bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of positive end-expiratory pressure on hypoxic pulmonary vasoconstriction in the dog
Authors: Domino K. B. , Pinsky M. R.
Published: December 2017

We studied the effects of uni- and bilateral positive end-expiratory pressure (PEEP) on pulmonary artery pressure-flow (Ppa/Q) relationships during unilateral hypoxia in anesthetized dogs. A bronchial divider was inserted, the right lung was ventilated with 100% O2, and the left lung was ventilated with either 100% O2 (hyperoxia) or a hypoxic gas mixture (hypoxia). Left lung blood flow (QL) and aortic flow (QT) were measured by electromagnetic flow probes. Simultaneous Ppa/Q relations for both lungs, with Q on the ordinate, were obtained by altering QT via an arteriovenous fistula and an inferior vena cava occluder. Ppa/Q slopes (delta Q/delta Ppa) and extrapolated zero-flow Ppa intercepts (Pzf) were obtained by linear regression analysis. Bilateral PEEP increased Pzf for both lungs (P less than 0.01) but did not alter delta Q/delta Ppa of either lung. Unilateral PEEP decreased ipsilateral blood flow (P less than 0.001) and increased Pzf for the ipsilateral lung (P less than 0.05). Left lung PEEP did not affect the slope of the left lung Ppa/Q relationship (delta QL/delta Ppa). Hypoxic ventilation of the left lung decreased QL (P less than 0.001), increased Pzf (P less than 0.05), and decreased delta QL/delta Ppa (P less than 0.001). Neither uni- nor bilateral PEEP altered this flow diversion away from the left lung or the reduction in delta QL/delta Ppa with left lung hypoxia. We conclude that PEEP and alveolar hypoxia increase pulmonary vascular resistance at different loci, such that their effects are additive. A net increase in 10 cmH2O of PEEP does not inhibit the pulmonary vascular response to regional alveolar hypoxia.
Prostaglandins mediate skeletal muscle arteriole dilation in hyperdynamic bacteremia
Authors: Cryer H. G. , Garrison R. N. , Harris P. D. , Greenwald B. H. , Alsip N. L.
Published: December 2017

Live Escherichia coli bacteremia during the high cardiac output (hyperdynamic) phase of sepsis causes constriction of large arterioles but dilation of small arterioles in skeletal muscle. This study examines the role of dilator prostaglandins, serotonin, and histamine in these differential microvascular responses in the decerebrate rat that avoids the effects of drug anesthesia. Topical application of meclofenamate, a prostaglandin synthesis inhibitor, to the cremaster muscle 60 min after induction of E. coli bacteremia enhanced the constriction of large arterioles from 20 +/- 8 to 46 +/- 9% less than baseline and blunted the dilation of small arterioles from 39 +/- 9 to 17 +/- 7% above baseline values in the cremaster microcirculation. Induction of E. coli bacteremia after pretreatment of the cremaster with meclofenamate constricted large arterioles to 40 +/- 4% less than baseline and small arterioles to 31 +/- 4% less than baseline. This indicates that prostaglandins initiate small arteriole dilation in response to E. coli, but some other dilator factor is activated by prostaglandins to maintain small arteriole dilation during E. coli bacteremia. Topical application of cyproheptadine, an antagonist of both histamine and serotonin receptors, to the cremaster muscle did not alter the E. coli-induced constriction of large arterioles or the dilation of small arterioles in the cremaster microcirculation.
Neural control of ANF release in hypoxia and pulmonary hypertension
Authors: Baertschi A. J. , Jiao J. H. , Carlson D. E. , Campbell R. W. , Teague W. G. , Willson D. , Gann D. S.
Published: December 2017

Hypoxia causes the release of atrial natriuretic factor (ANF), but the mechanisms are not yet understood. This study examined the relative contribution of pulmonary arterial hypertension, neural pathways, increased heart rate, or increased atrial size to the ANF response. Alveolar hypoxia [fractional concentration of O2 in inspired gas (FIo2) = 0.1] or pulmonary arterial hypertension (25-45 mmHg) was induced for 10 min in four series (n = 4-12 each) of anesthetized, mechanically ventilated pigs. During hypoxia, plasma ANF concentrations increased by 129 +/- 52 (SE) pg/ml (or 271 +/- 105%) over baseline (35 +/- 7 pg/ml; P less than 0.01) (series 1). There was also a significant increase of pulmonary arterial pressure, heart rate, central venous pressure, and pulmonary capillary wedge pressure. Repeated pulmonary hypertension induced by intravenous air infusion caused a repeated and reversible 125 +/- 14% increase (P less than 0.001) of plasma ANF, and this response was totally abolished by lesion of the cervical vagosympathetic trunks (series 2). Lesion of these nerves 1 h before hypoxia also decreased the ANF response to hypoxia by 45-58% (P less than 0.01), whereas responses of heart rate and atrial pressures were unchanged (series 3). The ANF response to hypoxia, expressed in percent of baseline, was not affected by 0.2 mg/kg propranolol (PR) (no PR: 145 +/- 63%; PR: 151 +/- 82%; not significantly different from series 1 and control, series 3), although the increase in heart rate (no PR: 61 +/- 15 beats/min) was almost abolished (PR: 17 +/- 5 beats/min) (series 4). Hypoxia caused no significant changes in right and left atrial peak volume regardless of propranolol, as measured with an electrical conductance catheter. The results indicate that a new neural reflex of probably pulmonary arterial origin mediates approximately 50% of the ANF response to hypoxia. The remaining ANF response remains to be explored further and cannot be explained by conventional release mechanisms such as atrial stretch and pulsatility alone.
Coupling of ATP-sensitive K+ channels to A1 receptors by G proteins in rat ventricular myocytes
Authors: Kirsch G. E. , Codina J. , Birnbaumer L. , Brown A. M.
Published: December 2017

