bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Ca2+ transients in neonatal and adult rat cardiomyocytes by angiotensin II and endothelin-1
Authors: Touyz R. M. , Fareh J. , Thibault G. , Tolloczko B. , Lariviere R. , Schiffrin E. L.
Published: December 2017

Vasoactive peptides may exert inotropic and chronotropic effects in cardiac muscle by modulating intracellular calcium. This study assesses effects of angiotensin II (ANG II) and endothelin-1 (ET-1) on intracellular free calcium concentration ([Ca2+]i) in cultured cardiomyocytes from neonatal and adult rats. [Ca2+]i was measured microphotometrically and by digital imaging using fura 2 methodology. Receptor subtypes through which these agonists induce responses were determined pharmacologically and by radioligand binding studies. ANG II and ET-1 increased neonatal atrial and ventricular cell [Ca2+]i transients in a dose-dependent manner. ANG II (10(-11) to 10(-7) M) failed to elicit [Ca2+]i responses in adult cardiomyocytes, whereas ET-1 increased [Ca2+]i in a dose-dependent manner. The ETA receptor antagonist BQ-123 significantly reduced (P 7< 0.05) ET-1 induced responses, and the ETB receptor agonist IRL-1620 (10(-7) to 10(-5) M) significantly increased (P < 0.05) [Ca2+]i in neonatal and adult cardiomyocytes. ET-1 binding studies demonstrated 85% displacement by BQ-123 and approximately 15% by the ETB receptor agonist sarafotoxin S6c, suggesting a predominance of ETA receptors. Competition binding studies for ANG II failed to demonstrate significant binding on adult ventricular myocytes, indicating the absence or presence of very few ANG II receptors. These data demonstrate that ANG II and ET-1 have stimulatory [Ca2+]i effects on neonatal cardiomyocytes, whereas in adult cardiomyocytes, ANG II-induced effects are insignificant, and only ET-1-induced responses, which are mediated predominantly via ETA receptors, are preserved. Cardiomyocyte responses to vasoactive peptides may thus vary with cardiac development.
Impact of aging on adenosine levels, A1/A2 responses, arrhythmogenesis, and energy metabolism in rat heart
Authors: Headrick J. P.
Published: December 2017

Adenosine formation, energy metabolism, A1 and A2 responses, and arrhythmogenesis were examined in hearts from young adult (4-6 mo) and aged rats (18-20 mo). Aging reduced heart rate from 308 +/- 9 to 252 +/- 13 beats/min and myocardial O2 consumption (MVO2) from 127 +/- 5 to 103 +/- 4 microliters O2.min-1.g-1 and increased atrioventricular conduction time from 47 +/- 4 to 61 +/- 8 ms. Differences in intrinsic rate were reduced by A1 antagonism with 10 microM 8-cyclopentyl-1,3-dimethylxanthine. Adenosine efflux and cardiac microdialysate [adenosine] in isovolumically working hearts increased twofold with aging, despite reduced MVO2. Enhanced [adenosine] was not due to altered uptake and catabolism but was associated with twofold higher cytosolic adenosine 5'-monophosphate concentration despite comparable energy state (free energy of ATP hydrolysis = -62.25 +/- 0.38 and -61.78 +/- 0.46 kJ/mol in young adult and aged hearts, respectively). Bradycardia (presumably A1 mediated) was 10-fold more sensitive in aged [-log dose required to produce 50% ectopy (pEC50) = 4.9 +/- 0.1] than in young adult hearts (pEC50 = 3.9 +/- 0.1). Adenosine also became potently arrhythmogenic with aging (-log dose required to produce 20% ectopy = 3.6 +/- 0.3 in young adult and 5.3 +/- 0.2 and aged hearts). Alternatively, vasodilation (presumably A2 mediated) was less sensitive with aging (pEC50 = 6.1 +/- 0.1 in young adult and 4.5 +/- 0.1 in aged hearts; pEC50 = 3.8 +/- 0.1 in young adult and 3.1 +/- 0.1 in aged aortic rings). The data indicate that aging 1) enhances interstitial [adenosine], probably via elevated myocardial adenosine 5'-monophosphate concentration, 2) enhances A1 sensitivity and arrhythmogenesis, and 3) reduces adenosine A2 sensitivity. These changes contribute to altered cardiovascular function in aged hearts.
Muscle chemoreflex causes renal vascular constriction
Authors: Mittelstadt S. W. , Bell L. B. , O'Hagan K. P. , Sulentic J. E. , Clifford P. S.
Published: December 2017

The purpose of this study was to investigate the effects of the muscle chemoreflex on vascular conductance in innervated and denervated kidneys. During each experiment, six dogs ran at 10 km/h for 8-16 min, and the muscle chemoreflex was stimulated by reducing hindlimb blood flow (HLBF) (0%-74%) at 4-min intervals. Small reductions in HLBF did not cause changes in arterial blood pressure or renal vascular conductance. However, further reductions of HLBF caused increases in arterial blood pressure and decreases in renal vascular conductance. Decreases in renal vascular conductance occurred in the denervated kidneys when the HLBF was reduced below 1,500 +/- 215 ml/min and occurred in the innervated kidneys when HLBF was reduced below 1,402 +/- 161 ml/min. There was not a significant difference between the reductions in HLBF required to cause a decrease in vascular conductance in the innervated and denervated kidneys. These results demonstrate that reductions in HLBF cause decreases in renal vascular conductance, which are not dependent on renal sympathetic nerve activity.
Differential stimulation of Na+ pump activity by insulin and nitric oxide in rabbit aorta
Authors: Gupta S. , Phipps K. , Ruderman N. B.
Published: December 2017

