bluuebunny/crossref_metadata_2025 huggingface dataset:
Determinants of midwall circumferential segmental length of the canine ventricular septum at end diastole
Authors: Dong S. J. , Beyar R. , Zhou Z. N. , Fick G. H. , Smith E. R. , Tyberg J. V.
Published: December 2017

The ventricular septum attaches to the insertion points of the ventricular free walls, separates, and is shared by both the left (LV) and right (RV) ventricles. Changes in the transseptal pressure gradient (PTS, the difference between LV and RV pressures) will change the stress in the septum and, therefore, the length of the septal segment (Ls). However, since most of the septal myocardial fibers are continuous with those of LV free wall and the septum appears to be an integral part of LV, one might also expect that if the LV transmural pressure (Plvtm; the difference between LV and pericardial pressure) is raised, Ls would increase even in the absence of any change in PTS. Therefore, we hypothesized that at end diastole, Ls depends on both Plvtm and PTS. To test this hypothesis, we measured Ls (sonomicrometry), LV and RV pressures (micromanometers), and pericardial pressure (flat liquid-containing balloon) in seven anesthetized open-chest dogs. Plvtm was increased through volume loading, whereas PTS was maintained constant at 10, 5, 0, -5, -10, and -15 mmHg by adjusting the degree of constriction of the pulmonary artery or aorta. These procedures were performed first with pericardium reapproximated and then after the pericardium had been opened widely. At each controlled PTS level, Ls increased linearly with the increase in Plvtm. Both the slope and the intercept of this Ls-Plvtm relation were affected by PTS in a nonlinear fashion. (ABSTRACT TRUNCATED AT 250 WORDS)
Echocardiographic assessment of LV mass in rabbits: models of pressure and volume overload hypertrophy
Authors: Plehn J. F. , Foster E. , Grice W. N. , Huntington-Coats M. , Apstein C. S.
Published: December 2017

We describe a method for the noninvasive measurement of left ventricular mass in small animals using two-dimensionally guided M-mode echocardiography. We compared echocardiographic cross-sectional area (CSA) and cubed-based volumetric indexes of left ventricular (LV) mass with postmortem wet weight in renovascular hypertension-induced pressure overload (group I) and acute aortic insufficiency-induced volume overload (group II) models of ventricular hypertrophy. CSA and cubed echocardiographic indexes correlated well with wet weight from a combination of group I and II animals and their controls (r = 0.89, P < 0.001 for both groups). Separate analyses of groups I and II also demonstrated significant relationships between mass indexes and wet weight using CSA and cubed formulas, respectively, in both pressure (r = 0.57, P = 0.01 and r = 0.71, P < 0.001) and volume (r = 0.90 and r = 0.89, P < 0.001) overload models. Echocardiographically predicted LV mass derived from cubed and CSA regression formulas was 89 and 56% sensitive for pressure overload hypertrophy in group I and 100% sensitive (both cubed and CSA methods) for volume overload hypertrophy in group II. Cubed and CSA mass regression formulas were 60 and 80% specific for hypertrophy in group I and 100 and 90% specific in group II. Normalization of predicted LV mass for body weight added little to the overall technique accuracy with measured sensitivities of 83 and 75% and specificities of 92 and 77%, respectively, for cubed and CSA methods. Two-dimensionally guided M-mode echocardiography provides a reasonably accurate method of LV mass determination in rabbits with pressure- or volume-overloaded ventricles.
End-systolic pressure length relations of stunned right and left ventricles after inotropic stimulation
Authors: Krams R. , Soei L. K. , McFalls E. O. , Winkler Prins E. A. , Sassen L. M. , Verdouw P. D.
Published: December 2017

Regional end-systolic pressure-segment length relationships (ESPSLR) were used to compare the degree of right and left ventricular stunning induced by a 10-min occlusion of the left anterior descending coronary artery and the response to subsequent atrial pacing (50 beats/min above intrinsic heart rate) without and with dobutamine (2 micrograms.kg-1.min-1) in nine anesthetized open-chest pigs. From the ESPSLR, the slope (Ees) (at 100 mmHg for the left and 25 mmHg for the right ventricle) and the total area of the pressure-length relationship (PLA) were determined. From the latter, the distribution into external work (EW) and potential energy (PE) as well as the efficiency of energy transfer (EET = EW/PLA) were calculated. In both the stunned left and right ventricular myocardium Ees and EW were reduced according to the same linear regression equations (delta Ees = 0.7 Ees,baseline - 11.4, r2 = 0.86 and delta EW = 0.4 EWbaseline + 2.3, r2 = 0.67), where Ees,baseline and EWbaseline are Ees and EW at baseline, respectively. EET of the stunned left and right ventricular segments decreased as PLA remained unchanged, due to an increase in PE. EET decreased from 0.84 +/- 0.02 to 0.71 +/- 0.03 (P < 0.05) in the stunned right ventricular segment and from 0.71 +/- 0.02 to 0.44 +/- 0.03 (P < 0.05) in the stunned left ventricular segment. Atrial pacing did not affect EET with respect to stunning levels, whereas the additional infusion of dobutamine restored Ees, EW, and PE and consequently EET to baseline values. In conclusion, the right ventricle is susceptible to stunning. During atrial pacing the EET was lower than expected from the Ees, which could, in agreement with the time-varying elastance concept, be explained by an increase in afterload (a consequence of the decrease in stroke volume). Dobutamine not only increased Ees, EW, and EET but also restored the relationship between Ees and EET in both ventricular stunned segments.
Spontaneous pressure-flow patterns in the kidney of conscious rats
Authors: Skarlatos S. , Metting P. J. , Britton S. L.
Published: December 2017

