bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential sympathetic regulation of automatic, conductile, and contractile tissue in dog heart
Authors: Ardell J. L. , Randall W. C. , Cannon W. J. , Schmacht D. C. , Tasdemiroglu E.
Published: December 2017

Sympathetic pathways mediating chronotropic, dromotropic, and inotropic responses during ansae subclavia stimulation were determined by sequential dissection around major cardiac vessels. Right sympathetic (RS) projections influencing ventricular contractile force converge at the common pulmonary artery and within the pulmonary artery nerves (PAN). RS projections influencing left atrial contractile force course within the PANs. RS pathways to pacemaker and right atrial contractile tissue were localized between the superior vena cava and ascending aorta. RS projections influencing conductile tissue converge between the common pulmonary artery and proximal right pulmonary artery. Left sympathetic (LS) projections to ventricular contractile tissue were localized at the common pulmonary artery, within the PANs, and in the ventral lateral cardiac nerve (VLCN). LS pathways influencing heart rate and conductile tissue were localized at the left pulmonary artery and coursing between the right pulmonary artery and left superior pulmonary vein. LS projections to atrial contractile tissue were localized within the PANs and coursing between the right pulmonary artery and left superior pulmonary vein. We conclude that there are parallel, yet distinct, projections of sympathetic efferents to automatic, conductile, and contractile tissue of the canine heart.
Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury
Authors: Granger D. N.
Published: December 2017

In this lecture, evidence is presented to support the following hypothesis regarding the roles of xanthine oxidase-derived oxidants and granulocytes in ischemia-reperfusion-induced microvascular injury. During the ischemic period, ATP is catabolized to yield hypoxanthine. The hypoxic stress also triggers the conversion of NAD-reducing xanthine dehydrogenase to the oxygen radical-producing xanthine oxidase. During reperfusion, molecular oxygen is reintroduced into the tissue where it reacts with hypoxanthine and xanthine oxidase to produce a burst of superoxide anion and hydrogen peroxide. In the presence of iron, superoxide anion and hydrogen peroxide react via the Haber-Weiss reaction to form hydroxyl radicals. This highly reactive and cytotoxic radical then initiates lipid peroxidation of cell membrane components and the subsequent release of substances that attract, activate, and promote the adherence of granulocytes to microvascular endothelium. The adherent granulocytes then cause further endothelial cell injury via the release of superoxide and various proteases.
Cardiovascular and sympathoadrenal responses to mental stress: influence of beta-blockade
Authors: Freyschuss U. , Hjemdahl P. , Juhlin-Dannfelt A. , Linde B.
Published: December 2017

Cardiovascular, sympathoadrenal, and subjective responses to mental stress induced by a color-word conflict test (CWT) were studied in 30 healthy males before and after intravenous administration of either placebo, beta 1-blockade by metoprolol (0.15 mg/kg), or nonselective beta-blockade by propranolol (0.15 mg/kg). CWT responses were reproducible. Mean arterial pressure increased by 20%. A mainly heart rate-dependent 65% increase in cardiac output (thermodilution) was associated with 25% decreases of both systemic (SVR) and calf vascular (CVR) resistances. Arterial plasma epinephrine (Epi) was doubled, and norepinephrine (NE) increased by 50%. Self-evaluated stress score correlated positively with changes in cardiac output and inversely with changes in SVR during CWT. Both metoprolol and propranolol halved heart rate responses; whereas increases in mean arterial pressure, Epi, and NE were uninfluenced. Metoprolol reduced the increase in stroke volume, and propranolol abolished it. SVR and CVR responses were attenuated by metoprolol and abolished by propranolol. The results suggest that mental stress accelerates the heart through neurogenic mechanisms and that peripheral vasodilatation is achieved through the concerted actions of reduced vasoconstrictor activity and elevated circulating Epi.
Intralipid effect on normal and hypoxic remodeled rat pulmonary vasculature
Authors: Ilkiw R. , Maruyama K. , Rabinovitch M.
Published: December 2017

Intralipid (IL) infusion has been associated with pulmonary vasoconstriction and decreased oxygenation and may worsen preexisting pulmonary vascular changes. To investigate this, we infused IL or 0.9% saline for 1 wk in normal Sprague-Dawley rats and in rats with vascular changes induced by a previous 2-wk exposure to chronic hypobaric hypoxia (air at 380 mmHg). At postmortem we quantitatively evaluated arterial changes in the left lung by light microscopy and alterations in endothelial cells in the right lung by electron microscopy. In rats maintained in room air, 1-wk IL infusion resulted in extension of muscle into alveolar wall and duct arteries (P less than 0.001 for both), medial hypertrophy of arteries 50–99 microns external diameter (P less than 0.01), reduced arterial density (P less than 0.05), and an increase in volume density of endothelial smooth endoplasmic reticulum (P less than 0.05). In post-hypoxia rats, however, IL infusion did not induce further progression of the more severe arterial and endothelial changes observed. To determine whether IL-associated vascular abnormalities may be related to vasoconstriction, different rats were instrumented under pentobarbital sodium anesthesia with indwelling cardiovascular catheters and, 2 days later, with the animals fully conscious, the hemodynamic response assessed. An acute 15-min IL infusion caused a significant increase in pulmonary artery pressure and mild hypoxemia (P less than 0.05 for both) in room air rats but not in the posthypoxia group. This response was not, however, sustained over a 2-day IL infusion. Thus IL induces pulmonary vascular abnormalities that do not appear to be related to vasoconstriction or hypoxemia. We speculate that differences in endothelial metabolism of IL in room air and posthypoxia rats may explain the lack of IL-related abnormalities in the latter group.
Sympathetic outflow to resting muscles during static handgrip and postcontraction muscle ischemia
Authors: Wallin B. G. , Victor R. G. , Mark A. L.
Published: December 2017

