bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial and systemic oxygenation during severe hypoxemia in ventilated lambs
Authors: Bernstein D. , Teitel D. F.
Published: December 2017

We studied the interrelationships among myocardial oxygenation, cardiac output, and systemic oxygenation during acute progressive hypoxemia in the paralyzed and mechanically ventilated lamb. Fractional inspired concentration of oxygen was reduced in five steps to a minimum of 0.05, decreasing arterial oxygen content (CaO2) from 10.9 +/- 2.4 to 2.8 +/- 0.5 ml/dl. Heart rate and stroke volume did not change at any step so that systemic oxygen transport decreased with CaO2. Systemic oxygen consumption fell at CaO2 less than 6 ml/dl. Left ventricular blood flow at maximal hypoxemia increased 277% (249 +/- 27 to 938 +/- 118 ml.min-1.100 g-1) so that left ventricular oxygen delivery and oxygen consumption were maintained. Evidence of anaerobic metabolism occurred when CaO2 was less than four (increase in arterial lactate and hypoxanthine), whereas at this level there was no evidence of inadequate myocardial oxygenation as determined by normal subepicardial: subendocardial blood flow and absence of net lactate production, although coronary sinus PO2 decreased. Although myocardial, cerebral, and adrenal blood flows increased, there was no redistribution of blood flow away from the viscera and skin.
Time delays in propagation of cardiac action potential
Authors: Israel D. A. , Edell D. J. , Mark R. G.
Published: December 2017

Recent work has suggested that discrete time delays could occur between cardiac cells under physiological conditions. To investigate the existence of such time delays, monolayers of 10-day chick-embryo ventricular myocytes were grown in cell culture on arrays of extracellular microelectrodes. The most closely spaced recording electrodes were on 20-microns centers. Some pairs of electrodes recorded from different points on the same cell, whereas other pairs straddled intercellular junctions. The preparation was electrically paced to obtain a repeatable propagation pathway. Arrival times of activation at each microelectrode were measured. After control recordings, the preparation was exposed to medium containing 20 mM NH4Cl for 15 min and then returned to normal medium. This intervention produces transient intracellular acidification that decreases intercellular coupling. After acidification, the average (multicellular) conduction velocity decreased to about two-thirds of the control value. Propagation velocity measured between most electrode pairs decreased proportionately. However, disproportionately long propagation delays of up to 410 microseconds were observed between some pairs of electrodes in various experiments. The delays recovered as pH returned to normal. The localized long delays were thought to be due to decreased intercellular coupling at gap junctions.
Regulation of cardiac pacemaker current If in excised membranes from sinoatrial node cells
Authors: Yatani A. , Brown A. M.
Published: December 2017

We have proposed that voltage-gated ionic channels are regulated by receptor-guanine-nucleotide binding (G) protein pathways that are membrane delimited (direct) or cytoplasmic (indirect). Since indirect pathways are known to couple muscarinic and beta-adrenergic receptors to hyperpolarization-activated current (If) channels, we tested our hypothesis that direct pathways might also be present by measuring If currents in rabbit sinoatrial node cells using the gigaseal patch clamp method. Whole cell If currents were increased by the beta-agonist isoproterenol (Iso) and decreased by the muscarinic agonist carbachol (Carb) at rates that were similar to the rate at which carbachol increased muscarinic K(+)-acetylcholine channel (K+[ACh]) current in the same cells. K+[ACh] currents are directly gated by a G protein, and the results therefore supported our hypothesis. Much stronger support came after we established for the first time that If could be recorded from excised inside out membrane patches in the absence of cytoplasmic substrates. Under these conditions Iso increased and Carb decreased cell-free patch If provided guanosine 5'-triphosphate and Mg2+ were present. Thus G proteins couple autonomic receptors to If within the plasma membrane, probably by a direct action.
Effects of anti-free radical agents on Na+, Ca2+, and function in reperfused rat hearts
Authors: Tani M.
Published: December 2017

The purpose of the present study was to determine whether the combined administration of superoxide dismutase (SOD) and catalase (CAT) or efforts to maintain the glutathione redox pathways with sulfhydryl agents could improve Na+ imbalance, reduce Ca2+ overload, and enhance recovery of function and metabolites upon reperfusion in isolated ischemic rat hearts, presumably by scavenging oxygen free radicals. After a 30-min exposure to zero-flow ischemia, left ventricular developed pressure (LVDP) and heart rate recovered to 31 and 81% of the preischemic value, respectively, ATP fell by approximately 40%, and 45Ca2+ uptake rose from 0.8 to 10.4 mumol/g dry tissue. A combination of SOD and CAT at low concentrations (5 X 10(4) and 7.5 X 10(4) U/l, respectively) had a beneficial effect on recovery of LVDP (to 59%), reperfusion 45Ca2+ uptake (to 7.9 mumol/g dry tissue), and recovery of Na+ imbalance. When sulfhydryl donors, such as glutathione, cysteine, N-acetyl-L-cysteine, or dithiothreitol, were administered 20 min before induction of ischemia, no significant protective effects were observed. These results indicated that the extracellular free radical scavengers, SOD and CAT, could attenuate partially the ionic imbalance in ischemic-reperfused myocardium and result in improved recovery of contractile function. Attempts to enhance the intrinsic scavenging system were not successful, suggesting that this system may not play an important role in disposing of free radicals.
Permeability of neutral vs. anionic dextrans in cultured brain microvascular endothelium
Authors: Sahagun G. , Moore S. A. , Hart M. N.
Published: December 2017

