambs. In newborn lambs, heart rate decreased in response to blood volume expansion, whereas heart rate remained constant after blood volume expansion in older lambs. The renal and endocrine responses to blood volume expansion were, however, similar in newborns and older lambs. These data provide evidence that when atrial pressures are matched, the renal and endocrine responses to blood volume expansion are similar, but there are differential cardiovascular and RSNA responses. Any reduced ability of the newborn kidney to excrete a volume load is therefore probably related to maturational differences in its distribution between the capacitance vessels and the heart.
Vascular endothelial growth factor administration in chronic myocardial ischemia
Authors: Harada K. , Friedman M. , Lopez J. J. , Wang S. Y. , Li J. , Prasad P. V. , Pearlman J. D. , Edelman E. R. , Sellke F. W. , Simons M.
Published: December 2017

Vascular endothelial growth factor (VEGF) is a potent mitogen capable of stimulating angiogenesis. We examined the effect of VEGF administration in a model of chronic porcine myocardial ischemia. Nineteen pigs were instrumented with proximal left circumflex coronary artery (LCX) Ameroid constrictors. In eight animals VEGF (2 microgram) with heparin (50 U) was administered extraluminally to the LCX myocardium with an osmotic pump for 4 wk and 11 other animals served as controls. VEGF-treated animals demonstrated higher flow in the LCX territory during both rest and pacing compared with untreated controls (rest: 1.35 +/- 0.1 vs. 0.80 +/- 0.09 ml.min-1.g-1; pacing; 2.01 +/- 0.37 vs. 1.01 +/- 0.07 ml.min-1.g-1, P < 0.05, VEGF vs. controls). The observed improvement in regional coronary flow in VEGF-treated animals resulted in better preservation of endothelium-dependent microvessel relaxation as well as fractional LV shortening in the LCX territory during pacing in the VEGF-treated than in control animals (controls: 7.1 +/ 2.6 vs. 3.6 +/- 2.0%, rest vs. pacing; VEGF: 6.9 +/- 2.9 vs. 6.3 +/- 2.9%, rest vs. pacing). We conclude that VEGF administration in a gradual coronary occlusion model in pigs results in improvement of coronary flow and preservation of regional hemodynamics in the compromised myocardium.
Blood pressure and heart rate responses to sudden changes of gravity during exercise
Authors: Linnarsson D. , Sundberg C. J. , Tedner B. , Haruna Y. , Karemaker J. M. , Antonutto G. , Di Prampero P. E.
Published: December 2017

Heart rate (HR) and blood pressure responses to sudden changes of gravity during 80- to 100-W leg exercise were studied. One group was exposed to sudden changes between 1.0 and 0 g in the head-to-foot direction (Gz+), starting upright and with repeated 30-s tilts to the supine position. Another group was exposed to sudden Gz+ changes between 1.8 and 0 g in an aircraft performing parabolic flight. Arterial blood pressure at the level of the carotid (carotid distending pressure, CDP) showed a large transient increase by 27-47 mmHg when Gz+ was suddenly decreased and a similar drop when Gz+ was suddenly increased. HR displayed a reverse pattern with larger transients (-22 to -26 min-1) in response to Gz+ decreases and more sluggish changes of lower amplitude in the other direction. Central blood volume, as estimated from the inverse of transthoracic impedance (1/TTI), varied in concert with Gz+. A model is proposed in which HR responses are described as a function of CDP and 1/TTI after a time delay of 2.3-3.0 s and including a low-pass filter function with time constants of 0.34-0.35 s for decreasing HR and time constants of 2.9-4.6 s for increasing HR. The sensitivity of the carotid component was around -0.8 to -1.0 min-1 . mmHg-1 (4-7 ms/mmHg). The cardiopulmonary baroreceptor component was an additive input but was of modest relative importance during the initial HR responses. For steady-state HR responses, however, our model suggests that inputs from carotid and cardiopulmonary receptors are of equal importance.
Systemic vascular effects during acute rejection of lung allografts
Authors: Schersten H. , Tazelaar H. D. , Cale A. R. , Miller V. M. , McGregor C. G.
Published: December 2017