The effect of insulin on Na+ pump activity, measured as ouabain-sensitive (OS) 86Rb uptake, was studied in the rabbit aorta. In the absence of insulin, incubation of endothelium-intact rings for 3 h in a medium containing a high concentration of glucose (44 mM) decreased OS 86Rb uptake by 42% compared with that observed at 5.5 mM glucose. Addition of insulin (0.1-10 microU/ml) increased OS86 86Rb uptake at both glycose concentrations and eliminated the differences between the groups. Insulin also increased OS 86Rb uptake in endothelium-intact and -denuded (ED) rings in the presence of the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine. Removal of the endothelium before the incubations did not diminish the insulin-induced increase in OS 86Rb uptake, which was concentration dependent. The NO donor sodium nitroprusside increased OS 86Rb uptake in ED rings, and its effect and that of insulin were additive. Phorbol 12,13-dibutyrate, a direct activator of protein kinase C (PKC), also increased OS 86Rb uptake in ED rings; however, its effect and that of insulin were not additive. The PKC inhibitor bisindolylmaleimide totally inhibited insulin-induced, but not sodium nitroprusside-induced, increases in OS 86Rb uptake. The results suggest that insulin activates the Na+ pump in the aorta and reverses the inhibition of the pump caused by hyperglycemia. This effect of insulin can occur at physiological concentrations, is independent of endothelium-derived NO, and is presumably mediated by an increase in PKC activity, In contrast, activation of the Na+ pump by NO appears to be independent of PKC.
Changes in arterioles, arteries, and local perfusion of the brain stem during hemorrhagic hypertension
Authors: Toyoda K. , Fujii K. , Ibayashi S. , Sadoshima S. , Fujishima M.
Published: December 2017

Cerebral arterioles have been regarded as the primary sites of autoregulatory responses, whereas the role of large arteries in the cerebral autoregulation is poorly understood. The goal of this study was to determine in vivo whether the basilar artery and its primary branches act as resistance vessels under hypotensive conditions by simultaneously measuring their diameters and local brain stem blood flow with laser-Doppler flowmetry. In 10 anesthetized rats, blood flow to the brain stem was well maintained during stepwise hemorrhagic hypotension when mean arterial blood pressure fell from 116 +/- 3 to 50 mmHg and decreased gradually between 50 and 30 mmHg. Diameter of the basilar artery (n = 10) and its large branches (n = 22), measured through an open cranial window, increased by 10% from the baseline value at 50 mmHg and reached their maximum at 30 mmHg (314 +/- 9 from 244 +/- 6 mum, and 149 +/- 4 from 117 +/- 3 mum, respectively). Small branches (n = 15) dilated to a larger extent compared with the larger arteries throughout hypotension and reached the maximum at 30 mmHg (69 +/- 3 from 48 +/- 2 mum). Below 30 mmHg, there was a steep fall in blood flow and reduction in diameter of all-sized arteries. Thus small vessels contribute to reductions in cerebrovascular resistance throughout the entire autoregulatory-range in the brain stem circulation. Large arteries, such as the basilar artery and its branches, also contribute to reductions in cerebrovascular resistance around the lower limits of cerebral blood flow autoregulation and may thus play a significant role in maintaining blood flow to the brain stem during severe systemic hypotension.
VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis
Authors: Li J. , Brown L. F. , Hibberd M. G. , Grossman J. D. , Morgan J. P. , Simons M.
Published: December 2017

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that is thought to function by interacting with two high-affinity receptors, flk-1 and flt-1. In an adult heart, angiogenesis can occur in a number of pathological conditions, including atherosclerosis, hypertrophy, and infarction. To determine the role played by VEGF, flk-1, and flt-1 in this process in vivo, we studied the expression of the growth factor and its receptors in a rat infarct model. After an acute myocardial infarction, we observed an initial rapid (1h) rise in VEGF (275%), flk-1 (375%), and flt-1 (400%) mRNA expression throughout the entire heart. Initial diffuse induction of VEGF, flk-1, and flt-1 expression in the left ventricle was later replaced by an increase predominantly limited to perimyocardial infarction area where angiogenesis was taking place. In situ hybridization showed at 6 h after infarction, viable myocytes adjacent to the infarct zone expressed markedly increased amounts of VEGF. At both 6 and 24 h, microvessels at the infarct edge overexpressed both flk-1 and flt-1 mRNAs; at 3 and 7 days new vessels infiltrating the infarct also overexpressed both receptors and continued for as late as 6 wk. In summary, acute myocardial infarction is accompanied by rapid and prolonged increase in expression of VEGF and its receptors with characteristic spatial and temporal kinetic. These findings suggest that the VEGF/VEGF receptor system plays an important role in the angiogenesis and stromal deposition associated with myocardial infarction.
Baroreceptor-induced inhibition of sympathetic neurons by GABA acting at a spinal site
Authors: Lewis D. I. , Coote J. H.
Published: December 2017