The luminal surface of vascular endothelium contains glycocalyx residues that establish an overall negative charge. Recent evidence has suggested that local endothelial surface charge properties may account for the permeability properties of various macromolecules. It has also been suggested that altered membrane charge on the luminal side may play a role in thrombogenesis and atherogenesis. The relationship of macromolecule charge to endothelial cell permeability was examined in vitro using mouse brain microvessel endothelial cells grown to confluence on a nitrocellulose filter separating a double-chamber system. Endothelial permeability to 4K and 10K fluorescein-labeled neutral dextrans was compared with the permeability to 4K and 10K fluorescein-labeled anionic dextrans (sulfated). After 1 h, there was significantly greater permeability of neutral fluorescein-labeled dextran than of anionic fluorescein-labeled dextran in each particle size. In addition, there was significantly greater permeability of 4K than 10K fluorescein-labeled dextrans of either charge. The findings indicate that charge in addition to size plays an important role in the movement of macromolecules across cultured microvascular endothelial cells.
Microvascular responses in rabbit skeletal muscle after fixed volume hemorrhage
Authors: Borgstrom P. , Bruttig S. P. , Lindbom L. , Intaglietta M. , Arfors K. E.
Published: December 2017

The effect of hemorrhage on the microvascular responses in the tenuissimus muscle was studied by means of intravital microscopy in rabbits anesthetized with urethan. The rabbits were bled 30% of their calculated blood volume within 3 min. Hemorrhage initially caused mean arterial pressure to drop from 70 +/- 7 to 26 +/- 5 mmHg. During the subsequent 30-min observation period it increased to 43 +/- 8 mmHg. The transverse arterioles (TRs), supplying both muscle tissue proper and adjacent connective tissue, gradually constricted to 75% of control over the 30-min period. Terminal arterioles (TEs) branching from the TR in the muscle tissue constricted to 65% in 10 min and then gradually relaxed, eventually reaching 80% of control diameter. The constriction of the TEs was confined to a short sphincterlike structure (10–20 microns) at the origin of the bifurcation. Upon constriction, the diameter of the sphincterlike structure was less than the critical diameter for erythrocyte passage. Given that the effective blood viscosity in the narrow TE is strongly dependent on luminal diameter, the overall effect on blood flow and its distribution in the tenuissimus muscle was a dramatic reduction of volume flow to 20–30% of the control value. During the early phase, the reduced flow was diverted to the connective tissue at the expense of nutrient flow to the muscle tissue. This early blood flow pattern gradually reversed, partially restoring nutrient flow to the muscle fibers.
Endothelin 1 causes pulmonary vasodilation in rats
Authors: Hasunuma K. , Rodman D. M. , O'Brien R. F. , McMurtry I. F.
Published: December 2017

Endothelin 1 (ET-1), a peptide produced by endothelial cells, causes transient dilation of some systemic vascular beds. To test whether low concentrations of ET-1 could also dilate the pulmonary vascular bed, we examined its effects in isolated blood- and salt solution-perfused rat lungs and in conscious catheterized rats. In blood-perfused lungs undergoing hypoxic (3% O2) vasoconstriction, repeated additions of 0.5 nM ET-1 to the perfusate elicited transient partial vasodilations. The higher concentration of 5 nM caused a larger transient vasodilation followed by vasoconstriction. In nine conscious rats exposed to 8% O2, intravenous ET-1 (0.2 nmol/kg) reversed the hypoxic pressor response by 63 +/- 8% without affecting cardiac output. In eight salt solution-perfused lungs vasoconstricted with 25 mM KCl, 0.5 nM ET-1 caused a maximum vasodilation of 35 +/- 3% with a half-life of 10.7 +/- 1.1 min. The vasodilation was not inhibited by blockers of cyclooxygenase (3.1 microM meclofenamate), platelet-activating factor receptors (10 microM Web 2086), histamine H1 receptors (50 microM chlorpheniramine), or endothelium-derived relaxing factor activity (10 microM hemoglobin and 50 microM methylene blue). However, it was reduced by approximately 50% with the K+ channel blockers, tetraethylammonium chloride (10 mM) and glybenclamide (10 microM), and the inhibitor of Na(+)-K+ pumping, ouabain (0.1 mM). These results indicate that ET-1 is a potent dilator of the pulmonary vascular bed of the rat and that the mechanism of dilation may involve activation of ATP-sensitive K+ channels and membrane hyperpolarization.
Rate dependence and supernormality in excitability of guinea pig papillary muscle
Authors: Davidenko J. M. , Levi R. J. , Maid G. , Elizari M. V. , Rosenbaum M. B.
Published: December 2017

It is well known that in most cardiac tissues an increase in rate results in a decrease of excitability and, eventually, conduction block. We used microelectrode techniques to evaluate the rate and time dependence of excitation latency in 27 isolated guinea pig papillary muscles (GPPM). Latency was measured as the interval between the stimulus onset and action potential upstroke. When the intensity of current was just suprathreshold, prolongation of the basic cycle length (BCL) from 300 to 1,000 ms produced an increase in latency or failure of excitation. Such behavior was observed with extracellular as well as intracellular stimulation. Rate-dependent changes in latency were maximal during the first 10-20 s following the rate change and reached a steady state in approximately 200 s. Application of premature beats revealed the presence of a "supernormal phase" in which latency abbreviated. Strength-interval and strength-duration curves demonstrated that changes in excitability accurately paralleled those observed in latency. Hence, supernormal excitability at the end of the phase 3 repolarization was consistently observed in all ventricular muscle experiments. Deceleration-induced decrease of excitability was attended by hyperpolarization, increase of action potential upstroke velocity (Vmax) and action potential amplitude, and decrease in membrane resistance. Our data suggest that paradoxical rate-related changes of excitability in GPPM are the result of changes in the passive membrane properties. Under conditions of depressed conductivity, this particular behavior may account for the occurrence of bradycardia-dependent block.
Mechanisms of substrate preference for oxidative metabolism during early myocardial reperfusion
Authors: Renstrom B. , Liedtke A. J. , Nellis S. H.
Published: December 2017

