bluuebunny/crossref_metadata_2025 huggingface dataset:
ATP raises [Ca2+]i via different P2-receptor subtypes in freshly isolated and cultured aortic myocytes
Authors: Pacaud P. , Malam-Souley R. , Loirand G. , Desgranges C.
Published: December 2017

In vascular smooth muscle, extracellular ATP induces an increase in intracellular [Ca2+] ([Ca2+]i). Various agonists have been used to characterize P2-purinoceptor subtypes involved in the ATP-induced [Ca2+]i rise, measured by indo 1 fluorescence, in both freshly isolated and cultured rat aortic smooth muscle cells. alpha, beta-Methylene-ATP increased [Ca2+]i via Ca2+ entry through P2x-receptor channels in freshly isolated but not in cultured cells. 2-Methylthio-ATP and ADP failed to release Ca2+ via P2y-receptor activation in freshly isolated cells, whereas such a response was obtained in cultured cells. UTP, by stimulating P2u receptors, released Ca2+ from intracellular stores in both freshly isolated and cultured cells. These results suggest that, in the course of the culture process, P2x-receptor activation-induced responses were lost, whereas P2y-receptor activation-induced [Ca2+]i rise appeared, these two phenomena being independent. Responses to P2x-receptor agonist were lost in all culture conditions, whereas functional P2y receptors appeared only in cells that were stimulated with serum to induce cell cycle progression. The phenotypic modulation of vascular myocytes was therefore associated with a change in the functional P2-purinoceptor subtypes.
Physiological relevance of T-tube model parameters with emphasis on arterial compliances
Authors: Shroff S. G. , Berger D. S. , Korcarz C. , Lang R. M. , Marcus R. H. , Miller D. E.
Published: December 2017

The T-tube model of systemic arterial circulation was examined with respect to the physiological relevance of model parameters. root aortic pressure [Pao(t)] and flow [Qao(t)] and descending aortic flow [Qb(t)] were measured in anesthetized, open-chest dogs under control conditions, during inflation of a balloon positioned in the left external iliac artery (n = 5), and during infusion of vasoactive drugs nitroprusside (NTP, n = 4) and phenylephrine (PHL, n = 5). With Pao(t) as the input, the model accurately predicted both Qao(t) and Qb(t) under all conditions (r2 > 0.96). The balloon inflation data established the ability of the model to discriminate between proximal and distal arterial mechanical properties. Furthermore, proximal properties (i.e., tube characteristic impedances and transit times) were independent of distal properties such as terminal compliances and resistances (or equivalently, wave reflections). The effects of NTP and PHL were pharmacologically consistent and served to further validate this model. NTP primarily affected distal (load) properties, whereas PHL altered both load and tube parameters. Physiological interpretation of model parameters, particularly compliance, is also discussed. The ability of the model to correctly discriminate between proximal and distal arterial properties is relevant because these properties may affect cardiovascular function differently.
High correlation of fractals for regional blood flows among resting and exercising skeletal muscles
Authors: Iversen P. O. , Nicolaysen G.
Published: December 2017

The regional blood flow distributions within single skeletal muscles are markedly uneven both at rest and during exercise hyperemia. Fractals adequately describe this perfusion heterogeneity in the resting lateral head of the gastrocnemius muscle as well as in the myocardium. Recently, we provided evidence that the fractal dimension for the blood flow distributions in this resting muscle was strongly correlated with that of the myocardium in the same rabbit. Prompted by this hitherto unknown observation, we have now examined 1) whether fractals also describe perfusion distributions within muscles with a varying metabolic activity, and 2) whether the fractal dimensions for blood flow distributions to these muscles were correlated. We used pentobarbital-anesthetized rabbits and cats. The regional distributions of blood flow within various skeletal muscles were estimated by microsphere trapping. The data unequivocally showed that the perfusion distributions could be described with fractals both in resting and in exercising muscle in both species, the corresponding fractal dimensions ranging from 1.36 to 1.41. The fractal dimensions were markedly correlated (r2 ranged from 0.82 to 0.88) when both various resting and resting plus exercising muscles were compared in the same animal. This surprising finding of high correlations for the fractal dimensions among various muscles within one animal provides a novel characteristic of blood flow heterogeneity.
Paraventricular nucleus histamine increases blood pressure by adrenoreceptor stimulation of vasopressin release
Authors: Bealer S. L. , Abell S. O.
Published: December 2017

The role of adrenoreceptor stimulation and the peripheral mechanism mediating the increase in mean arterial blood pressure (MAP) and heart rate (HR) during administration of histamine (HA) in the paraventricular nucleus/anterior hypothalamus (PVN/AH) was evaluated in conscious rats. HA administered through microdialysis probes in the PVN/AH region increased MAP (18 +/- 1 mmHg) and HR (81 +/- 10 beats/min). The pressor response was abolished by simultaneous administration of phentolamine (alpha 1- and alpha 2-antagonist) or prazosin (alpha 1-antagonist) but not altered by yohimbine (alpha 2-antagonist). The tachycardia was not effected by any adrenergic antagonist. Furthermore, ganglionic blockade did not reduce the increase in MAP (21 +/- 2 mmHg) during PVN/AH perfusion with HA, while V1-vasopressin receptor blockade abolished the pressor response (4 +/- 2 mmHg). These data suggest that HA administered to the PVN/AH increases blood pressure by local release of norepinephrine and alpha 1-adrenoreceptor stimulation of vasopressin secretion, while the tachycardia is not mediated by alpha-adrenoreceptors.
Central angiotensin II AT1-receptor antagonism in normal and heart-failed sheep
Authors: Rademaker M. T. , Fitzpatrick M. A. , Charles C. J. , Frampton C. M. , Richards A. M. , Nicholls M. G. , Espiner E. A.
Published: December 2017

