bluuebunny/crossref_metadata_2025 huggingface dataset:
Glibenclamide decelerates the responses of coronary regulation in the goat
Authors: Dankelman J. , Van der Ploeg C. P. , Spaan J. A.
Published: December 2017

The role of blocking ATP-sensitive potassium (KATP) channels by glibenclamide on the dynamic responses of coronary resistance to abrupt changes in perfusion pressure and heart rate was investigated. The left main coronary artery of the open-chest anesthetized goat was perfused with constant pressure (Pp). Pp and arterial flow were averaged per beat, and their ratio was calculated as index of coronary resistance. Responses of resistance index after heart rate (HR) and Pp changes before and after administration of glibenclamide were compared. Their rate of change was quantified by t50, the required time to obtain half of the complete response. During control, t50 for the dilating response induced by a decrease in Pp or increase in HR was 3.8 +/- 0.2 and 6.2 +/- 0.5 (SE) s, respectively. With glibenclamide these values were 24.4 +/- 1.6 and 14.9 +/- 2.1 s. For the constricting response, the numbers for control were 5.8 +/- 0.3 (increase Pp) and 7.2 +/- 0.8 (decrease HR) s. With glibenclamide these values were 22.1 +/- 1.5 and 16.0 +/- 2.9 s. The steady-state adjustment of coronary flow was not altered by glibenclamide. It was concluded that glibenclamide has a minor effect on coronary flow control but reduces the rate of change of coronary resistance index up to a factor of four. Because glibenclamide is supposed to act on KATP channels, it may be concluded that these channels play a major role in the dynamics of coronary blood flow regulation.
Protective effects of N-acetyl-L-cysteine in endotoxemia
Authors: Zhang H. , Spapen H. , Nguyen D. N. , Benlabed M. , Buurman W. A. , Vincent J. L.
Published: December 2017

Because oxygen free radicals have been implicated in the endothelial cell damage and in the myocardial depression occurring during severe sepsis, we investigated whether N-acetyl-L-cysteine (NAC) could influence the oxygen extraction capabilities during an acute reduction in blood flow induced by cardiac tamponade after endotoxin challenge. Sixteen anesthetized, saline-infused, and ventilated dogs received Escherichia coli endotoxin (2 mg/kg) 30 min before tamponade was induced by repeated bolus injections of warm saline into the pericardial space. Thirty minutes before endotoxin administration, nine dogs received NAC (150 mg/kg, followed by a 20 mg.kg-1.h-1 infusion); the other seven dogs served as a control group. The NAC group maintained higher cardiac index, oxygen delivery (DO2), and left ventricular stroke work index, but lower systemic and pulmonary vascular resistance, than the control group. The oxygen uptake (VO2) levels at critical DO2 (DO2crit) were identical in the two groups. However, DO2crit was significantly lower in the NAC than in the control group (8.1 +/- 1.7 vs. 10.8 +/- 1.8 ml.kg-1.min-1, P < 0.01). Critical oxygen extraction ratio and the slope of the VO2-to-DO2-dependent line were higher in the NAC than in the control group (72 +/- 14 vs. 53 +/- 15% and 0.80 vs. 0.56, respectively; both P < 0.05). The peak lactate and the maximal tumor necrosis factor (TNF) levels were lower in the NAC than in the control group (5.2 +/- 0.4 vs. 7.6 +/- 0.4 mM, and 0.14 +/- 0.03 vs. 1.21 +/- 0.58 ng/ml, respectively; both P < 0.01). NAC significantly increased glutathione peroxidase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Cytochrome P-450 inhibitors alter afferent arteriolar responses to elevations in pressure
Authors: Imig J. D. , Zou A. P. , Ortiz de Montellano P. R. , Sui Z. , Roman R. J.
Published: December 2017

The present study evaluated the effects of cytochrome P-450 inhibitors on the response of the renal microvasculature to changes in renal perfusion pressure and on autoregulation of glomerular capillary pressure using the rat juxtamedullary nephron microvascular preparation perfused in vitro with a cell-free perfusate containing 5% albumin. The basal diameters of the proximal and distal afferent arterioles averaged 28 +/- 1 (n = 32) and 18 +/- 1 micron (n = 23), respectively, at a control perfusion pressure of 80 mmHg. The diameters of these vessels decreased by 8% when perfusion pressure was elevated from 80 to 160 mmHg. After addition of cytochrome P-450 inhibitors (either 17-octadecynoic acid, 20 microM; 7-ethoxyresorufin, 10 microM; or miconazole, 20 microM) to the perfusate, the diameters of the proximal and distal afferent arterioles increased by 6% in response to the same elevation in perfusion pressure. Control glomerular capillary pressure averaged 43 +/- 1 mmHg (n = 32) at a renal perfusion pressure of 80 mmHg and increased by only 9 +/- 1 mmHg when perfusion pressure was elevated to 160 mmHg. Autoregulation of glomerular capillary pressure was impaired after addition of the cytochrome P-450 inhibitors, and it increased by 18 +/- 2 mmHg when perfusion pressure was varied over the same range. These results indicate that cytochrome P-450 inhibitors attenuate the vasoconstrictor response of afferent arterioles to elevations in renal perfusion pressure and impair autoregulation of glomerular capillary pressure, suggesting a possible role for cytochrome P-450 metabolites of arachidonic acid in these responses.
High-energy phosphate responses to tachycardia and inotropic stimulation in left ventricular hypertrophy
Authors: Bache R. J. , Zhang J. , Path G. , Merkle H. , Hendrich K. , From A. H. , Ugurbil K.
Published: December 2017