gamma-Aminobutyric acid (GABA) synapses are an important feature of sympathetic circuits in the spinal cord. The possibility that these spinal synapses participate in the reduction of sympathetic activity resulting from arterial baroreceptor activation was tested. For this purpose baroreceptors were stimulated by a rapid rise in blood pressure induced by intravenous phenylephrine, and the effect of this on a spinally evoked excitatory response in a renal sympathetic nerve was examined before, during, and after removal of tonic excitatory drive from the rostral ventrolateral medulla (RVLM). Stimulation of descending excitatory axons in the spinal cord at the fourth cervical spinal level evoked a biphasic excitatory response in a renal sympathetic nerve, with a latency of 56 +/- 6 ms and a duration of 230 +/- 24 ms. The magnitude of this spinally evoked response was significantly reduced (P < 0.001) during baroreceptor activation, thus confirming that there is a spinal component of the baroreceptor inhibitory reflex. Intrathecal administration of bicuculline reduced baroreceptor-mediated inhibition of the spinally evoked response to 48 +/- 18% of control inhibition (P<0.05). Subsequent removal of tonic excitatory drive by microinjection of glycine into the RVLM produced no significant further change in the baroreceptor-mediated inhibition. This suggests that a GABAA receptor-mediated effect at a spinal site is involved in the baroreceptor-induced inhibition. Reversing this procedure by first placing injections of glycine into the RVLM resulted in a reduction of baroreceptor inhibition to 60 +/- 16% (P < 0.05) of control baroreceptor inhibition. Subsequent intrathecal administration of bicuculline produced no significant further change in the baroreceptor-mediated inhibition of the spinally evoked response. This suggests that the GABAA-mediated effect of the baroreceptors at a spinal site is dependent on the integrity of neurons in the RVLM. We conclude that GABA in sympathetic circuits in the spinal cord plays a significant role in the modification of sympathetic vasomotor activity by the baroreceptor reflex.
Complement-induced endothelial dysfunction in rabbits: mechanisms, recovery, and gender differences
Authors: Lennon P. F. , Collard C. D. , Morrissey M. A. , Stahl G. L.
Published: December 2017

Activation of complement and attenuation of endothelium-dependent relaxation occur in a number of pathophysiological conditions. The aim of this study was to investigate the mechanisms of human complement activation and loss of endothelium-dependent relaxation in rabbit tissue, the duration of this loss, and the effects of gender and serum concentration. In rabbit thoracic aortic rings precontracted with phenylephrine, human serum (HS) concentration dependently induced a loss of endothelium-dependent relaxation to the receptor-dependent vasodilator acetylcholine (ACh) and receptor-independent vasodilator calcium ionophore A23187. Serum-induced loss of ACh-dependent relaxation was decreased when rings were bathed in 1) HS depleted of factor B, C2, or C8, 2) heat-inactivated HS, or 3) HS with complement inhibitor sCR1 or sCR1[desLHR-A]. Superoxide dismutase had no effect on serum-induced loss of ACh-dependent relaxation. Serum-induced loss of ACh-dependent relaxation returned to control values after removal of HS. Serum-induced loss of ACh-dependent relaxation was greater in male than in female aortic rings. These results suggest that 1) complement activation directly attenuates endothelium-dependent relaxation via the classical and alternative pathways independent of superoxide anion formation, 2) this attenuation is concentration dependent, reversible, and dependent on formation of C5b-9, and 3) endothelial tissue from males is more susceptible than that from females to the acute effects of complement activation.
Impaired Ca2+ handling is an early manifestation of pressure-overload hypertrophy in rat hearts
Authors: Chang K. C. , Schreur J. H. , Weiner M. W. , Camacho S. A.
Published: December 2017

Both cytosolic free Ca2+ ([Ca2+]i) decline and myocardial relaxation are slowed in severe hypertrophy and heart failure. However, it is not certain whether this occurs in mild to moderate hypertrophy. Therefore, we tested the hypotheses that slowing of [Ca2+]i decline 1) occurs in mild to moderate hypertrophy, 2) occurs in the absence of slowed relaxation, and 3) is related to the degree of hypertrophy. Experiments were performed on isolated rat hearts subjected to pressure overload. Indo 1 fluorescence was used as an index of [Ca2+]i. [Ca2+]i decline and myocardial relaxation were assessed by the time constant of exponential [Ca2+]i decline (tau Ca) and left ventricular (LV) pressure decline (tau p), respectively. Mean tau Ca was significantly increased in hearts from banded rats compared with sham-operated rats (59 +/- 13 vs. 45 +/- 5 ms, P = 0.03). In contrast, there was no difference in mean tau p (28 +/- 3 vs. 29 +/- 5 ms, P = not significant). There was a linear relationship between tau Ca and LV dry weight (r = 0.79). In summary, slowing of the [Ca2+]i transient decline occurred in mild to moderate hypertrophy. However, LV relaxation was unaffected. Furthermore, slowing of the [Ca2+]i transient decline was closely related to the degree of LV hypertrophy. These data suggest that slowing of [Ca2+]i decline is an early manifestation of pressure-overload hypertrophy that precedes slowing of relaxation.
Bidirectional augmentation of heart rate regulation by autonomic nervous system in rabbits
Authors: Kawada T. , Ikeda Y. , Sugimachi M. , Shishido T. , Kawaguchi O. , Yamazaki T. , Alexander J. , Sunagawa K.
Published: December 2017

Although the characteristics of the static interaction between the sympathetic and parasympathetic nervous systems in regulating heart rate (HR) have been well established, how the dynamic interaction modulates the HR response remains unknown. We therefore investigated dynamic interaction by estimating the transfer function from nerve stimulation to HR using a band-limited Gaussian white-noise technique. The transfer function relating dynamic sympathetic stimulation to HR had characteristics of a second-order low-pass filter. Simultaneous tonic vagal stimulation at 5 and 10 Hz increased gain of the transfer function by 55.0 +/- 40.1 and 80.7 +/- 50.5%, respectively (P < 0.05). The transfer function from dynamic vagal stimulation to HR had characteristics of a first-order low-pass filter. Simultaneous tonic sympathetic stimulation at 5 and 10 Hz increased the gain by 18.2 +/- 17.9 and 24.1 +/- 18.0%, respectively (P < 0.05). Thus interaction augmented dynamic gain bidirectionally, even though it affected mean HR antagonistically. By virtue of this interaction, the autonomic nervous system appears to extend its dynamic range of operation.
Contribution of Na+/Ca2+ exchange to action potential of human atrial myocytes
Authors: Benardeau A. , Hatem S. N. , Rucker-Martin C. , Le Grand B. , Mace L. , Dervanian P. , Mercadier J. J. , Coraboeuf E.
Published: December 2017