ATP-sensitive K+ (K+[ATP]) current is thought to be regulated by GTP-binding proteins (G proteins), but the pathways that couple receptor, G protein, and channel have not been defined. We studied regulation of tolbutamide-sensitive K+[ATP] current in neonatal rat ventricular myocytes. Application of 0.1 mM ATP to the intracellular side of membrane patches reduced K+ [ATP] channel activity, and addition of the nonhydrolyzable GTP analogue guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) at 0.1 mM restored activity. Application of 0.1 mM intracellular GTP plus 10 microM extracellular adenosine or 100 nM N6-cyclohexyladenosine had the same effect as GTP gamma S; hence K+[ATP] channels may be coupled to adenosine receptors via G proteins. To determine which G protein, we applied G alpha subunits, preactivated with GTP gamma S to the cytoplasmic side of membrane patches, and found that alpha i1, alpha i2, and alpha i3 mimicked the effect of GTP gamma S, but not alpha o or Gs, suggesting that Gi alpha acts via a membrane-delimited pathway. Adenosine receptor coupling may be important for activating K+[ATP] channels in ischemic muscle.
Recovery of contractility and pHi during respiratory acidosis in ferret hearts: role of Na(+)-H+ exchange
Authors: Cingolani H. E. , Koretsune Y. , Marban E.
Published: December 2017

During acute respiratory acidosis, cardiac contractile pressure first drops but then recovers substantially. We investigated the mechanism of this response in isovolumic perfused ferret hearts. Developed pressure (DP) and its first derivative (dP/dt) were measured before, during, and after hypercapnia induced by equilibrating the perfusate with 15% CO2, rather than the 5% CO2 used in control. Intramyocardial pH (pHi) was measured by phosphorus nuclear magnetic resonance (NMR) spectroscopy. After the onset of hypercapnia (1-2 min), DP and +dP/dt reached minimal mean values of 37 +/- 2 and 39 +/- 3% of control, respectively. This early decline in myocardial contactility was followed by a partial recovery such that DP and +dP/dt had returned to 66 +/- 6 and 62 +/- 4% of control, respectively, by 14 min of hypercapnia. pHi fell from 7.17 +/- 0.01 in control to 6.88 +/- 0.11 after approximately 2 min of hypercapnia. Thereafter, pHi recovered linearly with a mean slope of 0.011 +/- 0.003 pH U/min. Ethylisopropylamiloride (10(-6) M), a blocker of Na(+)-H+ exchange, prevented the recovery of pHi during hypercapnia and attenuated the recovery of contractility by 40%. We conclude that the recovery of contractility during respiratory acidosis at least partially reflects an underlying recovery of pHi mediated by Na(+)-H+ exchange.
Effects of hypercapnia and hypoxia on the cardiovascular system: vascular capacitance and aortic chemoreceptors
Authors: Rothe C. F. , Maass-Moreno R. , Flanagan A. D.
Published: December 2017

Aortic chemoreceptor influences on vascular capacitance after changes in blood carbon dioxide and oxygen were studied in mongrel dogs anesthetized with methoxyflurane and nitrous oxide. The mean circulatory filling pressure (Pmcf), measured during transient cardiac fibrillation, provided a measure of capacitance vessel tone. Hypercapnia, hypoxia, and hypoxic hypercapnia significantly increased most variables, except that hypercapnia caused the total peripheral resistance (TPR) to decrease. Hypocapnia caused a significant decrease in mean systemic (Psa) and pulmonary (Ppa) arterial blood pressures, cardiac output (CO), and central blood volume and an increase in TPR and heart rate. The changes in Pmcf on changing blood gas tensions could be described by the equation delta Pmcf = -1.60 + 0.036 (arterial PCO2) + 50.8/arterial PO2. Thus a 10 mmHg increase in arterial PCO2 caused a 0.36 mmHg increase in Pmcf with receptors intact. Cold block (2 degrees C) of the cervical vagosympathetic trunks did not significantly influence the measured variables at control. During severe hypercapnia, vagal cooling caused a small but significant decrease in Pmcf, Psa, Ppa, and CO but not TPR. During hypoxia, vagal cooling caused the Pmcf, Psa, and TPR to decrease. We conclude that although hypercapnia or hypoxia acts reflexly to increase the capacitance vessel tone (an increase in Pmcf), the aortic and cardiopulmonary chemoreceptors with afferents in the vagi have only a small influence on the capacitance system, accounting for only approximately 25% of the total body response.
Analysis of tricarboxylic acid cycle of the heart using 13C isotope isomers
Authors: Malloy C. R. , Sherry A. D. , Jeffrey F. M.
Published: December 2017

