bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulation of vascular Na(+)-K(+)-ATPase activity by nitric oxide: a cGMP-independent effect
Authors: Gupta S. , McArthur C. , Grady C. , Ruderman N. B.
Published: December 2017

An endothelium-derived factor with the properties of nitric oxide (NO) has been implicated in the regulation of Na(+)-K(+)-adenosinetriphosphatase (ATPase) activity in vascular smooth muscle. To examine this phenomenon further and to explore its modulation by guanosine 3',5'-cyclic monophosphate (cGMP), studies were carried out in the isolated rabbit aorta. Incubation of endothelium-denuded rings with NO (1 microM) or sodium nitroprusside (SNP, 10 microM) caused a time-dependent increase in ouabain-sensitive (OS) 86Rb uptake with the maximal stimulation (approximately 170%) seen after 20 min. In contrast, increases in cGMP concentration caused by NO and SNP (40- and 20-fold increases, respectively) were transient, with peak values observed after 2 min and significantly lower values by 10 min. The ability of NO or SNP to increase OS Rb uptake in endothelium-denuded rings was not mimicked by incubation with 8-bromo- or dibutyryl-cGMP or increases in cGMP caused by treatment with the phosphodiesterase inhibitor isobutylmethylxanthine. Depletion of intracellular cGMP levels by the guanylate cyclase inhibitor LY83583 also did not alter OS Rb uptake. SNP-stimulated OS Rb uptake was not inhibited by LY83583 in endothelium-denuded rings; however, it was completely prevented by the Na(+)-H+ exchange inhibitors amiloride and ethylisopropylamiloride. The results suggest that NO stimulates Na(+)-K(+)-ATPase activity in rabbit aorta by a mechanism independent of its ability to increase the intracellular cGMP concentration. They also suggest that NO may stimulate Na(+)-K(+)-ATPase activity secondary to increases in Na(+)-H+ exchange.
Effects of aging on induction of cardiocyte growth by extracardiac factors
Authors: Komatsu M. , Isoyama S. , Takishima T.
Published: December 2017

To examine the effect of aging on the induction of cardiac myocyte growth by extracardiac factors, we cultured myocytes obtained from neonates of the same litter and implanted them into the peritoneal cavity of developmental phase (2-mo-old), young adult (7-mo-old), and aged (18-mo-old) host Wistar rats. Hearts obtained from 2- to 4-day-old neonates were dissociated with gentle trypsinization, and cells were seeded in culture wells and inserts. The culture insert (9 mm in diam) has a thin membrane the pore size of which is 0.45 microns. After 24 h of usual extracorporeal incubation in the serum-supplemented medium, the inserts were implanted into the peritoneal cavity of the host rats of the three age groups. Zero, 24, 72, and 96 h after implantation into the peritoneal cavity, the inserts were removed from the peritoneal cavity. Surface area of plated myocytes, diameter, number, protein, and DNA content of the suspended cells were measured. Size, protein content per cell, and protein per DNA of cells implanted into the peritoneal cavity were significantly greater than those cultured in the usual extracorporeal method. Growth of the myocytes cultured in the peritoneal cavity of aged host rats was significantly less compared with that of myocytes implanted in the peritoneal cavity of younger rats. Thus aging attenuates the induction of cardiac myocyte growth by extracardiac factors.
Microvascular oxidative stress preceding leukocyte activation elicited by in vivo nitric oxide suppression
Authors: Suematsu M. , Tamatani T. , Delano F. A. , Miyasaka M. , Forrest M. , Suzuki H. , Schmid-Schonbein G. W.
Published: December 2017

This study was aimed to determine the mechanism by which endogenous nitric oxide suppression promotes leukocyte adhesion in vivo. The rat mesenteric microcirculation was superfused with NG-nitro-L-arginine methyl ester (L-NAME; 100 microM), and intracellular oxidant formation in several microcirculatory cellular components such as arteriolar and venular endothelium and mast cells was visually monitored by digital microfluorography assisted by carboxydichlorofluorescein (CDCF), a hydroperoxide-sensitive fluorogenic probe. Adherent leukocyte density was measured simultaneously. L-NAME induced a significant time-dependent increase in CDCF fluorescence in arteriolar and venular endothelium and mast cells followed by firm adhesion of leukocytes. L-NAME-induced CDCF elevation showed a different spatial distribution compared with that evoked by N-formylmethionyl-leucyl-phenylalanine, in which only local venular segments with adhering leukocytes exhibited CDCF fluorescence enhancement. The level of hydroperoxide formation in arterioles and venules evoked by 60-min L-NAME superfusion was equivalent to that induced by the superfusion of approximately 880 microM tert-butyl hydroperoxide for 10 min. Pretreatment with anti-intracellular adhesion molecule-1, anti-P-selectin, or anti-CD18 monoclonal antibody attenuated L-NAME-elicited venular leukocyte adhesion without abolishing CDCF fluorescence in situ. Pretreatment with desferioxamine (50 mg/kg iv; 1 h before L-NAME superfusion) significantly diminished the iron-catalyzed hydroperoxide formation in arterioles and venules, but not in interstitial mast cells, as well as subsequent venular leukocyte adhesion. These findings indicate that endogenous nitric oxide may modulate oxidative stress in mast cells, arteriolar and venular microvascular endothelium and thereby can play a crucial role in leukocyte recruitment in venules.
Analysis of responses to bradykinin and influence of HOE 140 in the isolated perfused rat lung
Authors: Nossaman B. D. , Feng C. J. , Kadowitz P. J.
Published: December 2017

