bluuebunny/crossref_metadata_2025 huggingface dataset:
Baroreflex frequency-response characteristics to aortic depressor and carotid sinus nerve stimulation in rats
Authors: Fan W. , Reynolds P. J. , Andresen M. C.
Published: December 2017

Dynamic cardiovascular regulation depends on baroreflexes and the processing of sensory information. We evaluated the influence of choice of anesthetic on the frequency-response characteristics of the baroreflex of rats by electrical stimulation of two major baroreceptor-containing nerves, the carotid sinus (CSN) and aortic depressor nerves (ADN). The ADN contains baroreceptors alone, and the CSN has both chemoreceptors and baroreceptors. Most studies were performed under pentobarbital sodium (PB; 65 mg/kg) anesthesia. We compared this to a combination of alpha-chloralose (80 mg/kg) and urethan (800 mg/kg) (CU). Stimulus trains were fixed at 60-s periods (0.1-ms shocks, supramaximal intensities, 1-200 Hz) and delivered in steady and burst patterns. Unilateral steady-frequency ADN stimulation in PB-anesthetized rats evoked reflex decreases in mean arterial pressure and heart rate that increased with frequencies between 1 and approximately 10 Hz before reaching a maximum. From 10 to 200 Hz, PB ADN reflex responses were sustained at these maximal levels. Cutting the opposite ADN or both CSNs did not alter ADN baroreflex relationships. Heart rate and mean arterial pressure depressor responses evoked by CSN stimulation in PB-anesthetized rats were smaller compared with ADN stimulation and were biphasic, with small pressor responses at 1 Hz. Maximal CSN depressor responses in PB-anesthetized rats occurred at approximately 20 Hz and were sustained at 20-200 Hz. Baroreflex responses for ADN stimulation in CU-anesthetized rats were similar to those in PB-anesthetized rats. In contrast, in CU-anesthetized rats, maximal CSN responses occurred at 20 Hz but declined at 50-200 Hz. Constant- and burst-stimulation responses were equivalent. The results suggest that rat aortic baroreflex responses are sustained even at very high input frequencies (> 100 Hz). The sustained high-frequency baroreflex responses seem to present a paradox in understanding central integration because other studies show substantial depression of sensory transmission at the first synapse in the nucleus tractus solitarius at frequencies as low as 10 Hz.
Dynamics of myocardial adaptation to low-flow ischemia and hypoxemia
Authors: Merati G. , Allibardi S. , Monti L. D. , de Jong J. W. , Samaja M.
Published: December 2017

We investigated whether one or more factors control performance in O2-limited hearts. For this purpose, we measured the dynamics of myocardial adaptation to reduced O2 supply with a specially designed setup, analyzing early changes after reduction in either flow of the perfusion medium or its PO2. For 10 min, 38 isolated rat hearts underwent low-flow ischemia or hypoxemia, matched for O2 supply. Early during ischemia, developed pressure declined at a rate of 311 +/- 25 mmHg/s; lactate release increased and then leveled off to 3.4 +/- 0.7 mumol/min within 2 min. During hypoxemia, pressure dropped initially, as observed during ischemia. However, it then increased before slowly decreasing. Lactate release during hypoxemia peaked at 13.0 +/- 2.3 mumol/min after 2 min, leveling off to 3.5 +/- 1.3 mumol/min. Glycogen decreased by 52 and 81% in ischemic and hypoxemic hearts, respectively (P < 0.05). Reexposure to ischemia or hypoxemia induced comparable changes in both groups. We conclude that, at the beginning of ischemia, a single factor does limit myocardial performance. This variable, which remains undisturbed for 10 min, is presumably O2 availability. In contrast, approximately 20 s after induction of hypoxemia, glycolytic ATP production can partially override low O2 availability by providing most of the energy needed. During repeated restriction of O2 supply, O2 availability alone limits performance during both ischemia and hypoxemia.
Transient outward current in catecholamine-induced cardiac hypertrophy in the rat
Authors: Meszaros J. , Ryder K. O. , Hart G.
Published: December 2017

We have demonstrated that a daily injection of isoproterenol (5 mg/kg ip) for 7 days induces a 30% increment in heart weight-to-body weight ratio and prolongs the action potential duration (APD) in male Wistar rats. The underlying mechanism of the prolonged APD was investigated in this model of hypertrophy by measuring the transient outward potassium current (Ito) in left ventricular myocytes of the rat with whole cell voltage-clamp techniques. Cell membrane capacitance was increased by 39%: 122 +/- 3 (n = 23) and 171 +/- 5 (SE) pF (n = 20) in control and hypertrophy, respectively (P < 0.001). Ito was evoked in sodium-free solutions containing 0.5 mM Ca2+ and 2 mM Co2+ by step depolarizations from a holding potential of -80 mV. The amplitude of the 4-aminopyridine-sensitive Ito (at 70 mV) was reduced by 28% in hypertrophy: 3.2 +/- 0.3 (n = 23) and 2.3 +/- 0.4 (SE) nA (n = 20) in control and hypertrophy, respectively (P < 0.05). When normalized for cell capacitance, the reduction was much larger: 26.4 +/- 2.5 and 13.1 +/- 1.8 pA/pF in control and hypertrophy, respectively (P < 0.001). The voltage dependence of Ito was similar in both cell types. No change was observed in the steady-state activation and inactivation kinetics in the two groups, nor was there a change in the time dependence of inactivation. The recovery from inactivation of Ito when fitted with a monoexponential function was not changed significantly in hypertrophy: time constants = 8.2 +/- 0.4 (n = 13) and 8.3 +/- 0.3 ms (n = 12) in control and hypertrophy, respectively. These results show that Ito density is decreased in catecholamine-induced cardiac hypertrophy, but current kinetics are not affected. The reduced Ito density may underlie the prolongation of APD in this model of hypertrophy.
Regional electrical activation and mechanical function in the partially ischemic left ventricle of dogs
Authors: Delhaas T. , Arts T. , Prinzen F. W. , Reneman R. S.
Published: December 2017