We previously reported in working swine hearts a preferred use of fatty acids during early myocardial reperfusion. The purpose of these studies was to test whether this pattern of substrate oxidation was the result of excess energy demands during mechanical recovery. Two groups of pig hearts (n = 15) were compared. Both received Intralipid with heparin (serum fatty acids, 1.02 +/- 0.05 mumol/ml) to ensure preferred substrate availability and both received [2-14C]pyruvate to monitor myocardial use of a carbohydrate substrate. In one group (n = 8) oxfenicine was administered to suppress fatty acid utilization. Left anterior descending (LAD) coronary flow was maintained at aerobic levels for 30 min, reduced by 60% for 45 min, and restored to aerobic levels for a final 50 min. Ischemia caused the expected decreased in global and regional mechanical performance. Recovery in motion during reflow was less in oxfenicine-treated hearts (73 vs. 32% decrease in systolic shortening from aerobic values in treated and control hearts, P less than or equal to 0.01 and P less than or equal to 0.05, respectively). Pyruvate oxidation declined dramatically in both groups during ischemia but recovered disparately. In control hearts CO2 production remained depressed during reperfusion (NS from ischemic values), whereas in treated hearts it increased 5.5-fold (but did not exceed aerobic values). Tissue levels of acetyl CoA and acetylcarnitine were not statistically different between perfusion beds (aerobic vs. reperfusion) within groups. Oxfenicine reduced levels of acetyl carnitine in both perfusion beds.(ABSTRACT TRUNCATED AT 250 WORDS)
Isoproterenol and myocardial O2 supply/consumption in hypertension-induced myocardial hypertrophy
Authors: Cimini C. M. , Weiss H. R.
Published: December 2017

Myocardial oxygen supply, O2 consumption (MVO2) and function were determined during base-line and isoproterenol infusion (0.5 microgram.kg-1.min-1) 30 days after New Zealand White rabbits were prepared as one-kidney, one-clip (1K,1C) Goldblatt hypertensive or uninephrectomized (sham) controls. Coronary blood flow and cardiac output, using radioactive microspheres, and small vessel O2 saturations, using microspectrophotometry, were measured in hypertrophied and nonhypertrophied hearts. After 30 days, 33% myocardial hypertrophy was evident in the 1K,1C animals. Base-line blood pressure was significantly higher in the 1K,1C animals compared with sham controls and remained higher during isoproterenol infusion. Base-line heart rate was not different between animal groups, and heart rate increased in both groups during isoproterenol. Cardiac output was similar between sham and 1K,1C animals during base-line conditions (316 +/- 40 vs. 365 +/- 51 ml/min, respectively). After isoproterenol, cardiac output increased in the sham animals (494 +/- 119 ml/min) but not in the 1K,1C group (317 +/- 85 ml/min). Isoproterenol elevated MVO2 threefold in both the sham and 1K,1C animals. Coronary blood flow was significantly increased to similar levels in both animal groups. O2 extraction significantly increased during isoproterenol in both groups. Therefore, impaired cardiac function was evident during isoproterenol stress in the hypertrophied myocardium independent of myocardial O2 supply or consumption restrictions.
A mathematical model of electrophysiological activity in a bullfrog atrial cell
Authors: Rasmusson R. L. , Clark J. W. , Giles W. R. , Robinson K. , Clark R. B. , Shibata E. F. , Campbell D. L.
Published: December 2017

We have developed a model of cardiac atrial electrical activity based on voltage-clamp measurements obtained from single cells isolated from the bullfrog atrium. These measurements have allowed us to simulate a number of processes thought to be important in action potential initiation, repolarization, and the excitation-contraction (EC) coupling process. In this atrial model, the cell membrane contains both channel-mediated (Na+, Ca2+, inward rectifier K+, delayed rectifier K+, linear background leak) and transporter-mediated (Na(+)-K+ pump, Na(+)-Ca2+ exchanger, Ca2+ pump) currents. The cell is surrounded extracellularly by a diffusion-limited space. The intracellular volume contains Ca2(+)-binding proteins (calmodulin, troponin). The model makes several important predictions. 1) Incomplete inactivation of the Ca2+ current provides an inward current the maintains the plateau of the action potential. 2) Activation of the delayed rectifier K+ current initiates repolarization. 3) Due to Ca2+ buffering by myoplasmic proteins the Na(+)-Ca2+ exchanger current is relatively small and has little influence on repolarization. 4) The Na(+)-K+ pump current does not play a major role in repolarization. 5) K+ accumulation and Ca2+ depletion may occur in the extracellular spaces. 6) Modulation of EC coupling is governed by interactions between the myoplasmic Ca2(+)-binding proteins; specifically, the inotropic "positive staircase effect" may be explained by interactions between Ca2+ and Mg2+ at a competitive binding site on troponin. When considered in conjunction with the results of our model of primary pacemaking in the sinus venosus [Rasmusson et al., Am. J. Physiol. 259 (Heart Circ. Physiol. 28): H352-H369, 1990], this atrial model shows how the presence or absence of certain transmembrane currents can change action potential characteristics and consequently alter the relative influence of the various transporter-mediated and channel-mediated currents.
Left ventricular dysfunction in early E. coli endotoxemia: effects of naloxone
Authors: Parker J. L. , Keller R. S. , Behm L. L. , Adams H. R.
Published: December 2017