Spatially localized nuclear magnetic resonance (NMR) spectroscopy was used to examine the effect of tachycardia and inotropic stimulation on myocardial ATP, creatine phosphate (CrP), and inorganic phosphate (Pi) in animals with left ventricular hypertrophy (LVH). Studies were performed in eight normal dogs and seven dogs with moderate LVH produced by banding the ascending aorta. 31P-NMR spectra were obtained from five layers across the LV wall, while blood flow (BF) was measured with microspheres during control conditions, pacing at 200 and 240 beats/min, and during dobutamine infusion (Dob). Myocardial ATP and CrP levels were normal in the LVH hearts during control conditions. Pacing did not alter the transmural distribution of perfusion or the levels of CrP, ATP, and Pi in normal hearts. In contrast, in four of seven LVH hearts, pacing decreased the subendocardial/subepicardial (ENDO/EPI) BF ratio and caused depletion of CrP and appearance of Pi characteristic of ischemia in the subendocardium. Dob produced greater increases in the heart rate x LV systolic pressure product (RPP) and greater increases of Pi and decreases of CrP in LVH than in normal hearts; however, at comparable elevations of RPP the alterations of Pi and CrP were similar in both groups. Although Dob decreased the ENDO/EPI in LVH hearts, Dob-induced alterations in CrP and Pi were uniform across the LV wall. Increasing myocardial BF with adenosine or carbochromen did not reverse the alterations in Pi or CrP produced by Dob. We conclude that 1) ENDO perfusion abnormalities during tachycardia in LVH do produce ENDO subendocardial ischemia; 2) when the degree of augmentation of mechanical performance is considered, the metabolic changes induced by Dob were similar in normal and LVH hearts; 3) Dob-induced alterations in Pi and CrP were not related to inadequate perfusion, since increasing coronary BF did not reverse these changes; and 4) alterations of Pi and CrP during Dob infusion were not more prominent in the ENDO, indicating that the decreased ENDO/EPI flow did not cause ENDO ischemia but may reflect relatively lower O2 demands in this region during inotropic stimulation.
Endothelium-dependent relaxations to adenosine in juvenile rabbit pulmonary arteries and veins
Authors: Steinhorn R. H. , Morin F. C. , Van Wylen D. G. , Gugino S. F. , Giese E. C. , Russell J. A.
Published: December 2017

We studied the actions of adenosine and its analogues 5'-(N-ethylcarboxamido)-adenosine (NECA) and N6-cyclohexyladenosine (CHA) in pulmonary vessels isolated from juvenile rabbits. Pulmonary arteries relaxed in a concentration-dependent fashion to all three compounds. Pretreatment with the methylxanthine 8-p-sulfophenyltheophylline shifted the concentration-response curves to adenosine and NECA rightward, indicating that the vasodilator effects were mediated by the adenosine receptor. The order of potency of adenosine compounds was NECA > adenosine > CHA, indicating that the A2-receptor mediates relaxations to adenosine in rabbit pulmonary arteries. Endothelium rubbing attenuated relaxations to adenosine at concentrations of < or = 3 x 10(-7) M and to all NECA concentrations. Inhibition of nitric oxide synthase with NG-nitro-L-arginine (L-NNA) similarly attenuated relaxations at concentrations of < or = 3 x 10(-7) M for adenosine and < or = 3 x 10(-8) M for NECA. With the use of the same methods, a substantial endothelial contribution was additionally observed in pulmonary veins to the vasodilator effects of NECA. We conclude that adenosine, and the more specific A2-receptor agonist NECA, dilate pulmonary arteries and veins isolated from young rabbits via a mechanism that is partially dependent on endothelium-derived nitric oxide.
Open Na+ channel blockade: multiple rest states revealed by channel interactions with disopyramide and quinidine
Authors: Zilberter Y. I. , Starmer C. F. , Grant A. O.
Published: December 2017

In voltage-clamp studies of atrial myocytes exposed to disopyramide or quinidine, pulse-train stimulation revealed use-dependent block that increased with increased pulse amplitude. Use-dependent block also became negligible at hyperpolarized holding potentials (< -150 mV), consistent with either rapid unbinding at the holding potential or trapping of the drug in a drug-complexed rest conformation followed by rapid unbinding during the next channel opening event. To explore the unbinding properties of hypothetically different rest-blocked conformations, we exposed cells to a postdepolarization "conditioning" potential after channels had become fully inactivated so as to vary the transition to different hypothetical rest-blocked channels. Pulse-train stimulation from -130 to -30 mV generated only a small amount of use-dependent block. Inserting a 120-ms subthreshold (e.g., -100 mV) postdepolarization conditioning potential before return to -130 mV increased use-dependent block. The fraction of steady-state block exhibited a bell-shaped dependence on the conditioning potential. These results are consistent with the existence of a mixture of rest-blocked channel conformations, each having direct access to the blocked-inactivated state. These intermediate rest conformations display radically different drug unbinding rates.
Mechanism of redistribution of cerebral blood flow during hypercarbia and seizures
Authors: Muhonen M. G. , Greene G. M. , Heistad D. D. , Loftus C. M.
Published: December 2017