Circulating leukocytes activated during rejection of organ allografts could potentially have generalized effects on systemic blood vessels of the transplant recipient. Experiments were designed, therefore, to determine the function of the endothelium and smooth muscle of arteries from nontransplanted organs in dogs who received single lung transplants. Dogs underwent single lung allotransplantation and were immunosuppressed for 5 days. Immunosuppression was then withheld for 3 days, allowing rejection to occur. Dogs were studied at this time (rejecting) or following treatment for rejection for an additional 6-8 days (treated). Arteries from unoperated, untreated dogs also were studied to provide baseline responses of healthy tissue. Rings cut from left circumflex coronary, nonoperated native pulmonary, and renal arteries were suspended in organ chambers for measurement of isometric force. Endothelium-dependent relaxations to the calcium ionophore A23187 were not affected by rejection in any of the arteries. Contractions to angiotensin I were reduced significantly only in native pulmonary arteries. Contractions to KCI and endothelin-1 increased in renal arteries with endothelium during rejection. These contractions in renal arteries were reduced following treatment of rejection. None of the responses of the coronary arteries were affected significantly by rejection of the lung allograft. These results demonstrate that contractions of arteries in the transplant recipient's native organs are altered during rejection of lung allografts. The effects are organ specific, may include production of endothelium-derived contractile factors in renal arteries, and can be partially reversed by treatment of rejection.
Effect of ACh and calmodulin inhibitor on O2 transfer from exocrine pancreatic microvessels of rats
Authors: Seiyama A. , Kosaka H. , Shiga T.
Published: December 2017

Effects of acetylcholine (ACh) and calmodulin (CaM) inhibitor, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), on the rate of O2 release (Ro2) from single exocrine pancreatic microvessels of anesthetized rats were investigated with dual-spot microspectroscopy. The surface of the pancreas was superfused with Krebs-Henseleit buffer containing various concentrations of ACh and/or W-7. Superfusion of ACh (> or = 20 microM) elevated Ro2 as well as pancreatic secretion approximately 2.5 times higher than that of control level, whereas superfusion of W-7 (> or = 100 microM) reduced approximately 50%. In both cases, O2 inflow in single microvessels, as quantified by oxyhemoglobin inflow into the microvessels, was maintained at control level. On the other hand, superfusion of both ACh and W-7 did not modify Ro2 and pancreatic secretion, despite significant reduction in O2 inflow. These results indicate that 1) the ACh-induced elevation of O2 release from single microvessels is accomplished by increased O2 extraction instead of increased O2 inflow in the microvessels, and 2) the activity of a W-7-sensitive Ca2+ binding protein, most likely CaM, is responsible for half of the microvascular O2 transfer and of the pancreatic exocrine secretion.
Effects of oxygen on regional hemodynamics in hemorrhagic shock
Authors: Bitterman H. , Brod V. , Weisz G. , Kushnir D. , Bitterman N.
Published: December 2017