The role of the brain renin-angiotensin system (RAS) in heart failure was examined by administering intracerebroventricular (ICV) infusions of the angiotensin II (ANG II) type 1 (AT1)-receptor antagonist losartan (0.1 followed by 0.5 mg.kg-1.3 h-1) to six concious sheep before (nonpaced) and after induction of heart failure by rapid left ventricular pacing (paced). In both nonpaced and paced states, ICV losartan abolished drinking, induced a significant diuresis (P < 0.05) and anti-natriuresis (P < 0.05), and increased plasma renin activity (P < 0.05) and ANG II (P < 0.01) and aldosterone levels (0.1 > P > 0.05). Plasma arginine vasopressin was suppressed by ICV losartan only in the paced state (P < 0.05). Hemodynamics were not altered by ICV losartan in the nonpaced animals. In the paced state, however, significant reductions in left ventricular systolic, mean arterial, and left atrial pressures were observed (decrements of 13 +/- 7, 12 +/- 5, and 3.4 +/- 0.7 mmHg, respectively, all P < 0.05). In conclusion, ANG II within the brain participates in the regulation of thirst and body electrolyte and fluid homeostasis in normal and heart-failed sheep and appears to play a role in regulating resting hemodynamic status in this model of heart failure.
Role of rapidly activating delayed rectifier K+ current in sinoatrial node pacemaker activity
Authors: Ono K. , Ito H.
Published: December 2017

A rapidly activating component of delayed rectifier K+ current (IK,r) was dissected using a selective blocker, E-4031, during the action potential clamp (AP clamp) in rabbit sinoatrial node cells. Application of E-4031 induced a large compensation current, of which amplitude was similar to or larger than the net current during repolarization and was maximum (2.2 +/- 0.2 pA/pF) at -46.0 +/- 1.8 mV (n = 13). During the slow diastolic depolarization, the compensation current gradually decayed and then abruptly decreased at the peak of action potential. The time-dependent change of IK,r was calculated using a mathematical model, in which independent gates of activation and inactivation were assumed based on the whole cell voltage-clamp experiments. The reconstructed IK,r corresponded well with the E-4031-sensitive current measured by the AP clamp method. Partial block of IK,r by E-4031 in spontaneously beating cells decreased the action potential amplitude, maximum rate of rise, and maximum rate of repolarization and induced a positive shift of the maximum diastolic potential. Complete block of IK,r terminated the spontaneous action potential at -37.4 +/- 2.9 mV (n = 3). It is concluded that IK,r plays an essential role in determining the maximum diastolic potential and ensures the firing of the following action potential in sinoatrial node cells.
Constitutive NOS expression in cultured endothelial cells is elevated by fluid shear stress
Authors: Ranjan V. , Xiao Z. , Diamond S. L.
Published: December 2017

The role of chronic fluid shear stress on endothelial constitutive nitric oxide synthase (cNOS) levels may have an important role in vessel diameter control. We subjected primary human umbilical vein endothelial cells (HUVEC) or bovine aortic endothelial cells (BAEC, passages 2-14) to steady laminar shear stress. In both cell types, the intracellular level of cNOS was elevated within 3 h of flow exposure at 25 dyn/cm2 and remained elevated at 6 and 12 h of flow exposure, compared with stationary controls, as indicated by digital immunofluorescence microscopy. Shear stress exposure for 6 h caused a 2.2 +/- 0.3- and 2.8 +/- 0.3-fold elevation of cNOS protein levels in BAEC (n = 3, P < 0.01) and HUVEC (n = 3, P < 0.01), respectively, in the presence or absence of 1 microM dexamethasone. Dexamethasone suppresses induction of the inducible NOS gene, indicating that cNOS was elevated by fluid shear stress. Flow exposure at 4 dyn/cm2 caused no enhancement of cNOS levels in either cell type. The flow induction of the cNOS protein levels was not blocked by preincubation of BAEC with 100-400 microM of NG-nitro-L-arginine methyl ester, indicating that flow-induced NO (or guanosine 3',5'-cyclic monophosphate) was not involved in the elevation of cNOS levels. Protein kinase C inhibitor H-7 (10 microM) had no effect on induction of NOS protein in BAEC exposed to 25 dyn/cm2. The cNOS mRNA levels were found to be elevated by two- to threefold in BAEC after 6 or 12 h of flow exposure at either 4 or 25 dyn/cm2, and this induction of NOS mRNA occurred in the presence of dexamethasone. The elevation of cNOS levels by chronic flow exposure may provide a mechanism for chronic regulation of vessel diameter by endothelial response to prevailing blood flow.
Angiotensin II mediates a sustained rise in nuclear and cytoplasmic calcium via multiple receptor subtypes
Authors: Munzenmaier D. H. , Greene A. S.
Published: December 2017

Alterations in nuclear calcium levels in response to angiotensin II (ANG II) may play an important role in the trophic actions of ANG II. This study utilized confocal microscopy and nuclear staining to test the hypothesis that both nuclear and cytoplasmic calcium levels are altered in response to ANG II stimulation of freshly dissociated aortic smooth muscle cells. Cells were loaded with the calcium indicator fluo 3 acetoxymethyl ester, and the calcium response to ANG II stimulation was analyzed over time with a laser-scanning confocal microscope. Additionally, the ratiometric calcium indicator fura 2 acetoxymethyl ester and conventional fluorescence microscopy were used to verify these observations. Results show that basal nuclear calcium exceeds cytoplasmic calcium in these cells. Stimulation by ANG II induces a sustained rise (separate from the rapid transient) in both nuclear and cytoplasmic calcium in excess of 20 min in duration. This rise was blockable by either the AT1 receptor antagonist DuP-753 or by the AT2 antagonist PD-123319. Thus ANG II stimulates a sustained rise in nuclear calcium by a mechanism that necessitates activation of both AT1 and AT2 receptors.
Radial columns in autoradiographs generated from tracer methods for measuring cerebral cortical blood flow
Authors: Bryan R. M. , Duckrow R. B.
Published: December 2017