After occlusion of an artery to the brain, hypercarbia and seizures may produce a paradoxical reduction in cerebral blood flow to the region supplied by collateral vessels. We measured pressure in an occluded branch of the middle cerebral artery and measured regional cerebral blood flow (rCBF) to collateral-dependent cerebrum in dogs (n = 25) to examine hemodynamic mechanisms that account for the reduction in flow. During hypercarbia (arterial PCO2 = 70 +/- 5 mmHg), rCBF to collateral-dependent cerebrum, measured with microspheres and identified using the shadow flow technique, decreased from 95 +/- 6 (mean +/- SE) to 71 +/- 9 ml.100 g-1.min-1 (P < 0.05), while flow to normal brain increased from 105 +/- 9 to 281 +/- 15 ml.100 g-1.min-1 (P < 0.05). Pressure in a branch of the middle cerebral artery decreased during hypercarbia from 50 +/- 6 to 25 +/- 3 mmHg (P < 0.05), concurrent with a significant increase in resistance of collateral vessels. Small vessel resistance was the same in collateral-dependent and normal brain. During bicuculline-induced seizures, with blood pressure maintained at control levels by withdrawal of blood, rCBF decreased in collateral-dependent cerebrum from 128 +/- 16 to 67 +/- 11 ml.100 g-1.min-1 (P < 0.05), and flow to normal brain increased from 169 +/- 14 to 418 +/- 17 ml.100 g-1.min-1 (P < 0.05). Small vessel resistance decreased in both regions, but the decrease was much greater in normal cerebrum. Changes in cerebral artery pressure and resistance of collateral vessels during seizure were similar to those during hypercarbia.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of vagal stimulation on left ventricular systolic and diastolic performance
Authors: Xenopoulos N. P. , Applegate R. J.
Published: December 2017

Vagal stimulation (VS) decreases heart rate and alters the loading conditions of the left ventricle (LV). However, its effects on LV performance are not clearly defined. To evaluate the effects of VS on LV performance, 20 anesthetized open-chest dogs were instrumented to measure LV pressure (LVP) and volume. VS resulted in a decrease in the slope of the end-systolic pressure-volume relationship, without pacing and with pacing, after ansae subclaviae resection and after ansae subclaviae resection plus beta-adrenergic blockade. VS did not alter the time constant of isovolumic relaxation (tau) or the LV end-systolic pressure-tau relationship during vena caval occlusion. No change was noticed in the LV chamber stiffness constant without and with pacing. However, a significant increase in the LV filling fraction at one-third and one-half of diastole was observed. We examined the mechanism of this increase by examining the relationship of left atrial pressure (LAP) and LVP. VS increased mean LAP 44% and increased the LAP-LVP gradient 42%. These data suggest that VS exerts a significant negative inotropic effect that is independent of its bradycardiac effect and the level of sympathetic tone. Despite the absence of lusitropic effects of VS, early filling of the LV is augmented most likely as a result of an increase in LAP.
Indomethacin reduces ischemia-induced alteration of blood-brain barrier transport in piglets
Authors: Zuckerman S. L. , Mirro R. , Armstead W. M. , Shibata M. , Leffler C. W.
Published: December 2017

Cerebral ischemia-reperfusion (Isc-Rep) alters blood-brain barrier (BBB) transport properties in piglets. Pretreatment with superoxide dismutase and catalase partially attenuates these effects. Activated O2 species produced with Isc-Rep in piglets are generated via prostaglandin (PG) H synthase. This experiment determines if products of PGH synthase alter BBB transport of sodium and albumin. Piglets anesthetized with nitrous oxide and halothane were divided into four groups: 1) control, 2) indomethacin (5 mg/kg iv) with no Isc-Rep, 3) Isc-Rep alone, and 4) Isc-Rep after pretreatment with indomethacin (Indo). Regional transfer coefficients (Kin) and regional cerebral blood flow (microspheres) were measured at 2 h reperfusion after 20 min total global cerebral ischemia. Kin values are represented as absolute values and also relative to blood flow to account for any changes in perfusion caused by ischemia and/or Indo. Indo alone did not alter sodium or albumin transfer compared with control animals. Isc-Rep alone caused a significant increase in sodium and albumin transport compared with all other groups (control cerebral sodium Kin was 18.2 +/- 2.7 cm3.g-1.s-1.10(6) vs. 32.9 +/- 3.1 for Isc-Rep, P < 0.05). In contrast, there was no significant difference in sodium or albumin transfer with Isc-Rep after Indo pretreatment (e.g., cerebral sodium Kin was 22.0 +/- 2.0 for Isc-Rep after Indo) compared with the control or Indo alone groups. Indo pretreatment effectively attenuates increased BBB transport of both sodium and albumin following cerebral ischemia. We conclude that products of PGH synthase are involved in BBB alterations of protein and cation transport that follow the early stages of cerebral reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparison of pressor responses to angiotensin I, II, and III in pulmonary vascular bed of cats
Authors: Cheng D. Y. , DeWitt B. J. , McMahon T. J. , Kadowitz P. J.
Published: December 2017

Pulmonary vascular responses to angiotensin (ANG) peptides were investigated in the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. Intralobar injections of ANG I, II, and III caused dose-related increases in lobar arterial pressure, whereas ANG (1–7) and ANG (3–8) (ANG IV) had modest pressor activity. ANG I, II, and III had similar activity and were more potent than norepinephrine and ANG (1–7) and ANG IV but less potent than the thromboxane A2 mimic, U-46619, in increasing lobar arterial pressure. The time course of responses to ANG I, II, and III was similar, and after administration of ANG receptor antagonists, DuP 532 and L-158,809, responses to ANG I, II, and III was reduced, whereas responses to norepinephrine, serotonin, and U-46619 were not altered. After administration of the ANG-converting-enzyme inhibitor, captopril, responses to ANG I were reduced. The converting-enzyme inhibitor enhanced pressor responses to ANG II and III but did not alter responses to norepinephrine, U-46619, or serotonin. Moreover, under elevated-tone conditions, pulmonary vasodilator responses to bradykinin were increased following administration of captopril, whereas vasodilator responses to acetylcholine and nitrovasodilators were not altered. These results demonstrate that ANG I, II, and III have similar pulmonary pressor activity and that responses are mediated by ANG II type 1 receptors. Pressor responses to ANG I are reduced, whereas vasodilator responses to bradykinin are enhanced by captopril.(ABSTRACT TRUNCATED AT 250 WORDS)
Coronary pressure-flow autoregulation protects myocardium from pressure-induced changes in oxygen consumption
Authors: Bai X. J. , Iwamoto T. , Williams A. G. , Fan W. L. , Downey H. F.
Published: December 2017