This study investigated mechanisms of the hemodynamic effects of oxygen in hemorrhagic shock induced by bleeding 30% of the total blood volume in anesthetized rats. An ultrasonic flowmeter was used to monitor regional blood flow. Changes in tissue perfusion were assessed by the laser-Doppler technique. The inhalation of 100% oxygen induced a significant increase in mean arterial blood pressure (MABP) and vascular resistance in the hindquarters, with a concomitant decrease in blood flow in the distal aorta and biceps femoris muscle. In contrast, oxygen did not change vascular resistance in the superior mesenteric artery (SMA) and renal beds and induced a significant increase in blood flow to the renal artery, SMA, and small bowel in hemorrhaged rats. L-Arginine (100 mg/kg iv) but not D-arginine or the vehicle (0.9% NaCl) completely abolished the effects of oxygen on blood pressure and reversed its effects on blood flow and resistance in the hindquarters and biceps femoris muscle. Administration of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (50 mg/kg iv) significantly increased MABP and the resistance in the three vascular beds. Pretreatment of hemorrhaged rats with a superoxide dismutase mimic, the NO-stable radical 2,2,6,6-tetramethylpiperidine-N-oxyl (5 mg/kg iv), resulted in significantly diminished effects of oxygen on hindquarter hemodynamics. These results demonstrate a differential effect of oxygen, which increases vascular resistance in the hindquarters without a significant effect in the splanchnic and renal beds, thus favoring an increase in splanchnic and renal perfusion. It is suggested that inactivation of NO by reactive oxygen species may underlie the effects of oxygen on hindquarter vascular tone during shock.
Diurnal heart rate variability in healthy subjects: effects of aging and sex difference
Authors: Yamasaki Y. , Kodama M. , Matsuhisa M. , Kishimoto M. , Ozaki H. , Tani A. , Ueda N. , Ishida Y. , Kamada T.
Published: December 2017

To study the effects of aging and gender, circadian profiles of heart rate variability were evaluated for 105 healthy volunteers by frequency domain analysis of a Holter electrocardiogram record. The low-frequency (LF) component representing cardiac beta-adrenergic function showed high values for the 0800-1200 period in male subjects and the 1200-2400 period in female subjects. The high-frequency (HF) component representing parasympathetic function showed a peak for the 0000-0600 period in both male and female subjects independent of age. Male subjects showed significantly higher %LF [LF/(LF + HF) x 100] than female subjects. LF showed consistently highly significant correlation with age. These basic findings can help elucidate the diurnal profile of cardiac nerve function and how it is affected by aging and sex difference.
Differential effects of EMD-53998 on calcium-pressure relationship in normal and ischemic guinea pig heart
Authors: Ishisu R. , Abe Y. , Onishi K. , Sekioka K. , Nakano T.
Published: December 2017

We investigated the effects of EMD-53998 and digoxin on Ca2+ transients and left ventricular (LV) function in indo 1-loaded Langendorff guinea pig hearts. EMD-53998 (10(-9) to 10(-5) M) and digoxin (10(-10) to 10(-6) M) increased +dP/dt and Ca2+ transients in normal hearts. The relative increase in Ca2+ transients by EMD-53998 was similar to digoxin. At 10(-5) M, EMD-53998 increased LV end-diastolic pressure. Low-flow ischemia decreased +dP/dt by 50%, while indo 1 ratio increased by 10-25%. EMD-53998 (10(-9) to 10(-6) M) effectively restored the depressed +dP/dt with little effect on indo 1 ratio, but at 10(-5) M, it markedly elevated LV end-diastolic pressure and the beneficial effect on contractile dysfunction disappeared. Digoxin (10(-10) to 10(-7) M) failed to improve LV function, but at 10(-6) M, it restored contractile dysfunction with a large increase in indo 1 ratio. The relation between indo 1 ratio and +dP/dt clearly showed that EMD-53998 restored contractile dysfunction by Ca2+ sensitization. These findings suggest that Ca2+ sensitization by EMD-53998 is an advantageous approach for ischemic contractile failure but impairs diastolic function.
Economy of contraction of cardiomyocytes as influenced by different positive inotropic interventions
Authors: Popping S. , Mruck S. , Fischer Y. , Kulsch D. , Ionescu I. , Kammermeier H. , Rose H.
Published: December 2017