Radial columns in the cerebral cortex, sometimes seen in autoradiographic methods for measuring cerebral blood flow, were studied. Radioactively labeled tracers were injected into the internal carotid artery in pentobarbital sodium-anesthetized rats. The cortical patterns of tracer uptake were determined using autoradiography. When tracers for measuring cerebral blood flow were administered, cortical columns were apparent in the autoradiograph. The darker columns (higher tracer concentration) in the image aligned with penetrating arterioles, suggesting that the tracer was being removed from the penetrating arterioles. In another experiment, [14C]glucose was used as a qualitative blood flow tracer. Modeling of glucose uptake predicts that 26-29% more glucose should be extracted in the dark columns than the light columns if the columns represent capillary blood flow. [14C]glucose did not produce the cortical columns consistent with the model prediction. We conclude that capillary blood flow in the cortex is not organized in radial columns of higher and lower flow. The results support the idea that the flow tracers are removed from blood primarily in the penetrating arterioles.
Regional systemic ANP differences in fetal lambs: role of coronary sinus outflow distribution
Authors: Smolich J. J. , Woods R. L.
Published: December 2017

Although it is known that the atrial natriuretic peptide (ANP) level in right ventricular (RV) blood supplying the caudal part of the fetus is greater than in left ventricular blood perfusing the cephalic part of the fetus, the extent to which any preferential passage of coronary sinus blood into the right ventricle contributes to regional differences between ANP levels in fetal cephalic and caudal arteries is unknown. To address this question, experiments were performed in eight late-gestation fetal lambs, 3-7 days after catheters were inserted into the left atrium, major arteries and veins, and coronary sinus (via the left hemiazygous vein). The plasma ANP level in the abdominal aorta (171 +/- 33 pg/ml) was higher than in the carotid artery (103 +/- 15 pg/ml; P < 0.05), and both were lower than in the coronary sinus (736 +/- 89 pg/ml; P < 0.005). The coronary sinus outflow, measured with radioactive microspheres injected into the hemiazygous vein, was preferentially distributed to the right ventricle (94.7 +/- 1.3%) and thence to the abdominal aorta (89.5 +/- 1.6%). This streaming of the coronary sinus outflow contributed 13.3 +/- 0.9 and 1.4 +/- 0.4 pg/ml to ANP levels in the abdominal aorta and carotid artery, respectively, and thereby accounted for 11.9 +/- 0.9 pg/ml of the abdominal aorta-carotid artery ANP difference of 68 +/- 25 pg/ml.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of atrial pacing site on rate-dependent AV nodal function in rabbit hearts
Authors: Amellal F. , Billette J.
Published: December 2017

The functional origin of the changes in atrioventricular (AV) nodal function with the atrial pacing site was studied in isolated rabbit heart preparations. The rate-dependent AV nodal properties of recovery, facilitation, and fatigue were characterized with premature stimulation protocols repeated for each of three atrial pacing sites (upper atrium, low crista terminalis, and low interatrial septum). The effects of the atrial pacing site, reference site from which the beginning of nodal activation is measured (low crista and low septum) and stimulation protocol on nodal conduction and refractory parameters, were assessed with multifactorial analyses of variance. The changes in nodal parameters with the stimulation protocol did not differ significantly with the pacing site, indicating that the rate-dependent nodal properties are not affected by the atrial origin of the impulse. Only the baseline value of nodal parameters varied with the atrial pacing and reference site. However, the comparison of data obtained while the low crista was the pacing and reference site to those obtained while the low septum was the pacing and reference site yield no statistically significant differences, thus indicating that changes in perinodal activation were largely responsible for the observed changes in baseline. Upper atrial and low crista pacing yielded very similar data. We conclude that 1) the atrial pacing site affects perinodal activation but not rate-dependent nodal function, 2) the two inputs are equally effective in activating the AV node, and 3) input summation is a minor factor in rate-dependent nodal function.
Effects of ischemic and adenosine preconditioning on interstitial fluid adenosine and myocardial infarct size
Authors: Lasley R. D. , Konyn P. J. , Hegge J. O. , Mentzer R. M.
Published: December 2017

The accumulation of adenosine during a brief coronary occlusion has been proposed to mediate the infarct size-limiting effect of ischemic preconditioning. The purpose of this study was to compare the effects of ischemic preconditioning and a transient adenosine infusion on myocardial interstitial fluid (ISF) adenosine levels and infarct size. Microdialysis fibers (10.0 mm length) were placed in the left ventricular myocardium of pentobarbital sodium-anesthetized rabbits to estimate ISF adenosine. Ischemic preconditioning was induced by 5 min of coronary artery occlusion and 10 min of reperfusion before 45 min of occlusion. Adenosine preconditioning was induced with 5 min of intravenous adenosine infusion (140 micrograms.kg-1.min-1) followed by a 10-min washout before the prolonged occlusion. Myocardial infarct size was determined by triphenyltetrazolium chloride staining after 3 h of reperfusion. Five minutes of ischemia and 5 min of adenosine infusion produced comparable increases in dialysate adenosine levels (from 0.19 +/- 0.02 to 0.69 +/0- 0.11 and 0.28 +/- 0.10 to 0.71 +/- 0.18 microM, respectively) that decreased to baseline before the prolonged ischemia; however, ischemic-preconditioned hearts exhibited elevated dialysate adenosine levels for the first 5 min of reperfusion. Ischemic-preconditioned hearts exhibited significantly reduced dialysate adenosine concentrations for the first 20 min of the prolonged occlusion (P < 0.05 vs. control), and infarct size was reduced from 41 +/- 6 to 10 +/- 4% of risk area. Adenosine preconditioning had no effect on dialysate adenosine levels during prolonged ischemia but did reduce infarct size to 25 +/- 5% of risk area. These results indicate that a transient increase in ISF adenosine can reduce myocardial infarct size, but adenosine alone does not fully replicate the protective effects of ischemic preconditioning.
Nature of heart failure in patients with ventricular septal defect
Authors: Stewart J. M. , Hintze T. H. , Woolf P. K. , Snyder M. S. , Seligman K. P. , Gewitz M. H.
Published: December 2017