Pressure-flow autoregulation minimizes changes in coronary blood flow (CBF) when coronary perfusion pressure (CPP) is altered. This investigation determined if autoregulation also minimizes CPP-induced changes in coronary vascular volume (CVV) and CVV-dependent changes in myocardial oxygen consumption (MVO2). In 11 anesthetized dogs, the left anterior descending coronary artery was cannulated, and responses to 20-mmHg changes in CPP were examined over a range of CPP from 60 to 180 mmHg. Changes in CPP had no significant effect on systemic hemodynamics or on left ventricular end-diastolic segment length, end-systolic segment length, or percent segment shortening. In hearts with effective pressure-flow autoregulation [closed-loop gain (GC) > 0.4], CVV increased 0.06%/mmHg change in CPP. For the same hearts, MVO2 increased 0.04%/mmHg change in CPP. In hearts with ineffective autoregulation (GC < 0.4), CVV increased 0.97%/mmHg (P < 0.001 vs. autoregulating hearts), and MVO2 increased 0.41%/mmHg (P < 0.001 vs. autoregulating hearts). MVO2 and CVV were correlated (r = 0.69, P < 0.0001) independently of autoregulatory capability, but only when autoregulation was poor and capacitance was elevated did CPP significantly affect MVO2. We conclude that pressure-flow autoregulation protects myocardium from CPP-induced changes in CVV, which in turn produces changes in oxygen consumption.
Physiological arginine vasopressin levels do not enhance baroreflex function in normal humans
Authors: Goldsmith S. R.
Published: December 2017

Physiological increases in arginine vasopressin (AVP) have been shown to potentiate baroreflex activity in experimental animals. Pharmacological amounts of AVP have been shown to decrease sympathetic nervous system activity in humans, whereas the role of smaller increases in plasma AVP is unclear, either for baroreflex function or sympathetic activity. The present study tested the hypotheses that in normal humans physiological increases in plasma AVP would 1) decrease basal sympathetic nervous system activity as measured by systemic venous norepinephrine (NE) spillover; 2) enhance or restrain the increases in heart rate (HR), forearm vascular resistance, and NE spillover during baroreceptor unloading during head-up tilt; and 3) augment the decline in HR and NE spillover during baroreceptor loading with head-down tilt and/or with phenylephrine infusion plus head-down tilt. In the baroreceptor unloading studies, HR, arterial pressure, forearm blood flow, plasma NE, NE clearance, and NE spillover were assessed during infusions of AVP (plasma AVP 16-20 pg/ml) or vehicle (given double blind) in the supine position. All variables then were assessed during 15 min of head-up tilt. In the baroreflex loading studies, the same assessments (except forearm blood flow) were made during 15 min of head-down tilt followed by 15 min of head-down tilt plus phenylephrine. Compared with vehicle, AVP had no effect on the responses of any variable in the supine position or on the expected reflex responses during head-up tilt and head-down tilt plus phenylephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
Zinc improves postischemic recovery of isolated rat hearts through inhibition of oxidative stress
Authors: Powell S. R. , Hall D. , Aiuto L. , Wapnir R. A. , Teichberg S. , Tortolani A. J.
Published: December 2017

We studied the cardiac protective qualities of zinc in the postischemic isolated rat heart. Hearts, perfused with Krebs-Henseleit buffer with or without zinc-bis-histidinate, were subjected to 20 min of "no-flow" normothermic global ischemia. Pre- and postischemic treatment with 0, 10, 20, or 30 microM zinc resulted in concentration-dependent enhancement of postischemic function as evidenced by decreased end-diastolic pressure (37 +/- 3, 25 +/- 5, 17 +/- 5, and 8 +/- 2 mmHg, respectively) and increased recovery of developed systolic pressure (41 +/- 6, 59 +/- 17, 76 +/- 18, and 87 +/- 16 mmHg, respectively) and maximum rate of rise in pressure (+dP/dtmax; 823 +/- 141, 1,413 +/- 396, 1,700 +/- 450, and 2,157 +/- 407 mmHg/s, respectively) as well as decreased lactate dehydrogenase efflux from the hearts (peak: 1,002%, 840%, 580%, and 440%, respectively). Only preischemic treatment resulted in an intermediate protective effect, whereas treatment starting at reperfusion worsened postischemic damage. In hearts perfused with zinc throughout the experiment, prolongation of the preischemic treatment interval further enhanced postischemic recovery. With the use of salicylate as a trap for .OH, it was determined that zinc virtually eliminated the early postischemic "burst" of this species normally observed in this preparation. Atomic absorption studies demonstrated that hearts treated with 30 microM zinc contained 27% less copper than control hearts by the end of the reperfusion period. In control hearts, electron microscopy revealed swollen mitochondria with marked loss of inner matrix density, whereas morphology of postischemic zinc-treated hearts was essentially normal. These studies indicate that zinc possesses cardiac cytoprotective qualities and support the concept that this metal can decrease .OH formation by affecting copper reactivity.
Administration of tumor necrosis factor-alpha in vivo depresses endothelium-dependent relaxation
Authors: Wang P. , Ba Z. F. , Chaudry I. H.
Published: December 2017