Although the opiate receptor antagonist naloxone (NAL) has been reported to improve in vivo systolic performance of the heart in different circulatory shock syndromes, the influence of this drug on intrinsic cardiac mechanical function during hypodynamic circulatory states is unknown. The present study was designed to determine the effects of in vivo NAL on contraction-relaxation properties of isovolumic left ventricular (LV) preparations isolated from guinea pigs 4 h after induction of gram-negative endotoxemia. Animals were given a 1 mg/kg ip injection of Escherichia coli endotoxin and immediately treated intravenously with either NAL (4 mg/kg iv bolus plus 4 mg.kg-1.h-1 infusion) or an equivalent volume of saline. Endotoxin produced significant reduction of LV contractile function in coronary-perfused hearts, a response unaffected by NAL therapy. For example, LV systolic pressure at approximately 10 mmHg end-diastolic pressure averaged 78 +/- 3 and 82 +/- 6 mmHg in hearts from saline and NAL control animals, respectively, but only 41 +/- 2 and 40 +/- 2 mmHg in endotoxin and endotoxin plus NAL groups, respectively. LV end-diastolic pressure-volume relationships in endotoxin hearts were shifted upward and to the left of controls in the direction of decreased diastolic compliance (P less than 0.05). Importantly, in vivo NAL prevented the endotoxin-induced decrease in LV compliance of the isolated heart preparations (P less than 0.05). Thus intrinsic cardiac complications of early (4 h) nonhypotensive endotoxemia included decreased diastolic compliance as well as diminished contractility of the left ventricle. Only the diastolic compliance changes were NAL responsive and therefore may involve endogenous opioid systems in their pathophysiological expression.
Influence of naloxone on response to acute cardiac tamponade in conscious dogs
Authors: Klopfenstein H. S. , Mathias D. W.
Published: December 2017

During progressive acute cardiac tamponade (CT) in conscious dogs, cardiac output (CO) falls continuously while arterial blood pressure (BP) is well maintained until an abruptly terminal decline. This response is primarily dependent on alpha-adrenergic mechanisms. During hemorrhagic shock, the opioid receptor blocker naloxone increases CO and BP and improves survival perhaps by reversing an opioid-induced cardiovascular depression. We produced 10 episodes of decompensated CT (DCT; 30% decline in BP) by intrapericardial saline infusion (20 ml/min) in five euvolemic conscious dogs. CT resulted in a decrease in CO and BP from base line (3.79 +/- 0.37 l/min and 89.6 +/- 5.2 mmHg, means +/- SE) to DCT (1.35 +/- 0.15 l/min and 57.5 +/- 3.1 mmHg; P less than 0.05). Naloxone (3 mg/kg iv) given at the onset of DCT resulted in a prompt sustained return of BP to base-line levels (P less than 0.05) with no change in CO. Four more animals were studied before and during naloxone (3 mg/kg iv then 0.3 mg.kg-1.min-1 iv). DCT occurred at a higher intrapericardial pressure (20.1 vs. 18.3 mmHg; P less than 0.025) if CT were induced during naloxone treatment than in its absence. Thus naloxone during DCT promptly reversed hypotension with no change in CO and, if present during induction of CT, naloxone allowed slightly higher levels of intrapericardial pressure to be tolerated. Further studies are needed to determine whether naloxone produced these effects solely by its actions on opioid receptors. This study suggests that the interaction between opioid and adrenergic influences plays a role in causing hypotension during CT.
Abolition of long-term vascular influence of renin-angiotensin system
Authors: Randall R. D. , Zimmerman B. G.
Published: December 2017

Rabbits were bilaterally nephrectomized for 24 h or received an angiotensin-converting enzyme (ACE) inhibitor chronically (5 days) before an acute experiment. Conductance responses to sympathetic nerve stimulation (SNS) (0.25, 0.75, and 2.25 Hz) and norepinephrine (NE) administration (0.2, 0.6, and 1.8 micrograms ia) were determined from simultaneous blood pressure and iliac blood flow measurements. Conductance responses to SNS were significantly reduced in nephrectomized (44, 26, and 20%) and chronic ACE inhibition (39, 31, and 24%) groups compared with normal controls, whereas conductance responses to NE were unchanged. Continuous infusion of angiotensin II (ANG II) for 24 h restored the depressed responses to SNS in nephrectomized and chronic ACE inhibition groups compared with normal controls but did not change conductance responses to NE. Acute ACE inhibition did not affect the conductance responses to SNS or NE compared with controls. Vascular tissue ACE activity was inhibited to a similar degree (50%) in both acute and chronic ACE inhibition groups compared with normal rabbits. Sodium depletion increased the conductance responses to SNS (30 and 24% at 0.25 and 0.75 Hz, respectively), but responses to NE were not affected. Chronic ACE inhibition significantly attenuated the conductance responses to SNS and slightly decreased responses to NE in sodium-depleted rabbits. Thus, in the anesthetized rabbit, the renin-angiotensin system potentiates the effect of SNS, presumably by ANG II acting at a prejunctional site, and this effect of ANG II appears to be long term in nature. Therefore, the renin-angiotensin system exerts a physiological role in the control of blood pressure in addition to the ability of this system to support arterial pressure in pathophysiological states.
Arteriolar reactivity in vivo is influenced by an intramural diffusion barrier
Authors: Lew M. J. , Duling B. R.
Published: December 2017