To assess the contributions of systolic and diastolic dysfunction to congestive heart failure (CHF) in ventricular septal defect (VSD), we studied 13 children with VSD at catheterization using a Millar catheter. Eight children had CHF, whereas five did not. Phenylephrine was infused at a rate of 5 micrograms.kg-1.min-1, and M-mode echocardiography and pressure were measured simultaneously. Systolic left ventricular (LV) function was assessed by maximum LV pressure (LVP), rate of pressure development (dP/dt), and by the end-systolic pressure-diameter relation (ESPDR). Systolic myocardial function was assessed by the end-systolic stress-strain relation. Diastolic chamber function was assessed by the isovolumic relaxation time constant (tau) and by the end-diastolic pressure-diameter relation (EDPDR). Diastolic myocardial function was measured by the end-diastolic stress-strain relationship. With phenylephrine, maximum LVP increased from 99 +/- 5 to 119 +/- 4 mmHg with CHF and from 106 +/- 6 to 149 +/- 10 mmHg without CHF. +dP/dt was lower with CHF (1,582 +/- 96 mmHg/s) than without CHF (2,300 +/- 200 mmHg/s). The maximum slope of the ESPDR was 39 +/- 8 with CHF and 94 +/- 14 mmHg/cm without CHF. The maximum slope of the midwall stress-strain relation was 223 +/- 37 with CHF and 395 +/- 93 g/cm2 without CHF. tau was 25 +/- 2 without CHF compared with 32 +/- 3 ms with CHF. The EDPDR was shifted leftward with failure, whereas the stress-strain relation was similar for all patients. CHF in patients with VSD results primarily from systolic dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)
Role of endogenous opioids and serotonin in the hemodynamic response to hemorrhage during hypoxia
Authors: Resta T. C. , Resta J. M. , Walker B. R.
Published: December 2017

Previous studies from our laboratory indicate that acute but not chronic hypoxia decreases the hemorrhage volume required to elicit reflex hypotension. Furthermore, chronically hypoxic animals exhibit an elevated hypotensive threshold during both normoxia and hypoxia compared with control animals. Because reports suggest that opioid and serotonergic mechanisms may be involved in mediating the sympathoinhibition that occurs with hemorrhage, we hypothesized that opioid and/or serotonergic systems are stimulated during hemorrhage under conditions of acute hypoxia and suppressed after chronic exposure to hypoxia and are thus responsible for the altered cardiovascular responses to hemorrhage under each condition. Control and chronically hypoxi rats were administered either the opioid receptor antagonist naltrexone (1 mg/kg), the selective 5-hydroxytryptamine receptor subtype 3 (5-HT3) serotonergic receptor antagonist MDL-72222 (0.5 mg/kg), or their respective vehicles intravenously before hemorrhage was initiated during normoxia or hypoxia (FIO2 = 0.12). In control animals, pretreatment with naltrexone increased the hemorrhage was initiated volume required to achieve hypotension in hypoxic but not normoxic conditions. Naltrexone had no effect on hypotensive threshold in chronically hypoxic animals under conditions of either normoxia or hypoxia. In addition, MDL-72222 had no effect on hypotensive threshold in either control or chronically hypoxic animals in either normoxic or hypoxic conditions. We conclude that endogenous opioids may contribute to the reflex hypotension that occurs during hypoxic hemorrhage in control rats, while no such involvement is evident in chronically hypoxic animals. Furthermore, peripheral 5-HT3 receptors are not likely involved in this response during either normoxic or hypoxic hemorrhage in control or chronically hypoxic rats.
Adrenergic responsiveness is reduced, while baseline cardiac function is preserved in old adult conscious monkeys
Authors: Sato N. , Kiuchi K. , Shen Y. T. , Vatner S. F. , Vatner D. E.
Published: December 2017