13C-nuclear magnetic resonance (NMR) spectroscopy provides a new approach to the analysis of metabolic pathways, because it detects an interaction between adjacent 13C nuclei. Previous models of isotope distribution in the tricarboxylic acid cycle were designed for analysis of radioisotope data and did not consider the information provided by 13C-13C coupling. A mathematical model of the tricarboxylic acid cycle was developed that preserves all isotope isomer (isotopomer) information and yields simple relationships between 13C-NMR spectra of glutamate and metabolic parameters under steady-state conditions. With the use of relative peak areas measured from the spectra of tissues supplied with 13C-enriched substrate(s), the relative fluxes through both oxidative (acetyl-CoA utilization) and nonoxidative (anaplerotic) pathways of the tricarboxylic acid cycle can be determined. Furthermore, with the judicious selection of 13C-labeling patterns in a mixture of substrates, direct substrate competition experiments can be performed. The perchloric acid extracts of Langendorff and working rat hearts oxidizing 13C-enriched fatty acids or carbohydrates are analyzed to illustrate this approach, and the importance of measuring the fractional enrichment of the available substrate is demonstrated. The technique can of course be used with all tissues, not just heart, and is applicable to the analysis of in vivo 13C-NMR spectra.
Sympathetic activity during graded central hypovolemia in hypoxemic humans
Authors: Rowell L. B. , Seals D. R.
Published: December 2017

To determine how hypoxemia (Hx) might alter muscle sympathetic nerve activity (MSNA) (microneurography, peroneal nerve), norepinephrine (NE) levels, and vasoconstriction during mild central hypovolemia, we exposed eight men to continuous graded lower body negative pressure (LBNP) (-5, -10, -15, -20, and -25 mmHg, 5 min per level) during both Hx (10 or 12% O2) and normoxia (Nx). Hx significantly augmented MSNA during LBNP. Total MSNA (average amplitude X burst frequency) rose at each level of LBNP by 2, 28, 93, 61, and 123% (Nx) and 32, 110, 127, 179, and 216% (Hx). Only at LBNP -20 and -25 mmHg did Hx significantly augment the increase in forearm venous NE concentration. Arterial pressure was unaffected by LBNP in Nx and Hx. Forearm blood flow (venous occlusion plethysmography) fell, and forearm vascular resistance (FVR) rose 23, 53, 65, 67, and 86% (Nx) vs. 22, 23, 60, 69, and 87% (Hx), but increments in FVR (absolute units) were significantly less in Hx. Correlations among MSNA and other variables were insignificant for pooled data owing to large inter-individual variations in slopes, but correlations were significant for total MSNA (and burst frequency) vs. FVR (Nx) and NE (Hx). Three men released epinephrine during LBNP; this was accompanied by forearm vasodilation and falling pressure, and in two men, decreased MSNA and bradycardia occurred (i.e., vasovagal reaction). Overall, we found no major defect in sympathetic control during graded hypovolemia and Hx as long as epinephrine levels did not rise.
Activated oxygen and arachidonate effects on newborn cerebral arterioles
Authors: Leffler C. W. , Busija D. W. , Armstead W. M. , Shanklin D. R. , Mirro R. , Thelin O.
Published: December 2017

We have observed that pial arteriolar dilation in response to hypercapnia and hypotension is abolished after cerebral ischemia in newborn pigs. We determined whether direct generation of activated oxygen on the brain surface (OX: xanthine oxidase, hypoxanthine, FeCl3, and FeSO4) or topical arachidonate altered pial arteriolar responsiveness in a manner similarly to cerebral ischemia. OX, which generated more brain surface superoxide than reperfusion after ischemia, dilated pial arterioles. This dilation was reversed within 10 min of the end of exposure. OX produced ultrastructural changes in pial vessel endothelium and appeared to cause intravascular aggregation of granulocytes. After OX, prostanoid-dependent pial arteriolar dilations in response to hypercapnia and hypotension were attenuated, whereas constrictor responses to norepinephrine and acetylcholine and dilator responses to prostaglandin E2 and isoproterenol were not affected. After OX, hypercapnia increased cortical periarachnoid cerebrospinal fluid prostanoids modestly, whereas acetylcholine produced the normal strong stimulation of prostanoid synthesis. Arachidonate (10(-4) M and 7 x 10(-4) M) also caused reversible pial arteriolar dilation but did not alter subsequent pial arteriolar responses. Therefore, although arachidonate did not mimic the effects of ischemia-reperfusion on pial arteriolar reactivity, OX produced alterations that are qualitatively similar, although quantitatively less, than those produced by ischemia.
Capillary permeability: atrial peptide action is independent of "protein effect"
Authors: Huxley V. H. , Meyer D. J.
Published: December 2017

Perfusion of exchange microvessels with the vasoactive hormone, atrial natriuretic peptide (AP), acutely and reversibly elevates hydraulic conductivity (Lp) by mechanisms that are, as yet, unknown. This, the first of two studies to characterize AP responses when perfusate composition was altered, specifically focuses on the action of AP when perfusate albumin was lowered to change the transcapillary barrier properties for water by passive mechanisms (protein effect). Perfusion of frog (Rana pipiens) mesenteric microvessels with 1 nM AP in 10 mg/ml bovine serum albumin (BSA) elevated Lp by a median 2.1-fold (range 1.2-2.7, n = 13) from control levels (10 mg/ml BSA). Reduction of perfusate albumin from 10 to 1 mg/ml elicited a small rise in Lp (1.8-fold, n = 10); Lp rose a further 2.1-fold (n = 6) when 1 nM AP was added to 1 mg/ml BSA. Likewise, protein-free perfusion elevated Lp from a median 2.2 to 5.1 X 10(-7) cm.s-1.cmH2O-1 (n = 11); 1 nM AP in protein-free perfusate elevated Lp a further 2.1-fold (n = 8). Thus, regardless of protein content, the response to the peptide was a consistent, twofold increase in exchange vessel Lp (n = 27). These data are consistent with the suggestion that the AP-activated rise in Lp (twofold) occurs via an increase in the effective area of the transcapillary pathway for water without influencing the selectivity properties of the paracellular, albumin-sensitive portion of the barrier.
Beta-receptor subtypes in the canine coronary circulation
Authors: Trivella M. G. , Broten T. P. , Feigl E. O.
Published: December 2017