Simultaneous microneurographic recordings were made of muscle sympathetic activity (MSA) in the radial and the peroneal nerves of seven healthy subjects during 2-min static handgrip (30% of maximal voluntary contraction) followed by 2 min of forearm ischemia induced by arterial occlusion. At rest sympathetic burst frequency was similar in both nerves, but relative burst strengths differed between the two neurograms, suggesting that sympathetic outflows to arm and leg were not identical. Both radial and peroneal MSA were unchanged during the first minute of handgrip and increased to a similar degree during the second minute. Thus previously reported differences in vascular resistance between forearm and calf during static handgrip cannot be explained by differences in MSA to arm and leg muscles. During forearm ischemia after handgrip, peroneal MSA remained at the same level as during the second minute of handgrip but there was a further increase of radial MSA. This shows that stimulation of chemosensitive endings in forearm muscles induces differentiation of sympathetic neural outflow to muscles in the leg and the contralateral arm.
Transfer function analysis of autonomic regulation. I. Canine atrial rate response
Authors: Berger R. D. , Saul J. P. , Cohen R. J.
Published: December 2017

We present a useful technique for analyzing the various functional components that comprise the cardiovascular control network. Our approach entails the imposition of a signal with broad frequency content as an input excitation and the computation of a system transfer function using spectral estimation techniques. In this paper, we outline the analytical methods involved and demonstrate the utility of our approach in studying the dynamic behavior of the canine cardiac pacemaker. In particular, we applied frequency-modulated pulse trains to either the right vagus or the cardiac sympathetic nerve and computed transfer functions between nerve stimulation rate and the resulting atrial rate. We found that the sinoatrial node (and associated automatic tissue) responds as a low-pass filter to fluctuations in either sympathetic or parasympathetic tone. For sympathetic fluctuations, however, the filter has a much lower corner frequency than for vagal fluctuations and is coupled with a roughly 1.7-s pure delay. We further found that the filter characteristics, including the location of the corner frequency and rate of roll-off, depend significantly on the mean level of sympathetic or vagal tone imposed.
Free radical defense mechanisms and neutrophil infiltration in postischemic skeletal muscle
Authors: Smith J. K. , Grisham M. B. , Granger D. N. , Korthuis R. J.
Published: December 2017

A growing body of experimental data indicates that reactive oxygen metabolites such as superoxide, hydrogen peroxide, and hydroxyl radicals may mediate the microvascular and parenchymal injury produced by reperfusion of ischemic skeletal muscle. One potential source of these reactive oxygen metabolites is the inflammatory neutrophil. To assess neutrophil accumulation in postischemic skeletal muscle, we measured tissue myeloperoxidase (MPO) activity in skeletal muscle biopsies taken during control, after 4 h of ischemia, and after 1 h of reperfusion. Tissue levels of reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were measured in the same samples to identify alterations in tissue free radical defense mechanisms due to ischemia-reperfusion. Reperfusion of ischemic skeletal muscle was associated with a dramatic increase in tissue neutrophil content (as reflected by a 26-fold increase over control in tissue MPO activity after 1 h of reperfusion) and a concurrent 50% decrease in GSH content. Tissue CAT and SOD activities were unaffected by ischemia-reperfusion. These results suggest a possible relationship between ischemia-reperfusion-induced injury, neutrophil infiltration, and the reduction in tissue GSH.
Serial study of factors influencing changes in cardiac output during human pregnancy
Authors: Robson S. C. , Hunter S. , Boys R. J. , Dunlop W.
Published: December 2017

Serial hemodynamic measurements were performed in 13 women on two occasions before conception and then at monthly intervals throughout pregnancy. Cardiac output (CO) was measured by Doppler and cross-sectional echocardiography at the aortic, pulmonary, and mitral valves. Cardiac chamber size and ventricular function were investigated by M-mode echocardiography. CO increased from a mean of 4.88 l/min before the conception to a maximum of 7.21 l/min at 32 wk, the increase being significant by 5 wk after the last menstrual period. Heart rate and left ventricular performance increased during the first trimester. Heart rate increased further during the second trimester, during which left atrial and left ventricular end-diastolic dimensions increased, suggesting an increase in venous return. Derived values of total peripheral vascular resistance fell during the first 20 wk. These changes were associated with a progressive increase in valve orifice area and left ventricular wall thickness during pregnancy.
Capillary tortuosity in rat soleus muscle is not affected by endurance training
Authors: Poole D. C. , Mathieu-Costello O. , West J. B.
Published: December 2017