To examine the physiological deficit to adrenergic stimulation with aging, five younger adult (3 +/- 1 yr old) and nine older adult (17 +/- 1 yr old) healthy monkeys were studied after instrumentation with a left ventricular (LV) pressure gauge, aortic and left atrial catheters, and aortic flow probes to measure cardiac output directly. There were no significant changes in baseline hemodynamics in conscious older monkeys. For example, an index of contractility, the first derivative of LV pressure (LV dP/dt) was similar (3,191 +/- 240, young vs. 3,225 +/- 71 mmHg/s, old) as well as in isovolumic relaxation, tau (24.3 +/- 1.7 ms, young vs. 23.0 +/- 1.0 ms, old) was similar. However, inotropic, lusitropic, and chronotropic responses to isoproterenol (Iso; 0.1 micrograms/kg), norepinephrine (NE; 0.4 micrograms/kg), and forskolin (For; 75 nmol/kg) were significantly (P < 0.05) depressed in older monkeys. For example. Iso increased LV dP/dt by by 146 +/- 14% in younger monkeys and by only 70 +/- 5% in older monkeys. Iso also reduced tau more in younger monkeys (-28 +/- 7%) compared with older monkeys (-13 +/- 3%). Furthermore, peripheral vascular responsiveness to Iso, NE, For, and phenylephrine (PE; 5 micrograms/kg) was significantly (P < 0.05) reduced in older monkeys. For example, phenylephrine (5 micrograms/kg) increased total peripheral resistence by 69 +/- 4% in younger monkeys and by only 45 +/- 3% in older monkeys. Thus in older monkeys without associated cardiovascular disease, baseline hemodynamics are preserved, but adrenergic receptor responsiveness is reduced systemically, not just in the heart.
Identification and activation of autocrine renin-angiotensin system in adult ventricular myocytes
Authors: Zhang X. , Dostal D. E. , Reiss K. , Cheng W. , Kajstura J. , Li P. , Huang H. , Sonnenblick E. H. , Meggs L. G. , Baker K. M. , et al.
Published: December 2017

To date, the demonstration that the molecular components of the renin-angiotensin system (RAS) are present in adult ventricular myocytes is lacking. In addition, whether the RAS is upregulated under conditions of overload and myocyte hypertrophy in vivo remains to be determined. By employing an in vivo model of ischemic cardiomyopathy in rats, we document that adult myocytes express genes for renin, angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin II (ANG II) receptors. Moreover, renin, ACE, and ANG II receptor mRNAs increased in stressed myocytes undergoing cellular hypertrophy. At the protein level, the percentage of myocytes containing renin, ANG I, and ANG II was significantly increased in the overloaded heart. The number of binding sites for ANG II per myocyte also markedly increased under this setting. These results provide direct evidence of the existence of a myocyte RAS, which may be activated in pathological states of the heart to support myocyte growth and contractile function.
Microheterogeneity of myocardial blood flow in rabbit hearts during normoxic and hypoxic states
Authors: Matsumoto T. , Goto M. , Tachibana H. , Ogasawara Y. , Tsujioka K. , Kajiya F.
Published: December 2017

The goal of this study was to evaluate microheterogeneity of myocardial blood flow and its dependence on arterial O2 tension (PaO2). We measured within-layer distribution of regional blood flows in the left ventricles of anesthetized rabbits in both normoxic and hypoxic states with myocardial region sizes in the range of 0.01-1.0 mm2. A novel method of digital radiography combined with the technique of 3H-labeled desmethylimipramine deposition enabled us to visualize and accurately quantitate regional blood flow at such high levels of resolution. To analyze myocardial blood flow patterns, we computed the coefficient of variation (CV) and the correlation between adjacent regional flows (CA). The CA values were larger in the hypoxic state (PaO2 = 26 +/- 5 mmHg) than in the normoxic state (PaO2 = 97 +/- 20 mmHg) at all levels of resolution (P < 0.001). In the normoxic state, there was a transmural difference in CA (P < 0.001); CA increased with depth of the left ventricle (from subepicardium to subendocardium). However, the relation between CA and the depth of the left ventricle was not statistically significant in the hypoxic state. The CV values were smaller in the hypoxic state than in the normoxic state at all levels of resolution (P < 0.001). When the degree of resolution was reduced from 0.01 to 1.0 mm2, CV decreased by 75% in the normoxic and by 69% in the hypoxic state. Thus we conclude that 1) the decrease in PaO2 increases similarity of blood flows in nearby regions and decreases myocardial blood flow heterogeneity, and 2) similarity of regional blood flows increases with depth of the left ventricle in the normoxic state, but this transmural difference disappears in the hypoxic state.
Coronary and total peripheral resistance changes during sleep in a porcine model
Authors: Zinkovska S. M. , Rodriguez E. K. , Kirby D. A.
Published: December 2017

Changes in autonomic tone in the vasculature during sleep may have important implications for silent ischemia and sudden cardiac death. Few models exist in which both cardiac output and coronary blood flow are continuously measured during natural sleep and autonomic mechanisms are assessed. Catheters were chronically implanted in the aorta to measure mean arterial pressure (MAP), and flow probes were placed on the ascending aorta and the circumflex coronary artery of 18 pigs. Electrodes determined sleep stage as either non-rapid eye movement (NREM) or rapid eye movement (REM) sleep. The MAP was 73 +/- 3 mmHg in the quiet awake state, did not change in NREM, and decreased to 64 +/- 2 mmHg in REM sleep (P < 0.05). In NREM sleep, heart rate did not change from awake state values of 136 +/- 8 beats/min but increased by 5 beats/min in REM sleep (P < 0.05). Coronary vascular resistance decreased from awake state values of 2.7 +/- 0.2 to 2.2 +/- 0.2 mmHg.ml-1.min in REM (P < 0.05); total peripheral resistance decreased from awake values of 0.061 +/- 0.004 mmHg.ml-1.min to 0.050 +/- 0.003 in REM sleep (P < 0.05). Those changes appear to have been mediated primarily by reduction of alpha-adrenergic activity. Spectral analysis of heart rate suggests that power in the high-frequency range (a presumed indicator of parasympathetic tone) was lower in REM sleep than NREM sleep.
A technique to assess aortic distensibility and compliance in anesthetized and awake rats
Authors: Van Gorp A. , Van Ingen Schenau D. S. , Willigers J. , Hoeks A. P. , De Mey J. G. , Struyker Boudier H. A. , Reneman R. S.
Published: December 2017