The inhibitory effects of HOE 140, a novel bradykinin B2 receptor antagonist, on pulmonary vascular and airway responses to bradykinin (BK) were investigated under conditions of controlled pulmonary blood flow and ventilation and constant left atrial pressure in the isolated blood-perfused rat lung. Under baseline conditions, BK produced dose-related increases in pulmonary arterial perfusion pressure without changing airway pressure. However, when pulmonary arterial pressure was raised to a high steady level, increases in pulmonary arterial pressure in response to BK were enhanced and BK then produced dose-related increases in airway pressure. Responses to BK were reproducible with respect to time and were not different when the inspired fraction of O2 was 0.21 or 0.95 and HOE 140 was 0.8 nM/ml (50 micrograms/kg) and decreased both pulmonary vascular and airway responses to the peptide. HOE 140 had no significant effect on pulmonary vascular responses to angiotensin II, serotonin, nitric oxide, sodium nitroprusside, albuterol, or pinacidil. Additionally, in these experiments, HOE 140 had no effect on the pulmonary arterial pressor response to ventilatory hypoxia. These results suggest BK has significant vasoconstrictor and bronchoconstrictor effects that are mediated by B2 receptors and are dependent on the baseline level of tone in the airways and in the pulmonary vascular bed. The present results suggest that HOE 140 is a highly selective, BK B2 receptor antagonist in the pulmonary vascular bed of the rat. These data also suggest that HOE 140 may be a useful probe for studying the role of BK in the pulmonary vascular bed in physiological and pathophysiological conditions.
Role of endogenous atrial natriuretic peptide on systemic and renal hemodynamics in heart failure rats
Authors: Nishikimi T. , Miura K. , Minamino N. , Takeuchi K. , Takeda T.
Published: December 2017

To investigate the role of endogenous atrial natriuretic peptide (ANP) in rats with heart failure (HF), we administered HS-142-1 (HS; 3 mg/kg body wt iv), a novel nonpeptide ANP-receptor antagonist, to rats with surgically induced myocardial infarction and sham-operated rats. HF was characterized by a higher left ventricular end-diastolic pressure and higher plasma ANP concentration vs. controls. HS administration significantly reduced the plasma and urinary levels of guanosine 3',5'-cyclic monophosphate in rats with HF [plasma concentration 10.6 +/- 2.6 vs. 2.7 +/- 0.4 nM (P < 0.05); urinary excretion 48 +/- 8 vs. 12 +/- 2 pmol/min (P < 0.05)]. Systemic and renal hemodynamics were unaffected by HS administration. Urine flow (-35%) and urinary sodium excretion (-50%) were significantly decreased after HS only in those rats with HF that had no changes in systemic and renal hemodynamics. These results suggest that the elevated ANP levels in HF do not contribute directly to the maintenance of systemic hemodynamics but rather compensate for the HF mainly via diuresis and natriuresis, achieved by the inhibition of renal tubular reabsorption rather than by renal vasodilatation.
Myogenic activation of canine small renal arteries after nonchemical removal of the endothelium
Authors: Liu Y. , Harder D. R. , Lombard J. H.
Published: December 2017

Myogenic activation of isolated small arteries (200-500 microns) of the dog kidney was evaluated by measuring vessel diameters during stepwise elevations of transmural pressure before and after removal of the endothelium by mechanical rubbing or air perfusion. Myogenic activation was unaffected by mechanical rubbing, but air perfusion caused the arteries to constrict and attenuated the myogenic response; i.e., vessel diameters increased as transmural pressure was elevated. However, air-perfused arteries still constricted in response to norepinephrine and dilated during superfusion with Ca(2+)-free solution, demonstrating that loss of the myogenic response did not result from an inability of the vessel to contract. Intact arteries contracted with 1 microM norepinephrine exhibited normal myogenic responses, demonstrating that loss of myogenic activation in the air-perfused vessels was not a nonspecific effect secondary to constriction of the artery. These results suggest that myogenic activation of small renal arteries is independent of the endothelium and that the method of endothelial removal may affect conclusions regarding the role of the endothelium in mediating the myogenic response.
Refractory period response of cardiac Purkinje tissue to alpha 1- and alpha 2-adrenergic influences
Authors: Cable D. G. , Rath T. E. , Dreyer E. R. , Martins J. B.
Published: December 2017

Our purpose was to characterize Purkinje responses in vivo to alpha 1- and alpha 2-adrenergic stimulation in sinoaortically denervated and vagotomized dogs pretreated with metoprolol (1 mg/kg). We measured Purkinje relative refractory period (PRRP) responses to norepinephrine (NE) and phenylephrine (PE) with prazosin and/or yohimbine, WB-4101, and chloralethylclonidine (CEC) in varying doses. Results were as follows: PE infusion (25 micrograms.kg-1.min-1) prolonged PRRP (9.6 +/- 1.4 ms; a 4.1 +/- 0.4% change). Prazosin blocked PRRP prolongation with PE at 7 x 10(-8) M/kg (P < 0.05). Yohimbine did not attenuate PRRP prolongation with PE either alone or in combination with prazosin. NE infusion (0.8 micrograms.kg-1.min-1) also prolonged PRRP (9.2 +/- 2.3 ms; a 4.8 +/- 1.0% change). In contrast neither prazosin nor yohimbine at any dose (up to 10(-6) M/kg) totally blocked the prolongation with NE infusion. However, with prazosin (2 x 10(-7) M/kg) pretreatment, yohimbine blocked PRRP prolongation, significant at 7 x 10(-8) M/kg (P < 0.05). In separate experiments with yohimbine pretreatment at 7 x 10(-8) M/kg, PRRP prolongation with either PE or NE infusion was blocked equipotently with WB-4101 and CEC at 7 x 10(-8) M/kg. However, CEC did not block mean arterial pressure (MAP) responses to PE or NE infusion unlike WB-4101. We concluded that both subclasses of alpha 1-adrenergic antagonists equipotently block PRRP prolongation by alpha-agonists despite different effects on MAP. Purkinje refractoriness is also prolonged by alpha 2-adrenergic stimulation acting at the cell membrane.
Hemodynamic analysis of arterial pressure lability in sympathectomized rat
Authors: Zhang Z. Q. , Julien C. , Gustin M. P. , Cerutti C. , Barres C.
Published: December 2017