Although depressed endothelium-dependent relaxation occurs during early sepsis, the precise mechanism responsible for this remains unknown. Because the elevated levels of plasma tumor necrosis factor (TNF) play a major role in the pathophysiology of sepsis, we investigated whether TNF-alpha administration alters endothelium-dependent relaxation. To study this, recombinant TNF-alpha (1.2 x 10(7) U/mg) was infused intravenously (0.25 mg/kg body wt) for 0.5 h in normal rats, and mean arterial pressure was monitored. At 1 h after the completion of TNF-alpha or vehicle infusion, the aorta and a pulmonary artery were isolated, cut into 2.5-mm rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) M) was applied to achieve near-maximal contraction, and dose responses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were determined. In additional studies, aortic rings from normal animals were incubated with TNF-alpha for 2 h in vitro, and vascular reactivity was determined. The results indicate that TNF-alpha administration significantly reduced acetylcholine-induced vascular relaxation both in vivo and in vitro. Such a reduction was sustained at least 80 min after the completion of 2-h incubation with TNF-alpha. In contrast, TNF did not alter nitroglycerine-induced vascular relaxation. Thus TNF-alpha depresses endothelium-dependent relaxation in vitro as well as in vivo. Because TNF-alpha infusion increases plasma TNF levels without decreasing mean arterial pressure, the depressed endothelium-dependent relaxation observed during early sepsis may be due to the elevated circulating levels of TNF.
Effect of 2,3-butanedione monoxime on myocyte resting force during prolonged metabolic inhibition
Authors: Ikenouchi H. , Zhao L. , Barry W. H.
Published: December 2017

The chemical phosphatase 2,3-butanedione monoxime (BDM) has been reported to inhibit both Ca(2+)-induced myofilament force development and rigor due to ATP depletion. However, during prolonged hypoxia in cultured ventricular myocytes BDM delays but does not prevent a marked increase in resting force. To investigate the mechanisms involved we measured the effects of BDM on intracellular Ca2+ concentration ([Ca2+]i; indo 1), force development (video motion detector), and ATP contents (luciferase assay) in cultured embryonic chick ventricular myocytes and adult rabbit ventricular myocytes subjected to prolonged metabolic inhibition with 1 mM NaCN and 20 mM 2-deoxyglucose. In the absence of metabolic inhibition, 20 mM BDM depressed force development even when [Ca2+]i was markedly elevated by exposure to zero-Na solution or 10 mM caffeine in chick cells, and 30 mM BDM completely inhibited Ca(2+)-induced force development in rabbit myocytes. During metabolic inhibition, 20 mM BDM delayed the onset of an increase in resting force (from 5.44 +/- 0.87 to 13.67 +/- 1.34 min in chick myocytes; from 19.13 +/- 2.23 to 32.43 +/- 3.30 min in rabbit myocytes, means +/- SE, n = 8-9). However, the rates of ATP depletion and rise in [Ca2+]i after metabolic inhibition were not altered by BDM. In the presence of BDM, during prolonged metabolic inhibition in both chick and rabbit myocytes, abrupt spontaneous or evoked alterations in [Ca2+]i were associated with corresponding changes in force. During the initial increase in resting force induced by metabolic inhibition, exposure to BDM caused a partial transient relaxation. We conclude that the delayed increase in resting force during metabolic inhibition in the presence of BDM is due to redevelopment of Ca2+ sensitivity of the myofilaments in the presence of an increased [Ca2+]i as a consequence of severe ATP depletion, whereas in the absence of BDM the more rapidly developing increase in resting force during metabolic inhibition is initially due to a rise in [Ca2+]i followed by development of rigor.
Two ranges in blood pressure power spectrum with different 1/f characteristics
Authors: Wagner C. D. , Persson P. B.
Published: December 2017

Most time series of biological systems contain a considerable amount of 1/f noise. This form of noise is characterized by fluctuations in which power steadily increases at lower frequencies. To determine the origin of 1/f noise, blood pressure (BP) was measured over 4 h in conscious foxhounds. The power spectrum of BP was obtained by fast Fourier analysis. After log-log transformation, the power spectrum (log power vs. log frequency) characteristically revealed a linear regression. Surprisingly, there were two 1/f ranges. The first 1/f region was located within a low-frequency range (< 10(-1.7) Hz; slope -0.9; r = -0.9). The second 1/f range was identified at 10(-1.4) to 10(-1) Hz (slope -1.2; r = -0.7). After baroreceptor denervation (n = 7), the steepness of both slopes increased significantly (P < 0.05 for lower 1/f range, P < 0.001 for higher 1/f range), and the difference in slopes was clearly greater (slope in lower range -1.2; r = 0.96 vs. -3.1, r = -0.92 in the higher range; P < 0.001). Neither alpha-receptor (n = 6) nor beta-receptor blockade (n = 4) considerably changed the slopes after denervation. However, autonomic blockade (n = 5) restored the slope in the low-frequency range (-0.9; r = -0.9). In conclusion, there are two independently modulated 1/f frequency ranges in BP time series. Baroreceptors especially attenuate 1/f noise in the higher frequency range.
Fatty acid, tricarboxylic acid cycle metabolites, and energy metabolism in vascular smooth muscle
Authors: Barron J. T. , Kopp S. J. , Tow J. , Parrillo J. E.
Published: December 2017

The influence of octanoate on O2 consumption, tricarboxylic acid (TCA) cycle intermediates, and high-energy phosphates was examined in intact resting porcine carotid artery to investigate the role of fatty acid in energy metabolism and its integration with glucose metabolism in vascular smooth muscle. Incubation of resting arteries with octanoate (0.5 mM), which was previously shown to inhibit aerobic glycolysis (6), inhibited lactate production by 64% and increased O2 consumption by 30%. The increase in O2 consumption with octanoate was approximately equal to that calculated to account for the ATP production lost by inhibition of aerobic lactate production by octanoate. In glucose-free medium, the level of high-energy phosphate was reduced but was restored when octanoate was included in the incubation medium. This was associated with an increase in O2 consumption. These results suggest that the energy requirements of resting carotid artery can be largely met by the oxidative metabolism of fatty acid. Octanoate induced anaplerosis of the TCA cycle, as indicated by a 70% increase in the level of citrate. Extracellular glucose was necessary for octanoate-induced anaplerosis, probably by providing the extra carbon via pyruvate carboxylation, whereas a coupled transamination involving aspartate was a less important anaplerotic mechanism.
Effect of acute edema on left ventricular function and coronary vascular resistance in the isolated rat heart
Authors: Rubboli A. , Sobotka P. A. , Euler D. E.
Published: December 2017