During normoxia, asynchronous electrical activation of the left ventricle significantly affects regional mechanical performance. Regional fiber strain and external work during the ejection phase are found to be lower in early-activated than in late-activated regions. Because electrical activation is known to be delayed during ischemia, the present study was designed to investigate the influence of this electrical asynchrony on regional fiber strain, if any, during moderate and severe myocardial ischemia. Regional electrical activation time (t(ea)) and fiber strain during the ejection phase (ef,e) were measured in the epicardial layers of the left ventricular anterior wall during normoxia and after 15 min of total occlusion (n = 5) or 30, 60, 120, and 180 min of partial occlusion of the left anterior interventricular coronary artery (LAICA; n = 11). Myocardial blood flow (MBF) was assessed with radioactive microspheres. Blood gases, pH, and lactate and Pi contents were determined in arterial, local venous, and coronary sinus blood. During normoxia, t(ea) and ef,e were similar in various epicardial regions of the left ventricular anterior wall. During total LAICA occlusion, in the ischemic area, subepicardial MBF decreased from 0.86 +/- 0.36 (SD) to 0.18 +/- 0.09 ml.g-1.min-1 and subepicardial ef,e decreased from -0.11 +/- 0.02 to -0.01 +/- 0.01, whereas the delay in t(ea) between the normoxic basal-lateral and ischemic apical-medial areas increased slightly but significantly from 1.9 +/- 8.0 to 7.5 +/- 8.0 ms. After a 180-min partial occlusion of the LAICA, in the ischemic area, subepicardial MBF decreased from 0.62 +/- 0.17 to 0.49 +/- 0.18 ml.g-1.min-1 and ef,e decreased from -0.08 +/- 0.01 to -0.03 +/- 0.01. No significant change in the difference in t(ea) between the normoxic and ischemic areas could be detected (5.1 +/- 4.8 and 5.2 +/- 5.8 ms in the control situation and after 180-min partial occlusion, respectively). These findings indicate that in the ischemic epicardium 1) mechanical function is more affected than electrical impulse conduction and 2) delayed activation, if any, is accompanied by decreased instead of increased fiber strain, as found in the normoxic left ventricle.
Nonspecific inhibition of adenosine-activated K+ current by glibenclamide in guinea pig atrial myocytes
Authors: Song Y. , Srinivas M. , Belardinelli L.
Published: December 2017

The ATP-sensitive K+ (KATP) channel blocker glibenclamide was reported to inhibit the K+ current activated by adenosine. This study investigated whether the inhibition by glibenclamide of the adenosine-induced current is due to a specific blockade of KATP channels in guinea pig atrial myocytes. In the absence of adenosine, the basal background current was an inward rectifier K+ current (IK1). Glibenclamide at concentrations of 10, 30, and 100 microM reduced the basal background K+ current by 15 +/- 6, 43 +/- 10, and 63 +/- 11%, respectively. In the presence of adenosine (10 microM), glibenclamide (30 microM) decreased the adenosine-induced K+ current by 39 +/- 3%. A similar inhibitory effect of glibenclamide on the outward K+ currents activated by either the muscarinic agonist carbachol or the nonhydrolyzable GTP analogue guanosine 5'-[gamma-thio]triphosphate was observed. A low concentration (1 microM) of glibenclamide did not significantly attenuate the current elicited by adenosine, although it completely abolished the outward K+ current activated by pinacidil, a KATP channel opener. Thus we conclude that the inhibition of adenosine-induced K+ current by glibenclamide at high concentrations (> 1 microM) is not due to a specific blockade of KATP channels, but rather, resulted from a blockade of IK1.
Characterization of the effects of histamine in porcine tracheobronchial lymph vessels
Authors: Reeder L. B. , DeFilippi V. J. , Ferguson M. K.
Published: December 2017

We characterized the responses of lymphatic vascular smooth muscle to histaminergic-receptor stimulation and blockade and explored the mechanisms underlying the histamine-stimulated release of endothelium-derived relaxing factor (EDRF). Fresh porcine tracheobronchial lymph vessel rings mounted in organ baths were stimulated by the cumulative addition of histamine or H1, H2, and H3 receptor-specific agonists in the presence or absence of receptor-specific antagonists. Histamine had a contractile effect on lymphatic vascular smooth muscle that was H1 receptor mediated. No important effects were elicited by H2- or H3-receptor stimulation. Histamine also caused the release of EDRF as demonstrated by an increase in smooth muscle tone in the absence of endothelium and after inhibition of nitric oxide synthase. This effect was strong at high concentrations of histamine and was mediated by H1-receptor stimulation. The results suggest that histamine may contribute to the regulation of lymphatic vascular smooth muscle tone under pathological conditions, an effect that may be controlled through modification of H1-receptor activity.
KATP channels mediate late preconditioning against infarction produced by monophosphoryl lipid A
Authors: Mei D. A. , Elliott G. T. , Gross G. J.
Published: December 2017