The total capillary length available for blood-tissue transfer is determined by the number and orientation of the capillaries. Therefore, whether capillary tortuosity changes with exercise training has important implications for peripheral gas exchange. To determine the effects of exercise training on capillary orientation and capillary length per volume of muscle fiber [Jv(c,f)] female rats were trained by treadmill running (30 m/min, up to 60 min/day, 5 days/wk) for 4 wk. Muscles from control and trained rats were perfusion fixed at sarcomere lengths (l) ranging from 1.59 to 2.15 microns, and morphometric techniques were used to estimate capillary orientation and Jv(c,f). Training increased (P less than 0.05) musculus soleus oxidative capacity 35% [as estimated from citrate synthase activity: 24.7 +/- 1.4 to 34.7 +/- 1.0 (SE) mumol.g-1.min-1], capillary-to-fiber ratio 30% (2.17 +/- 0.06 to 2.83 +/- 0.05), and Jv(c,f) 32% (1,886 +/- 73 to 2,496 +/- 180 mm-2). Capillary tortuosity (as determined from comparisons of transverse and longitudinal sections) was a direct function of l in control and trained rats and contributed 17-73% of capillary length above that estimated from capillary counts on transverse sections. We conclude that capillary tortuosity in m. soleus is unchanged by training. Therefore, Jv(c,f) increases as a consequence of increased capillary number. M. soleus citrate synthase activity is best correlated with Jv(c,f) and not with capillary counts on transverse sections. We hypothesize that training-induced muscle changes of capillary geometry improve O2 delivery to skeletal muscle and may therefore alter the metabolic response (e.g., lactate accumulation) to exercise after training.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of long-term tilt on mechanical and electrical properties of rat saphenous vein
Authors: Monos E. , Contney S. J. , Cowley A. W. , Stekiel W. J.
Published: December 2017

Femoral vein pressure in adult male Sprague-Dawley rats kept in specially designed tubelike cages rose immediately from a control value of 2.9 +/- 0.2 (SE) mmHg to a gravity-induced sustained value of 5.9 +/- 0.2 mmHg on initiation of a 2-wk 45 degrees head-up tilt period. Femoral arterial pressure was not altered by tilting. In 2 wk mean external diameter, but not total wall thickness, of in vitro distal saphenous vein segments from tilted rats was increased approximately 30% above that of segments from nontilted controls at each of four successive 5-mmHg intralumenal pressure (IP) increments applied between 0 and 20 mmHg. Consequently, in tilted rats isobaric stress was increased 38% at low and 24% at high IP, whereas incremental distensibility was decreased at mid IP. Vascular smooth muscle (VSM) in tilted rat vein, but not artery, was hyperpolarized relative to controls both in vitro at normal physiological pressures [membrane potential (Em) = -58.2 +/- 0.8 vs. -52.4 +/- 0.8 mV, respectively] and in situ during local neural blockade (Em = -61.3 +/- 2.3 vs. -53.5 +/- 0.5 mV, respectively). The conclusion is that a moderate chronic elevation of IP in a vein results in hyperpolarization of its VSM and an elevation of its total capacity due to an as yet unexplained mechanism of physiological adaptation.
Adaptations of carotid arteries of young and mature rabbits to reduced carotid blood flow
Authors: Langille B. L. , Bendeck M. P. , Keeley F. W.
Published: December 2017

Adaptive responses of rabbit common carotid arteries were examined after 70-80% reductions in blood flow produced by ipsilateral external carotid artery ligation. These flow reductions elicited growth inhibition of arterial wall tissue in immature rabbits. Specifically, experimental carotid arteries exhibited DNA levels significantly lower, by 35%, than contralateral control arteries 1 mo after external carotid ligation. Lower elastin contents (38%) were also observed, although collagen contents were not affected. These changes were accompanied by a relative reduction in wall mass of 30% and a 31% reduction in internal diameter. Adult rabbits exhibited decreased internal diameter (21%) after flow reduction, but no significant change in vessel mass or wall constituents was observed. Early diameter reductions were vasoconstrictor in origin, but the vessel functioned as a smaller artery rather than as a partially constricted normal vessel after 1 mo, i.e., both maximally dilated and maximally constricted diameters were reduced. A reduction in endothelial cell number was detected for the narrowed vessels. Manipulation of local flow conditions indicated that the vessels responded to changes in mean blood flow rather than the pulsatile component of flow.
Chronic whole body sympathectomy fails to protect ischemic rabbit hearts
Authors: Matsuki T. , Cohen M. V. , Holt G. , Ayling J. , Hearse D. J. , Downey J. M.
Published: December 2017

We determined whether chronic chemical sympathetic denervation could protect the rabbit heart against ischemia. Rabbits received 10 mg/kg 6-hydroxydopamine (6-HD) twice during the first week, then 100 mg.kg-1.wk-1 for the following 7 wk. After this interval the rabbits were anesthetized, the chests were opened, and in each a coronary branch was occluded for 45 min followed by reperfusion for 3 h. Collateral flow was determined with radioactive microspheres during coronary occlusion. Flow to the ischemic myocardium of the 6-HD group (0.06 +/- 0.03 ml.min-1.g-1) was not significantly different from that in the control group (0.04 +/- 0.02 ml.min-1.g-1). Infarct size was determined with triphenyltetrazolium chloride staining. Average infarct size calculated as a percentage of risk zone was similar in the 6-HD and control groups (59 +/- 15 and 60 +/- 12%, respectively). We conclude that chronic chemical sympathectomy does not induce collateral growth in the rabbit heart. Furthermore, endogenous catecholamines do not contribute to injury in the ischemic rabbit heart.
Pentobarbital anesthesia alters pulmonary vascular response to neural antagonists
Authors: Nyhan D. P. , Goll H. M. , Chen B. B. , Fehr D. M. , Clougherty P. W. , Murray P. A.
Published: December 2017