The endothelium of the hamster cheek pouch arteriole in vitro is able to greatly reduce the potency of luminally applied water-soluble drugs by acting as a barrier to diffusion from the lumen to the smooth muscle [Lew, Rivers, and Duling. Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H10-H16, 1989]. Lipid-soluble drugs appear unaffected by the diffusion barrier, presumably because their ability to cross cell membranes allows them to freely cross the endothelium. We compared the effects of two alpha 1-adrenoceptor agonists, phenylephrine (water soluble) and SKF 89748A (lipid soluble), on systemic blood pressure and the arterioles of the hamster cheek pouch in vivo. Both agonists were able to activate the arterioles when applied topically to the outside of the arterioles (extraluminal application). The agonists were also injected as a brief bolus into the aortic arch at doses chosen to elicit similar peak pressor responses. At all levels of pressor response, the arteriolar responses to phenylephrine were smaller than those to SKF 89748A. In the cremasteric vasculature SKF 89748A was similarly found to be more effective in activating the arterioles after intravascular administration than was phenylephrine. We conclude that an intramural diffusion barrier exists in the arteriolar wall in vivo and that it can influence vascular reactivity.
Changes in adrenal oxygen consumption during catecholamine secretion in anesthetized dogs
Authors: Breslow M. J. , Tobin J. R. , Mandrell T. D. , Racusen L. C. , Raff H. , Traystman R. J.
Published: December 2017

Prior attempts to study adrenal medullary O2 metabolism during catecholamine secretion have been unsuccessful because venous blood from medulla mixes with venous blood from the much larger cortex. To circumvent this problem, eight adult mongrel dogs were pretreated for 5-6 wk with the adrenocorticolytic agent 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane (o,p'-DDD). Prednisolone (5 mg/day) and fludrocortisone (0.1 mg.10 kg-1.day-1) were administered orally to prevent adrenocortical insufficiency. Animals were then anesthetized with pentobarbital sodium and subjected to splanchnic nerve stimulation (NS) at 20 and 4 Hz to elicit catecholamine secretion. NS at 20 Hz increased epinephrine secretion from 1.6 +/- 0.7 to 1,780 +/- 762 ng.min-1.g medulla-1 but had no effect on medullary O2 consumption. Medullary blood flow (MQ) increased from 216 +/- 63 to 1,522 +/- 182 ml.min-1.100 g-1, and O2 extraction decreased from 2.7 +/- 0.7 to 0.8 +/- 0.2%. NS at 4 Hz increased epinephrine secretion from 3.1 +/- 1.4 to 76 +/- 17 ng.min-1.g medulla-1 and MQ from 226 +/- 66 to 649 +/- 122 ml.min-1.100 g-1 but had no effect on adrenal O2 consumption or extraction. Cortical blood flow was 342 +/- 98 ml.min-1.100 g-1 at baseline and was unaffected by NS. Gross weight of cortex was reduced by 80% in o,p'-DDD-treated animals, and histological examination of glands from three animals showed only rare islands of glomerulosa cells remaining. These data suggest that increases in MQ during NS do not occur in response to changes in O2 consumption.
Cardiovascular effects of posterior hypothalamic stimulation in baroreflex-denervated rats
Authors: Barron K. W. , Heesch C. M.
Published: December 2017

The overall purpose of this study was to examine the effect of sinoaortic baroreceptor denervation (SAD) on the cardiovascular and sympathetic outflow responses to electrical stimulation of the posterior hypothalamus. In anesthetized rats that had undergone SAD 7-10 days before experimentation, electrical stimulation of the posterior hypothalamus elicited greater increases in mean arterial pressure, iliac vascular resistance, mesenteric vascular resistance, and lumbar sympathetic nerve activity than in sham-operated baroreceptor-intact animals. Similarly, the pressor effects of intravenous norepinephrine were also augmented in the baroreceptor-denervated group compared with the baroreceptor-intact group. When posterior hypothalamic and intravenous norepinephrine pressor stimuli, which produced equivalent pressor responses in sham-operated baroreceptor-intact animals, were compared in baroreceptor-denervated animals, the pressor effects of the central hypothalamic stimulus were enhanced to a greater degree than the norepinephrine pressor effects. These data provide evidence that arterial baroreceptor reflexes exert greater buffering of pressor stimuli initiated from the central nervous system compared with pressor responses due to peripheral vascular vasoconstrictor agents.
Protective effects of an adenosine deaminase inhibitor on ischemia-reperfusion injury in isolated perfused rat heart
Authors: Zhu Q. Y. , Chen S. G. , Zou C. M.
Published: December 2017

We tested the effect of the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenosine (EHNA) on ischemia-reperfusion injury in isolated perfused rat heart. In the ischemia-reperfusion group (n = 10), ventricular fibrillation occurred within 3 min of reperfusion after the 40-min ischemic period. The incidence of ventricular fibrillation was 90% with a mean duration of 3.15 +/- 0.97 (SE) min. Resting tension increased significantly. By contrast, the incidence of ventricular fibrillation after reperfusion in the EHNA-treated (5 microM) group (n = 10) was 20% (P less than 0.01), and the duration was 0.30 +/- 0.21 min (P less than 0.01). Resting tension was significantly lower and around the normal level in the EHNA-treated group (P less than 0.01). Contraction amplitude and heart rate recovered to nearly normal compared with the ischemia-reperfusion group (P less than 0.01). Coronary flow was greater in the EHNA-treated group (P less than 0.01). It is concluded that EHNA protects the heart, possibly by accumulation of adenosine that benefits the hearts and by blocking the xanthine oxidase pathway for free radical generation.
Assessment of muscle blood flow by laser-Doppler flowmetry during hemorrhage in SHR
Authors: Lombard J. H. , Roman R. J.
Published: December 2017