The cardioprotective effect of myocardial preconditioning (PC) to reduce infarct size has been shown to last approximately 90 min (early PC), and then a second window of protection (SWOP or late PC) appears 24 h later. Although much work has been done to characterize early PC, little has been done to investigate potential mediators of SWOP. To that end, we have used monophosphoryl lipid A (MLA), a nontoxic endotoxin derivative, to produce SWOP and have examined the role of ATP-sensitive potassium (KATP) channels in mediating its cardioprotection. Adult mongrel dogs were given MLA (3, 10, or 35 micrograms/kg i.v.) 24 h before a 60-min left anterior descending coronary artery occlusion and 3 h of reperfusion. After reperfusion, the hearts were stained for myocardial infarction with triphenyltetrazolium. MLA produced a dose-dependent reduction in infarct size that was associated with an enhanced shortening of the monophasic action potential duration during early ischemia. To further examine the role of KATP channels, animals were treated with MLA (35 micrograms/kg) and 24 h later were administered either glibenclamide (0.3 mg/kg i.v.) or 5-hydroxydecanoate (7.5 mg/kg intracoronary over 20 min), two structurally distinct KATP-channel antagonists. Both glibenclamide and 5-hydroxydecanoate abolished the cardioprotection produced by MLA. These results demonstrate that the cardioprotective effect of late PC produced by MLA is dependent on functional KATP channels and is the first study to suggest that late PC may be the result of an increased KATP current during ischemia.
Exogenous opioids influence the microcirculation of injured peripheral nerves
Authors: Schaafsma L. , Sun H. , Zochodne D.
Published: December 2017

Local microvessels of peripheral nerve trunks (vasa nervorum) dilate following capsaicin-induced inflammation or local nerve trunk injury. In previous work, we observed that morphine blocked capsaicin-induced dilation of vasa nervorum presumably through the action of local opioid receptors. In the present work, we studied injury-related hyperemia of the rat sciatic vasa nervorum using laser Doppler and hydrogen clearance microelectrode measurements of local perfusion. Systemic morphine reversed hyperemia by vasoconstricting both extrinsic and intrinsic microvessels supplying 48-h-old “neuroma” preparations or crush zones of peripheral nerve trunks. Morphine did not constrict microvessels of contralateral uninjured or sham exposed but uninjured sciatic nerves. In contrast to the injured nerves, contralateral uninjured nerves exposed to morphine frequently had a rise in local perfusion, indicating vasodilation. The vasoconstrictive actions of morphine were blocked by pretreatment with naloxone and were not mimicked by saline injections alone. Systemic doses of selective opioid agonists to mu-, kappa-, and delta-receptors also selectively constricted microvessels of injured nerves. Local blood flow in older experimental neuromas at 7 days had partial sensitivity to morphine, whereas at 14 days perfusion flow was not influenced by morphine. Exogenous opioids dampen early but not later inflammatory microvasodilation and could have important influences on the nerve regenerative milieu.
A test of the role of flow-dependent dilation in arteriolar responses to occlusion
Authors: McGahren E. D. , Dora K. A. , Damon D. N. , Duling B. R.
Published: December 2017

At an arteriolar bifurcation, occlusion of one of the branch arterioles has been reported to result in an increase in flow, shear stress, and vasodilation in the opposite unoccluded branch. This dilator response in the unoccluded branch, often referred to as the "parallel occlusion response," has been cited as evidence that flow-dependent dilation is a primary regulator of arteriolar diameter in the microcirculation. It has not been previously noted that, during this maneuver, flow through the feed arteriole would be expected to decrease and logically should cause that vessel to constrict. We tested this prediction in vivo by measuring red blood cell (RBC) velocity and diameter changes in response to arteriolar occlusion in the microcirculatory beds of three preparations: the hamster cheek pouch, the hamster cremaster, and the rat cremaster. In all preparations, a vasodilation was observed in the feed arteriole, despite a decrease in both flow and calculated wall shear stress through this vessel. Unexpectedly, we found that dilation occurred in the unoccluded branch arterioles even in those cases in which RBC velocity and shear stress did not increase in the unoccluded branch arterioles. All values returned to the baseline level after the removal of occlusion. The magnitude of the dilation of the feed and branch arterioles varied between species and tissues, but feed and branch arterioles within a given preparation always responded in a similar way to each other. We conclude from our experiments that mechanisms other than flow-dependent dilation are involved in the vasodilation observed in the microcirculation during occlusion of an arteriolar branch.
Estimation of nonmechanical VO2 in isolated rabbit heart: comparison of mechanical unloading and BDM method
Authors: Higashiyama A. , Watkins M. W. , Chen Z. , LeWinter M. M.
Published: December 2017

To understand the mechaneoenergetics of heart muscle, it is important to be able to accurately partition energy consumption into its two major components, that used for nonmechanical activity [mainly excitation-contraction (E-C) coupling and basal metabolism] and that used for mechanical activity (cross-bridge cycling). In most experiments in the beating heart, this has been accomplished by assuming that the unloaded oxygen consumption (VO2) represents nonmechanical VO2 and subtracting it from total VO2 to yield mechanical VO2. However, unloaded VO2 is "contaminated" by an uncertain amount of energy consumption for cross-bridge cycling under unloaded conditions. We recently, reported an alternative method to estimate nonmechanical VO2 using the negative inotropic drug 2,3-butanedione monoxime (BDM), which, in theory, should not include cross-bridge cycling-related energy consumption. In the present study, we compared changes in unloaded VO2 and the BDM estimate of nonmechanical VO2 as E-C coupling was varied by changing the perfusate Ca2+ concentration ([Ca2+]) in the isolated rabbit heart. An isolated, red blood cell-perfused, isovolumically contracting balloon in left ventricle preparation was employed. In one group (n = 8), contractility (maximal elastance), unloaded VO2, and the BDM estimate of nonmechanical VO2 were assessed at a perfusate [Ca2+] of 2.5 mM and then at 5.0 mM. In a second group (n = 6), perfusate was 1.0 and 2.5 mM. The change in contractility in each group as [Ca2+] was increased was comparable. Unloaded VO2 was systematically greater than the BDM estimate of nonmechanical VO2 under all conditions. However, the absolute change in both estimates was similar in both groups. In conclusion, over the range of perfusate [Ca2+] employed in this study, changes in unloaded VO2 and the BDM estimate of nonmechanical VO2 are similar. These results support the use of unloaded VO2, which is easier to measure and has less estimation error in individual cases than the BDM-derived value for nonmechanical VO2, as an accurate index of change in E-C coupling energy consumption.
Beta 2-adrenergic receptors enhance contractility by stimulating HCO3(-)-dependent intracellular alkalinization
Authors: Jiang T. , Steinberg S. F.
Published: December 2017