In the present study the effects of the novel cardiotonic agent EMD-57033 on contraction and energetic demand of isolated, electrically stimulated cardiomyocytes were investigated and compared with the effects of enhancement of extracellular calcium and of the beta-mimetic isoproterenol. In a specially designed setup [H. Rose, K.H. Strotmann, S. Popping, Y. Fischer, D. Kulsch, and H. Kammermeier. Am. J. Physiol. 261 (Heart Circ. Physiol. 30): H1329-H1334, 1991] parameters of contractile behavior and metabolic demand (O2 consumption) of isolated cardiac myocytes were measured. For a given enhancement of contractile performance (cell shortening) the increase in energetic demand (VO2) after application of EMD-57033 were markedly lower than on treatment with elevated extracellular Ca2+ concentration or with isoproterenol. This economization of positive inotropic effects was proposed to be due to two factors. First, stimulation-related ion cycling was only slightly enhanced with marked increase in contraction amplitude after application of EMD-57033. Second, calcium sensitization reflected in a leftward shift of the calcium concentration needed for half-maximum force development could be interpreted to be mediated by modulation of the cross-bridge dynamics of the myofilaments, where reduction of the switch-off rate of the cross bridges and prolongation of their force-generating states were presumed to be involved. Lowered pH (7.0) decreased economy of contraction. EMD-57033 restored contraction amplitude and economy of contraction at lowered pH.
Parasympathetic inhibition of sympathetic effects on sinus rate in anesthetized dogs
Authors: Furukawa Y. , Hoyano Y. , Chiba S.
Published: December 2017

The intracardiac parasympathetic neural elements that control sinus rate are found in the fatty tissue overlying the atrial junctions of the right pulmonary veins of mammalian hearts. We refer to these nerves as the sinus rate-related parasympathetic nerves (SRRPN). Thus, to elucidate the role of SRRPN, we studied the effects of cervical vagus stimulation on the positive chronotropic responses to cardiac sympathetic nerve stimulation and isoproterenol infusion before and after the SRRPN were removed in the open-chest anesthetized dog heart. Before SRRPN denervation, cervical vagus stimulation suppressed the sinus rate and the positive chronotropic response to sympathetic nerve stimulation or isoproterenol infusion. After SRRPN denervation, cervical vagus stimulation hardly decreased the sinus rate. On the other hand, even after SRRPN denervation, cervical vagus stimulation suppressed the rate increased by sympathetic stimulation. Cervical vagus stimulation also attenuated the sinus rate increased by isoproterenol. The inhibition by vagus stimulation of the chronotropic response to sympathetic stimulation was greater than that of the response to isoproterenol. The attenuation by cervical vagus stimulation was abolished by atropine. These results suggest that 1) a small number of vagus nerves to the sinoatrial nodal area different from the SRRPN decrease the sinus rate increased by adrenergic interventions and 2) the same activation that causes relatively small effects on sinus rate is capable of causing much larger changes in sinus rate during increased sympathetic tone or in the case of beta-adrenoceptor agonist treatment in the heart in situ.
Age dependence of cerebrovascular response mechanisms in domestic pigs
Authors: Zuckerman S. L. , Armstead W. M. , Hsu P. , Shibata M. , Leffler C. W.
Published: December 2017

Hypercapnia-induced cerebral vasodilation in the newborn pig is a prostanoid-associated response. In some adult models, hypercapnic cerebral vasodilation is associated with the generation of nitric oxide (NO). Acetylcholine (ACh) produces a NO-dependent cerebral vasodilation in many adult models, but topical ACh is a prostanoid-associated cerebral vasoconstrictor in the newborn pig. We hypothesized that mediators influencing cerebral response can be age dependent. Juvenile domestic pigs were compared with newborn pigs, and pial arteriolar diameters were measured by use of a closed cranial window during hypercapnia and topical ACh (10(-5) M). Four different conditions were explored: control, topical N omega-nitro-L-arginine (L-NNA, 10(-3) M), indomethacin (5 mg/kg i.v.), and both L-NNA and indomethacin. All animals were anesthetized with alpha-chloralose. As opposed to the complete block in the newborn, indomethacin only partially attenuated the hypercapnic cerebral vasodilation in the juvenile pig.L-NNA, which had no effect on the response of the newborn, produced a partial attenuation of the hypercapnic response of the juvenile. The combination of indomethacin and L-NNA blocked the response in both age groups. Topical ACh in both age groups initially produced cerebral vasoconstriction, but, in the juvenile, this was followed by a sustained cerebral vasodilation. Indomethacin blocked the early vasoconstriction in both age groups. L-NNA, which had no effect in the response of the newborn to ACh, blocked the vasodilation seen in the juvenile. The combination of both inhibitors blocked all response to ACh in the juvenile. These data indicate that although the cerebral vascular responses to ACh and hypercapnia are prostanoid associated and NO independent in the newborn pig, NO assumes an increasing role in dilatory responses with development.
Altered endothelium-dependent responses in lambs with pulmonary hypertension and increased pulmonary blood flow
Authors: Reddy V. M. , Wong J. , Liddicoat J. R. , Johengen M. , Chang R. , Fineman J. R.
Published: December 2017