The Ca2+ dye indo 1 was used to record internal Ca2+ (Cai) transients in order to investigate the role of the Na+/Ca2+ exchange current (INa/Ca) in whole cell patch-clamped human atrial myocytes After the activation of the L-type Ca2+ current by test pulses (20 ms) at +20 mV, a tail current (I(tail)) was activated at a holding potential of -80 mV with a density of -1.29 +/- 0.06 pA/pF. The time course of I(tail) followed that of Cai transients I(tail) was suppressed by dialyzing cells with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, applying 5 mM caffeine, or substituting external Na+ with Li+, indicating that this current was mainly generated by INa/Ca. Two types of action potential were recorded: type A, which is characterized by a narrow early plateau followed by a late low plateau phase, and type B, which is characterized by a small initial peak followed by a prolonged high plateau phase. Type B action potentials were found in larger cells than type A action potentials (membrane capacitance 81.8 +/- 4.5 and 122.4 +/- 7.0 pF in types A and B, respectively, P < 0.001). Substitution of external Na+ with Li+ shortened the late plateau of the type A action potential and the prolonged plateau of the type B action potential. Suppression of Cai transients by caffeine shortens the late part of both types of action potentials, whereas its lengthening effect on the initial phase of action potentials can result from several different mechanisms. The beat-to-beat dependent relationship between Cai transients and action potentials could be mediated by Ina/Ca- Delayed afterdepolarizations were present in a significant proportion of atrial myocytes in our experimental conditions. They were reversibly suppressed by Li+ substitution for Na+, suggesting that they are generated by INa/Ca. We conclude that INa/Ca plays a major role in the development of action potentials and delayed afterdepolarizations in isolated human atrial myocytes.
Biomechanics of the deconditioned left ventricle
Authors: Fogel M. A. , Gupta K. , Baxter B. C. , Weinberg P. M. , Haselgrove J. , Hoffman E. A.
Published: December 2017

To determine if strain and wall motion are enhanced in the left ventricle (LV) in a chronically afterload-reduced milieu, a magnetic resonance tagging technique was used to examine 19 subjects: 11 with transposition of the great arteries who have undergone an atrial inversion operation (TGA-LV, 11.6 +/- 4.3 yr postoperative) and eight normal adults. Finite strains (E1), regional twist, and radial motion were calculated at the atrioventricular valve and apical short axis levels in four anatomic wall regions. Strain was greatest in TGA-LV patients (-0.20 +/- 0.02 at the atrioventricular valve septal wall) and was significantly greater than controls in six out of eight regions. Marked differences were noted in the distribution of strain between TGA-LV and normal subjects as well as within the TGA-LV group. Ten of 11 LV of TGA-LV patients twisted clockwise in the lateral or inferior walls and counterclockwise in other walls (more counterclockwise than control subjects), whereas control LV twisted uniformly counterclockwise. The lateral wall of TGA-LV demonstrated the greatest radial inward motion, whereas controls demonstrated uniform radial inward motion. We conclude that the biomechanics of the LV faced with a chronic afterload reduction is enhanced; a marked increase in regional strain is observed in TGA-LV patients. Abnormalities in the distribution of strain were also observed. Markedly abnormal clockwise twist and increased lateral wall motion were demonstrated in TGA-LV patients.
Reflex vagal control of atrial repolarization
Authors: Euler D. E. , Olshansky B. , Kim S. Y.
Published: December 2017

The reflex vagal control of atrial repolarization was investigated in eight open-chest, anesthetized dogs. A monophasic action potential was recorded from the right atrium, and the action potential duration to 90% repolarization (APD90) was determined every cardiac cycle. beta-Adrenergic receptors were blocked with timolol (0.1 mg/kg). Under baseline conditions, sinus slowing during sinus arrhythmia was accompanied by a significant shortening of APD90 (24 +/- 4.0 ms). Transient occlusion (30 s) of the descending thoracic aorta increased systolic aortic pressure from 138 +/- 2.8 to 181 +/- 3.3 mmHg (P < 0.01). Heart rate decreased from 99 +/- 3.6 to 42.5 +/- 3.4 beats/min (P < 0.01), and APD90 shortened from 168 +/- 5.1 to 94 +/- 3.3 ms (P < 0.01). Release of the occlusion caused arterial hypotension (95 +/- 2.8 mmHg) and an overshoot in both rate (126 +/- 5.2 beats/min) and APD90 (189 +/- 2.3 ms). Aortic occlusion during atrial pacing (130-160 beats/min) decreased APD90 from 147 +/- 7.0 to 78 +/- 3.4 ms (P < 0.01). Cervical vagotomy or atropine eliminated changes in rate and APD90 evoked by aortic occlusion. The results indicate that there is parallel central vagal control of both sinus rate and atrial repolarization. Sinus bradycardia during reflex vagal activation does not prevent the acceleration of atrial repolarization.
The need to account for residual strains and composite nature of heart wall in mechanical analyses
Authors: Kang T. , Yin F. C.
Published: December 2017

We studied 19 excised, passive rabbit left ventricular walls to delineate the forms of the strain-energy functions (W) for myocardium and epicardium, to quantify residual strains across the wall, and to investigate whether the mechanical behavior of the intact wall can be predicted by accounting for the above properties. The unloaded dimensions and the stress-strain responses to equibiaxial and uniaxial loadings were obtained first for the intact wall and then individually for the epicardium and myocardium. Results show that the previously proposed W for canine myocardium and epicardium are suitable. The unloaded intact wall has residual strains: the epicardium is stretched and the myocardium shrunk from their respective isolated, unloaded states. The predicted mechanical responses of the intact wall to biaxial loadings were inaccurate when the residual strains were not taken into account. Accounting for these, however, yielded reasonable predictions. Thus information on the unloaded reference state and properties of each portion is needed to accurately predict the behavior of the intact wall.
Nitroglycerin relaxes rat tail artery primarily by lowering Ca2+ sensitivity and partially by repolarization
Authors: Chen X. L. , Rembold C. M.
Published: December 2017