Previous studies established that beta 2-adrenergic receptors enhance the amplitude, without abbreviating the kinetics, of the twitch in adult rat ventricular myocytes. The present study was designed to identify the dominant signaling mechanism mediating this response. Myocytes from adult rat ventricles were loaded with the pH-sensitive fluorophore 2',7'-bis(carboxyethyl)-5(6')-carboxyfluorescein, and simultaneous measurements of intracellular pH and contraction were performed during electrical field stimulation under basal conditions and after stimulation with isoproterenol or the selective beta 2-receptor agonist zinterol. Inhibition of protein kinase A with H-7 completely inhibited the isoproterenol-dependent, but not the zinterol-dependent, positive inotropic response. The effect of zinterol to increase twitch amplitude was associated with an alkalinization of 0.07 +/- 0.02 pH unit, which was not prevented by inhibition of the Na+/H+ exchanger with hexamethylene-amiloride. Rather, removal of bicarbonate from the extracellular buffer prevented the beta 2-receptor-dependent alkalinization as well as the positive inotropic response. These results indicate that beta 2-adrenergic receptors induce a positive inotropic response in adult rat ventricular myocytes via a adenosine 3',5'-cyclic monophosphate-independent mechanism that involves intracellular alkalinization due to activation of a bicarbonate-dependent intracellular pH regulatory mechanism.
Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity
Authors: Liu L. , Nattel S.
Published: December 2017

Although sympathetic activation is believed to promote atrial fibrillation (AF), the effects of sympathetic stimulation on AF have not been systematically studied. In seven morphine-chloralose-anesthetized dogs, autonomic decentralization increased atrial effective refractory period (ERP) and reentrant wavelength (WL) and decreased the duration of AF induced by burst atrial pacing. Graded bilateral stellate ansa stimulation decreased ERP and WL to values similar to those before decentralization but did not return AF duration to predecentralization values. Sympathetic and bilateral vagal stimulation were adjusted in six additional dogs to produce similar effects on ERP and WL. Despite comparable effects on mean WL, the duration of AF was increased by vagal stimulation from 14 +/- 5 (control) to 372 +/- 96 s (P < 0.001) but was not altered significantly (26 +/- 10 s) by sympathetic stimulation. Vagal stimulation increased the variability in atrial refractoriness, as indicated by the standard deviation of ERP at seven atrial sites and of activation frequency during AF at 112 recording sites, whereas sympathetic stimulation had no significant effect on these indexes of ERP heterogeneity. We conclude that sympathetic stimulation is much less effective than vagal stimulation in promoting AF and that heterogeneity in atrial ERP may be important in determining the ability to sustain AF.
Hypoxia enhances agonist-induced pulmonary arterial contraction by increasing calcium sequestration
Authors: Vandier C. , Delpech M. , Rebocho M. , Bonnet P.
Published: December 2017

The effects of hypoxia on norepinephrine-induced contraction to explain why rabbit pulmonary arteries must be precontracted to observe a hypoxic response were studied. A force transducer was used to record the tone of isolated rabbit intrapulmonary artery rings placed in an organ chamber perfused with a physiological solution at 37 degrees C. Norepinephrine (10(-7) M) induced a phasic followed by a tonic contraction, and hypoxia increased the former and decreased the latter. Removal of external calcium (zero calcium solution) abolished the tonic contraction but left the phasic contraction intact. In the zero calcium solution, hypoxia increased the amplitude of the phasic contraction (9.8 +/- 7.4 vs. 13.3 +/- 11.9 mN) and decreased the 50% relaxation time (59 +/- 38 vs. 48 +/- 22 s). Hypoxia also increased the caffeine (5 mM)-induced contraction. This hypoxic increase in amplitude was abolished by ryanodine (100 microM). The hypoxic decrease in the 50% relaxation time was reduced by cyclopiazonic acid (1-10 microM). Therefore, hypoxia increases the reuptake of calcium by calcium pumps sensitive to cyclopiazonic acid in the caffeine- and ryanodine-sensitive stores.
cADP-ribose releases Ca2+ from cardiac sarcoplasmic reticulum independently of ryanodine receptor
Authors: Lahouratate P. , Guibert J. , Faivre J. F.
Published: December 2017

Cyclic ADP-ribose (cADPR), an endogenous metabolite of beta-NAD+, activates Ca2+ release from endoplasmic reticulum in sea urchin eggs via the ryanodine receptor (RyR) pathway. A similar role has been proposed in cardiac sarcoplasmic reticulum (SR), although this remains controversial. We therefore investigated the ability of cADPR to induce Ca2+ release from canine cardiac SR microsomes using fluo 3 to monitor extravesicular Ca2+ concentration. We found that cADPR induced Ca2+ release in a concentration-dependent manner, whereas neither its precursor, NAD+, nor its metabolite, ADP-ribose, elicited a consistent effect. In addition, an additive effect on calcium release between cADPR and 9-Me-7-Br-eudistomin-D (MBED), an activator of RyR, was found as well as no cross-desensitization between cADPR and MBED. Specific blockers of the RyR did not abolish the cADPR-induced Ca2+ release. These results provide evidence for cADPR-induced Ca2+ release from dog cardiac SR via a novel mechanism which is independent of RyR activation.
Left ventricular volumes and function in the embryonic mouse heart
Authors: Tanaka N. , Mao L. , DeLano F. A. , Sentianin E. M. , Chien K. R. , Schmid-Schonbein G. W. , Ross J.
Published: December 2017