Male Sprague-Dawley rats, treated with either saline (n = 14) or guanethidine (n = 12) from 1 to 13 wk of age, were instrumented for the measurement of mean arterial pressure (MAP) and indexes of regional blood flows (pulsed Doppler flow probes) in the subdiaphragmatic aorta, superior mesenteric artery, and distal aorta (hindquarters). Hemodynamic parameters were simultaneously recorded in the conscious rats on a beat-to-beat basis by a computer. Chronic sympathectomy did not change the MAP level but nearly doubled its spontaneous variability, mainly due to large decreases in MAP associated with regional vasodilations that were slightly delayed with respect to the onset of the decreases in pressure, especially in the aortic and mesenteric circulations. In the hindquarters vascular bed, the onset of vasodilations sometimes coincided with the onset of the decreases in MAP. During depressor episodes, blood flow varied little (aortic and mesenteric circulations) or even increased (hindquarters). This hemodynamic pattern was not affected by acute beta-adrenoceptor blockade. We conclude that chronic sympathectomy sensitizes the cardiovascular system to decreases in arterial pressure mainly by unmasking local autoregulatory responses of regional circulations. The sympathetic control of vascular tone overrides these responses and considerably limits the MAP variability.
Influence of atrial natriuretic factor on heart rate variability in normal men
Authors: Butler G. C. , Senn B. L. , Floras J. S.
Published: December 2017

To study the effects of atrial natriuretic factor (ANF) on sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) control of heart rate, we gave ANF (50 micrograms over 3 min, then 50 ng.kg-1.min-1) and saline (vehicle) to six normal men [age 22 +/- 2 (SE) yr] during supine rest on two separate study days according to a random double-blind design. R-R interval data were sampled at 1,000 Hz over 7-min time segments, then analyzed by coarse graining spectral analysis of heart rate variability (HRV) to yield indicators of PNS and SNS activity. From the harmonic component of HRV, the integrated power in the low-frequency region (0.0–0.15 Hz, PL) and in the high-frequency region (0.15–0.50 Hz, PH) were calculated. Total spectral power (PT) was obtained and used to normalize the PNS indicator as PH/PT. The quantity PL/PH was taken as an indicator of SNS activity. By the 20th min of its infusion, ANF lowered PT, PH, and the SNS indicator (4.20 +/- 1.9 to 2.37 +/- 0.65; P < 0.05) but did not significantly change the PNS indicator (PH/PT). In contrast, 20-min saline infusion had no effect on these variables. These observations are consistent with our previous documentation of a relative sympathoinhibitory action of ANF on muscle sympathetic nerve activity and support the concept that ANF acts on the autonomic nervous system to decrease sympathetic outflow.
Changes in regional vascular capacitance during prostacyclin-induced cardiac vagal reflex in pigs
Authors: Wang Y. , Drakonakis C. , Alderman J. L. , Rutlen D. L.
Published: December 2017

The purpose of this study was to determine the effects of the prostaglandin I2 (prostacyclin; PGI2)-induced cardiac vagal reflex on intestinal and liver blood volumes and the intestinal vascular pressure-volume (P-V) relationship. In anesthetized pigs, blood volumes were measured by blood-pool scintigraphy. Portal venous pressure was varied by graded inflation of a portal vein constrictor to determine the intestinal vascular P-V relationship. Proximal right coronary infusion of PGI2 at a rate of 0.15 micrograms.kg-1.min-1 for 6 min increased intestinal blood volume by 7.0 +/- 1.2% (P < 0.01, means +/- SE) and shifted the intestinal vascular P-V relationship away from the pressure axis (i.e., a volume increase at a given venous pressure). This change was associated with decreases in liver blood volume and left ventricular end-diastolic pressure by 4.5 +/- 1.2 (P < 0.01) and 17 +/- 2% (P < 0.05), respectively. PGI2 also reduced central venous pressure by 16 +/- 2% from 3.2 +/- 0.5 mmHg (P < 0.05) and portal venous pressure by 7.0 +/- 0.6% from 7.6 +/- 0.6 mmHg (P < 0.05). These responses were abolished by bilateral vagotomy. The results demonstrate that intracoronary PGI2 infusion increases intestinal blood volume. This increase is mediated by a cardiac vagal reflex. The PGI2-induced shift in the intestinal vascular P-V relationship suggests that intestinal blood volume increases by an active change in vascular capacitance, whereas reductions in liver blood volume and left ventricular end-diastolic pressure appear to be due to passive mechanisms related to the shift of blood volume to the intestinal circulation.
Polyamine effects on [Ca2+]i homeostasis and contractility in isolated rat ventricular cardiomyocytes
Authors: Ventura C. , Ferroni C. , Flamigni F. , Stefanelli C. , Capogrossi M. C.
Published: December 2017