At least five mechanisms are hypothesized to account for guanosine 3',5'-cyclic monophosphate (cGMP)-induced relaxation of arterial smooth muscle: 1) repolarization, 2) inhibition of Ca2+ release, 3) inactivation of L-type Ca2+ channels, 4) enhancement of Ca2+ efflux/sequestration, and 5) decreasing the intracellular Ca2+ concentration ([Ca2+]i) sensitivity of force. The goal of this study was to investigate the physiological relevance of these five mechanisms in the intact rat tail artery. We stimulated deendothelialized rat tail artery with phenylephrine or high extracellular K+ concentration ([K+]o) and then relaxed the tissue by adding nitroglycerin to increase guanosine 3',5'-cyclic monophosphate concentration. We measured membrane potential (Em) with microelectrodes, [Ca2+]i with fura 2, and isometric force with a strain-gauge transducer. We found that decreases in the [Ca2+]i sensitivity of force accounted for most of the nitroglycerin-induced relaxation of tissues prestimulated with maximal (1 microM) phenylephrine or 30 mM [K+]o. In submaximally (0.1-0.3 microM) phenylephrine-prestimulated tissues, nitroglycerin-induced relaxation was caused primarily by a decrease in the [Ca2+]i sensitivity of force and partially by repolarization and the resultant decrease in [Ca2+]i. Nitroglycerin also partially attenuated transient increases in [Ca2+]i and force induced by 100 microM phenylephrine in the absence of extracellular Ca2+, indicating that nitroglycerin also inhibited intracellular Ca2+ release. Nitroglycerin-induced relaxation was not associated with inactivation of Ca2+ channels or enhancement of Ca2+ efflux/sequestration. These data suggest that nitroglycerin relaxes precontracted rat tail artery primarily by decreasing the [Ca2+]i sensitivity of force.
Chronic exercise decreases adrenergic agonist-induced vasoconstriction in spontaneously hypertensive rats
Authors: Chen H. I. , Chiang I. P.
Published: December 2017

This study was conducted to investigate the effects of chronic exercise on adrenergic agonist-induced vascular responses in spontaneously hypertensive rats (SHR). Four-week-old male SHR and Wistar-Kyoto rats were divided into control and trained groups. The trained groups ran on a drum exerciser at 70% of peak oxygen consumption for 60 min/day 5 days/wk for 10 wk. Resting systolic blood pressure and heart rate were measured by a tail-cuff method, and changes in these parameters were considered as indexes of effective training. At the end of experiments, thoracic aortas and carotid arteries were isolated. Vasoconstricting responses to norepinephrine (NE) or phenylephrine (PHE) were studied. To clarify the role of endothelium-derived nitric oxide (EDNO) in the alteration of NE-induced vasoconstriction after chronic exercise, we measured the changes in vasoconstricting responses to NE (10(-8) M) after treatment with N omega-nitro-L-arginine. Vasorelaxing responses to PHE or clonidine were also studied. Our results showed that 1) vasoconstricting responses to NE or PHE in the endothelium-intact thoracic aorta were reduced, whereas PHE- or clonidine-induced EDNO release was enhanced by exercise training, and 2) the latter could be eliminated by N omega-nitro-L-arginine. Therefore, training may decrease adrenergic agent-induced vasoconstricting responses by increasing their stimulated EDNO release in hypertensive and normotensive rats.
Estimated functional diameter of alveolar septal microvessels in zone 1
Authors: Conhaim R. L. , Rodenkirch L. A.
Published: December 2017

To estimate the functional diameter of alveolar septal microvessels in zone 1, we perfused isolated rat lungs with fluorescent latex particles of specific diameters (0.24, 0.49, 1.05, or 4.0 microns) at pulmonary artery pressures (Ppulmart) that were either 5 or 10 cmH2O less than the air inflation pressure (Pinflat, 25 cmH2O). We then prepared samples for histology. Using a confocal, laser-scanning fluorescence microscope, we measured latex particle densities within the septal plane that ranged from 0.08 +/- 0.04 particles/microns2 (0.24-microns diameter particles) to 0.02 +/- 0.01 particles/microns2 (1.05-microns diameter particles). We found that 4.0-microns diameter particles were not able to enter septa at all. Latex particles were not present in all alveoli When Ppulmart was 5 cmH2O less than Pinflat, 32 +/- 6% of septa contained 0.24-microns diameter particles, but, when Ppulmart was 10 cmH2O less than Pinflat, 5 +/- 6% of septa contained these particles. Percentages were smaller for larger particles. We conclude that, when Ppulmart is both 5 and 10 cmH2O less than Pinflat, the functional diameter of accessible septal microvessels is > 1.05 but < 4.0 microns. Furthermore, the number of accessible septa decreases as the difference between Ppulmart and Pinflat widens.
Effect of alpha 1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans
Authors: Lorenzoni R. , Rosen S. D. , Camici P. G.
Published: December 2017