To investigate early endothelial function associated with increased pulmonary blood flow, vascular shunts were placed between the ascending aorta and main pulmonary artery in 18 late-gestation fetal sheep. Four weeks after delivery, the lambs were instrumented to measure vascular pressures and blood flows, and blood was collected to measure plasma concentrations of guanosine 3',5'-cyclic monophosphate [cGMP, the second messenger to nitric oxide (NO)-mediated vasodilation] and L-arginine (the precursor for NO synthesis). The responses to the endothelium-dependent vasodilators acetylcholine (ACh, 1.0 microgram/kg) and ATP (0.1 mg.kg-1.min-1), the endothelium-independent vasodilators M & B-22948 (a cGMP-specific phosphodiesterase inhibitor, 2.5 mg/kg) and inhaled NO (40 ppm), and N omega-nitro-L-arginine (an inhibitor of NO synthase, 5 mg/kg) were then compared with responses in 12 age-matched controls. Vasodilator responses in control lambs were determined during pulmonary hypertension induced by U-46619 (a thromboxane A2 mimic). Shunted lambs displayed a selective impairment of endothelium-dependent pulmonary vasodilation, an augmented pulmonary vasoconstricting response to NO synthase inhibition, increased plasma cGMP concentrations, and decreased L-arginine concentrations. Taken together, these data suggest that lambs with pulmonary hypertension and increased pulmonary blood flow have early aberrations in endothelial function, as manifested by increased basal NO activity, that cannot be further increased by agonist-induced endothelium-dependent vasodilators.
Local and conducted vasomotor responses in isolated rat cerebral arterioles
Authors: Dietrich H. H. , Kajita Y. , Dacey R. G.
Published: December 2017

We tested the hypothesis that conduction of vasomotor responses occurs in cannulated and isolated rat cerebral penetrating arterioles. Both at the site of stimulation (local) and 500-650 microns distant from it, we observed the diameter responses and time courses thereof to pressure-ejected vasoactive stimuli. ATP locally caused an initial constriction (response onset at 0.3 s, average diameter 85% of control at 450-ms pulse with a maximum at 1.6 s after stimulation) followed by a secondary dilation (111% at 7 s). Conducted vasodilation of 111% was observed over a distance of 520 microns. Prostaglandin F2 alpha (PGF2 alpha) constricted the vessels locally (80%) and caused conducted vasodilation (110%). For both ATP and PGF2 alpha the local constriction occurred simultaneously to the conducted vasodilation. Adenosine dilated the vessels (123%) but produced only inconsistent conducted vasodilation. Hydrogen ions initially constricted the vessels (88%) and then dilated them to 113%. Thus, although ATP and PGF2 alpha are strong promoters of conduction, adenosine and hydrogen ions are not. Paradoxically, ATP and PGF2 alpha caused conducted vasodilation even though the initial local response was a vasoconstriction, indicating that in cerebral arterioles conduction may be mediated through endothelial cell mechanisms rather than through smooth muscle cell communication.
Oxygen consumption in the avascular guinea pig retina
Authors: Cringle S. , Yu D. Y. , Alder V. , Su E. N. , Yu P.
Published: December 2017