A noninvasive ultrasonic technique, based on tracking arterial wall displacements with a vessel wall-tracking device attached to a conventional B-mode imager, to assess end-diastolic aortic diameter (d) and aortic diameter changes during the cardiac cycle (delta d) in anesthetized and awake rats is presented. From these parameters and invasively measured aortic pulse pressure (delta P), aortic distensibility and compliance, the relative and absolute increases in lumen cross-sectional area for a given increase in delta P, respectively, can be calculated. d, delta d, and delta P could be determined with good intra-session (variations per day) and inter-session (variations between days) coefficients of variation (CV). The CVs for delta d were smaller in awake (4.6-6.0%) than in anesthetized rats (7.9-11.0%), probably due to variations in delta P during anesthesia (CV: 9.0-12.3%). The CVs for d in awake (3.3-6.5%) and anesthetized rats (2.6-5.0%) were comparable. In awake rats the CV for delta d, but not for d, increased after implantation of the aortic catheter. It is concluded that d, delta d, and delta P of the aorta can be reliably measured noninvasively in anesthetized and awake rats, allowing the in vivo assessment of aortic distensibility and compliance. The technique is sensitive enough to detect effects of agents on aortic wall properties.
Nitric oxide and nitroglycerin reversal of pulmonary vasoconstriction induced by alpha-activation during exercise
Authors: Koizumi T. , Hermo C. I. , Bjertnaes L. J. , Banerjee M. , Newman J. H. , Kubo K.
Published: December 2017

We have previously shown in sheep that pulmonary vascular resistance decreases rapidly after the onset of constant exercise, followed by a slower and smaller second vasodilation. The second phase is partly regulated by alpha- and beta-adrenoceptor activation. We examined the effect of inhaled nitric oxide (NO; 40 ppm) and intravenous nitroglycerin on beta-adrenergic blockade-induced pulmonary vasoconstriction during exercise. In paired studies, we exercised eight sheep at a constant rate of 4 miles per hour for 4 min on a treadmill and measured the hemodynamic response during beta-blockade (propranolol, 1 mg i.v.) with and without 40 ppm inhaled NO or continuous infusion of nitroglycerin (3.2-4.0 micrograms.kg-1.min-1). beta-Blockade resulted in a higher pulmonary vascular resistance during steady-state exercise (40-240 s) than in the unblocked state; reduction in pulmonary vascular resistance during the second phase of exercise was smaller with beta-blockade (13-16%) than with control exercise (26-30%). Inhaled NO and nitroglycerin reversed the beta-blockade-related pulmonary vasoconstriction to the levels of control exercise. Inhaled NO and intravenous nitroglycerin also reversed the pulmonary vasoconstriction produced by intravenous phenylephrine at rest. We conclude that exogenous NO, delivered by gas inhalation or via nitroso compounds, opposes and fully reverses alpha-receptor-activated pulmonary vasoconstriction during exercise in sheep.
Effects of Mg2+ on Ca2+ waves and Ca2+ transients of rat ventricular myocytes
Authors: Terada H. , Hayashi H. , Noda N. , Satoh H. , Katoh H. , Yamazaki N.
Published: December 2017

It has been shown that the occurrence of the transient inward current, which is responsible for triggered activity, was often associated with propagating regions of increased intracellular Ca2+ concentration ([Ca2+]i), i.e., the “Ca2+ wave.” To investigate the mechanism of antiarrhythmic action of Mg2+, we have studied effects of high concentrations of Mg2+ on Ca2+ waves in isolated rat ventricular myocytes. [Ca2+]i was estimated using the Ca(2+)-indicating probe indo 1. Ca2+ waves in myocytes, stimulated at 0.2 Hz, were induced by perfusion of isoproterenol (10(-7) M). High Mg2+ concentration suppressed Ca2+ waves in a concentration-dependent manner (36% at 4 mM, 70% at 8 mM, and 82% at 12 mM). The Ca2+ channel blocker verapamil also suppressed Ca2+ waves in a similar way. In contrast with marked depression of Ca2+ transients by verapamil, Ca2+ transients were not affected by high Mg2+ concentration (8 mM). High Mg2+ concentration also reduced frequencies of Ca2+ waves in the absence of electrical stimulation, whereas verapamil failed to reduce frequencies of Ca2+ waves. Reduction in frequency of Ca2+ waves by high Mg2+ concentration was associated with slowing of propagation velocity of Ca2+ waves. To examine whether suppressive effects of high Mg2+ concentration on Ca2+ waves were related to an increase in intracellular Mg2+ concentration ([Mg2+]i), the effect of high-Mg2+ solution on [Mg2+]i was examined in myocytes loaded with mag-fura 2. An increase in extracellular Mg2+ concentration from 1 to 12 mM increased [Mg2+]i from 1.06 +/- 0.16 to 1.87 +/- 0.22 mM (P < 0.01) in 30 min. To examine the effect of high Mg2+ concentration on amount of releasable Ca2+ in the sarcoplasmic reticulum, the effect of high Mg2+ concentration on the Ca2+ transient induced by a rapid application of caffeine was examined. High-Mg2+ solution increased the peak of the caffeine-induced Ca2+ transient. These results suggest that the inhibitory effect of Mg2+ on Ca2+ waves was not due to inhibition of the sarcolemmal Ca2+ channel but could be due to a decreased propensity for the sarcoplasmic reticulum to divest itself of excess Ca2+.
Parallel changes of blood flow and heterogeneity of capillary plasma perfusion in rat brains during hypocapnia
Authors: Vogel J. , Abounader R. , Schrock H. , Zeller K. , Duelli R. , Kuschinsky W.
Published: December 2017