The principal difficulty in determining the subtype of coronary vascular beta-receptors in vivo is to avoid the local metabolic coronary vasodilation that occurs secondary to activation of myocardial beta-receptors. Therefore, a nonbeating cardiac preparation without chronotropic or inotropic effects is needed. In this study, the coronary circulation was perfused at constant pressure in closed-chest chloralose-anesthetized dogs. The increase in coronary blood flow due to intracoronary injections of the combined beta 1- and beta 2-agonist isoproterenol was determined during prolonged asystoles after the cessation of cardiac pacing in atrioventricular heart-blocked animals. Both beta 1-selective (practolol and L 650,744) and beta 2-selective (ICI 118,551) antagonists blocked isoproterenol-induced coronary vasodilation. In contrast, isoproterenol vasodilation in the femoral circulation was blocked by beta 2- but not by beta 1-selective antagonists. In conclusion, both beta 1- and beta 2-receptors in coronary resistance vessels are stimulated by isoproterenol to produce vasodilation during prolonged asystoles, when cardiac chronotropic and inotropic effects are absent.
Heart and brain nucleotide pools during hemorrhage and resuscitation
Authors: Horton J. W. , McDonald G.
Published: December 2017

Sequential 31P nuclear magnetic resonance (NMR) spectra were measured in adult dogs to determine the relationship between cardiac function and myocardial intracellular pH (pHi) and phosphorylated energy metabolites during 2 h of hemorrhagic shock. Simultaneous measurements of coronary blood flow (radioactive microspheres), arterial and coronary sinus pH, blood gases, and oxygen content were performed. In addition, changes in brain NMR spectra were correlated with changes in cerebral blood flow during shock. Two hurs of hypovolemic shock resulted in significant decreases in phosphocreatine (PCr), PCr-to-ATP ratio, and pHi, whereas Pi rose significantly relative to baseline values. Return of shed blood and crystalloid fluid resuscitation improved cerebral and coronary perfusion and returned cardiac contractile function to near baseline values. We conclude that severe and sustained hemorrhagic shock produced significant alterations in brain and heart phosphorylated metabolites as well as significant intracellular acidosis; however, these changes in energy metabolites were reversible with adequate fluid resuscitation from shock.
Hemodynamic consequences of ventricular interaction as assessed by model analysis
Authors: Santamore W. P. , Burkhoff D.
Published: December 2017

Because of close anatomic association, the pressure and volume in one ventricle can directly influence the pressure and volume in the opposite ventricle. To examine the importance of ventricular interdependence in controlling the circulation, we developed a computer model in which ventricular interdependence could be turned on and off. Left ventricular chamber contractility, as judged by maximal elastance (Emax), was enhanced on the order of 10% as a result of ventricular interaction, whereas right ventricular Emax was affected by as much as 60% under physiological conditions. With increases in systemic vascular resistance, ventricular interaction caused a smaller stroke volume (SV) decrease than with no interaction. For canine data (SV = 21.4 ml), doubling systemic vascular resistance decreased SV by 3.7 without ventricular interdependence, 3.5 with diastolic ventricular interdependence, and 3.3 ml with diastolic and systolic ventricular interdependence. In contrast, with increases in pulmonary vascular resistance, ventricular interaction caused a greater decrease in SV than with no interaction present. Decreasing left ventricular free wall elastance or right ventricular free wall elastance decreased SV. Diastolic ventricular interdependence reduced the SV changes, whereas systolic ventricular interdependence accentuated the SV changes with alterations in right and left ventricular free-wall elastance. The results of the present simulation demonstrate the importance of ventricular interdependence in the observed responses of the right ventricle to volume overload, pressure overload, and ischemia.
Position of interventricular septum during heart cycle in anesthetized dogs
Authors: Piene H. , Myhre E. S.
Published: December 2017

The impact of the transseptal pressure gradient (TSP) during the entire heart cycle has not been assessed. This study explores in anesthetized open-chest dogs the interventricular septum's relative position to the anteroposterior transverse diameter (Dap) of the left ventricle (LV). By varying preload and afterload for both LV and right ventricle (RV) and inotropy in LV, a wide range of TSP was generated. By ultrasonomicrometry the distance between the Dap and the midpoint of septum was recorded. 1) Loops of the septal-LV free-wall diameter vs. Dap showed that the LV transverse cross section independent of loading conditions tended to reach a circular form during systole. 2) Paradoxical movement of the intraventricular septum occurred when TSP was less than zero but was not dependent on an increase of TSP. 3) TSP's influence on septum's position was reduced to one-tenth when changing from end diastole to end systole. 4) During systole independent of level of LV performance, LV pressure had approximately 50% less influence on septal position than RV pressure. 5) During depressed LV performance a similar pattern was evident during diastole. 6) The pericardium had no influence on septum's position. This study demonstrates that the position of the intraventricular septum is significantly influenced by the time-varying elastance of LV and the septum itself, and that RV pressure changes have a greater impact on septal position than LV pressure changes.
Acetylcholine-induced vasodilatation in rabbit hindlimb in vivo is not inhibited by analogues of L-arginine
Authors: Mugge A. , Lopez J. A. , Piegors D. J. , Breese K. R. , Heistad D. D.
Published: December 2017