In electrically stimulated myocytes loaded with the fluorescent Ca2+ indicator indo 1-acetoxymethyl ester, spermine induced a dose-dependent (100–500 microM) negative inotropic effect, which was associated with a decrease in the magnitude of the cytosolic Ca2+ concentration ([Ca2+]i) transient but not with changes in myofilament responsiveness to Ca2+. Spermidine induced a less pronounced negative inotropic effect, whereas putrescine did not modify myocyte contraction. In the unstimulated state, spermine did not alter resting [Ca2+]i. Superfusion of the cardiac myocytes with 10 mM alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, did not modify cellular responses to isoproterenol (10(-9)-10(-7) M). beta-Adrenergic stimulation did not affect either ornithine decarboxylase activity or intracellular polyamine levels within a 10-s to 15-min period of treatment. In summary, only exogenously administered polyamines were able to influence myocyte contractility. Their negative inotropic effect resulted from changes in [Ca2+]i homeostasis and required cellular depolarization.
Ratiometric methodology for NAD(P)H measurement in the perfused rat heart using surface fluorescence
Authors: Scott D. A. , Grotyohann L. W. , Cheung J. Y. , Scaduto R. C.
Published: December 2017

The surface fluorescence of the isolated perfused rat heart has been evaluated for the purpose of NAD(P)H quantitation. With the use of excitation at 340, 380, 415, and 430 nm with emission detection at 500 +/- 20 nm, the intensities at 340 and 380 nm excitation were found to be linearly related during NAD(P)H oxidation/reduction induced by changes in substrate availability. Changes in cardiac NAD(P)H caused similar changes at 340 and 380 nm excitation, but those at 340 nm were of greater magnitude. Isolated cardiac mitochondria exhibited essentially identical optical properties during changes in NAD(P)H content induced by changes in substrate availability and by NAD(H) oxidation/reduction caused by coupled phosphorylation of ADP. The changes in redox status of both isolated mitochondria and the intact perfused heart can be expressed by a 340/380 excitation fluorescence ratio because of these relationships. This value assumed a minimum and maximum value under conditions of complete oxidation and reduction, respectively. Use of this ratio in the perfused heart avoids the artifacts caused by cardiac motion and tissue stretch. Removal of motion artifacts with an excitation ratio could only be accomplished if the measurements at 340 and 380 nm were estimated at the same point in the cardiac cycle. A method of cardiac waveform reconstruction and signal averaging is described to obtain these data from sequential measurements. With these techniques, the reduction of cardiac NAD(P)H can be expressed as a percentage of the range obtained between minimum and maximum reduction. The described technique is of general utility in the assessment of cardiac bioenergetics.
Reflex stimulation of cardiac sympathetic nerve activity during static muscle contraction in cats
Authors: Matsukawa K. , Wall P. T. , Wilson L. B. , Mitchell J. H.
Published: December 2017

Reflex response of cardiac sympathetic nerve activity (CSNA) during static contraction of the triceps surae muscle was studied using anesthetized cats. A 1-min contraction was evoked by stimulating the peripheral ends of the cut L7 and S1 ventral roots. CSNA increased 48 +/- 13% immediately after the onset of contraction, which was abolished by cutting the L4-S1 dorsal roots. This rapid increase in CSNA preceded rises in heart rate (13 +/- 1 beats/min) and arterial blood pressure (33 +/- 6 mmHg). When tension development was altered by changing the frequency of ventral root stimulation or the initial muscle length, the CSNA increase depended on the tension developed. Passive stretch of the muscle, which primarily activates mechanoreceptors, increased CSNA by 41 +/- 22%. When the contraction was sustained for 5 min, CSNA remained elevated throughout the contraction despite a fall in tension, suggesting that the later increase in CSNA is caused by factors other than a mechanical event of contraction (e.g., metabolic products). Thus it is suggested that cardiac sympathetic outflow is stimulated due to a reflex arising from the contracting muscle. The increase in CSNA at the initiation of contraction is likely to be caused by a reflex from muscle mechanoreceptors, which is followed by a subsequent increase due to a reflex from muscle metaboreceptors.
Geometry of coronary capillaries in hyperthyroid and hypothyroid rat heart
Authors: Heron M. I. , Rakusan K.
Published: December 2017

Coronary capillary geometry was studied in male rats treated with 3,3',5-triiodo-L-thyronine (T3; Hyper), 6-N-propyl-2-thiouracil (PTU; Hypo), or a sequence of PTU and T3 (Hypo/Hyper). Ventricular mass and heart-to-body mass ratios revealed myocardial hypertrophy in Hyper, atrophy in Hypo, and a return of ventricular mass to control (Con) values in Hypo/Hyper rats. From cross-sectional analysis, capillary densities for Hyper and Hypo/Hyper were comparable with Con, despite increased left ventricular mass. Hypo rats demonstrated increased capillary density. In Hyper and Hypo rats, tissue area surrounding individual capillaries (capillary domain) decreased, compared with Con, for capillaries close to the feeding arteriole. In Hyper and Hypo/Hyper, capillaries distal to the feeding arteriole had similar domain areas as Con; in Hypo, this area was smaller. From longitudinal analysis, capillary segment lengths were significantly shorter in all groups compared with Con. Our data suggest that while hypothyroidism induced myocardial atrophy and hyperthyroidism induced myocardial hypertrophy, both thyroid states stimulated capillary proliferation.
Venous return in lower limb during heat stress
Authors: Abraham P. , Leftheriotis G. , Desvaux B. , Saumet M. , Saumet J. L.
Published: December 2017