Plasma perfusion patterns were investigated in brain capillaries during decreased cerebral blood flow induced by hyperventilation. Anesthetized rats were decapitated 3-4 s after being given an intravenous bolus injection of Evans blue dye. the measured steep increase of the arterial dye concentration at this moment ensures that different capillary plasma transit times are reflected in different intracapillary dye concentrations. The observed heterogeneity of capillary plasma transit time was expressed as the coefficient of variation (means +/- SD) of the intracapillary dye concentrations. For comparison, cerebral blood flow was determined at comparable PCO2 values in a second experimental group. At arterial PCO2 values between 40 and 25 mmHg, the cerebral blood flow and the coefficient of variation of the intracapillary dye concentration decreased with decreasing PCO2, whereas at PCO2 values <25 mmHg cerebral blood flow and coefficient of variation did not correlate with the arterial PCO2. However, it cannot be excluded that the coefficient of variation of the intracapillary dye concentration increases between 25 and 14 mmHg and decreases between 14 and 10 mmHg. It is concluded that the reduction of cerebral blood flow measured during moderate hypocapnia is paralleled by a decreased heterogeneity of the brain capillary perfusion. During severe hypocapnia this relationship is lost, indicating a potential disturbance of the cerebral microcirculation.
Oxygen saturation and pH changes in cremaster microvessels of the rat
Authors: Kobayashi H. , Takizawa N.
Published: December 2017

Recent studies have shown a considerable extent of diffusive O2 transfer from precapillary vessels, but the occurrence of O2 influx into postcapillary vessels (diffusive shunting) is still controversial. In this study, we investigated diffusive shunting between pre- and postcapillary vessels in muscle tissue and pH changes in the microvessels in an attempt to determine the physiological significance of the parallel arrangement of arterial and venous vessels in tissue oxygenation. We used rat cremaster muscles and controlled the breathing of anesthetized rats using urethane with FIO2 set at 0.3 and 0.12. We employed a noninvasive spectrophotometric method of measuring pH, using a pH-sensitive dye (1-hydroxypyrene-3,6,8-trisulfonic acid) and the O2 saturation level of hemoglobin (SO2) in microvessels from small arteries down to arterioles and from venules up to small veins. At FIO2 0.30, pH significantly decreased from 7.39 +/- 0.02 to 7.26 +/- 0.05 (SD) in precapillary vessels and remained close to constant during passage through postcapillary vessels. At FIO2 0.12, pH decreased from 7.36 +/- 0.03 to 7.01 +/- 0.06 in precapillary vessels and then increased in postcapillary vessels from 6.75 +/- 0.19 to 7.27 +/- 0.08. At FIO2 0.30, SO2 decreased from 98.6 +/- 5.4 to 64.2 +/- 4.5% in precapillary vessels and increased from 62.5 +/- 6.5 to 89.4 +/- 4.1% in postcapillary vessels. At FIO2 0.12, SO2 decreased from 47.0 +/- 5.5 to 25.1 +/- 3.8% in precapillary vessels and remained close to constant in postcapillary vessels. In conclusion, during hyperoxia, diffusive shunting of O2 was enhanced, and during hypoxia, acid was accumulated in peripheral vessels. It is speculated that acid accumulated due to back-diffusion of CO2 from venous to arterial microvessels, liberating O2 bound to hemoglobin via the Bohr effect. The diffusive shunting of O2 and counterdiffusion and accumulation of CO2 may contribute to the homeostasis of tissue oxygenation levels.
Nitric oxide does not modulate myocardial contractility acutely in in situ canine hearts
Authors: Crystal G. J. , Gurevicius J.
Published: December 2017

The study was designed to assess the influence of nitric oxide (NO) on myocardial contractility in vivo. The left anterior descending coronary artery (LAD) of 28 anesthetized, open-chest dogs was perfused with arterial blood via an extracorporeal circuit. In the LAD bed, segmental shortening (SS), an index of local myocardial contractility, was measured with ultrasonic crystals. Coronary blood flow (CBF) was measured by Doppler flow transducer and used to calculate myocardial oxygen consumption (MVO2). Studies were performed with coronary perfusion pressure (CPP) constant (n = 23) or with CBF constant (n = 5). Measurements were obtained 1) during intracoronary infusions of the NO donors sodium nitroprusside (SNP, 80 ng/min) and nitroglycerin (NTG, 40 micrograms/min) and of a stimulator of endogenous NO release, acetylcholine (ACh, 20 micrograms/min), and 2) after inhibition of basal NO synthase activity with either NG-nitro-L-arginine methyl ester (L-NAME, 300 micrograms/min ic for 15 min) or NG-monomethyl-L-arginine (L-NMMA 2mg/min ic for 15 min). Decreases in SS (-38%) and MVO2 (-42%) during intracoronary isoflurane infusion verified responsiveness of preparation to negative inotropic agents. With CPP constant, SNP, NTG, and ACh caused increases in CBF (177, 28, and 280%, respectively) with no changes in SS or MVO2. Neither L-NAME nor L-NMMA affected SS, MVO2, or CBF. With CBF constant, the SNP- and ACh-induced decreases in CPP were accompanied by no changes in SS. In conclusion, NO had no direct influence on myocardial contractility or oxygen demand under baseline conditions, or when its local concentration was increased acutely with SNP, NTG, or ACh. An augmented SS secondary to increased CBF per se, i.e., Gregg's phenomenon, did not obscure potential negative inotropic effects of SNP and ACh with CPP constant.
Functional hyperemia in striated muscle is reduced following blockade of ATP-sensitive potassium channels
Authors: Saito Y. , McKay M. , Eraslan A. , Hester R. L.
Published: December 2017