In the present study we aimed to assess the effect of alpha 1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans. Myocardial blood flow, at baseline and after dipyridamole, was measured with positron emission tomography and 15O-labeled water in 11 normal volunteers at control and during alpha 1-blockade with doxazosin. Baseline myocardial blood flow during alpha 1-blockade was not different from control, whereas coronary resistance was significantly lower (73.48 +/- 18.31 vs. 89.84 +/- 27.96 mmHg.min.ml-1.g-1; P < 0.05). After dipyridamole, myocardial blood flow during alpha 1-blockade was significantly higher (3.50 +/- 0.75 vs. 2.58 +/- 0.54 ml.min-1.g-1; P < 0.01) and coronary resistance lower (25.30 +/- 7.37 vs. 33.89 +/- 7.04 mmHg.min.ml-1.g-1; P < 0.01) compared with control. In conclusion, in normal humans, dipyridamole-induced increase in myocardial blood flow is limited by alpha 1-mediated coronary vasoconstriction.
Increased ventricular contractility is not sufficient for effective positive inotropic intervention
Authors: Binkley P. F. , Van Fossen D. B. , Haas G. J. , Leier C. V.
Published: December 2017

Positive inotropic intervention with dobutamine in patients with congestive heart failure is accompanied by complementary vascular changes, as measured by the aortic input impedance spectrum, that promote the efficient transfer of augmented myocardial contractile power. It is unknown whether this is a nonspecific response to increased ventricular contractility or is a function of the properties of the positive inotropic agent employed. Therefore, the influence of two different positive inotropic interventions, dobutamine and dopamine, on ventricular-vascular coupling was examined in 15 patients with congestive heart failure. Significant reductions in characteristic aortic impedance, wave reflection, and low-frequency impedance moduli were noted with dobutamine and were not seen with dopamine. Consequently, a significantly (P = 0.0008) greater increase in pulsatile, rather than steady-state, power output was noted with dopamine that was reflective of a significantly diminished efficiency of power transfer. Therefore, optimal transfer of increased ventricular contractile power in patients with congestive heart failure requires increases in large vessel compliance and complementary changes in ventriculoarterial coupling.
Protein kinase C modulates microvascular permeability through nitric oxide synthase
Authors: Ramirez M. M. , Kim D. D. , Duran W. N.
Published: December 2017

Protein kinase C (PKC) serves important functions in signal transduction. We hypothesized that PKC modulation of microvascular permeability to macromolecules is mediated by nitric oxide (NO). To test this hypothesis, we stimulated PKC topically with 10(-7) M phorbol 12,13-dibutyrate (PDBu) in the hamster check pouch microcirculation. NG-monomethyl-L-arginine (L-NMMA) at 10(-4) M was superfused in a bicarbonate buffer solution throughout the experiment to inhibit the activity of NO synthase. We evaluated changes in transport of fluorescein isothiocyanate-labeled 150,000 mol wt dextran by integrated optical intensity (IOI) using intravital fluorometry and computer-assisted digital image analysis. Postcapillary areas were recorded. PDBu increased IOI from baseline to a value of 46.8 +/- 6.3 units (+/- SE). Pretreatment with L-NMMA decreased the PDBu-stimulated increment to 10.8 +/- 0.9 units. These results demonstrate that PKC-activated modulation of macromolecular transport operates through a mechanism involving the production of NO.
Nitric oxide-dependent opposite effects of somatostatin on arterial and venous caliber in situ
Authors: Szentivanyi M. , Nadasy G. L. , Dezsi L. , Mozes G. , Tulassay T. , Monos E.
Published: December 2017

The vascular effects of somatostatin (ST) and its mechanism of action are not well understood. In the present study, we investigated the direct effects of ST on the vascular tone of rat saphenous artery and vein using videomicroangiometry in situ. ST was administered either in superfusion or in infusion. We found opposite effects in arteries and veins: ST (10(-12)-10(-7) M) dilated the artery (outer diameter increased from 533 +/- 28 to 600 +/- 29 microns, administered in superfusion) and contracted the vein (from 709 +/- 26 to 640 +/- 26 microns and from 775 +/- 30 to 708 +/- 60 microns in superfusion and infusion, respectively). These effects of ST were completely abolished after deendothelization (air bolus maintained for 6 min in vessel lumen) and after local infusion of NG-nitro-L-arginine (L-NNA; 10(-4) M), a nitric oxide (NO) synthesis inhibitor. An NO-dependent basal vasodilator tone in the rat saphenous vein responsible for 10.9 +/- 0.3% of the total vessel diameter was found. After ST administration the venous diameter reduction was similar to that measured after deendothelization or L-NNA. We conclude that ST in situ induces NO release from endothelial cells of rat saphenous artery causing vasodilation, whereas, in contrast, it inhibits the basal NO-dependent vasodilator tone of the saphenous vein inducing vasoconstriction.
Renal hemodynamics in rats with myocardial infarction: selective antagonism of angiotensin receptor subtypes
Authors: Mento P. F. , Maita M. E. , Wilkes B. M.
Published: December 2017

Rats with congestive heart failure demonstrate striking intrarenal vasoconstriction that contributes to reduced renal excretory function. The importance of specific angiotensin II receptor subtypes (AT1, AT2) for mediating changes in renal hemodynamics was studied in anesthetized rats 1 mo after myocardial infarction (MI) created by coronary artery ligation. AT1 antagonism with losartan alone decreased mean arterial pressure (MAP), total peripheral resistance (TPR), and renal resistance (RR) in control and MI rats to a similar extent without affecting renal blood flow (RBF) or RBF as a percentage of cardiac output (%RBF/CO). In contrast, AT2 antagonism with PD-123319 alone significantly reduced MAP and RR in MI rats without affecting these parameters in control rats. TPR and %RBF/CO were not changed significantly in either group. In contrast, combined AT1- and AT2-receptor inhibition lowered TPR and RR and increased RBF and %RBF/CO, thus the effects of renin or ACE inhibition were mimicked in MI rats. We conclude that angiotensin II acts at both AT1 and AT2 receptor sites in rats with reduced cardiac mass to modulate renal hemodynamics.
Skeletal muscle microvascular and tissue injury after varying durations of ischemia
Authors: Harris A. G. , Leiderer R. , Peer F. , Messmer K.
Published: December 2017