We used ultrasound to study venous return during heat stress. We measured venous cross-sectional area (CSA) and blood flow velocity (BFV) of nine femoral veins and nine saphenous veins. During heat stress, saphenous CSA increased from 4.7 +/- 2.6 mm2 (mean +/- SD) to 9.1 +/- 2.3 mm2 (P < 0.01), whereas femoral CSA was 22.7 +/- 9.5 mm2 at rest and 22.0 +/- 9.6 mm2 during heat stress (NS). Meanwhile, BFV increased from 0.06 +/- 0.02 to 0.30 +/- 0.10 m/s (P < 0.01) in the saphenous vein and from 0.14 +/- 0.08 to 0.38 +/- 0.23 m/s (P < 0.005) in the femoral vein. Maximal venous outflow (MVO) was the product of CSA and BFV. During heat stress, MVO showed an eightfold increase in the saphenous veins (from 22.7 +/- 18.2 to 180.7 +/- 86.7 ml/min) and a 2.5-fold increase in the femoral veins (from 143.4 +/- 52.9 to 354.0 +/- 126.9 ml/min). The results showed that one-half of the cutaneous blood flow increase during heat stress returned through the deep collecting veins in the lower limb. Thereafter, although there was no venodilation of deep veins compared with superficial veins, the deep veins remain the main pathway for the venous return during heat stress.
Sympathetic activation decreases medium-sized arterial compliance in humans
Authors: Boutouyrie P. , Lacolley P. , Girerd X. , Beck L. , Safar M. , Laurent S.
Published: December 2017

This study used a precise noninvasive method in normotensive humans to determine the effects of sympathetic activation on arterial compliance. A recently developed, high-resolution echo-tracking system capable of measuring systolic/diastolic variations of arterial diameter was coupled to a Finapres system and used to calculate instantaneous systolic/diastolic pressure-diameter and compliance-pressure curves for a muscular medium-sized artery, the radial artery. Two standardized tests of sympathetic system activation, a cold pressor test (2 min) and a mental stress test (2 min of mental arithmetic), were performed at an interval of 8 days in random order in nine healthy volunteers [30 +/- 9 (SD) yr]. Radial arterial parameters were recorded every 30 s for 9 min, which included 2 min of cold pressor test or mental stress test. During both tests, radial arterial mean diameter did not change despite t he increase in mean arterial pressure (P < 0.001); stroke change in diameter decreased (P < 0.01), whereas pulse pressure increased (P < 0.01). Arterial compliance, calculated for the instantaneous level of mean arterial pressure, decreased significantly (P < 0.01). Compliance (C) calculated at 100 mmHg (C100) was arbitrarily chosen as a reference point for comparing compliance among the different periods of the test. C100 decreased significant (P < 0.05) during both tests (from 2.93 +/- 1.27 to 2.04 +/- 0.94 and from 3.29 +/- 1.73 to 2.63 +/- 1.55 mm2.mmHg-1.10(-3) during mental stress and the cold pressor test, respectively). These results indicate that sympathetic activation is able to decrease radial arterial compliance in healthy subjects. The reduction in arterial compliance probably resulted from complex interactions between changes in distending blood pressure and changes in radial arterial smooth muscle tone.
Evidence of low- and high-frequency oscillations in human AV interval variability: evaluation with spectral analysis
Authors: Nollo G. , Del Greco M. , Ravelli F. , Disertori M.
Published: December 2017

The spontaneous beat-to-beat variation of atrioventricular (AV) interval was analyzed in time and frequency domains and compared with atrial cycle length (A-A) variability. The analysis was applied in humans at rest and tilt position during sinus rhythm and atrial pacing. The AV intervals showed spontaneous oscillations of small amplitude with a relative standard deviation of 1.8%. Spectral analysis of AV interval series showed the existence of two main oscillatory components at low frequency (LF; 0.04-0.13 Hz) and at high frequency (HF; 0.17-0.4 Hz), synchronous with those of A-A interval series. The same LF and HF fluctuations were found in AV interval variability during atrial pacing. Tilt maneuver inducing a sympathetic stimulation and vagal withdrawal increased LF power and decreased HF power of A-A interval spectra (P < 0.05). On the contrary, tilt decreased the LF (46%, P < 0.05) and HF power (29%, P = NS) of AV conduction spectra. In parallel, tilt decreased (P < 0.0001) the mean A-A interval, leaving the mean AV interval unchanged. When heart rate was held constant by atrial pacing, tilt reduced the mean AV interval, the LF power (65%, P < 0.05), and HF power (10%, P = NS). These results indicate a direct influence of the autonomic nervous system on the LF and HF oscillations of AV conduction. The decrease of AV interval oscillations during tilt demonstrates a marked reduction of autonomic modulation of AV conduction mainly attributable to parasympathetic withdrawal.
Modulation of leukocyte migration in mesenteric interstitium
Authors: Bienvenu K. , Harris N. , Granger D. N.
Published: December 2017

Intravital videomicroscopy was used to monitor the migration of leukocytes in rat mesenteric interstitium following exposure of the mesentery to either N-formylmethionyl-leucyl-phenylalanine (FMLP), leukotriene B4 (LTB4), platelet-activating factor (PAF), or ischemia-reperfusion (I-R). All inflammatory stimuli resulted in interstitial migration rates that were higher than those measured in unstimulated extravasated leukocytes. The median migration rate of cells stimulated with FMLP was significantly higher than those observed during superfusion with either LTB4 or PAF or following exposure to I-R. The enhanced leukocyte migration rates elicited by I-R were not attenuated by treatment with PAF- and LTB4-receptor antagonists, suggesting that these lipid mediators are not the inflammatory mediators responsible for I-R-induced leukocyte migration. Additional experiments revealed that the rate of leukocyte migration associated with FMLP stimulation was not significantly altered by either inhibitors of neutrophilic elastase and cathepsin G, a monoclonal antibody directed against the leukocyte adhesion glycoprotein CD11/CD18, or by altering interstitial hydration. This in vivo model provides a useful new approach for defining the factors that modulate leukocyte migration within the extravascular compartment.
Diminished heat shock protein 70 mRNA induction in aged rat hearts after ischemia
Authors: Nitta Y. , Abe K. , Aoki M. , Ohno I. , Isoyama S.
Published: December 2017