Skeletal muscle blood flow was assessed via laser-Doppler flowmetry (LDF) in the gracilis muscle of anesthetized 12- to 15-wk-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) control rats subjected to graded hemorrhage. Tissue perfusion was assessed at 20 specific sites in the muscle before and 20 min after each of five successive 1-ml withdrawals of blood. Mean LDF signals recorded from the gracilis muscle of SHR and WKY were similar during the prehemorrhage control period. After hemorrhage, mean arterial pressure and calculated vascular resistance of the gracilis muscle were higher in SHR than in WKY, and SHR exhibited a greater reduction of LDF signal in response to hemorrhage than WKY. Although SHR and WKY had a similar number of low flow sites (LDF signal less than 0.17 V) during the control period, successive blood volume withdrawals led to a significantly greater increase in the number of poorly perfused areas in the muscles of the hypertensive animals. The results of this study suggest that LDF is a useful tool to assess tissue perfusion during circulatory stress and that hemorrhage causes a greater decrease in skeletal muscle blood flow in SHR than in WKY. More severe reductions in tissue perfusion may contribute to the reduced ability of hypertensive animals to survive after hypotensive hemorrhage.
Endothelium-dependent, flow-induced dilation of isolated coronary arterioles
Authors: Kuo L. , Davis M. J. , Chilian W. M.
Published: December 2017

Flow-mediated dilation has been documented in large conduit coronary arteries but not in coronary arterioles. The goal of this study was to determine whether this response occurs in coronary arterioles and whether it competes with myogenic constriction. Subepicardial arterioles (40-80 microns) were isolated and cannulated with two glass micropipettes connected to independent reservoir systems. During zero flow, myogenic responses were studied over the range of intraluminal pressure (IP) between 20 and 140 cmH2O. Myogenic constrictions and dilations was observed when IP was increased (greater than 60 cmH2O) and decreased (less than 60 cmH2O), respectively. Flow was initiated by simultaneously moving the reservoirs in equal and opposite directions, thus generating a pressure gradient (delta P) without changing the mean luminal pressure (range delta P = 4-60 cmH2O). Flow-induced responses were studied at low, intermediate, and high myogenic tones by setting IP at 20, 60, and 100 cmH2O, respectively. The threshold for flow-induced dilation was delta P = 4 cmH2O, and maximum dilation was observed at delta P = 20 cmH2O. Red cell velocities in isolated arterioles at delta P of 4 and 60 cmH2O were 1.2 +/- 0.2 and 15.9 +/- 1.3 mm/s, respectively, which are within the range of those reported for coronary microvessels in vivo. The magnitude of the flow-induced dilation was greatest at the intermediate tone (60 cmH2O IP) but was attenuated at lower and higher IP. After mechanical removal of the endothelium, spontaneous tone and myogenic responses were preserved, but flow-induced dilation and bradykinin-induced dilation were abolished.(ABSTRACT TRUNCATED AT 250 WORDS)
Differential effects of hemorrhage on adrenal and renal nerve activity in anesthetized rats
Authors: Togashi H. , Yoshioka M. , Tochihara M. , Matsumoto M. , Saito H.
Published: December 2017

Evidence that sympathetic outflow to organs with different functions reacts nonuniformly to various stimuli has accumulated. To clarify the difference in outflow characteristics of adrenal and renal nerves, the neural and neurochemical mechanisms involved in the response to hemorrhage were examined in anesthetized rats. Hemorrhage (2, 5, and 10 ml/kg) increased adrenal nerve activity (ANA) and decreased renal nerve activity (RNA) in a bleeding volume-dependent manner, accompanied with a decrease in mean arterial blood pressure and heart rate. Bilateral vagotomy attenuated the response in ANA and completely abolished the response in RNA. Sinoaortic denervation (SAD) and vagotomy combined with SAD inversely decreased ANA during hemorrhage. However, SAD appears to have no effect on the response in RNA, which was completely abolished by combined denervation. Our results suggest that the differential effects of hemorrhage on ANA and RNA may be due to different contributions via the afferent neural pathways from the baro- and cardiopulmonary receptors. Because naloxone attenuated the dissociated response to hemorrhage, the endogenous opioid system may be involved.
Myocardial high-energy phosphates in reactive hyperemia
Authors: Schwartz G. G. , Schaefer S. , Gober J. , Meyerhoff D. J. , Smekal A. , Massie B. , Weiner M. W.
Published: December 2017

This study used 31P nuclear magnetic resonance (NMR) spectroscopy to determine whether the magnitude and duration of myocardial reactive hyperemia (RH) reflect a commensurate derangement of myocardial high-energy phosphate (HEP) metabolism, or if coronary blood flow (CBF) and HEP metabolism are dissociated during RH. Twelve open-chest anesthetized pigs were studied during and after 24 s occlusion of the anterior descending coronary artery. CBF velocity was measured with a Doppler probe. NMR time resolution (4.8 s) was obtained by summing corresponding short blocks of data from multiple occlusions. During occlusion, phosphocreatine (PCr) declined to 65 +/- 5% (mean +/- SE) of control accompanied by increased spectral intensity of the Pi + phosphomonester region. By 20 s of reflow, HEPs had returned to control levels, but CBF was still elevated at 282 +/- 18% of control and remained elevated for an additional 53 +/- 7 s, during which 44 +/- 6% of total RH flow occurred. Therefore, the control of CBF is not closely coupled to the levels of myocardial HEPs during RH and the duration of RH does not reflect prolonged depletion of myocardial HEPs.
Positive inotropic effects of low concentrations of leukotrienes C4 and D4 in rat heart
Authors: Karmazyn M. , Moffat M. P.
Published: December 2017