Oxygen consumption across the retina of a mammal with a naturally avascular retina has not previously been investigated. The oxygen consumption across the avascular retina of the guinea pig was measured in vivo by spatial analysis of the intraretinal oxygen profile. The avascular nature of the guinea pig retina allows the inner retina to be included in the analysis without disrupting the normal physiological state of the retina. Oxygen-sensitive microelectrodes (1-micron tip) were used to make high-resolution measurements of oxygen tension through the retina of anesthetized, mechanically ventilated guinea pigs (n = 10). Oxygen profiles were then analyzed in terms of oxygen tension as a function of distance from the choriocapillaris/Bruch's membrane, and the data were fitted to an established mathematical model of retinal oxygen consumption. The average oxygen consumption of the full thickness of the guinea pig retina was 1.1 +/- 0.09 ml O2.min-1 x 100 g-1 (n = 10). The average oxygen consumption of the outer half of the retina was 2.07 +/- 0.17 ml O2.min-1 x 100 g-1, while that of the inner half was only 0.12 +/- 0.04 ml O2.min-1 x 100 g-1. A localized region of high oxygen consumption was identified in the outer retina in every case, and this region accounted for an average of 93.9 +/- 2.0% of the total retinal oxygen consumption. Only 5.2 +/- 1.4% of the total oxygen consumption was attributable to the inner half of the retina. When choroidal oxygen tension was increased via a combination of systemic hyperoxia and hypercapnia, high oxygen levels could be sustained in all retinal layers. Under these conditions of an excess oxygen supply, the inner retina still consumed only 0.45 +/- 0.11 ml O2.min-1 x 100 g-1, which was 13.8 +/- 2.5% of the total retinal oxygen consumed. The relatively low oxygen consumption in the inner retina of the guinea pig may reflect an interesting adaptation to the constraints imposed by the absence of a retinal circulation in this species.
Endothelium-derived nitric oxide mediates hypoxic vasodilation of resistance vessels in humans
Authors: Blitzer M. L. , Lee S. D. , Creager M. A.
Published: December 2017

Endothelium-derived nitric oxide (EDNO) contributes to basal systemic vascular resistance under normoxic conditions. The purpose of this investigation was to determine whether EDNO contributes to the regulation of limb vascular resistance during hypoxia in healthy humans. Forearm blood flow was assessed by venous occlusion plethysmography. Hypoxia was induced by delivering a mixture of N2 and O2 via a gas blender adjusted to reduce the PO2 to 50 mmHg. During hypoxia, forearm blood flow increased from 2.4 +/- 0.2 to 3.0 +/- 0.3 ml.100 ml-1.min-1 (P < 0.001), and forearm vascular resistance decreased from 38 +/- 3 to 29 +/- 3 units (P < 0.001). The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 2,000 micrograms/min intra-arterially) was administered to eight subjects. The percent increase in forearm vascular resistance after administration of L-NMMA was greater during hypoxia than normoxia (67 +/- 14 vs. 39 +/- 15%, P < 0.05). L-NMMA reduced the forearm vasodilator response to hypoxia from 27 +/- 3 to 11 +/- 5% (P = 0.01). To exclude the possibility that this attenuated response to hypoxia was a consequence of vasoconstriction and not specific for nitric oxide synthase inhibition, six subjects received intra-arterial phenylephrine. Phenylephrine did not affect the vasodilator response to hypoxia (17 +/- 3 vs. 21 +/- 6%, P = NS). It is concluded that EDNO contributes to hypoxia-induced vasodilation in the forearm resistance vessels in healthy humans.
Actomyosin interaction modulates resting length of unstimulated cardiac ventricular cells
Authors: Sollott S. J. , Ziman B. D. , Warshaw D. M. , Spurgeon H. A. , Lakatta E. G.
Published: December 2017