We investigated the effects of pentobarbital sodium anesthesia on vasoregulation of the pulmonary circulation. Our specific objectives were to 1) assess the net effect of pentobarbital on the base-line pulmonary vascular pressure-to-cardiac index (P/Q) relationship compared with that measured in conscious dogs, and 2) determine whether autonomic nervous system (ANS) regulation of the intact P/Q relationship is altered during pentobarbital. P/Q plots were constructed by graded constriction of the thoracic inferior vena cava, which produced stepwise decreases in Q. Pentobarbital (30 mg/kg iv) had no net effect on the base-line P/Q relationship. In contrast, changes in the conscious intact P/Q relationship in response to ANS antagonists were markedly altered during pentobarbital. Sympathetic alpha-adrenergic receptor block with prazosin caused active pulmonary vasodilation (P less than 0.01) in conscious dogs but caused vasoconstriction (P less than 0.01) during pentobarbital. Sympathetic beta-adrenergic receptor block with propranolol caused active pulmonary vasoconstriction (P less than 0.01) in both groups, but the magnitude of the vasoconstriction was attenuated (P less than 0.05) during pentobarbital at most levels of Q. Finally, cholinergic receptor block with atropine resulted in active pulmonary vasodilation (P less than 0.01) in conscious dogs, whereas vasoconstriction (P less than 0.01) was observed during pentobarbital. Thus, although pentobarbital had no net effect on the base-line P/Q relationship measured in conscious dogs, ANS regulation of the intact pulmonary vascular P/Q relationship was altered during pentobarbital anesthesia.
Low-frequency oscillations in arterial pressure and heart rate: a simple computer model
Authors: Madwed J. B. , Albrecht P. , Mark R. G. , Cohen R. J.
Published: December 2017

We have previously reported that low-frequency oscillations in arterial blood pressure (ABP) and heart rate (HR) occur when conscious dogs experience severe blood loss. These low-frequency oscillations are generated by enhancement of the sympathetic nervous system and inhibition of the parasympathetic nervous system. We have developed a simple computer model to elucidate those properties critical to the generation of these oscillations. Our model incorporates several important features: 1) arterial baroreceptor feedback loops, which relate ABP to targeted HR and total peripheral resistance (TPR) values; 2) two effector outputs, HR and TPR, which are controlled by the outputs of vagal, beta-adrenergic, and alpha-adrenergic effector mechanisms; 3) a fixed beat-to-beat stroke volume; and 4) a wind-kessel model, which represents the peripheral circulation. Each effector mechanism is modeled as a low-pass filter in series with a delay. The vagal effector mechanism slows the HR after a 100-ms delay and reaches maximal HR at that time. The beta-adrenergic effector mechanism speeds HR after a 2.5-s delay and then increases to maximal HR 7.5 s later. The alpha-adrenergic effector mechanism begins vasoconstriction after a 5-s delay and then reaches maximal contraction 15 s later. Computer simulations of inhibition of the vagal effector mechanism and activation of the adrenergic effector mechanisms elicit low-frequency oscillations in ABP and HR. These oscillations are similar to those observed experimentally in the dog during hemorrhage. We conclude that the slow temporal response of the alpha-adrenergic effector mechanism controlling TPR is the critical element in predicting the observed low-frequency oscillations in ABP and HR.
Hypoxia stimulates release of endothelium-derived relaxant factor
Authors: Pohl U. , Busse R.
Published: December 2017

It was tested whether hypoxia stimulates the release of endothelium-derived relaxant factor (EDRF). In paired segments (with and without endothelium) of either femoral artery (n = 49) or aorta (n = 42) from rabbits, selective luminal hypoxia (Po2 = 24 +/- 8 mmHg) was induced, whereas the Po2 at the adventitial side was kept above 300 mmHg. Hypoxia induced a dilation of 11 +/- 2% in aortic segments with endothelium, whereas the paired segments without endothelium dilated by only 1.2 +/- 0.2% (P less than 0.001). Similar results were obtained in femoral segments (11.8 +/- 1.5% dilation in segments with endothelium vs. 1.4 +/- 0.2% in segments without; P less than 0.001). Likewise in 19 out of 36 bioassay experiments, perfusate from endothelium-intact rabbit aortas or cultured bovine aortic endothelial cells exposed to hypoxia elicited dilation (10.7 +/- 3.2%) in the detector. The EDRF-inhibitors, hemoglobin (5 microM) and dithiothreitol (200 microM), significantly inhibited the hypoxia-induced dilation of intact segments as well as of assay segments perfused with effluent from hypoxic donors. These results suggest that hypoxia stimulates the release of EDRF from native and cultured endothelium. Low partial pressures of oxygen, such as those that exist in small arteries and arterioles, might therefore be a physiological stimulus for continuous release of EDRF.
Effect of enkephalins on cardiac output and regional blood flow in conscious dogs
Authors: Rosen C. L. , Cote A. , Haddad G. G.
Published: December 2017

To investigate the effects of enkephalins on cardiac output and regional blood flow, we administered D-Ala-D-Leu-enkephalin (DADLE) intracisternally (ic) to 14 chronically instrumented unanesthetized dogs. Measurements were made at base line, 20, 45, and 75 min after DADLE (25 or 125 micrograms/kg) and 15 min after naloxone (5 micrograms/kg ic). After 125 micrograms/kg DADLE, all animals developed hypoventilation, bradycardia, and decreased O2 consumption without hypotension. Cardiac output decreased (-34%), but brain blood flow increased (+110%). Blood flow decreased to the diaphragm (-38%), heart (-21%), skeletal muscle (-40%), skin (-67%), pancreas (-79%), and gastrointestinal tract (-26%). After 25 micrograms/kg DADLE, there were no consistent changes in cardiac output or regional blood flow. Four additional animals (without DADLE) were exposed to altered inspired gases to reproduce the blood gas changes after DADLE. These animals developed hyperventilation without bradycardia and increased brain (+114%) and diaphragm (+649%) blood flow. We conclude that centrally administered enkephalins produce 1) a parallel decrease in ventilation, heart rate, O2 consumption, and cardiac output and 2) a major blood flow redistribution, primarily dictated by the effects of opioids on ventilation, heart rate, and metabolism.
Alpha 2-adrenoceptor stimulation can augment coronary vasodilation maximally induced by adenosine in dogs
Authors: Hori M. , Kitakaze M. , Tamai J. , Iwakura K. , Kitabatake A. , Inoue M. , Kamada T.
Published: December 2017