Nitric oxide (NO) or related nitroso compounds are an endothelium-derived relaxing factor (EDRF), originating from metabolism of L-arginine, L-Arginine analogues with chemically altered guanidino moity are potent and specific inhibitors of EDRF(NO) release. We evaluated effects of two L-arginine analogues, NG-monomethyl-L-arginine (L-NMMA, 100 microM) and N omega-nitro-L-arginine (L-NARG, 30 microM), on acetylcholine-, substance P-, and nitroglycerin-induced relaxation in the blood-perfused rabbit hindlimb in vivo and femoral arteries in vitro. L-NMMA and L-NARG selectively inhibited the vasodilator response to acetylcholine in rabbit femoral arteries in vitro, whereas endothelium-independent response to nitroprusside increased. L-NMMA (1.6 mg/min ia) in the blood-perfused rabbit hindlimb in vivo increased vascular resistance in the hindlimb by 23 +/- 3% (means +/- SE; n = 10) but did not inhibit the vasodilator responses to acetylcholine or substance P. L-NARG (10 mg/kg iv) increased systemic blood pressure by 26 +/- 3% (n = 7) and vascular hindlimb resistance by 22 +/- 9% (n = 8), and blood flow to hindlimb musculature, measured with microspheres, decreased by 46 +/- 5% (n = 6). Pretreatment with L-NARG, however, did not impair vasodilator responses to acetylcholine and substance P. These findings are consistent with the view that basal tone in resistance vessels in the rabbit hindlimb may be mediated by nitroso compounds, whereas agonist-stimulated vasodilation may be mediated by other mechanisms that do not involve the NO-synthesizing enzyme.
Rhythmic smooth muscle activity in hamster aortas is mediated by continuous release of NO from the endothelium
Authors: Jackson W. F. , Mulsch A. , Busse R.
Published: December 2017

Hamster aortas display endothelium-dependent, agonist-induced rhythmic contractions. However, the mechanism responsible for these oscillations is not known. Therefore, we investigated the possible role of nitric oxide (NO) on phenylephrine-induced rhythmicity in rings and segments of thoracic aortas of the hamster. We found that hamster aortas release NO, as detected by activation of purified soluble guanylate cyclase. The release of NO was abolished by mechanical removal of the endothelium or by exposure of the vessels to NG-nitro-L-arginine (NAG), a stereospecific selective inhibitor of NO synthesis. Correlated with the tonic release of NO was an elevation in guanosine 3',5'-cyclic monophosphate (cGMP) content in the vessels that could also be abolished by removal of the endothelium or treatment with NAG. The same procedures inhibited phenylephrine-induced isometric tension or diameter oscillations. Rhythmicity could be restored by exposure to the nitrovasodilator sodium nitroprusside, which increased cGMP levels in the aortas, or by exposure to the permeant analogue of cGMP, 8-BrcGMP. The beta-adrenergic agonist isoproterenol, as well as the cAMP analogue dibutyryl cAMP, failed to produce rhythmic contractions in either preparation. These data indicate that endothelium-derived NO, which stimulates the production of cGMP in the vascular smooth muscle, is the signal that leads to the observed rhythmic oscillations in smooth muscle mechanical activity.
Adaptational changes of MHC gene expression and isozyme transition in cardiac overloading
Authors: Imamura S. , Matsuoka R. , Hiratsuka E. , Kimura M. , Nakanishi T. , Nishikawa T. , Furutani Y. , Takao A.
Published: December 2017

Distribution of cardiac myosin heavy-chain (MHC) isozymes is regulated during development by hemodynamic change and hormonal stimuli. To understand the evolution of cardiac hypertrophy and the underlying processes, the interaction between acute or chronic cardiac over-loading and serum thyroid hormone levels was studied. Biochemical, physiological, and pathological studies were performed using coarctated (Coa) rats with or without administration of thyroid hormone (Thy) and on sham-operated (Sham) rats and normal rats with or without administration of Thy. The results showed that 1) although serum Thy levels in Coa and Sham rats were nearly the same at all timing points, a significant induction of beta-MHC mRNA and isozyme occurred in Coa rats; 2) in Coa rats where Thy was administered, there was no increase in beta-MHC mRNA and isozyme as seen in Coa rats, and this level was nearly the same as in Sham rats, whereas serum Thy levels were significantly high, as in the normals with administration of Thy; and 3) 77 days after surgery, the hypertrophy was completed, judging from pathological findings at this time, and beta-MHC mRNA and isozyme reached similar levels in all groups, except for the normals with administration of Thy. These results demonstrate the following: 1) the MHC isoform transitions induced by pressure overload are not induced by decreases in serum Thy levels, and the regulation of MHC gene expression is responsive to other triggers in addition to Thy; and 2) the first adaptational process of the heart to hemodynamic overload is the MHC isoform transition, and the second adaptational process of that is the hypertrophy itself.
Ca2+ sensitivity of isolated arterioles from the hamster cheek pouch
Authors: Hynes M. R. , Duling B. R.
Published: December 2017