This study was designed to determine the role of ATP-sensitive potassium channels in the control of the arteriolar diameter during functional hyperemia. The hamster cremaster muscle was prepared for in vivo microscopy and stimulated electrically for 1 min before and after topical application of 10 microM glibenclamide to block ATP-sensitive potassium channels. Glibenclamide treatment resulted in a small, though not significant, decrease in resting arteriolar diameter (P > 0.05). Glibenclamide almost completely inhibited the vasodilation of the first-order and the third-order arterioles in response to topical application of 1 microM cromakalim (P < 0.05). During muscle stimulation, the first-order arterioles dilated from 69 +/- 3 to 89 +/- 3 microns (n = 7), and the third-order arterioles dilated from 16 +/- 1 to 35 +/- 2 microns (n = 7). In this set of experiments glibenclamide treatment resulted in a significant decrease (approximately 4 microns) in the resting diameters of the first-order arterioles, but had no significant effect on the resting diameter of third-order arterioles. Glibenclamide treatment significantly attenuated the vasodilation associated with muscle contraction to 72 +/- 3 and to 21 +/- 3 microns, respectively (P < 0.05). These results suggests that ATP-sensitive potassium channels are an important mediator in the vasodilatory response to muscle stimulation in the hamster cremaster muscle.
Roles of Cl- channels and Ca2+ mobilization in stretch-induced increase of SA node pacemaker activity
Authors: Arai A. , Kodama I. , Toyama J.
Published: December 2017

Ionic mechanisms underlying the enhancement of cardiac pacemaking activity by mechanical stretch were investigated in the isolated rabbit sinoatrial (SA) node. A 5-s stretch of 0.2-2.0 g was applied to small tissue strips (1.5 mm x 3.0 mm) of the SA node using a mechanical stimulator. Spontaneous excitation cycle length (SPCL) was monitored by recording endocardial surface potential through modified bipolar electrodes with high-gain amplification. Influence of neurotransmitters released from nerve terminals was eliminated by atropine and propranolol. A stretch > 0.2 g caused a significant shortening of SPCL; there was a positive correlation between the force and the maximum shortening of SPCL. Treatment of the preparation with gadolinium (10 microM) or glibenclamide (1 microM) did not affect the force-response relationship. The positive chronotropic response to mechanical stretch > 0.5 g was reduced significantly by treatment with 4,4'-dinitrostilbene-2,2'-disulfonic acid (5mM), 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (1 mM), or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (50 microM). The positive chronotropic response was also reduced in a low-Ca2+ (0.36 mM) medium and by bath application of ryanodine (0.1 microM) or thapsigargin (2 microM). These findings suggest the possible involvement of mechanosensitive Cl- channels and intracellular Ca2+ mobilization in the stretch-induced enhancement of pacemaking activity in the mammalian SA node, although other conceivable mechanisms cannot be ruled out.
Effects of constant cardiac autonomic nerve stimulation on heart rate variability
Authors: Bailey J. R. , Fitzgerald D. M. , Applegate R. J.
Published: December 2017

Heart rate variability is used to assess cardiac autonomic tone. We bought to determine the relationship of graded direct stimulation of efferent cardiac autonomic nerves on heart rate variability in an anesthetized canine model. Time and frequency domain variables were measured at denervated baseline and during electrical stimulation of the vagi and ansae subclaviae over a wide range of frequencies. Vagal and ansae stimuli produced significant changes in heart rate that correlated with the intensity of stimulation. Vagal stimulation resulted in small increases in time domain indexes of heart rate variability and in the power spectrum from 0.04 to 0.40 Hz, but with no correlation between stimulus intensity and changes in these indexes. By contrast, ansae stimulation had no effect on time or frequency domain measures. In the absence of central modulation of autonomic outflow, indexes of heart rate variability reflect the presence of vagal input but do not correlate with the level of vagal tone and are unaffected by changes in mean sympathetic tone.
Anaplerotic effects of propionate on oxidations of acetate and long-chain fatty acids
Authors: Liedtke A. J. , Hacker T. , Renstrom B. , Nellis S. H.
Published: December 2017

Studies were performed to test the influence of propionate as a competing myocardial substrate on acetate and palmitate metabolism in reperfused pig hearts after an exposure of mild-to-moderate regional ischemia. Experiments were conducted in intact, working pig hearts (n = 10) using an extracorporeal coronary perfusion technique. Half the animals received 2 mM propionate selectively into the anterior descending (LAD) perfusate. Perfusion conditions in the LAD circulation were divided into three intervals: an aerobic, preischemic period (0–20 min); an ischemic period affected by a 60% reduction in LAD flow (20–60 min); and an aerobic, postischemic period (60–100 min). Steady-state infusions of (1(–14)C) acetate and [9, 10(-3)H] palmitate were begun at 60 min perfusion to monitor metabolism during reperfusion. Propionate had no effect on oxidation of acetate except for a slight delay in CO2 appearance. Propionate significantly suppressed oxidation of long-chain fatty acids (-38 delta %, P < 0.018), which was not explained by a selective scavenging of CoA units or carnitine by propionate, which might otherwise enhance fatty acid activation, transfer, or oxidation. Propionate by indirect estimates had no apparent effect on glucose metabolism. Propionate-treated hearts, despite shifts in substrate preference, were not further compromised in energy metabolism as levels of creatine phosphate and adenine nucleotides were comparable to control hearts. Recovery of regional mechanical function was also comparable between groups but incompletely, with respect to preischemic performance, compatible with myocardial stunning. The data show in reperfused myocardium that propionate is capable of altering the preferred use of fatty acids, but that anaplerotic entry of carbon units during this reperfusion interval was sufficient to prevent a selective imbalance of energy metabolism or deficit in mechanical recovery.