This study describes miniaturized technology for the in vivo analysis of the volume and function of the embryonic mouse heart and the application of this technology to study the normal embryonic left ventricle (LV) at two stages of development. With the use of microsurgical techniques, embryos from embryonic day (ED) 10.5 (ED10.5) to ED16 were delivered individually from litters of normal dams, and cardiac visualization was achieved with the use of intravital microscopy by transillumination, with the umbilical circulation intact. At ED10.5-11, the heart could be imaged in color in the intact embryo, whereas at ED12.5 it was necessary to open the chest; at ED13.5-14.5, fluorescent imaging with the use of microinjection of fluorescein-conjugated albumin was necessary to visualize the LV chamber. At ED10.5-11, the LV end-diastolic volumes averaged 0.16 microliter (n = 14), and at ED13.5-14.5, they averaged 0.57 microliter (n = 16). At both ages there was a positive linear relationship between the LV end-diastolic volume and the stroke volume despite substantial variations in individual heart rates, reflecting the relative uniformity of the LV ejection fractions within each age group. The average of the individual ejection fractions was 27.4% at ED10.5-11 and 58.4% at ED13.5-14.5, the latter being within the normal range for the adult rodent heart. These methods will be useful for assessing in vivo cardiac function at ED10.5 and older murine embryos in litters of transgenic or gene-targeted mice when the mutation leads to later embryonic lethality.
Interrelating of ventricular pressure and intracellular calcium in intact hearts
Authors: Baran D. , Ogino K. , Stennett R. , Schnellbacher M. , Zwas D. , Morgan J. P. , Burkhoff D.
Published: December 2017

Although the mechanistic link between variations in intracellular calcium and its effects on myofilament regulatory proteins and subsequent impact on cardiac muscle force production have been known for some time, characterization of cardiac contractile properties are predominantly confined to phenomenological descriptions of the relationship between either muscle length and force or ventricular pressure and volume. However, as recognition of the limitations of these theories grow, investigators have begun to look toward more fundamental theories of cardiac contraction to explain whole heart function. The goal of the present study was first to explore, on a theoretical level, the degree of complexity required in a biochemical model necessary to adequately explain both equilibrium and twitch contraction behavior of cardiac muscle. Central to this analysis was a critical examination of the evidence for and against the importance of a calcium-free, force-generating state. Next, we determined whether such theories can actually account for the interrelationships between the experimentally measured time courses of pressure generation and the calcium transient measured from intact ventricles during both normal twitches as well as during complex contraction sequences. The results of this analysis provide strong support for a four-state model, including the calcium-free, force-generating state. These results will help guide the continuing quest for a mechanistic theory of ventricular function.
Incidence of arrhythmias and heart rate variability in wild-type rats exposed to social stress
Authors: Sgoifo Andrea , De Boer Sietse F. , Westenbroek Christel , Maes Frans W. , Beldhuis Hans , Suzuki Takanori , Koolhaas Jaap M.
Published: December 2017

Psychological stressors of different natures can induce different shifts of autonomic control on cardiac electrical activity, with either a sympathetic or a parasympathetic prevalence. Arrhythmia occurrence, R-R interval variability, and plasma catecholamine elevations were measured in male wild-type rats exposed to either a social stressor (defeat) or a nonsocial challenge (restraint). Electrocardiograms were telemetrically recorded, and blood samples were withdrawn through jugular vein catheters from normal, freely moving animals. Defeat produced a much higher incidence of arrhythmias (mostly ventricular premature beats), which were mainly observed in the 60-s time periods after attacks. The social challenge also induced a much stronger reduction of average R-R interval, a lower R-R interval variability (as estimated by the time-domain parameters standard deviation of mean R-R interval duration, coefficient of variance, and root mean square of successive differences in R-R interval duration), and higher elevations of venous plasma catecholamines compared with restraint. These autonomic and/or neuroendocrine data indicate that a social stressor such as defeat is characterized by both a higher sympathetic activation and a lower parasympathetic antagonism compared with a nonsocial restraint challenge, which results in a higher risk for ventricular arrhythmias.
Parasympathetic inhibition of sympathetic effects on atrioventricular conduction in anesthetized dogs
Authors: Hoyano Yuji , Furukawa Yasuyuki , Kasama Miho , Chiba Shigetoshi
Published: December 2017

To investigate the selective parasympathetic control of atrioventricular (AV) conduction during sympathetic activation, we studied the effects of cervical vagus nerve stimulation on the positive dromotropic responses to sympathetic interventions before and after surgical dissection of dual fatty tissues at the junction of the inferior vena cava and inferior left atrium and at the right atrial side of the atrial junctions of the right pulmonary veins in open-chest anesthetized dogs. In atrial-paced hearts, vagus stimulation at low frequencies prolonged atrio-His (A-H) interval and at high frequencies induced second- and third-degree AV blocks. Vagus stimulation additively prolonged A-H interval shortened by stimulation of the ansae subclaviae or isoproterenol infusion. After dissection of dual fatty tissues, vagus stimulation prolonged A-H interval by only 7%. However, during sympathetic stimulation but not during isoproterenol infusion, vagus stimulation prolonged the shortened A-H interval. Atropine abolished the responses to vagus stimulation. These results suggest that even during sympathetic activation, regional vagus inputs selectively control A-H interval, and even after denervation of the regional parasympathetic nerves, presynaptic parasympathetic inhibition of the positive cardiac responses to sympathetic activation works in the heart in situ.
Role of neuronal NO synthase in relationship between NO and opioids in hypoxia-induced pial artery dilation
Authors: Wilderman M. J. , Armstead W. M.
Published: December 2017