The impact of acute myocardial edema on coronary flow and left ventricular performance was studied in isolated isovolumic rat hearts. After 15 min of aortic perfusion with Krebs-Henseleit buffer, hearts (10/group) were either removed for determination of water content or perfused for another 90 min. Three groups were perfused at a constant pressure of 60, 100, or 140 mmHg, and two groups were perfused at 60 or 140 mmHg with adenosine added. Compared with the 15-min group, there was a significant increase in water content in all groups except the 60-mmHg group (P < 0.005). There was a direct linear relationship between increases in coronary vascular resistance over time and water content (P < 0.0001). A decrease in developed pressure and peak +dP/dt was observed only in those groups that accumulated water. An inverse linear relationship was found between changes in developed pressure and water content (P = 0.0001). Water content had no effect on end-diastolic pressure below 5 ml/g; above 5 ml/g, a direct linear relationship was evident (P = 0.009). The results suggest that myocardial edema increases vascular resistance and decreases systolic performance. End-diastolic pressure is less influenced by edema than either systolic or coronary vascular function.
Compliance of isolated porcine coronary small arteries and coronary pressure-flow relations
Authors: Giezeman M. J. , VanBavel E. , Grimbergen C. A. , Spaan J. A.
Published: December 2017

Compliance of small arteries is important for the interpretation of arterial pressure-flow relations. Six coronary small arteries (mean diameter 189 +/- 46 microns) were cannulated. Pressure-cross-sectional area (CSA) relations were obtained from isolated vessels by slowly varying pressure between 10 and 120 mmHg. Subsequently, small pressure variations were superimposed on constant mean pressures of 10, 30, and 50 mmHg with frequencies of 0.1-10 Hz. Normalized compliance (C0) was calculated as the compliance divided by the CSA at 50 mmHg. In vessels without tone, static C0 was 27.5 +/- 8.9, 6.4 +/- 1.1, and 3.8 +/- 1.0 x 10(-3) mmHg-1 at 10, 30, and 50 mmHg, respectively. At a frequency of 0.1 Hz, C0 decreased to one-third of static C0 at any pressure. Under these conditions, the phase shift between pressure and CSA was rather constant and ranged from -21 to -5 degrees. In four small arteries, smooth muscle tone was induced by the administration of acetylcholine. Activation decreased dynamic C0 by 60%. Two models of coronary input impedance were evaluated: the first model includes viscoelastic properties of the arterial wall and the second takes into account the blood inertia effect. The second model predicts much better the wall mechanics of single small arteries. The viscoelastic model overestimates the frequency dependence of compliance by a factor of 2 and the phase lag by a factor of 4. Moreover this model predicts a strong frequency dependence of induction of tone on compliance and phase lag, whereas this dependence is absent in the experimental results.
Spontaneous leukocyte rolling in venules in untraumatized skin of conscious and anesthetized animals
Authors: Janssen G. H. , Tangelder G. J. , Oude Egbrink M. G. , Reneman R. S.
Published: December 2017

Intravital bright-field videomicroscopy was used to investigate whether leukocyte rolling can be observed under normal physiological conditions. We studied skin venules in trained conscious rats and anesthetized rats and mice without touching the skin itself. Leukocyte rolling was spontaneously present in all hindpaw venules of Lewis rats (diam 8-27 microns) and also in all mouse ear venules (Swiss, 13-38 microns; BALB/c, 12-56 microns). Rolling levels (in leukocytes/min, median and range) were 8 (3-15) in conscious rats, 9 (3-19) in anesthetized rats, 30 (5-160) in anesthetized Swiss mice, and 10 (3-22) in anesthetized BALB/c mice. These levels appeared to be independent of time. Noninvasive mechanical stimulation induced an average increase of 32%. Fluorescent labeling of leukocytes in vivo with acridine orange had no influence. In Swiss mice, the rolling velocity was < 50 microns/s for > 75% of the leukocytes (median 31 microns/s); this parameter did not correlate with reduced velocity (17-68 s-1) and hence wall shear rate. Our finding that leukocyte rolling is spontaneously present in skin venules of anesthetized and conscious animals suggests a constant vigilance of the host defense mechanisms in the skin.
Hyperperfusion and cardioplegia effects on myocardial high-energy phosphate distribution and energy expenditure
Authors: Zhang J. , Shorr L. , Yoshiyama M. , Merkle H. , Garwood M. , Homans D. C. , Bache R. J. , Ugurbil K. , From A. H.
Published: December 2017