We sought to determine whether resting or diastolic cardiac myocyte length during low stimulation rates is regulated by myofilament interaction. Cytosolic Ca2+ concentration ([Ca2+]i, via indo 1 fluorescence) and length, in the presence and absence of 2,3-butanedione monoxime (BDM), a potent inhibitor of force production in striated muscle, were measured in rat and guinea pig cardiac myocytes at rest and after electrical stimulation. In tetanized cells BDM reduced steady contraction amplitudes for a given [Ca2+]i. In an actomyosin-sliding filament assay without Ca2+ or regulatory proteins, BDM decreased actin filament velocity along myosin. BDM increased both diastolic and resting cell lengths without changes in [Ca2+]i. The resting cell length also increased when [Ca2+]i was reduced by removing extracellular Ca2+, an effect further enhanced by BDM and by loading cells with the intracellular Ca2+ chelator, 1,2-bis(2-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethylester. Thus myofilament interaction is present in cardiac cells, both at rest or during low rates of stimulation, and this myofilament interaction is regulated, in part, by the ambient [Ca2+]i.
Extreme vasoreactivity of rat epineurial arterioles to vasopressin
Authors: Sasaki H. , Low P. A.
Published: December 2017

Vasopressin is a potent vasoconstrictor to most blood vessels but is a vasodilator to some. The role of vasopressin in the regulation of nerve blood flow (NBF) is not known. We undertook a dose-effect study of vasopressin on NBF and evaluated its interactions with alpha-adrenoreceptors and its effect on ischemic conduction failure. NBF was measured using microelectrode hydrogen polarography. Vasopressin was administered topically (to epineurium). Topical epineurial application of vasopressin caused a concentration -dependent reductin of NBF (EC 50 = 6.6 x 10(-9) M; asymptote = 73.9% NBF reduction). The topical application of subthreshold concentrations of vasopressin and norepinephrine alone resulted in no change in NBF, but combined application resulted in a dramatic reduction in NBF (72.3%). The ratio of amplitudes of muscle compound action potential evoked on proximal to distal stimulation was used as an index of the presence of an ischemic conduction block. This ratio was significantly reduced following the combined topical application of supramaximal concentrations of vasopressin and norepinephrine. These findings suggest that vasopressin is a potent neural vasoconstrictor and that vasoconstriction caused by combined vasopressin and norepinephrine can produce partial conduction block of sciatic-tibial nerve [corrected].
Effects of cardiac contraction and coronary sinus pressure elevation on collateral circulation
Authors: Sato M. , Saito T. , Mitsugi M. , Saitoh S. , Niitsuma T. , Maehara K. , Maruyama Y.
Published: December 2017

Controlled coronary sinus occlusion was shown to retard necrosis of ischemic myocardium. To elucidate this mechanism, regional myocardial blood flow measurement was performed with and without coronary sinus pressure elevation to 30 mmHg (CS30). Colored microspheres were injected into left and right coronary arteries after coronary perfusion of the left anterior descending (LAD) coronary artery was stopped in seven isolated canine hearts with induced atrioventricular block, either paced at 120 beats/min by direct right ventricular stimulation [beating heart (B)] or during asystole induced by stopping pacing [nonbeating heart (NB)]. Regional myocardial blood flow in the LAD perfused area in the control state in the NB with normal coronary sinus pressure (NB-CScont; 0.27 +/- 0.13 ml.min-1.g-1, means +/- SE) was significantly greater than those in B-CScont (0.19 +/- 0.09 ml.min-1.g-1; P < 0.05) and in NB with CS30 (NB-CS30; 0.19 +/- 0.09 ml.min-1.g-1; P < 0.05). Regional myocardial blood flow of the LAD area in B with CS30 (B-CS30; 0.23 +/- 0.10 ml.min-1.g-1) was significantly greater in comparison with that at B-CScont and NB-CS30 (P < 0.05). The augmentative effect of the LAD area regional myocardial blood flow was observed only in the periphery of the ischemic region but not in its center. Cardiac contraction and CS30 impede regional myocardial blood flow in the ischemic bed independently. The coexistence of these two factors enhances regional myocardial blood flow. In conclusion, coronary sinus pressure elevation in B may participate in augmenting collateral flow.