To determine whether alpha 2-adrenoceptor stimulation can augment adenosine-induced coronary vasodilation, 34 open-chest dogs were studied. When a small dose of clonidine (up to 0.24 micrograms.kg-1.min-1 ic) was administered under beta-adrenoceptor blockade, coronary blood flow [312 +/- 16 (SE) ml.100 g-1.min-1] maximally induced by intracoronary infusion of adenosine was further increased (P less than 0.05) by 66 +/- 16 ml.100 g-1.min-1, despite no significant changes in coronary perfusion pressure, myocardial oxygen consumption, and coronary venous adenosine concentration. However, when a larger dose of clonidine (0.36–0.60 micrograms.kg-1.min-1) was infused, adenosine-induced flow progressively decreased. This biphasic action of the alpha 2-adrenoceptor activity was also observed when the dose of norepinephrine was increased during alpha 1-adrenoceptor blockade with prazosin. Norepinephrine up to 0.24 micrograms.kg-1.min-1 (ic) further increased adenosine-induced coronary blood flow by 24 +/- 5% (P less than 0.001), whereas hyperemic flow was decreased by a larger dose of norepinephrine. In contrast to the alpha 2-adrenoceptor stimulation, the alpha 1-adrenoceptor stimulation (norepinephrine with yohimbine) progressively decreased coronary blood flow. Furthermore, with a small dose of clonidine, reactive hyperemic flow significantly increased compared with that without clonidine (303 +/- 13 vs. 355 +/- 13 ml.100 g-1.min-1, P less than 0.001), but a larger dose of clonidine adversely reduced reactive flow (254 +/- 18 ml.100 g-1.min-1, P less than 0.001). Adenosine release during reactive hyperemia with and without intracoronary infusions of clonidine were not altered significantly.(ABSTRACT TRUNCATED AT 250 WORDS)
Trypsin activation of atrial muscarinic K+ channels
Authors: Kirsch G. E. , Brown A. M.
Published: December 2017

The atrial muscarinic K+ channel normally is opened by the activated G protein, Gk. Based on the assumption that an inactivating particle keeps the channel closed, several protein-modifying agents including trypsin, papain, glyoxal, and phenylglycoxal that remove Na+-channel inactivation were tested. K+ channels were studied in inside-out excised membrane patches from primary cultures of neonatal rat atrial myocytes. Of the agents tested, only trypsin activated muscarinic K+ channels, and it did so irreversibly. Trypsin was effective in the absence of muscarinic agonist or intracellular Mg2+ and guanosine 5'-triphosphate. Heat-denatured trypsin was ineffective, and trypsin inhibitor blocked the effect. Because trypsin is known to inactivate G proteins, the effect was probably on the K+ channel or a structure closely associated with it. Trypsin activation produced single-channel currents in which inward rectification, single-channel conductance, mean open time, and burst duration were indistinguishable from muscarinic activation. Trypsin cleaves proteins at lysine or arginine residues, and the arginine-specific reagents, glyoxal and phenylgloxal, did not activate K+ channels. We conclude that trypsin disrupts an inhibitory gating mechanism that normally holds the channel closed in the absence of activated Gk. The inhibitory gate is physically distinct from the gate that mediates bursting and must contain at least one trypsin cleavage point located at a lysine residue accessible from the cytoplasmic surface of the cell membrane.
Selective inhibition of angiotensin II-mediated vasoconstriction by lipoxygenase blockade
Authors: Stern N. , Golub M. , Nozawa K. , Berger M. , Knoll E. , Yanagawa N. , Natarajan R. , Nadler J. L. , Tuck M. L.
Published: December 2017

We have previously demonstrated that the lipoxygenase (LO) pathway has a specific role in the effect of angiotensin II (ANG II) on aldosterone secretion. To elucidate whether the LO pathway also participates in the vascular effects of ANG II, the nonselective LO inhibitor phenidone (PHE; 30 mg/kg) was administered to rats 1 h before graded dose ANG II infusion. PHE reduced the LO product 12-hydroxyeicosatetraenoic acid (12-HETE) in deendothelialized aortas by an average of 36% as determined by radiometric detection with high-performance liquid chromatography and radioimmunoassay methods. In parallel, the peak systolic pressor response to ANG II was lowered from 36.2 +/- 3.7 to 16.8 +/- 2.0 mmHg. The peak pressor responses to ANG II were also reduced by two other LO inhibitors, baicalein (30 mg/kg) and esculetin (60 mg/kg) (13.9 +/- 2.4 and 22.1 +/- 4.7 mmHg, respectively; P less than 0.01 compared with control rats for both), but not by the cyclooxygenase inhibitor indomethacin. The LO inhibitors baicalein (7.5 X 10(-5) M) and PHE (10(-4) M) markedly attenuated the in vitro contractile response to ANG II of femoral artery rings. In contrast, neither the in vivo nor in vitro constrictor responses to norepinephrine were affected by baicalein. Thus lipoxygenase blockade induces a direct and selective inhibition of ANG II-induced vasoconstriction. The LO pathway may have an important role in mediating the pressor effect of ANG II.
Cardiac function during long-term hypoxemia in fetal sheep
Authors: Alonso J. G. , Okai T. , Longo L. D. , Gilbert R. D.
Published: December 2017