When isolated from the hamster cheek pouch, cannulated, and perfused, 60- to 90-microns arterioles spontaneously contracted to 67 +/- 4% of maximum diameter. Vessel sensitivity to variations in extracellular Ca2+ was then evaluated. Tone, regardless of its source, was highly dependent on the concentration of Ca2+ in the bathing solution. The magnitude of responses to changing Ca2+ depended upon which vessel surface (luminal or abluminal) the change was made. For K(+)-induced tone the Ca2+ concentration-response curve was right shifted 60-fold for luminal vs. abluminal changes. These results suggest that restricted diffusion of Ca2+ from lumen to smooth muscle dramatically reduces smooth muscle Ca2+ concentration and that under standard in vitro conditions the smooth muscle layer is effectively isolated from luminal contents. Both the cytosolic and stored Ca2+ in these microvessels were dependent on the Ca2+ concentration in the bathing solution. Abrupt removal of Ca2+ from bath produced a rapid maximal dilation with a mean time to half-maximal response (t1/2 max) of 14 +/- 4 s. Ca2+ replacement induced a return to the previous level of tone with a mean t1/2 max of 8 +/- 3 s. The magnitude of transient responses to caffeine (10 mM) was inversely related to the time of exposure to zero Ca2+ with a rapid decay in magnitude (t1/2 max = 2.7 +/- 0.8 min). These data suggest that the smooth muscle cells of arterioles have a particularly rapid transmembrane Ca2+ flux that is tightly controlled by an intracellular regulatory mechanism, which may explain the generally increased dependence of smaller vessels on extracellular Ca2+.
Hypoxia- or hyperoxia-induced changes in arteriolar vasomotion in skeletal muscle microcirculation
Authors: Bertuglia S. , Colantuoni A. , Coppini G. , Intaglietta M.
Published: December 2017

Arteriolar vasomotion was characterized in the skin muscle of the unanesthetized hamster skinfold window preparation and related to the specific arterioles that give rise to the different types of activity. The arterioles were classified according to the Strahler method: order 0 was assigned to capillaries and order 4 to the largest arterioles. The arterioles showed vasomotion with a specific range of frequencies that varied according to the vessel order; the highest fundamental frequency (9.1 +/- 3.9 cycles/min) was detected in the smallest order 1 arterioles and the lowest frequency (2.1 +/- 0.9 cycles/min) in order 4 vessels. Hypoxia (8, 11, and 15% O2 gas mixture inspiration) increased the frequency of vasomotion, decreased mean and effective diameters, and reduced capillary blood flow. The effects were more pronounced with an 8 and 11% O2 gas mixture. Hypoxia caused high-frequency vasomotion to shift from order 1 and 2 arterioles to the beginning of order 3 arterioles, which in this condition dominated the daughter vessels and generated the prominent activity (24 +/- 4 cycles/min, 11% O2 gas mixture). Hypertoxia (100% O2) induced differentiated arteriolar responses. The smallest vessels showed prolonged constriction, decreased mean and effective diameters, and reduced frequency of vasomotion. Capillary blood flow was restricted. Order 3 vessels did not constrict or dilate.
Enkephalin lowers vascular resistance in dog hindlimb via a peripheral nonlimb site
Authors: Caffrey J. L. , Gu H. , Barron B. A. , Gaugl J. F.
Published: December 2017

The intravenous administration of methionine enkephalin in anesthetized dogs produces an abrupt decline in mean arterial pressure, left ventricular pressure, and the maximal rate of left ventricular pressure development. All of these changes are prevented by receptor blockade with the opiate antagonist, naloxone. To evaluate peripheral vascular contributions to these responses, experiments were conducted in a constant pressure-isolated perfused hindlimb. In this model, the sharp decline in mean arterial pressure associated with enkephalin injection (5 micrograms/kg iv) coincided with an equally sharp decline in vascular resistance (rise in blood flow) in the hindlimb. Both were blocked by naloxone pretreatment (1 mg/kg). When equal doses of enkephalin were administered directly into the femoral inflow (external iliac artery), both arterial pressure and hindlimb flow responses were all but eliminated. This observation ruled out significant direct vascular interactions in the response and indicated a site of action outside the hindlimb. Additional catheters were placed in the bracheocephalic artery and descending aorta to permit the comparison of arterial injections conducted, respectively, into the cerebral or abdominal circulations. Injections introduced into the descending aorta consistently produced the greatest response, followed by injections (in descending order of effectiveness) into the jugular, the brachiocephalic, and external iliac. The response in the hindlimb vasculature was initiated at a site somewhere between the diaphragm and terminal aorta. The vascular response to enkephalin was subsequently eliminated by blocking ganglionic transmission with the nicotinic antagonist mecamylamine. These observations suggest that the opioids probably interrupt local vasomotor traffic via opiate receptors in regional sympathetic ganglia or in the spinal cord.
Nocturnal variations in subcutaneous blood flow rate in lower leg of normal human subjects
Authors: Sindrup J. H. , Kastrup J. , Jorgensen B. , Bulow J. , Lassen N. A.
Published: December 2017

Subcutaneous adipose tissue blood flow rate was measured in the lower leg of 22 normal human subjects over 12- to 20-h ambulatory conditions. The 133Xe washout technique, portable CdTe(Cl) detectors, and a portable data storage unit were used. The tracer depot was applied on the medial aspect of the right lower leg 10 cm proximal to the malleolar level by means of the epicutaneous, atraumatic labeling technique. The change from upright to supine position from day 1 in the beginning of the night period elicited an instantaneous blood flow rate increment of 30-40% in accordance with a decrease in central and local postural sympathetic vasoconstrictor activity. During sleep, characteristic variations in subcutaneous blood flow were disclosed. The 133Xe washout curve could be divided into three segments with significantly different slopes. Approximately 90 min after the subject went to sleep, an additional blood flow rate increment of considerable magnitude was observed. The mean increase was 84%, but in several cases a greater than 200% increment was measured (maximum 244%). The intra-individual coefficient of variation for the nocturnal blood flow response was in triplicate measurements 25% (n = 9). The hyperemic phase lasted approximately 100 min after which the blood flow rate returned to the level measured at the beginning of the night period. The blood flow rates measured on the second day did not differ from those on the first day. Control measurements performed under similar thermal conditions, but with the subjects kept awake, did not reveal any hyperemic phases. This points toward changes in cardiovascular regulatory mechanisms during sleep.(ABSTRACT TRUNCATED AT 250 WORDS)
Response time of cardiac mitochondrial oxygen consumption to heart rate steps
Authors: Van Beek J. H. , Westerhof N.
Published: December 2017