We examined the effects of leukotrienes (LT) B4, C4, D4, and E4 (0.010-2.5 ng/ml) on contractile and coronary function in isolated rat hearts. Concentration-dependent effects were examined either by the cumulative addition of LTs or by addition of specific concentrations to individual preparations. Neither LTB4 nor LTE4 produced myocardial or coronary effects at any concentration, irrespective of addition protocol. At 0.010 ng/ml, both LTC4 and LTD4 produced an increase in force that was associated with a 30% elevation in coronary pressure. Further cumulative addition of either leukotriene resulted in a negative inotropic effect and a further increase in coronary pressure. In contrast, following single additions of LTC4 or LTD4 (0.01-0.50 ng/ml) a positive inotropic effect and an increased coronary pressure were observed. LTC4 or LTD4 at 0.5 ng/ml produced a negative inotropic effect in hearts pretreated with 0.01 ng/ml of LTD4 or LTC4, respectively. Reversal of this addition protocol resulted in a negative inotropic effect of either 0.01 ng/ml LTD4 or LTC4. Verapamil and nifedipine significantly attenuated the positive inotropic and coronary constricting effect of 0.5 ng/ml LTC4 and LTD4. The addition of either LT following BAY K 8644 resulted in a negative inotropic effect, in contrast to the positive inotropic influence seen with leukotriene alone. Our results demonstrate a positive inotropic effect of low concentrations of LTC4 and LTD4 concomitant with coronary artery constriction, a phenomenon determined by leukotriene addition protocols and suggestive of LTC4/LTD4 receptor interaction. The effects of calcium channel antagonists and BAY K 8644 on the inotropic response suggest a leukotriene-mediated activation of the calcium channel resulting in increased intracellular calcium concentrations.
Atrial natriuretic factor release and natriuresis in rats with high-output heart failure
Authors: Garcia R. , Lachance D. , Thibault G.
Published: December 2017

We investigated whether rats with high-output heart failure [aortocaval (AC) shunts] release atrial natriuretic factor (ANF) and excrete sodium after moderate volume expansion (VE) as do sham-operated controls. Mean arterial blood pressure was lower (92.5 +/- 4.4 vs. 114.0 +/- 1.3 mmHg) and relative heart weight was higher (545.6 +/- 35.1 vs. 253.8 +/- 9.8 mg/100 g body wt) in animals with AC shunts than in their controls. Central venous pressure (CVP) was elevated (3.61 +/- 0.36 vs. 0.37 +/- 0.94 mmHg) and heart rate decreased (332.5 +/- 8 vs. 370.0 +/- 9.9 beats/min) in AC rats. This group also presented lower basal urinary sodium excretion (UNaV), urinary volume, and hematocrit than their sham-operated controls. Basal plasma COOH- and NH2-terminal ANF levels were greatly elevated in AC shunt animals (165.43 +/- 55.73 and 1,692.98 +/- 305.63 fmol/ml, respectively) when compared with the controls (14.27 +/- 1.49 and 331.67 +/- 29.84 fmol/ml, respectively). VE was performed in conscious rats 3 times at 15-min intervals with human plasma protein fraction. The effect of VE on CVP, left-ventricular end-diastolic pressure, the increases in plasma COOH- and NH2-terminal ANF, and the diuretic and natriuretic responses were similar in both experimental groups. U(NA)V was positively correlated with plasma COOH- (r = 0.50, P less than 0.01) and NH2- (r = 0.60, P less than 0.001) terminal ANF only in the controls. One main peak of immunoreactive ANF corresponding to the elution time of a small peptide such as ANF-(99-126) was detected in the plasma of AC animals after VE. We conclude that ANF release and natriuresis are conserved after moderate VE in a rat model of moderate high-output experimental heart failure.
Autoradiographic delineation of skeletal muscle alpha 1-adrenergic receptor distribution
Authors: Martin W. H. , Tolley T. K. , Saffitz J. E.
Published: December 2017

We used light microscopic autoradiography to quantify the distribution of alpha 1-adrenergic receptors in vessels and muscle fibers of slow-twitch (type I), fast-twitch (types IIa and IIb), and mixed fiber muscles of the rat hindquarter. Frozen cross sections of soleus, vastus lateralis, and gastrocnemius muscles were incubated under equilibrium binding conditions with 10-200 pM [3H]prazosin with or without 10(-5) M phentolamine. Because of the low concentration of bound radioligand, specific binding could not be detected with scintillation spectrometry in whole tissue sections scraped from slides. However, quantitative autoradiographic analysis after extended intervals of emulsion exposure revealed a low but significant level of specific binding in muscle fibers. No difference in alpha 1-receptor density was observed among types I, IIa, and IIb fibers. Small blood vessels had a much greater alpha 1-receptor density than muscle fibers. Resistance arterioles (20-100 microns diam) and small arteries (100-500 microns diam) contained 5.8 +/- 0.9 and 31.6 +/- 7.6 (+/- SE) times more binding sites per unit section area, respectively, than did surrounding muscle fibers (both P less than 0.001). Ratios of specific grain densities in fibers and blood vessels did not vary with radioligand concentration, indicating that observed grain densities reflected differences in receptor concentration rather than radioligand affinity by fiber and vessel receptors. The densities of vascular alpha 1-receptors did not vary in slow- and fast-twitch muscles, but resistance arterioles were six and eight times more numerous in soleus than in gastrocnemius and vastus muscles, respectively (both P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Comparison between force-velocity and end-systolic pressure-volume characterization of intrinsic LV function
Authors: van der Linden L. P. , van der Velde E. T. , Bruschke A. V. , Baan J.
Published: December 2017