Vulnerability of aged hearts to ischemia may be due to defects in protective mechanisms provided by heat shock proteins (HSPs). To determine whether there is a defect in the induction of HSPs by ischemia in old hearts, HSP72 and HSP73 (inducible and constitutive HSP70, respectively) mRNA induction was examined in young (2-mo-old; n = 36) and old (18-mo-old; n = 32) rat hearts. Transient (10- or 20-min) ischemia was applied by tightening a snare placed around left coronary arterial branches 3 days before examination to avoid the effect of operation on induction. HSP72 mRNA was induced markedly in young hearts after 10-min ischemia, peaked at 2 h, but was induced only slightly in old hearts. HSP73 mRNA was also induced in young hearts, peaked at 4 h, but was not induced in old hearts. The mRNAs were markedly induced in old hearts as well after 20-min ischemia, which was accompanied by the induction of HSP72 protein. Thus the age-related modulation of HSP72 and HSP73 mRNAs suggests a defective sensing mechanism for ischemia in old hearts.
Measurement of aortic input impedance in rats
Authors: Mitchell G. F. , Pfeffer M. A. , Westerhof N. , Pfeffer J. M.
Published: December 2017

Measurement of aortic input impedance in the rat is complicated by a high basal heart rate but is possible if appropriate compensation is made for frequency-dependent errors in modulus and phase resulting from analog filters in the equipment and from nonalignment of pressure and flow sensors. Because input impedance is a complex quantity, accurate values for both phase and modulus are required before meaningful interpretation of the data can be made. We measured aortic pressure and electromagnetic ascending aortic blood flow in mature, ether-anesthetized, open-chest male Wistar rats. Pressure and flow waveforms were averaged in the time domain and converted to Fourier series. Flow moduli were corrected for the measured frequency response of the flowmeter. Phase spectra were corrected by the classic frequency-domain and two new time-domain methods. Compensation for instrumentation errors was assessed at two different flowmeter filter settings in five animals. Reproducibility, variability, and the effects of vasoconstriction were assessed in 43 animals. Three methods of estimating characteristic impedance from the impedance spectra were evaluated and found to produce comparable results at baseline and following pharmacological elevation of blood pressure with graded methoxamine infusion. Physiologically equivalent values for phase, as assessed by comparing oscillatory power calculated from the impedance spectra, were obtained with each of the phase-correction techniques. The new time-domain methods facilitate the assessment of aortic input impedance in this small animal model because they do not require measurement of the spatial separation between pressure and flow transducers and pulse wave velocity in the proximal aorta.
Ontogeny of NO activity and response to inhaled NO in the developing ovine pulmonary circulation
Authors: Kinsella J. P. , Ivy D. D. , Abman S. H.
Published: December 2017

To determine maturation-related changes in nitric oxide (NO) activity in the developing pulmonary circulation, we studied the hemodynamic effects of endogenous NO inhibition under basal conditions in the premature ovine fetus and the response to birth-related stimuli and exogenous NO in 30 fetal sheep at three different gestational ages. At 0.95 term, pulmonary vasodilation during inhaled NO (20 parts per million) was equivalent to the dilator response to 100% O2, but at 0.86 term vasodilation during inhaled NO was greater than the dilator response to 100% O2 (P < 0.05). At 0.78 term, left pulmonary arterial flow (QLPA) did not increase with exposure to either NO or 100% O2. Intrapulmonary infusion of nitro-L-arginine (L-NA) increased basal pulmonary vascular resistance 38% in the premature fetus at 0.78 term. L-NA treatment decreased the ventilation-induced rise in QLPA by 60% compared with controls (P < 0.05). Inhaled NO but not 100% O2 increased QLPA after L-NA treatment to levels achieved with ventilation alone in the controls. We conclude that in the premature pulmonary circulation (0.78 term) 1) basal pulmonary vascular resistance is modulated by endogenous NO, 2) pulmonary vasodilation at birth is partly mediated by endogenous NO activity, and 3) inhaled NO causes potent vasodilation.
CPT-1 inhibition by etomoxir has a chamber-related action on cardiac sarcoplasmic reticulum and isomyosins
Authors: Vetter R. , Rupp H.
Published: December 2017

To characterize the effect of an altered substrate utilization for cardiac sarcoplasmic reticulum (SR) Ca2+ transport, normotensive rats were treated for 5 wk with 15 mg.kg-1.day-1 enantiomeric etomoxir, which inhibits mitochondrial carnitine palmitoyltransferase-1 (CPT-1) and fatty acid synthesis. Ca2+ uptake rates of left and right ventricular homogenates were differentially (P < 0.05, two-way analysis of variance) increased by 38 and 13%, respectively. Increased (P < 0.05) transport rates were also observed in the presence of ryanodine. The differences were considerably reduced in the protein kinase A-stimulated state. The levels of phosphorylated phospholamban (PLB) and troponin I as well as immunoreactive PLB were not affected. By contrast, phosphoenzyme levels (E-P) of the SR Ca2+ pump were increased in left ventricular (LV) homogenates. Values of LV E-P and Ca2+ uptake were linearly correlated (P < 0.05) with the myosin V1 proportions in control (31.7 +/- 1.8% V1) and treated (58.3 +/- 2.5% V1) rats. Thus in the left ventricle the metabolic influences have a coordinated action on two distinct proteins involved in relaxation or contraction. The chamber-specific differences in SR function suggest a more pronounced effect of etomoxir in functional states characterized by a reduced Ca2+ transport rate and myosin V1 proportion.
Transient blood-brain barrier passage of polar compounds at low pH
Authors: Oldendorf W. H. , Stoller B. E. , Tishler T. A. , Williams J. L. , Oldendorf S. Z.
Published: December 2017