The purpose of this study was to examine the effect of varying durations of ischemia on several microvascular parameters in the awake hamster chamber model. The goal was to characterize the microvascular damage that occurs in skeletal muscle as a result of ischemia and reperfusion. The chamber tissues were subjected to 1-5 h of ischemia, and then the following parameters were measured: vessel diameter, endothelial thickness, macromolecular leakage, red blood cell velocity, adherent leukocytes, rolling leukocytes, freely flowing leukocytes, functional capillary density, and propidium iodide-positive cell nuclei. In control animals there was no significant difference in any parameters over the entire observation period. After 1 or 2 h of ischemia an increase in rolling and adherent leukocytes was measured. After 3 h of ischemia there was a significant increase in the mean endothelial thickness and in the number of nonviable cells. After 4 h of ischemia a significant difference in the extent of macromolecular leakage and the functional capillary density was additionally observed. After 5 h of ischemia this damage was more pronounced and often so severe that approximately 50% of the vessels demonstrated no reflow.
Firing properties of identified parasympathetic cardiac neurons in nucleus ambiguus
Authors: Mendelowitz D.
Published: December 2017

This study tests the hypothesis that identified parasympathetic cardiac neurons in the nucleus ambiguus possess pacemaker-like activity or, alternatively, that these neurons are inherently silent. To test this hypothesis and to examine the firing properties of these neurons, parasympathetic cardiac neurons were identified by the presence of a fluorescent tracer previously applied to their terminals surrounding the heart. Perforated patch-clamp electrophysiological techniques were used to study the spontaneous and depolarization-evoked firing patterns of these identified parasympathetic cardiac neurons in an in vitro brain stem slice. Parasympathetic cardiac neurons were silent. On injection of depolarizing current, however, these neurons fired with both little delay and spike frequency adaptation. Hyperpolarizing prepulses elicited a significant delay before depolarization-evoked firing The Ca(2+)-activated K+ channel blocker apamin, but not charybdotoxin, increased the depolarization-activated firing frequency of these neurons and inhibited the afterhyperpolarization. In summary, parasympathetic cardiac neurons do not have pacemaker-like properties, but they do possess discharge characteristics that would enable them to closely follow excitatory synaptic activation for prolonged periods.
Contractile actions of C5a on isolated porcine coronary resistance and conductance arteries
Authors: Rendig S. V. , Gray S. , Amsterdam E. A.
Published: December 2017

The comparative effects of the complement component C5a on coronary resistance and conductance arteries have not been evaluated. To clarify the coronary contractile actions of this anaphylatoxin, we studied the effects of C5a on development of isometric tension in isolated porcine coronary conductance and resistance arteries. Internal diameters of conductance and resistance vessels were 367 +/- 21 and 88 +/- 4 microns, respectively. Vessel ring segments were suspended in a microvessel myograph, stretched to the peaks of their length-tension curves, and precontracted with 30 mM K+ physiological salt solution. Dose-response curves to C5a (2, 10, and 50 nM) were obtained. At 50 nM, the C5a-induced increase in tension in resistance arteries (4.1 +/- 0.9 to 5.7 +/- 1.4 mN, 35.8 +/- 3.4%) was significantly greater (P < 0.05) than in conductance arteries (10.7 +/- 2.2 to 12.4 +/- 2.6 mN, 15.6 +/- 3.0%). A specific thromboxane A2 receptor antagonist, SQ-29548, virtually eliminated C5a-induced increases in tension. C5a did not impair endothelium-dependent relaxation in either conductance or resistance vessels, as indicated by the half-maximal effective dose (ED50) calculated from bradykinin dose-response curves before and after exposure of the vessels to 50 nM C5a (resistance: pre-C5a ED50 = 2 nM, post-C5a ED50 +/- 3 nM; conductance: pre-C5a ED50 +/- 13 nM, post-C5a ED50 +/- 14 nM). These results indicate that 1) C5a has a greater vasoconstrictive effect on isolated porcine resistance than conductance coronary arteries; 2) C5a-induced coronary constriction is mediated by thromboxane A2; and 3) C5a does not impair endothelium-dependent relaxation of isolated porcine coronary arteries.
Role of KATP channels on modulating diaphragmatic microvascular flow during hemorrhagic hypotension
Authors: Chang H. Y. , Chen C. W. , Hsiue T. R. , Chen C. R.
Published: December 2017

The effects of glibenclamide (GLB), a specific blocker of ATP-sensitive potassium (KATP) channels, and tetraethylammonium (TEA) on modulating the regulation of diaphragmatic microcirculation were assessed in anesthetized mechanically ventilated rats. With bicarbonate-buffered Ringer solution continuously suffusing the left hemidiaphragm, microcirculatory blood flow was recorded by laser-Doppler flowmetry (QLDF). Hemorrhagic hypotension (HH) was induced via bleeding into a pressure reservoir. Five sets of experiments were performed. In set 1 (n = 6), the vasodilator effect of diazoxide (3 x 10(-4) M) was abolished after a 30-min suffusion with GLB, whereas the vasodilator effect of sodium nitroprusside (3 x 10(-6) M) remained the same. In set 2 (vehicle + HH; n = 23), a stepwise reduction in systemic arterial blood pressure (ABP) induced two distinct patterns of microvascular responses. Regulation of QLDF could be observed in pattern A animals in a range of ABP from 113 to 52 mmHg, whereas QLDF in pattern B animals rose progressively with declining ABP. In set 3 (GLB + HH; n = 17), baseline values of QLDF were not significantly affected after a 30-min suffusion of GLB (10(-5) M). During HH, two microvascular patterns similar to those in set 2 were observed. GLB significantly potentiated the reduction in QLDF in pattern A animals. In contrast, GLB had no effect on QLDF in pattern B animals. In set 4 (TEA + HH; n = 17), similar microvascular responses, compared with the vehicle group, were observed during HH after a 30-min suffusion of TEA (2 x 10(-3) M). In set 5 (n = 5), baseline values of QLDF were not significantly altered during sham hypotension. We conclude that 1) KATP channels are functional but not active in the resting diaphragmatic microcirculation and 2) KATP channels can modulate regulation of the microcirculation in the resting diaphragm during HH.
Effect of neonatal sympathectomy on development of angiotensin II-induced hypertension
Authors: Csiky B. , Simon G.
Published: December 2017