Nitric oxide (NO) contributes to hypoxia-induced pial artery dilation, at least in part, via the formation of guanosine 3′,5′-cyclic monophosphate (cGMP) and subsequent release of Met-enkephalin and Leu-enkephalin in the newborn pig. In separate studies, these opioids were also observed to elicit NO-dependent pial dilation. The present study was designed to investigate the role of the neuronal isoform of NO synthase (NOS) in hypoxic pial dilation, associated opioid release, and opioid dilation in piglets equipped with a closed cranial window. Tetrodotoxin (10−6 M) attenuated the dilation resulting from hypoxia ([Formula: see text]∼35 mmHg; 25 ± 1 vs. 14 ± 1%). Similarly, 7-nitroindazole, sodium salt (7-NINA, 10−6M), a purported neuronal NOS inhibitor, attenuated hypoxic pial dilation (26 ± 1 vs. 14 ± 2%). Hypoxic dilation was accompanied by elevated cerebrospinal (CSF) cGMP, which was blocked by 7-NINA (433 ± 19 and 983 ± 36 vs. 432 ± 19 and 441 ± 19 fmol/ml for control and hypoxia in absence and presence of 7-NINA, respectively). Additionally, hypoxic dilation was also accompanied by elevated CSF Met-enkephalin, which was attenuated by 7-NINA (1,027 ± 47 and 2,871 ± 134 vs. 779 ± 78 and 1,551 ± 42 pg/ml for control and hypoxia in absence and presence of 7-NINA, respectively). In contrast, Met-enkephalin (10−10, 10−8, and 10−6 M) induced dilation that was unchanged by 7-NINA (7 ± 1, 12 ± 1, and 18 ± 1 vs. 6 ± 1, 10 ± 1, and 17 ± 1%, respectively). N-methyl-d-aspartate (NMDA, 10−8 and 10−6 M), an activator of neuronal NOS, induced pial dilation that was blocked by 7-NINA (10 ± 1 and 20 ± 2 vs. 1 ± 1 and 2 ± 1%, respectively). However, sodium nitroprusside-induced dilation was unchanged by 7-NINA. These data indicate that neuronal NOS contributes to hypoxic pial artery dilation but not to opioid-induced dilation. Furthermore, these data suggest that neuronally derived NO contributes to hypoxic dilation, at least in part, via formation of cGMP and the subsequent release of opioids.
Endogenous nitric oxide on arterial hemodynamics: a comparison between normotensive and hypertensive rats
Authors: Chen Hsing I. , Hu Cheng Tao
Published: December 2017

Endogenous nitric oxide (NO) plays an important role in maintaining a vasodilator tone. In the present study, we compared the effects of NO blockade on the steady and pulsatile components of arterial hemodynamics between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto strain (WKY), 22–26 wk of age. In the first series of experiments, various doses (1–30 mg/kg iv) of N G-nitro-l-arginine methyl ester (l-NAME) were administered to block the NO release in anesthetized WKY and SHR. In both WKY and SHR, l-NAME caused a dose-dependent increase in arterial pressure (AP) with a decrease in heart rate (HR). The maximal effects ofl-NAME on AP and HR occurred at a dose of 10 mg/kg. Both the AP increase and HR decrease were higher in SHR (AP, +38 ± 4 mmHg; HR, −49 ± 5 beats/min) than WKY (AP, +22 ± 3 mmHg; HR, −33 ± 5 beat/min). In other series, the technique of impedance spectral analysis was employed to investigate the effects ofl-NAME (10 mg/kg iv) on the arterial hemodynamics. The aortic pressure and flow waves were recorded and subjected to Fourier transform for the analysis of impedance spectra. Both in WKY ( n = 12) and in SHR ( n = 12),l-NAME significantly increased AP and total peripheral resistance (TPR). The pulsatile and frequency-dependent hemodynamics including characteristic impedance, wave reflection, and ventricular work were only slightly altered. Despite higher resting values of AP and TPR in SHR (mean AP, 154 ± 7 mmHg; mean TPR, 204 ± 17 × 103dyn ⋅ s ⋅ cm−5) than WKY (mean AP, 94 ± 6 mmHg; mean TPR, 98 ± 12 × 103dyn ⋅ s ⋅ cm−5), the magnitudes of AP and TPR increments after NO blockade were significantly higher in SHR (AP, +37 ± 3 mmHg; TPR, +124 ± 16 × 103dyn ⋅ s ⋅ cm−5) than in WKY (AP, +24 ± 3 mmHg; TPR, +45 ± 7 × 103dyn ⋅ s ⋅ cm−5). The continuous formation of endogenous NO affects predominantly the AP and peripheral resistance in both WKY and SHR. The windkessel functions, such as impedance spectra, pulse-wave reflection, and ventricular work, are less affected after NO blockade. In addition, the effects of NO release on the AP and TPR appear to be enhanced in rats with established hypertension.
Impairment of contraction increases sensitivity of epicardial lymph pressure for left ventricular pressure
Authors: Vanteeffelen Jurgen W. G. E. , Merkus Daphne , Bos Luc J. , Vergroesen Isabelle , Spaan Jos A. E.
Published: December 2017