The brain uptake index (BUI) of polar 14C-labeled test compounds with molecular weights (MWs) of 79-70,000 was examined using the single-pass carotid injection technique in pentobarbital-anesthetized rats. Compounds were injected in 40 mM malonate, pH 2.5, and 10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, pH 7.4. BUI is defined as (14C-labeled test compound/[3H]H2O in brain)/(14C-labeled test compound/[3H]H2O in injectate) x 100 at a 5-s decapitation time. Increased BUIs of compounds in pH 2.5 buffer were MW dependent with a threshold < 5,000. BUI, extraction, and permeability-surface area product (PS) were significantly greater at pH 2.5 compared with pH 7.4 (P < 0.05). Washouts of [14C]butanol and [3H]H2O at pH 2.5 and pH 7.4 were calculated. Cerebral blood flow and PS increased at low pH. Other buffers, oxalate, glycine, and lactate were used at low pH and also increased BUIs. The duration of the blood-brain barrier (BBB) opening at pH 2.5 was 60 s as estimated by penetrance of the normally excluded dye fluorescein. A plot of BUI or PS at pH 2.5 vs. (MW)1/2 suggests that transient BBB tight junction opening contributed to the passage of polar compounds at low pH.
Mechanism of the negative inotropic effect of adenosine in guinea pig atrial myocytes
Authors: Wang D. , Belardinelli L.
Published: December 2017

The ionic basis of the negative inotropic effect of adenosine on guinea pig atrial myocytes was studied. Membrane potentials and currents were measured using a whole cell patch-clamp technique. The contractility was assessed by video quantitation of cell twitch amplitude. Adenosine shortened action potential duration [measured at 90% repolarization (APD90)] and decreased twitch amplitude in a concentration-dependent manner. The maximal effects of adenosine (100 microM) were to reduce APD90 from 102 +/- 14 to 34 +/- 8 ms (n = 11) and twitch amplitude from 4.3 +/- 0.9 to 1.5 +/- 0.4 microns (n = 8). The concentration of adenosine that caused one-half of the maximal reductions of twitch amplitude and of APD90 was 0.6 microM. Reductions in APD90 and in twitch amplitude were parallel and highly correlated (r = 0.98). Decreases in twitch amplitude by adenosine could be mimicked by application of voltage-clamp pulses with durations similar to the durations of action potentials in the presence of adenosine. Clamp pulse could reverse adenosine-induced but not cadmium chloride-induced decreases in twitch amplitude. Adenosine activated the inwardly rectifying K+ current (IK,Ado), but did not significantly decrease the L-type Ca2+ current (ICa,L). Adenosine reduced the effects of BAY K 8644 on APD90 and twitch amplitude but did not attenuate the BAY K-induced increase in ICa,L. The effects of adenosine on APD90 and twitch amplitude could be reversed after activation of IK,Ado was inhibited by intracellular application of cesium and tetraethylammonium chloride.(ABSTRACT TRUNCATED AT 250 WORDS)
Transition from compensatory hypertrophy to dilated, failing left ventricles in Dahl salt-sensitive rats
Authors: Inoko M. , Kihara Y. , Morii I. , Fujiwara H. , Sasayama S.
Published: December 2017

To establish an experimental model for studying a specific transitional stage for compensatory hypertrophy to heart failure, we studied the pathophysiology of the left ventricle (LV) in Dahl salt-sensitive (DS) rats fed a high-salt diet. DS rats fed an 8% NaCl diet after the age of 6 wk developed concentric LV hypertrophy at 11 wk, followed by marked LV dilatation at 15-20 wk. During the latter stage, the DS rats showed labored respiration with LV global hypokinesis. All the DS rats died within 1 wk by massive pulmonary congestion. The dissected left ventricles revealed chamber dilatation and a marked increase in mass without myocardial necrosis. In contrast, corresponding Dahl salt-resistant (DR) rats fed the same diet showed neither mortality nor any of these pathological changes. The in vivo LV end-systolic pressure-volume relationship shifted to the right with a less steep slope in the failing DS rats compared with that in age-matched DR rats. Isometric contractions of LV papillary muscles isolated from these DS rats showed reduced tension development in the failing stage, but normal tension development in the hypertrophied stage. In conclusion, the DS rat fed a high-salt diet is a useful model showing rapidly developing congestive heart failure, in which the transition from compensatory hypertrophy to decompensatory dilatation of LV is easily and consistently manifested.
Force-frequency relations during heart failure in pigs
Authors: Eising G. P. , Hammond H. K. , Helmer G. A. , Gilpin E. , Ross J.
Published: December 2017

In isolated cardiac muscle from patients with severe heart failure (HF) the force-frequency relation (FFR) is often negative, but the characteristics of the FFR under basal conditions and its responsiveness to adrenergic stimulation have not been studied in the intact, failing heart. Severe HF was produced in pigs (n = 6) by continuous rapid left ventricular (LV) pacing (225 beats/min). In the conscious resting state, high-fidelity LV pressure and its maximum first derivative (LV dP/dtmax) were obtained over a range of atrial pacing rates (100-225 beats/min) before (control) and after HF. Before HF, the relationship between increased heart rate and LV dP/dtmax (a measure of the FFR) was flat, but during dobutamine infusion the FFR showed a significant positive slope (P < 0.003). After HF, the basal FFR was depressed, but the slope of the FFR was not increased by dobutamine. After HF, responses of dP/dtmax to slowing of HR by a specific sinus node inhibitor confirmed the absence of a negative basal FFR. In conclusion, the basal LV FFR in conscious pigs with severe HF was not negative. Unlike the normal heart, in HF beta-adrenergic receptor stimulation did not amplify the FFR, a phenomenon that could play an important role in the impaired response to exercise in patients with HF.
Acute compensation to abrupt occlusion of rat femoral artery is prevented by NO synthase inhibitors
Authors: Unthank J. L. , Nixon J. C. , Dalsing M. C.
Published: December 2017