We tested, in the early stage of angiotensin II (ANG II)-induced hypertension, whether sympathectomy prevented the autopotentiation of vasoconstrictor responses by ANG II and, in the chronic, established phase of hypertension, whether the antihypertensive effect of sympathectomy, if any, was related to the prevention of structural vascular changes. Neonatally and sham-sympathectomized male Sprague-Dawley rats received 100 or 200 ng x kg(-1) x min(-1) ANG II intraperitoneally for 7-10 days or 200 ng x kg(-1) x min(-1) ANG II subcutaneously for 4 wk. Sham-treated sympathectomized and sham-sympathectomized rats were controls. Vasoconstrictor responses to ANG II, norepinephrine (NE), arginine vasopressin, and periarterial nerve stimulation were measured in the mesentery of rats, and thereafter, in the chronically treated rats, mesenteric resistance arteries were fixed in situ for morphometric measurements. In ANG II-treated sham-sympathectomized rats: 1) tail systolic blood pressure was unchanged after 7-10 days and increased by 23 mmHg at 4 wk (P < 0.001); 2) vasoconstrictor responses were selectively increased to ANG II (autopotentiation; P = 0.026) and nerve stimulation (P = 0.031) at 7-10 days and nonselectively increased to all stimuli at 4 wk (P < 0.05 to P < 0.01); and 3) after 4 wk, the wall-to-lumen ratio of resistance arteries was increased (P < 0.02). In ANG II-treated sympathectomized rats, there were no changes in systolic blood pressure or vasoconstrictor responses at either 7-10 days or 4 wk, but structural vascular changes developed to the same extent as in sham-sympathectomized ANG II-treated rats. Autopotentiation of vasoconstrictor responses appears to be due to an interaction between ANG II and the sympathetic nervous system, because it is prevented by sympathectomy. The dissociation of function and structure in the chronic stage of ANG II administration to sympathectomized rats suggests that structural vascular changes by themselves are insufficient to cause hypertension, but increased vascular reactivity or vasoconstrictor input is also needed.
Maximum oxidative phosphorylation capacity of the mammalian heart
Authors: Mootha V. K. , Arai A. E. , Balaban R. S.
Published: December 2017

It is difficult to estimate the maximum in vivo aerobic ATP production rate of the intact heart independent of limitations imposed by blood flow, oxygen delivery, and maximum mechanical power. This value is critical for establishing the kinetic parameters that control oxidative phosphorylation, as well as for providing insights into the limits of myocardial performance. In this study, the maximum ADP-P(i)-driven heart mitochondrial respiratory rate (MV(O2 mito)) was determined with saturating levels of oxygen, substrates, and cofactors at 37 degrees C. These rates were normalized to cytochrome alpha1 alpha3 (cytochrome oxidase; Cyt a) content. To extrapolate this rate to the intact heart, the Cyt a content of the myocardium (nmol Cyt a/g wet wt myocardium) was determined in the same hearts. The maximum ADP-P(i)-driven mitochondrial respiratory rates were 676 +/- 31 and 665 +/- 65 nmol O2 x min(-1) x nmol Cyt a(-1) in the dog and pig, respectively. The Cyt a content in the two species was 43.6 +/- 2.4 and 36.6 +/- 3.1 nmol Cyt a/g wet wt, respectively. With these values, the MV(O2 mito) was calculated to be 29.5 (dog) and 24.3 (pig) micromol O2 x min(-1) x g wet wt myocardium(-1). Comparison with in vivo studies shows that the exercising heart can utilize 80-90% of its maximum oxidative capacity, implying there is little aerobic ATP production reserve in the mammalian heart.
Closed-loop identification of carotid sinus baroreflex open-loop transfer characteristics in rabbits
Authors: Kawada T. , Sugimachi M. , Sato T. , Miyano H. , Shishido T. , Miyashita H. , Yoshimura R. , Takaki H. , Alexander J. , Sunagawa K.
Published: December 2017

In the circulatory system, a change in blood pressure operates through the baroreflex to alter sympathetic efferent nerve activity, which in turn affects blood pressure. Existence of this closed feedback loop makes it difficult to identify the baroreflex open-loop transfer characteristics by means of conventional frequency domain approaches. Although several investigators have demonstrated the advantages of the time domain approach using parametric models such as the autoregressive moving average model, specification of the model structure critically affects their results. Thus we investigated the applicability of a nonparametric closed-loop identification technique to the carotid sinus baroreflex system by using an exogenous perturbation according to a binary white-noise sequence. To validate the identification method, we compared the transfer functions estimated by the closed-loop identification with those estimated by open-loop identification. The transfer functions determined by the two identification methods did not differ statistically in their fitted parameters. We conclude that exogenous perturbation to the baroreflex system enables us to estimate the open-loop baroreflex transfer characteristics under closed-loop conditions.