To examine right ventricular function during long-term hypoxemia, we instrumented 12 fetal sheep with intravascular catheters and an electromagnetic flow probe on the pulmonary artery. In six cases, hypoxemia was induced by infusing N2 gas into the maternal trachea for 2 wk. Maternal arterial PO2 was less than 60 Torr, and fetal arterial PO2 was reduced from approximately 26 to approximately 19 Torr. Six cases served as nonhypoxic controls. We studied fetal cardiac function by increasing either preload with a volume infusion of 5% (wt/vol) dextrose or afterload by administering methoxamine (alpha-adrenergic agonist). In hypoxic animals, right ventricular output (QRV) and stroke volume (SV) were not affected on the first 2 days but fell 30% on day 3. Fetal arterial pressure (Pfa) increased 20%, hemoglobin concentration increased approximately 30%, and fetal heart rate (FHR) showed minimal changes. Within 2 wk, QRV recovered to normal values, whereas ventricular sensitivity to arterial pressure was reduced. We observed no change in plasma concentration of "cardiac enzymes" or differences in fetal growth between groups. In conclusion, during prolonged hypoxemia, right ventricular function showed a triphasic response (primary maintenance, secondary depression, and subsequent recovery), achieving a new steady state 2 wk after the start of hypoxia, characterized by decreased sensitivity to afterload, associated with polycythemia and hypertension.
Acute effects of partial compression of ductus arteriosus on fetal pulmonary circulation
Authors: Abman S. H. , Accurso F. J.
Published: December 2017

To determine the acute effects of increased pulmonary artery pressure and flow on the fetal pulmonary circulation, we studied the response of pulmonary blood flow and vascular reactivity to partial compression of the ductus arteriosus in 22 chronically prepared late-gestation fetal lambs. An inflatable occluder was placed loosely around the ductus arteriosus for compression. Partial compression of the ductus rapidly increased mean pulmonary artery pressure from 45 +/- 1 to 60 +/- 1 mmHg (mean +/- SE) and left pulmonary artery blood flow from 65 +/- 6 to 151 +/- 11 ml/min at 30 min (P less than 0.001; 12 animals). Despite keeping pulmonary artery pressure constant, pulmonary blood flow steadily declined and by 2 h was not different from base-line values. Pulmonary vascular resistance initially fell during the first 30 min of partial compression but then steadily increased and remained elevated above base-line values for at least 30 min after the release of the occluder (P less than 0.001). The decline of pulmonary vascular resistance during the first 30 min of compression was blunted after treatment with the cyclooxygenase inhibitor, meclofenamate (P less than 0.001; 6 animals). Rapid incremental ductus compressions demonstrated a decrease in the slope of the pressure-flow relationship from 3.30 +/- 0.27 (control) to 1.59 +/- 0.21 ml.min-1.mmHg-1 during the postcompression period (P less than 0.001; 12 animals). The vasodilation response to small increases of fetal PO2 was markedly blunted during the postcompression period (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Laser backscatter studies of intracellular Ca2+ oscillations in isolated hearts
Authors: Stern M. D. , Weisman H. F. , Renlund D. G. , Gerstenblith G. , Hano O. , Blank P. S. , Lakatta E. G.
Published: December 2017

We measured intensity fluctuations of 633 nm laser light backscattered from the epicardial surface of isolated, perfused rat and rabbit hearts. Scattered light intensity fluctuations (SLIF) were detected from verapamil-arrested rat hearts. The frequency of SLIF was increased by maneuvers that raise intracellular calcium. SLIF were abolished by removal of extracellular calcium with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid and by blockade of sarcoplasmic reticulum calcium release by ryanodine. SLIF were not accompanied by any surface electro-cardiogram and were not abolished by 144 mM extracellular potassium. SLIF were absent in rabbit hearts under base-line conditions but could be provoked by calcium loading using zero potassium and ouabain. We conclude that backscatter SLIF monitor the microscopic motion caused by intracellular calcium oscillations in the intact heart. We measured SLIF from rat hearts during 60 min of global ischemia at 30 degrees C, followed by reflow. Ischemia reduced SLIF frequency to zero within 30 min. Reflow caused an overshoot of SLIF frequency to as much as five times control, suggesting that reflow causes major calcium overload of cells that are at least transiently viable.
Influence of endothelin on piglet cerebral microcirculation
Authors: Armstead W. M. , Mirro R. , Leffler C. W. , Busija D. W.
Published: December 2017

The purpose of this study was to determine responses of the newborn pig cerebral microcirculation to endothelin. Pial arterioles were observed directly using a closed cranial window in chloralose-anesthetized piglets. Topical application of endothelin derived from porcine endothelial cells produced increases in pial arteriolar diameter at the lowest concentration (0.1 ng/ml) (159 +/- 6 to 180 +/- 8 microns) and concentration-dependent decreases in pial arteriolar diameter at higher concentrations (141 +/- 6, 127 +/- 5, and 110 +/- 4 microns at 1, 10, and 100 ng/ml, respectively). Indomethacin (5 mg/kg iv) and aspirin (50 mg/kg iv) blocked dilator responses to endothelin and attenuated constrictor responses. Endothelin produced concentration-dependent increases in cortical periarachnoid cerebrospinal fluid levels of 6-ketoprostaglandin (6-keto-PG) F1 alpha, PGE2, PGF2 alpha, and thromboxane B2. Thus endothelin can produce either dilation or constriction of cerebral arterioles in newborn pigs, depending on concentration. Furthermore, prostanoids appear to mediate vasodilation induced by the lowest concentration of endothelin and contribute to constriction induced by higher concentrations of endothelin.
Decreased cardiopulmonary reflexes with aging in normotensive humans
Authors: Cleroux J. , Giannattasio C. , Bolla G. , Cuspidi C. , Grassi G. , Mazzola C. , Sampieri L. , Seravalle G. , Valsecchi M. , Mancia G.
Published: December 2017