In the present study, cardiac contraction was regionally impaired to investigate the relationship between contractility [maximum first time derivative of left ventricular pressure (dPLV/d tmax)] and PLVon epicardial lymph pressure (Plymph) generation. Measurements were performed in open-chest anesthetized dogs under control conditions and while local contraction was abolished by intracoronary administration of lidocaine. Lidocaine significantly lowered dPLV/d tmaxand PLVpulse to 77 ± 9 (SD; n = 5) and 82 ± 5% of control, respectively, whereas Plymphpulse increased to 186 ± 101%. The relative increase of maximum Plymphto PLVrelated inversely to the change in dPLV/d tmaxafter lidocaine administration. Additional data were obtained when PLVwas transiently increased by constriction of the descending aorta. The ratio of pulse Plymphto PLVduring aortic clamping increased after lidocaine administration, from 0.063 ± 0.03 to 0.15 ± 0.09. The results suggest that transmission of PLVto the cardiac lymphatic vasculature is enhanced when regional contraction is impaired. These findings imply that during normal, unimpaired contraction lymph vessels are shielded from high systolic PLVby the myocardium itself.
Cytochrome P-450 pathway in acetylcholine-induced canine coronary microvascular vasodilation in vivo
Authors: Widmann Mark D. , Weintraub Neal L. , Fudge Jonathan L. , Brooks Leonard A. , Dellsperger Kevin C.
Published: December 2017

In the canine coronary microcirculation, acetylcholine (ACh)-induced vasodilation of large (≥100 μm) epicardial arterioles (LgA), but not small (<100 μm) epicardial arterioles (SmA), is blocked by nitric oxide (NO) synthase inhibitors in vivo. We hypothesized that the ACh-induced vasodilation of SmA is mediated by a cytochrome P-450 metabolite of arachidonic acid (AA). Epicardial coronary microvascular diameters in dogs were measured at baseline and after treatment with topically applied ACh (1, 10, and 100 μM), AA (1, 5, and 10 μM), or sodium nitroprusside (SNP; 10–100 μM). Coronary microvascular diameters were compared among control dogs ( group OO); dogs pretreated with N ω-nitro-l-arginine (l-NNA; 70 μM topically) ( group NO); dogs pretreated withl-NNA plus clotrimazole (Clo; 1.6 μM topically) or 17-octadecynoic acid (ODYA; 2 μM topically), cytochrome P-450 monooxygenase inhibitors ( groups NC and NY, respectively); dogs pretreated with Clo alone ( group OC); and dogs pretreated with l-NNA plus Clo with AA as the agonist ( group AA). ACh-induced vasodilation of LgA was abolished byl-NNA alone, whereas in SmA,l-NNA was without effect. Clo alone did not inhibit ACh-induced dilation in either SmA or LgA. However, the combinations ofl-NNA plus either Clo or ODYA abolished ACh- and AA-induced dilation of SmA (100 μM ACh: NC, 3 ± 5%; NY, 8 ± 2%; 10 μM AA: 6 ± 3%) but did not affect responses to SNP. These results suggest that the ACh-induced vasodilation of SmA is mediated in part by cytochrome P-450 metabolites of AA and provide the first evidence that the cytochrome P-450 pathway contributes to the regulation of coronary resistance vessels in vivo.
Simplification of the quasiperiodic route to chaos in agonist-induced vasomotion by iterative circle maps
Authors: De Brouwer S. , Edwards D. H. , Griffith T. M.
Published: December 2017

We have shown that the patterns of vasomotion induced by histamine in isolated rabbit ear resistance arteries can be described in terms of iterative circle maps that model the dynamics of coupled nonlinear oscillators. Cyclopiazonic acid (CPA), an inhibitor of the sarcoplasmic reticulum Ca2+-adenosinetriphosphatase pump, consistently transformed chaotic behavior into characteristic periodic oscillations known as mixed-mode responses, which consist of mixtures of large- and small-amplitude excursions and represent frequency-locked states. Quasiperiodicity, which reflects the interaction of oscillators with incommensurate frequencies, was also observed, although in a smaller number of experiments. The patterns of mixed-mode complexes found at different CPA concentrations allowed the derivation of firing numbers, i.e., number of large oscillations/sum of number of small and large oscillations, and the sequences in which they emerged conformed to Farey arithmetic. Two-dimensional return maps derived by Poincaré section of phase space representations of the dynamics were used to compute the mean number of rotations per iteration on the circle, i.e., the winding number. Plots of winding number against firing number revealed a devil’s staircase-type structure. Experiments with verapamil, a voltage-operated L-type Ca2+-channel antagonist, confirmed that influx of extracellular Ca2+was essential to sustain chaos, quasiperiodicity, and mixed-mode responses. Nonlinear coupling between cytosolic and membrane events in rabbit ear arteries thus results in a self-organized dynamics that collapses to that predicted by the theory of simple circle maps.
Are interatrial band myocytes maximally hypertrophied in normal canine hearts?
Authors: Dolber Paul C. , Bauman Robert P. , Rembert Judith C. , Greenfield Joseph C.
Published: December 2017

In canine right atrial hypertrophy, the cross-sectional area ( A xs) of right atrial myocytes increases, whereas the A xs of the broader interatrial band myocytes does not. In the current study, myocyte reconstructions showed that right atrial myocyte length increased in proportion to A xs in right atrial hypertrophy. On the other hand, mean interatrial band myocyte length in both normal and right atrial hypertrophy dogs was roughly inversely proportional to mean A xs, as expected if interatrial band myocyte volume was constant. Plotting mean A xs vs. myocyte length for individual interatrial band myocytes revealed a distribution whose border defined a maximal volume curve; many myocytes were well beneath that curve. Mononuclear myocytes (generally diploid) were limited by a 65,000-μm3 curve, which many binuclear myocytes (generally tetraploid) surpassed; myocyte ploidy thus constrained myocyte volume. However, because many mononuclear and binuclear myocytes had lower volumes, their failure to hypertrophy cannot be attributed to attainment of the maximal volume possible for their ploidy.
Influence of the Thyroid Gland on Jejunal Secretion in the Dog
Authors: Russell Raymond A. , Nasset E. S.
Published: December 2017