We investigated the time course of cardiac mitochondrial O2 consumption following steps in heart rate in 16 isolated rabbit hearts perfused with Tyrode solution. The time course was characterized by the mean response time, i.e., the first statistical moment (mean time) of the impulse response function. Like the mean transit time for an indicator, it provides an important characteristic of the response time course. The venous O2 content transients during steps in heart rate were measured and corrected for O2 diffusion and vascular transport using a mathematical model with experimental information derived from O2 washout following steps in arterial O2 concentration or perfusion flow. We deduce from these washout experiments that the effective O2 solubility in heart tissue is 86 +/- 13% (mean +/- SE) of solubility in water. The measured venous mean response time following a step in heart rate at 37 degrees C was 17.6 +/- 1.1 s. The mean response time of cardiac mitochondrial O2 consumption to changes in heart rate after correction for O2 transport was 7.7 +/- 0.7 s.
Influence of brain renin-angiotensin system on renal sympathetic and cardiac baroreflexes in conscious rabbits
Authors: Dorward P. K. , Rudd C. D.
Published: December 2017

The role of the brain renin-angiotensin system (RAS) in the baroreflex regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR) was studied in conscious rabbits. RSNA and HR were recorded during slow ramp changes in mean arterial pressure (MAP) before and after intraventricular infusion of 1) angiotensin II (ANG II), 2) ANG II receptor antagonist, [Sar1,Ile8]ANG II, or 3) converting enzyme inhibitor (CEI, enalaprilat). Central ANG II increased resting MAP and RSNA by 10.6 +/- 0.9 mmHg and 21 +/- 7%, respectively, but did not alter HR. There was a marked increase of 107 +/- 15% in the maximum RSNA evoked by slowly lowering MAP. In contrast, maximum reflex tachycardia was only modestly elevated, and baroreflex inhibition of RSNA and HR during MAP rises was unaffected. Central [Sar1,Ile8]ANG II had no effect on RSNA or HR, either at rest or during baroreflex responses, while CEI slightly enhanced maximal reflex responses. Thus exogenous ANG II causes a powerful excitation of renal sympathetic motoneurons, the magnitude of which is revealed when tonic baroreceptor inhibition is removed during transient pressure falls. However, in quietly resting conscious rabbits, we found no evidence for a tonic influence of endogenous ANG II on these neurons, and the physiological stimuli required for their activation by the brain RAS remain to be found.
Existence and participation of xanthine oxidase in reperfusion injury of ischemic rabbit myocardium
Authors: Terada L. S. , Rubinstein J. D. , Lesnefsky E. J. , Horwitz L. D. , Leff J. A. , Repine J. E.
Published: December 2017

Using a highly specific assay that minimizes enzyme inactivation in vitro, we found that rabbit myocardial tissue contained low levels of xanthine oxidase (XO) and xanthine dehydrogenase (XD) activity that were effectively inhibited by pretreatment of hearts with allopurinol. In parallel, allopurinol treatment also improved ventricular developed pressure, peak systolic pressure, and coronary flow in isolated hearts subjected to 30 min of normothermic global ischemia and 30 min of reperfusion. Although function was protected by allopurinol treatment, creatine kinase (CK) release was not altered by allopurinol. Inhibition of myocardial XO with allopurinol did not increase myocardial ATP or phosphocreatine. In addition, allopurinol did not scavenge superoxide anion or hydrogen peroxide in vitro. The results support the possibility that relatively low amounts of XO activity, similar to levels reported in human myocardium, may contribute to cardiac ischemia-reperfusion injury.
Modification of cardiac adrenergic receptors by oxygen free radicals
Authors: Kaneko M. , Chapman D. C. , Ganguly P. K. , Beamish R. E. , Dhalla N. S.
Published: December 2017

To examine the effects of oxygen free radicals on alpha- and beta-adrenergic receptors, rat heart crude membranes were incubated with xanthine plus xanthine oxidase, H2O2, or H2O2 plus Fe2+. The assay of beta-adrenergic receptors involving [3H]dihydroalprenolol (DHA) binding revealed that the maximal number of binding sites (Bmax) and dissociation constant (Kd) were increased by xanthine plus xanthine oxidase. H2O2 increased the Kd value for [3H]DHA binding. When a hydrophilic ligand, [3H]CGP-12177, was used for the beta-adrenergic receptor assay, an increase in Kd value without any changes in Bmax value was evident on treating the membranes with xanthine plus xanthine oxidase. The assay of alpha-adrenergic receptors involving [3H]prazosin binding showed a decrease in the number of binding sites and an increase in Kd value only after a prolonged period of incubation. Both H2O2 and H2O2 plus Fe2+ increased the Kd value for [3H]prazosin without changes in Bmax. Changes in both alpha- and beta-adrenergic receptors similar to those with crude membranes were also seen by employing the purified heart sarcolemmal membranes. These data indicate that adrenergic receptors in the sarcolemmal membranes are modified by oxygen free radicals.
Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation
Authors: Koller A. , Kaley G.
Published: December 2017