Arterial baroreflex is impaired in the normotensive elderly. However, no information is available on the effects of aging on another major reflex mechanism of cardiovascular control, i.e., cardiopulmonary reflex. Three groups of normotensive subjects divided according to age were evaluated during leg raising, which increased central venous pressure, and during lower body negative pressures, which reduced central venous pressure without altering blood pressure and heart rate. These maneuvers stimulated and deactivated cardiopulmonary receptors with only little involvement of arterial baroreceptors. During lower body negative pressures, central venous pressure decreased similarly in three groups, but reflex increases in forearm vascular resistance, plasma norepinephrine, and plasma renin activity were smaller in elderly than in middle-aged and young subjects. Furthermore, during leg raising, comparable increases in central venous pressure caused reflex vascular and humoral responses that were smaller in elderly than in middle-aged and young subjects. Elderly subjects had smaller changes in left ventricular diameter in response to changes in central venous pressure. Blood pressure and vascular responses to cold pressor test were similar in the three groups, excluding a hyporeactivity of older subjects to neural stimuli. Thus aging is associated with an impairment of the cardiopulmonary reflex. This may originate from an impaired ability of cardiac receptors to sense alterations in central blood volume because of an age-dependent reduction in cardiac compliance.
Influence of mean pressure on aortic impedance and reflections in the systemic arterial system
Authors: Alexander J. , Burkhoff D. , Schipke J. , Sagawa K.
Published: December 2017

The present investigation sought to determine the extent to which primary changes in mean arterial pressure (MAP) might influence the calculated aortic impedance. In seven open-chest, anesthetized, autonomically blocked dogs, we measured aortic impedance using white-noise analysis at various levels of MAP achieved by adjusting the height of a left atrial reservoir rather than by pharmacological intervention. Impedance spectra so obtained were parameterized according to best-fit wind-kessel models (Ra, Rc, Ca) and three parameters to characterize wave reflections: the frequency at which the phase of the impedance approached or crossed through 0 degree (phi 0), the frequency of the first minimum of the impedance modulus (fmin), and the amplitude of the first oscillation of the impedance modulus (a 1). The dependency of each of these parameters on MAP was investigated. In addition, we calculated the reflection coefficient spectrum (RCS). Results show that windkessel parameters were not significantly influenced by MAP and that the reflection parameters and the RCS depended on increased levels of MAP in a manner consistent with an increase in pulsewave velocity.
Dependence of left ventricular twist-radial shortening relations on cardiac cycle phase
Authors: Beyar R. , Yin F. C. , Hausknecht M. , Weisfeldt M. L. , Kass D. A.
Published: December 2017

Cardiac models have proposed tight coupling between the systolic twisting motion of the left ventricle about its longitudinal axis and muscle shortening. Whether a similar relationship holds during diastole is unknown. The present study determined the dynamic twist-radial shortening relationship throughout the cardiac cycle in six in situ canine left ventricles. Radiopaque markers (15–26) were implanted throughout the myocardial midwall in six canine left ventricles. Three-dimensional marker location was determined by computer analysis of biplane cineradiograms (60 frames/s), and the results were transformed to cardiac cylindrical coordinates. Mean chamber twist was defined as the gradient along the long axis of circumferential rotation relative to end diastole. Changes in chamber dimension were indexed by average radial shortening, normalized to span from 0 at end diastole to 1.0 at end systole. During systole, ventricular twist and radial shortening were linearly related with an average slope of -0.058 radians (r = 0.99). However, during early diastolic relaxation there was substantial untwist (48 +/- 20% of total) despite only an approximately 15% increase in mean radial dimension resulting in a much steeper twist-percent shortening relationship (-0.24 radians, r = 0.96). During most of the remainder of diastolic filling, the twist-shortening relation was shallower (-0.02, r = 0.91) than the corresponding systolic relation (P less than 0.05). Thus the twist-radial shortening relation depends on the phase of the cardiac cycle. These data suggest that models of chamber mechanics that incorporate twisting motion need to account for the matrix surrounding the muscles in addition to the shortening and lengthening of the muscle fibers.
Effects of vasopressin on pulmonary and systemic vascular mechanics
Authors: Wallace A. W. , Tunin C. M. , Shoukas A. A.
Published: December 2017

The direct effects of vasopressin on the resistance and capacitance properties of the pulmonary and systemic vasculature were studied in nine aneural dogs on systemic and pulmonary bypass. The systemic and pulmonary pressure-flow, the systemic and pulmonary arterial pressure-volume, and the systemic and pulmonary venous pressure-volume relationships were determined for five levels of infused vasopressin. Vasopressin levels of approximately 10, 30, 150, 300, and 500 pg/ml were achieved by intravenous infusions. Samples of venous blood were drawn before and after each set of pressure-flow and pressure-volume relationships for the determination of vasopressin level by radioimmunoassay. A linear relationship was found between vasopressin level and systemic vascular resistance. Systemic vascular resistance increased 0.072 +/- 0.011 mmHg.kg.min.ml-1 for a change in vasopressin level of 100 pg/ml. Vasopressin did not affect pulmonary vascular resistance or any vascular compliance. High doses of infused arginine vasopressin were necessary to elicit substantial vasoconstriction.
Release of superoxide-dependent relaxing factor(s) from endothelial cells
Authors: Hong K. W. , Rhim B. Y. , Lee W. S. , Jeong B. R. , Kim C. D. , Shin Y. W.
Published: December 2017