Page 103: Raymond A. Russell and E. S. Nasset, "Influence of the Thyroid Gland on Secretion in the Dog." In table 1, under Dog 2, the last line should be as follows:

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Influence of X-Irradiation Upon Water Consumption by the Rat
Authors: Smith Douglas E. , Tyree Ella B.
Published: December 2017

Water consumption was measured daily after a) single, total-body exposures of intact and adrenalectomized rats to x-radiation and b) single, partial-body irradiations of intact rats. The intakes of 20% sucrose and of 1% NaCl were measured in hypophysectomized and adrenalectomized, irradiated rats, respectively. Beginning on the first day after exposure there occurred increases and decreases in water consumption which were related to x-ray dosage and to the portion of the body irradiated. The variation in response was very high between individuals. Adrenalectomy abolished the polydipsia which immediately follows irradiation. The possible influence of the pituitary-adrenal system upon the irradiation-induced changes in water consumption is discussed.
Acute Erythrocyte Destruction in Severe Thermal Injury
Authors: Jones D. M. , Alpen E. L. , Davis A. K.
Published: December 2017

Measurements of the acute post burn erythrocyte deficit have been made in the rat by means of Fe59-labeled red cells. The burns used were moderate to severe flash burns ranging from 8 cal/cm2 (minimal third degree) to 16 cal/cm2 (severe third degree). Destruction of red cells ranges from 8% at 8 cal/cm2 to 25% at 16 cal/cm2. These burns are equivalent to those that might be expected to occur in exposed skin as the result of a nuclear detonation. Increasing duration of exposure to the radiant energy source did not affect the extent of red cell destruction. Increasing burn area from 15% to 22% did not affect the red cell deficit. The extent of red cell destruction is greater than that reported for thermal burns of a contact nature. The reasons for this difference have been discussed. It has also been shown that an additional small deficit in red cell volume in excess of that caused by direct heat effects on cells can be expected as the result of a continuing hemolytic process.
Excitation and Inhibition of Spinal Motoneurons
Authors: Edisen Adele E. U.
Published: December 2017

Spinal cord motoneurons of the cat were stimulated by a needle electrode and reflexly via dorsal root impulses. Responses to direct stimulation originated in dendrites, initial axon segment, or myelinated axon, but apparently not in the cell body. The sites were differentiated by latency changes of the response as needle position and stimulus strength are varied, by ability to follow repetitive stimulation, and by responses to asphyxia duration and anesthesia depth. Facilitatory afferent impulses increased the excitability of the motoneurons, whether the direct test stimulus was activating either dendrites or initial axon segment, but inhibitory afferent impulses decreased the direct response only when dendrites were being activated. Facilitation is therefore nonlocalized and can be accounted for by the usual eddy currents. Inhibition is interpreted as a partial depolarization and impedance decrease of the cell body, induced by afferents reaching it directly and resulting in a short circuiting of eddy currents from excited dendrites to initial axon segment. The central delay of the spinal cord monosynaptic response (about 0.8 msec.) is accounted for by conduction time in the afferent fibers (0.5 msec.), determined by antidromic stimulation of these and by the time lag of afferent conditioning effects, and in the motoneurons, 0.2–0.3 msec. It is thus doubtful if any true ‘synaptic delay’ exists. The long intramedullary afferent conduction time also fully accounts for the lag seen in afferent inhibition, in harmony with the existence of a direct inhibitory pathway.
Inhibition of Phosphorylation During Electrical Excitation of Frog Nerves
Authors: Abood L. G. , Goldman E.
Published: December 2017

Phosphorylation was studied in isolated frog sciatic nerves during excitation, using radioactive P32 as a tracer. The various phosphorylated intermediates were separated by means of the anion exchange resin, Dowex-1. Stimulation for a period of 30 minutes resulted in an increase of almost all P-intermediates studied, with the exception of phosphocreatine (PCr). DPN showed the greatest increase (58%). With the exception of orthophosphate (P) the radioactive specific activity of all fractions decreased; PCr, G-6-P and ATP decreasing over 15% and DPN 34%. The activity of P increased 20% over the control. The relative specific activity of all fractions from stimulated nerves decreased, over 25% in the case of PCr, ATP and G-6-P, and 30% in the case of DPN. Specific activity-time relations were studied, and here, too, there was a clear indication that phosphorylation was inhibited during excitation of frog nerves. Insofar as oxidative and glycolytic metabolism increase phosphorylation and oxidation during excitation, it is believed that an actual ‘uncoupling’ occurs during activity in nervous tissue. Results are discussed in relation to alternative pathways of energy transfer and noncarbohydrate sources of energy.
Effect of Estrogen on Thyroid Uptake of I131 in Adrenalectomized Rats
Authors: Feldman Joseph D.
Published: December 2017

The administration of estrogen to adrenalectomized castrate and castrate male rats more than doubled the thyroid uptake of 1131 as compared with controls receiving saline. The presence or absence of the adrenal did not influence this estrogen effect.
Changes in Pancreatic Enzymes Brought About by Amino Acid Additions to the Diet
Authors: Magee D. F. , Hong S. S.
Published: December 2017

Rats fed 7% casein as the sole source of protein were divided into eight groups. Two of these were controls receiving an extra 1% casein. The remaining groups were fed equal amounts of a diet containing 1% of the following dl amino acids; isoleucine, methionine, phenylalanine, leucine, lysine or tryptophane. At the end of 3 weeks feeding all the animals were killed after a 24-hour fast and the enzyme activities in the pancreases were determined. It was found, by comparison with the controls, that no amino acid supplement increased amylase. Methionine increased lipase and protease activity and phenylalanine and isoleucine increased protease activity alone.