This study examines the hypothesis that high-energy phosphate (HEP) compound levels in unstimulated in vivo myocardium are defined by 1) the level of perfusion and 2) non-perfusion-dependent metabolic characteristics. This hypothesis was tested by determining 1) the effects of pharmacological hyperperfusion of functioning myocardium on transmural HEP compound distribution, contractile function, and myocardial oxygen consumption rate (MVO2) as well as 2) the effect of KCl cardioplegia on transmural myocardial HEP compound distribution. Creatine phosphate (CP) and ATP were measured across the anterior left ventricular wall using spatially localized 31P-nuclear magnetic resonance (NMR). At baseline, the CP-to-ATP (CP/ATP) ratio was significantly lower in the subendocardium than in the subepicardium. This transmural HEP gradient was abolished by hyperperfusion without significant effects on contractile function or MVO2. Similarly, KCl arrest significantly increased CP and CP/ATP in all myocardial layers, and the transmural gradient of CP/ATP was abolished again. These studies indicate that in present experimental model 1) myocardial performance is not constrained by inadequate perfusion in any myocardial layer although modest oxygen limitation affects the kinetics of oxidative phosphorylation in the inner myocardial layers and 2) in all myocardial layers, submaximal activation of intermediary metabolism and oxidative phosphorylation reactions results in lower steady-state CP and higher ADP levels relative to their respective values when energy expenditure is markedly reduced by KCl arrest.
Evaluation of spontaneous baroreflex modulation of sinus node during isometric exercise in healthy humans
Authors: Iellamo F. , Hughson R. L. , Castrucci F. , Legramante J. M. , Raimondi G. , Peruzzi G. , Tallarida G.
Published: December 2017

The purpose of this study was to 1) evaluate the baroreflex (BR) modulation of the sinus node during isometric exercise in humans by analyzing the variations in pulse interval (PI) in response to beat-by-beat spontaneous changes in systolic arterial pressure (SAP), thus avoiding external intervention to alter arterial pressure (AP); and to 2) evaluate the specific influence of muscle chemoreflex on the SAP-PI relationship. Sixteen healthy males were studied during rest, handgrip at 30% of maximum voluntary contraction [isometric handgrip (IHG)], post-IHG arrested forearm circulation (AFC), and recovery. AP and PI were measured continuously and noninvasively. A BR response was defined by series of at least three consecutive beats in which SAP and PI of the following beat either increased or decreased in a linear fashion. In nine subjects, forearm (FVR) and calf vascular resistances (CVR) were determined. Mean slope (by linear regression) of SAP-PI sequences did not significantly differ between rest, IHG, and AFC (14.1 +/- 2.0, 12.2 +/- 1.6, and 13.2 +/- 1.4 ms/mmHg, respectively), i.e., BR sensitivity was unchanged. IHG resulted in a rightward shift of the regression line relating SAP to PI. The shift was maintained during AFC, when PI returned to control and AP fell slightly but remained significantly elevated. CVR, which did not change during IHG, significantly increased during AFC, whereas FVR increased during both IHG and AFC, but not significantly. The data indicate that arterial BR is "reset" to a higher operating point during isometric exercise. Muscle chemoreflex appears to be partially involved in this modification.(ABSTRACT TRUNCATED AT 250 WORDS)
Interleukin-1 enhances beta-responsiveness of cardiac L-type calcium current suppressed by acidosis
Authors: Rozanski G. J. , Witt R. C.
Published: December 2017

Modulation of the beta-adrenergic control of the cardiac L-type Ca2+ current (ICa) by human recombinant interleukin-1 beta (IL-1) was examined in guinea pig ventricular myocytes using the whole cell voltage-clamp technique. ICa was evoked in Cs(+)-loaded myocytes by depolarizing pulses from a holding potential of -40 mV. In the presence of an acidic external solution (pH 5.8), the response of ICa to isoproterenol (Iso; 0.01 and 1 microM) was markedly decreased compared with control myocytes studied at pH 7.4. However, when cells were pretreated with 1 ng/ml IL-1 and then exposed to acid media, beta-responsiveness was significantly increased compared with untreated cells. Despite this effect of IL-1, maximum ICa density with 0.01 and 1 microM Iso was still 51 and 58%, respectively, less than that measured at pH 7.4. The enhanced beta-responsiveness produced by IL-1 was eliminated by adding amiloride to block Na+/H+ exchange or protein kinase C inhibitors staurosporine (10 nM) and calphostin C (50 nM). However, a direct activator of protein kinase C, phorbol 12-myristate 13-acetate, did not mimic the effects of the cytokine. These data demonstrate that IL-1 partially restores the beta-adrenergic control of cardiac Ca2+ channels suppressed under acidic conditions. Moreover, they suggest that IL-1 acts by enhancing Na+/H+ exchange through a second messenger pathway that may involve protein kinase C. These cellular mechanisms may play a role in altering ventricular function during cytokine-mediated inflammatory processes that are initiated by myocardial ischemia.
Flow velocity in the superficial lymphatic network of the mouse tail
Authors: Leu A. J. , Berk D. A. , Yuan F. , Jain R. K.
Published: December 2017

The present study had two goals: 1) to establish an animal model in which a large network of the initial lymphatics of the skin can be investigated in vivo and 2) to measure effective flow velocity (defined as axial component of the flow velocity) in the lymph capillary network of the skin for the first time. A fluorescence microlymphography technique was used to stain the lymph capillaries in the superficial layer of the skin of the nude mouse tail in 10 female animals (mean age 45.8 +/- 2.4 days; mean wt 21.2 +/- 0.8 g). With the use of densitometric image analysis, effective flow velocity along the tail was measured. The network consisted of a honeycomb-like layer of hexagonally shaped meshes that could be stained in all animals. Effective lymph flow velocities were in the range of 1.4-20.4 microns/s with a mean value of 7.7 +/- 5.9 microns/s; median value was 6.2 microns/s (4.5-10.5; 25 and 75% percentiles). This new animal model allows studies of a large network of lymph capillaries in the skin and should provide new insight into the physiology and pathophysiology of the initial lymphatics.
Activation of ATP-sensitive potassium channels lowers threshold for ischemic preconditioning in dogs
Authors: Yao Z. , Gross G. J.
Published: December 2017