The hemodynamic significance of endothelium-derived relaxing factor (EDRF)-mediated mechanisms in vascular responses to abrupt rat femoral artery occlusion was investigated. Temporary arterial occlusion was produced before and after inhibition of nitric oxide synthase by N omega-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA). Iliac artery blood flow and arterial pressures proximal and distal to the occlusion were measured. Normal vascular compensation included a return of resistance to preocclusion levels and a rise in distal pressure to a plateau within 5 min postocclusion. After treatment with L-NAME and L-NMMA, postocclusion resistance remained elevated by 53 and 36%, respectively. Collateral dilation after occlusion, as indicated by the rise in distal pressure, was prevented by L-NAME but not L-NMMA. Increases in adrenergic tone and mean arterial pressure by phenylephrine did not prevent compensation, suggesting the effects of L-NAME and L-NMMA did not result from elevated sympathetic activation or pressure. The results are consistent with the hypothesis that the stimulated release of endothelium-derived relaxing factor mediates the acute vascular compensation to abrupt arterial occlusion.
Arterial compliance may influence baroreflex function in athletes and hypertensives
Authors: Kingwell B. A. , Cameron J. D. , Gillies K. J. , Jennings G. L. , Dart A. M.
Published: December 2017

The present study investigated arterial compliance as a possible influence on mean arterial pressure-heart rate (MAP-HR) reflex function in athletes and hypertensives. Aortic stiffness and systemic arterial compliance (SAC) were estimated in 25 elite male athletes and 25 age-matched sedentary controls. Blood pressure did not vary between groups, but SAC was higher in the athletic compared with the sedentary group (0.46 +/- 0.04 vs. 0.37 +/- 0.02 arbitrary compliance units; P = 0.03). In five hypertensives and six age-matched normals and in a subgroup of seven athletes and seven age-matched controls the sigmoidal MAP-HR reflex was assessed using phenylephrine and nitroprusside. In athletes compared with sedentary subjects MAP-HR reflex sensitivity was the same; however, the maximum tachycardia in response to blood pressure reduction was lower in the athletic group (87.1.1 +/- 3.7 vs. 97.1 +/- 2.9 beats/min; P = 0.05). Athletes had a higher blood pressure corresponding to 95% of the HR range (64.2 +/- 3.2 vs. 54.0 +/- 2.1 mmHg; P = 0.02), but there was no difference in the blood pressure corresponding to 5% of the HR range. The blood pressure excursion necessary to traverse the baroreceptor transducer range (MAPd) was therefore less in athletes compared with normals. The beta-index of aortic stiffness correlated closely with MAPd (R = 0.70; P < 0.01). In hypertensives reflex sensitivity was reduced, the minimum HR was elevated, and the MAPd was 56% greater compared with normals.(ABSTRACT TRUNCATED AT 250 WORDS)
Propionyl-L-carnitine-mediated improvement in contractile function of rat hearts oxidizing acetoacetate
Authors: Russell R. R. , Mommessin J. I. , Taegtmeyer H.
Published: December 2017

Prior evidence has suggested that propionyl-L-carnitine improves function in ischemic hearts by providing carnitine for dissipation of acyl-CoA derivatives and propionate for enrichment of the citric acid cycle. Because contractile failure in hearts oxidizing ketone bodies is due to sequestration of free coenzyme A, which can be reversed by the addition of anaplerotic substrates that enrich the citric acid cycle, experiments were performed to determine whether the addition of propionyl-L-carnitine (2 mM) can improve performance in working rat hearts utilizing acetoacetate (7.5 mM). Whereas the addition of propionyl-L-carnitine to acetoacetate resulted in a sustained improvement in the work output of the heart, the addition of propionate (2 mM) or L-carnitine (2 mM) alone to acetoacetate had negligible effects on contractile function. Propionyl-L-carnitine increased the uptake of acetoacetate by 130%, whereas beta-hydroxybutyrate release was minimal and unchanged compared with other groups. These observations show that rates of acetoacetate oxidation are increased commensurate with increased contractile function. Tissue metabolite data indicate that the utilization of propionyl-L-carnitine did not lead to accumulation of citric acid cycle intermediates in the span from citrate to 2-oxoglutarate but to an increase in the tissue content of malate. The results show that addition of propionyl-L-carnitine in hearts oxidizing acetoacetate results in improved mechanical performance that is comparable to the mechanical performance of hearts perfused with glucose as the only substrate. This improvement is most likely conferred by anaplerosis, as suggested by enhanced rates of acetoacetate utilization and citric acid flux.
Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms
Authors: McQuillan Lynda P. , Leung Gordon K. , Marsden Philip A. , Kostyk Sandra K. , Kourembanas Stella
Published: December 2017

Pages H1921–H1927M: Lynda P. McQuillan, Gordon K. Leung, Philip A. Marsden, Sandra K. Kostyk, and Stella Kourembanas. “Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms.” Part C of Fig. 1 was inadvertently masked during the printing process. The correct Fig. 1 is reproduced here.

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