We reanalyzed experiments in in situ hearts of 16 open-chest anesthetized dogs, in which two different loading interventions were performed, i.e., an occlusion of the descending aorta (InP) and a rapid volume infusion (InV). Previous studies had demonstrated that the end-systolic elastance (Ees) of the InP was substantially larger than the Ees of the InV suggesting either a load dependency of Ees as such, or an increase in contractility during InP. The data were reanalyzed in the light of the muscular pump concept by plotting peak normalized velocity of circumferential shortening versus a global representative force approximating the left ventricle by a sphere. In all but one experiment the points of the two interventions are located on a single relationship over a very broad range of forces (from 397 to 2,461 g between the control states of experiments and from 602 to 3,278 g difference between control and highest load within experiments). The virtual independence of the force-velocity relation (FVR) and the dependence of the end-systolic pressure-volume relation (ESPVR) on the type of loading intervention can be ascribed to the fact that the former is assessed early during ejection and is therefore less influenced by shortening deactivation and internal resistance than the ESPVR. We conclude that the FVR offers a more consistent characterization of intrinsic LV function than the ESPVR.
Interstitial adenosine in guinea pig hearts: an index obtained by epicardial disks
Authors: Tietjan C. S. , Tribble C. G. , Gidday J. M. , Phillips C. L. , Belardinelli L. , Rubio R. , Berne R. M.
Published: December 2017

Epicardial porous disks were used to estimate left ventricular interstitial fluid adenosine in the isolated guinea pig heart perfused at constant flow. To validate this technique, adenosine was infused with 0.5 microM dipyridamole and 5 microM erythro-4-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA) to inhibit adenosine uptake and deamination, respectively. Under these conditions, with 6 or 12 microM adenosine in the arterial infusate, the venous and steady-state left ventricular disk adenosine values equaled those of the perfusion fluid, reflecting the expected equilibration between vascular and left ventricular interstitial fluid (disk) compartments. The concentration of endogenous adenosine in the interstitial fluid as estimated by the epicardial disks under control conditions was 0.28 +/- 0.03 microM with a concomitant coronary sinus concentration of 0.004 +/- 0.001 microM. We conclude that a marked adenosine gradient exists between the interstitial fluid and the vascular space and that disk adenosine measurements provide a useful index of left ventricular interstitial fluid adenosine.
Abluminal effects of endothelin in cerebral microvasculature assessed by laser-Doppler flowmetry
Authors: Willette R. N. , Sauermelch C. F.
Published: December 2017

Laser-Doppler flowmetry was used to assess the intraparenchymal effects of endothelin 1 (ET-1) on cortical microvascular perfusion (CP). The initial part of this study examined effects of the intraparenchymal microinjection technique on local cortical microvascular responsivity. In anesthetized rats, the microinjection of vehicle (saline) beneath the cortical surface did not alter CO2 responsivity or autoregulation of the cortical microvasculature. In addition, predictable monophasic changes in local CP were elicited by the intraparenchymal microinjection of known vasodilators and vasoconstrictors, i.e., nitroprusside and prostaglandin F2 alpha, respectively. These experiments demonstrate normal responsivity of the cortical microvasculature after intraparenchymal microinjection. In the second part of this study, intraparenchymal microinjections (100 nl) of ET-1 (1-1,000 fmol) were evaluated. Microinjections of less than 10 fmol of ET-1 did not alter CP. However, doses between 10 and 1,000 fmol of ET-1 elicited monophasic dose-related reductions in CP. At 1,000 fmol, the highest dose studied, ET-1 produced a complex microvascular response consisting of an initial profound reduction in CP followed by alternating cycles of increased perfusion ultimately lapsing back to a prolonged period of hypoperfusion. No significant changes in blood pressure were observed after ET-1 administration, and no significant changes in any of the hemodynamic variables were observed after vehicle microinjection. These results suggest that abluminal microvascular actions of ET-1 mediate cerebral vasoconstriction and hypoperfusion.
Lanthanum blocks a specific component of IK and screens membrane surface change in cardiac cells
Authors: Sanguinetti M. C. , Jurkiewicz N. K.
Published: December 2017

Delayed rectifier outward K+ current (IK) in guinea pig ventricular myocytes represents the sum of two currents: a slowly activating delayed rectifier K+ current (IK.s) and a relatively rapidly activating delayed rectifier K+ current (IK.r), which rectifies at positive potentials and is specifically blocked by the class III antiarrhythmic agent, E-4031. La3+ was previously reported to block an unidentified component of IK in these cells. We used the whole cell voltage-clamp technique on isolated myocytes and confirmed these results: we show that the current blocked by La3+ (greater than or equal to 1 microM) is IK.r. This block is not caused by La3+ displacement of surface-bound Ca2+. Thus, in the presence of either E-4031 or La3+, IK represents the activation of a single current, IK.s. La3+ (10 microM-1 mM) also caused a positive shift in the voltage dependence of the activation curve of IK.s. When we assumed that La3+ acts to bind and screen negative surface charges on the outer sarcolemmal membrane, the external surface potential of these cells (in 1.8 mM Ca2+) could be estimated to be -19 mV. A modification of the Gouy-Chapman equation was used to estimate the equilibrium constant for La3+ binding (10.7 mM-1) and the minimum spacing between the negative charges on the surface membrane (22 A).