The purpose of the present study was to determine whether enhanced activation of myocardial ATP-dependent potassium channels (KATP) with a potassium channel opener, bimakalim, can reduce the time necessary to produce the protective effect of ischemic preconditioning and to determine whether this effect is mediated via accelerating the rate of action potential shortening during preconditioning. Barbital-anesthetized dogs were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 4 h of reperfusion. Ten minutes of preconditioning was found to markedly reduce myocardial infarct size from 30.6 +/- 4.7 to 7.1 +/- 2.6%. Subsequently, it was observed that either 3 min of LAD occlusion or a 3-min intracoronary infusion with 0.3 micrograms/min of bimakalim did not reduce myocardial infarct size. However, intracoronary infusion with bimakalim during the 3-min preconditioning period markedly reduced myocardial infarct size to a similar extent as that of ischemic preconditioning (12.2 +/- 1.9%). In addition, it was observed that bimakalim markedly accelerated the ischemia-induced shortening of the action potential during preconditioning. These results are the first to demonstrate that activation of KATP channels with a potassium channel opener reduces the threshold of time necessary to produce preconditioning in anesthetized dogs. These data also suggest that KATP channel activation may produce this effect by enhancing the rate of ischemic myocardial action potential shortening during preconditioning.
Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms
Authors: McQuillan L. P. , Leung G. K. , Marsden P. A. , Kostyk S. K. , Kourembanas S.
Published: December 2017

Normal blood vessel tone is maintained by a balance of vasoconstrictors and vasodilators produced by endothelial cells in the vasculature. Nitric oxide (NO) is a potent vasodilator that causes vascular smooth muscle cell relaxation by elevating intracellular guanosine 3',5'-cyclic monophosphate (cGMP) levels. The physiological mechanisms regulating NO production in the vasculature are not completely understood. We report here that production of this vasodilator by vascular endothelial cells can be significantly suppressed by hypoxia. Exposing human endothelial cells to low PO2 results in 40–60% reduction in the steady-state mRNA levels of endothelial constitutive NO synthase (eNOS), the major enzyme responsible for NO production in these cells. The lower levels of eNOS mRNA result from decreased transcription of the gene as well as reduced message stability. In endothelial-smooth muscle cell co-culture experiments, hypoxic endothelial cells stimulated significantly less cGMP production by smooth muscle cells than the corresponding normoxic controls. This inhibitory effect of hypoxia on NOS production by endothelial cells occurs after 24 h of hypoxia and persists for at least 48 h. These new findings suggest that hypoxia might cause changes in blood vessel tone through compound mechanisms: by increasing the production of endothelium-derived vasoconstrictors and, as shown here, by suppressing the production of vasodilators like NO.
Cerebral blood flow and oxygen delivery during hypoxemia and hemodilution: role of arterial oxygen content
Authors: Todd M. M. , Wu B. , Maktabi M. , Hindman B. J. , Warner D. S.
Published: December 2017

To determine the role of arterial O2 content (CaO2) in the cerebral blood flow (CBF) responses to hypoxemia and hemodilution, CaO2 was progressively reduced from approximately 18 to approximately 6 ml O2/dl in normocapnic, normothermic, pentobarbital-anesthetized rabbits. This was done either by reducing PaO2 (hypoxemia, minimum PaO2 approximately 26 mmHg) or arterial hematocrit (isovolemic hemodilution with hetastarch, minimum hematocrit approximately 14%) while CBF was measured with radioactive microspheres. As CaO2 decreased, CBF increased in both groups but was greater in hypoxemic animals at CaO2 values < or = 9 ml O2/dl. For example, at a CaO2 approximately 6 ml O2/dl, CBF in hypoxemic animals was 110 +/- 38 ml.100 g-1.min-1 (means +/- SD) compared with 82 +/- 22 ml.100 g-1.min-1 in hemodiluted animals (means +/- SD). While calculated cerebral O2 delivery (cerebral DO2) was well maintained in hypoxemic animals, it decreased significantly during hemodilution (from 7.95 +/- 2.92 baseline to 5.08 +/- 1.10 ml O2/dl.100 g-1.min-1 at the lowest CaO2 value). This decrease in cerebral DO2 was offset by an increase in oxygen extraction ratio during hemodilution. By contrast, the small increase in oxygen extraction ratio seen with hypoxemia did not achieve significance. These results suggest that there are different adaptive responses to acute hypoxemia or hemodilution . They also imply that at similar CBF and CaO2 values, tissue O2 availability may be greater during hemodilution than during hypoxemia.
Gender difference in bioassayable endothelium-derived nitric oxide from isolated rat aortae
Authors: Kauser K. , Rubanyi G. M.
Published: December 2017

Gender differences in the production/release of endothelium-derived nitric oxide (EDNO) was assessed by determining the ability of intact endothelium to suppress serotonin- (10(-7)-10(-5) M) and phenylephrine-induced (10(-9)-(10(-5) M) contractions in thoracic aortae isolated from male and female Wistar rats mounted in organ chambers for isometric tension recording or tested in bioassay experiments. The endothelium suppressed these contractions significantly more in aortae from female than from male rats. In the bioassay, the perfusate from intact female thoracic aortic segments produced a significantly greater relaxation of the detector rings than that from the aortae isolated from male rats. Acetylcholine (10(-9)-10(-5) M), used to investigate agonist-induced release of EDNO, evoked significantly greater endothelium-dependent relaxation in aortae from female rats. The unstimulated release of 6-ketoprostaglandin F1 alpha and thromboxane B2 from intact thoracic aortic rings from male and female rats was not significantly different. There was no difference in smooth muscle reactivity to sodium nitroprusside (10(-10)-10(-6) M) in rings without endothelium. These results indicate that EDNO production/release is higher in thoracic aortae isolated from female rats.