In the present work, an experimental system was designed to study superoxide anion radical, implicated as the cause of vascular dilatation. To circumvent its direct effect, we employed a two-bath system. When the endothelial cells (EC) were exposed to electrical field stimulation (EFS) or to a hypoxanthine-xanthine oxidase system in bath A plus its physiological buffer solution suffused on a helical strip of cat basilar artery in bath B, the contraction to 5-hydroxytryptamine (5-HT) was depressed to approximately 40-50% of the control value. The reduction was not elicited on EFS in a state of calcium deficiency or in the absence of EC. The depression could be prevented by pretreatment with superoxide dismutase (SOD), but not with an effective dose of catalase, dimethyl sulfoxide (DMSO), mannitol, or indomethacin. The percent depression of contraction was paralleled by an increase in SOD-inhibitable cytochrome c reduction, which was not associated with cyclic guanosine 3',5'-monophosphate formation. These results suggest that superoxide-dependent relaxing factor is released from EC differently than the endothelium-derived relaxing factor mediated by acetylcholine.
Contractile function of isolated feline cardiocytes in response to viscous loading
Authors: Kent R. L. , Mann D. L. , Urabe Y. , Hisano R. , Hewett K. W. , Loughnane M. , Cooper G.
Published: December 2017

The classical force-velocity relationship is a standard measure of the contractile function of isolated linear cardiac muscle, but no such simple index of contractile function exists for the isolated mammalian cardiocyte. Therefore, this study established an analogous viscosity-velocity relationship for the characterization of cardiocyte contractile function. For this purpose, force was imposed on unfettered adult feline cardiocytes as a series of defined viscous loads, which provided resistance to cardiocyte shape changes during contraction. This was done by increasing the viscosity of the Krebs superfusate (37 degrees C, pH 7.4) in graded, reproducible steps from 1 to 500 centipoise by the addition of methylcellulose. Sarcomere motion within each contracting cardiocyte was measured as movement of the diffraction pattern cast onto a photodiode array by a laser beam passing through the cell. Both the rate and extent of sarcomere shortening varied inversely with increasing viscosity, whereas neither resting sarcomere length nor osmolarity was altered. Further, increased inotropism effected by paired-pulse stimulation of cardiocytes caused an upward shift of the entire viscosity-velocity relationship. Thus the cardiocyte viscosity-velocity relationship is analogous in form to the force-velocity relationship of isolated linear cardiac muscle and provides a simple reproducible method for characterizing the contractile performance of relatively large numbers of cardiocytes isolated from a single specimen of myocardium.
Subpressor angiotensin II infusions do not stimulate sympathetic activity in humans
Authors: Goldsmith S. R. , Hasking G. J.
Published: December 2017

Angiotensin II (ANG II) exerts significant direct and indirect pressor and chronotropic effects in experimental animals. The indirect effects have been shown to be due to interactions with the sympathetic nervous system at several levels. To test the hypothesis that ANG II in subpressor doses enhances the activity of the sympathetic nervous system in humans either at rest or in response to a stimulus from baroreceptor unloading, we measured mean arterial pressure (MAP), heart rate (HR), plasma norepinephrine (NE), and plasma NE kinetics during infusions of ANG II at 2 ng.kg-1. min-1 [or 5% dextrose in water (D5/W) control in six healthy volunteers in the supine position and during 60 degrees head-up tilt. No changes in any measured variable occurred during either infusion in the supine position. During upright tilt with D5/W, HR increased (58 +/- 8.4 to 68 +/- 7.7 beats/min, P less than 0.005), MAP rose slightly (90 +/- 3.9 to 94 +/- 4.0 mmHg, P less than 0.005), and plasma NE increased (213 +/- 3.8 to 366 +/- 83 pg/ml, P less than 0.005). The responses of the variables to tilt during ANG II were not different from those with D5/W.(ABSTRACT TRUNCATED AT 250 WORDS)
Atriopeptin 24 regulates myocardial function via Frank-Starling mechanism in conscious dogs
Authors: Patel M. B. , Hintze T. H.
Published: December 2017

Recent studies have shown that the infusion of atriopeptins decreases blood volume because of the diuresis and also because of changes in vascular volume. In dogs chronically instrumented for the measurement of left ventricular pressure and internal left ventricular diameter, infusion of atriopeptin 24 (500 ng.kg-1.min-1 for 1 h), steady-state plasma levels of 6,000 pg/ml resulted in 5.9 +/- 1.7% decrease in left ventricular (LV) end-diastolic diameter (EDD) from 34.7 +/- 2.3 mm (P less than 0.05) and no significant change in LV first derivative of pressure with time (dP/dt), LV first derivative of dimension with time, LV dP/dt divided by internal diastolic circumference or percent shortening. Hematocrit increased from 42 to 46% (P less than 0.05). During pacing, infusion of atriopeptin 24 still reduced LV EDD by 7.5 +/- 1.8% from 32 +/- 2.8 mm (P less than 0.05), although there were no changes in the indexes of inotropic state. These results were unaffected by combined autonomic receptor blockade or by ganglionic blockade. Inflation of a hydraulic occluder around the aorta during the infusion of atriopeptin 24 to return LV EDD to preinfusion levels did not cause any index of myocardial contractility to increase significantly. At lower infusion rates that resulted in plasma atriopeptin levels of 2,000 pg/ml, atriopeptin 24 still reduced LV EDD without effect on inotropic state. Thus in the conscious dog, atriopeptins reduce preload independent of neuronal influences and without affecting inotropic state.