In the presence of intact endothelium, in control conditions, calculated wall shear rate (WSR) (means +/- SE: 2,658 +/- 123 s-1; n = 21) was independent of arteriolar diameter (16.2-27.2 microns; correlation coefficient: r = 0.12, P greater than 0.05) in cremaster muscle of pentobarbital-anesthetized rats. An increase in blood flow velocity (due to parallel arteriolar occlusion) elicited a significant increase in WSR (to 4,981 +/- 253 s-1) followed by a delayed (6-15 s) increase in diameter (from: 22.5 +/- 0.6 to 29.5 +/- 0.8 microns), which consequently resulted in a significant decrease in WSR (to 3,879 +/- 203 s-1). As a result of the increased flow velocity and dilation, calculated arteriolar blood flow increased by 230%. After impairment of the endothelium of arterioles by a light-dye technique, basal WSR became significantly higher (3,604 +/- 341 s-1), and despite a greater increase in WSR (10,360 +/- 1,471 s-1) the dilation was absent. Now an inverse linear correlation was found between arteriolar diameter and WSR both before (r = 0.58, P less than 0.05) and during increased flow velocity conditions (r = 0.85, P less than 0.05). Also, arteriolar blood flow that was already less after impairment of endothelium increased by only 66% during the period of increased flow velocity due to the absence of dilation. Results suggest that an increase in wall shear stress is the stimulus for the endothelium-dependent mechanism that elicits "flow dependent" arteriolar dilation.(ABSTRACT TRUNCATED AT 250 WORDS)
Block of calcium-activated potassium channels in mammalian arterial myocytes by tetraethylammonium ions
Authors: Langton P. D. , Nelson M. T. , Huang Y. , Standen N. B.
Published: December 2017

The effects of tetraethylammonium ions (TEA+) and tetrapentylammonium ions (TPeA+) on Ca2(+) -activated K+ (KCa) channels were studied in membrane patches from mesenteric arterial myocytes. External TEA+ produced a flickery block. The concentration dependence for reduction in mean unitary current was consistent with 1:1 binding, with dissociation constants (Kd) in rat and rabbit of 196 and 159 microM at 0 mV, and the block was weakly voltage dependent. Rate constants for blocking and unblocking were 380 mM-1.ms-1 and 73 ms-1, respectively. In patches containing several channels TEA+ reduced average current to the same extent as mean unitary current, implying that TEA+ block is independent of the channel state. Block was unaffected by raising external K+ to 120 mM. External TPeA+ blocked with slower kinetics and lower affinity than TEA+ (Kd, 1.49 mM). The sulfonylurea glibenclamide (10-100 microM), the hyperpolarizing vasodilator cromakalim (5 microM), and internal ATP (1 mM) were without effect on channel activity. We conclude that TEA+ is a relatively effective blocker of single KCa channels of arterial smooth muscle and should block macroscopic currents equally well, whereas external TPeA+ is about eight times less effective.
Length dependence of passive stiffness in single cardiac myocytes
Authors: Brady A. J.
Published: December 2017

Passive elastic properties have been studied in detergent-skinned isolated single cardiac myocytes of rat, guinea pig, and rabbit in an attempt to determine whether a measurable difference exists in passive cellular elastic characteristics of these mammalian species. Although the cross-sectional area of isolated cardiac myocytes is complex, a small but statistical difference appears to exist in the elastic modulus of detergent-skinned mammalian cardiac myocytes at 2.2 microns sarcomere length (SL) in the order rat is greater than rabbit, which is greater than guinea pig. The stiffness of rat cells increases least rapidly with increases in SL, and that of the rabbit cells increases most rapidly. In comparison with intact cardiac tissue in the literature, the proportion of stress contributed by skinned myocytes may be as much as half that of the trabeculae at 2.2 microns SL and approximately 10% of that of papillary muscles. Below 2.2 microns SL, the relative cellular proportion increases such that cellular elements may be a major contributor at 1.9 microns SL. Above 2.2 microns SL, the relative cellular contribution declines such that by 2.4 microns SL the cellular contribution is insignificant. It is concluded that at functional SLs intracellular elastic elements may contribute measurably to total cardiac passive elasticity, but at extended lengths the extracellular structures constitute the major limitation to extension.
A novel type of depolarization-activated K+ current in isolated adult rat atrial myocytes
Authors: Boyle W. A. , Nerbonne J. M.
Published: December 2017

To determine the types of voltage-gated K+ channels controlling action potential repolarization in atrial cells, we have characterized the properties of depolarization-activated K+ channels in isolated adult rat atrial myocytes using the whole cell patch-clamp recording technique. On membrane depolarization, Ca2(+)-independent outward K+ currents in these cells begin to activate at approximately -40mV. At all test potentials, the currents activate rapidly after a delay, and there is little or no decay of the peak outward current amplitude during brief (100 ms) depolarizations. In addition, the currents show little steady-state inactivation at membrane potentials negative to -60 mV. The currents are blocked effectively by 1-5 mM 4-aminopyridine but are relatively insensitive to extracellular tetraethylammonium at concentrations up to 50 mM. Based on the measured time- and voltage-dependent properties and the pharmacological sensitivity of the currents, we suggest that the depolarization-activated K+ channels underlying the macroscopic currents in adult rat atrial myocytes are distinct from those described previously in other myocardial preparations, including adult rat ventricular myocytes. Interestingly, the outward K+ currents characterized here in isolated adult rat atrial myocytes are remarkably similar to those of several recently described "delayed rectifier" K+ channel genes isolated from rat brain cDNA libraries and expressed in Xenopus oocytes, suggesting that similar K+ currents are likely present in cells of the mammalian central nervous system.