We have developed a model that permits a quantitative analysis of the contribution of different mechanisms to the spontaneously occurring pressure-flow patterns of a vasculature. In this study we evaluated the spontaneous relationship between arterial pressure (P) and renal blood flow (F) in resting conscious rats during control conditions, autonomic ganglionic blockade (hexamethonium), and nonselective alpha-adrenoreceptor blockade (phentolamine). In a total of 250 trials in 29 rats, we measured the average P and F for each cardiac cycle over 13-min periods (approximately 4,000 cardiac cycles/trial). The P and F values for each cardiac cycle were expressed as percentage change from each 13-min average (beat-to-beat changes). The slope and angle of each consecutive beat-to-beat P-F change were calculated and collated into one of eight zones representing the physiological mechanisms responsible for the concurrent spontaneous changes in P and F. Our results reveal that, in the absence of any chemical or mechanical intervention (control), the renal circulation demonstrated a baroreflex-like P-F pattern approximately 38% of the time. An autoregulatory-like P-F pattern occurred, at the most, 35% of the time. Autonomic ganglionic blockade significantly (P < 0.05) decreased the baroreflex-like pattern and increased the presence of P-F patterns indicative of autoregulation. alpha-Adrenoreceptor blockade resulted in a P-F pattern that was qualitatively similar to that produced by hexamethonium, but with considerably more variability. These results indicate that, in the resting conscious undisturbed state, the autonomic nervous system exerts a tonic influence on the renal circulation that facilitates arterial pressure regulation via a baroreflex-like pattern.
Metabolic inhibition enhances Ca(2+)-activated K+ current in smooth muscle cells of rabbit portal vein
Authors: Miller A. L. , Morales E. , Leblanc N. R. , Cole W. C.
Published: December 2017

The effect of metabolic inhibition on macroscopic and single-channel K+ currents in isolated rabbit portal vein myocytes was investigated by patch-clamp technique. Depression of adenosine triphosphate synthesis was produced by 2-deoxy-D-glucose (10 mM) and either cyanide (2 mM) or dinitrophenol (50 microM). Outward quasi-steady-state current evoked by a ramp protocol and outward time-dependent current during step depolarizations were increased during metabolic inhibition. The reversal potential for quasi-steady-state current shifted negatively toward equilibrium potential of K+ during treatment consistent with a role for K+ conductance and hyperpolarization of membrane potential. The macroscopic K+ current affected was 1) voltage dependent, 2) inhibited by intracellular Ca2+ chelation and low tetraethylammonium ion (1 mM) but unaffected by 4-aminopyridine (2 mM), and 3) associated with a rise in intracellular Ca2+ assessed by indo 1. Metabolic inhibition caused an increase in voltage-dependent large-conductance K+ channel (120–130 pS) activity in cell-attached patches of myocytes bathed in physiological solution (140 mM K+ in pipette). The channels were blocked in a flickery fashion by tetraethylammonium ion (0.5 mM) and inhibited with charybdotoxin (100 nM). We conclude that metabolic inhibition increases the activity of large-conductance Ca(2+)-activated K+ channels in vascular smooth muscle.
Tyrosine kinase inhibitors impair fibroblast growth factor signaling in coronary endothelial cells
Authors: Hawker J. R. , Granger H. J.
Published: December 2017

We examined the effect of various tyrosine kinase inhibitors on basic fibroblast growth factor (bFGF)-induced cell signaling and DNA synthesis in coronary venular endothelial cells (CVEC). Two tyrosine kinase inhibitors, genistein and methyl 2,5-dihydroxycinnamate, showed reversible, dose-dependent inhibition of bFGF-stimulated DNA synthesis in CVEC with half-maximal inhibitory concentrations of 12 and 3 microM, respectively. Both compounds exhibited preferential inhibition of bFGF vs. serum-induced DNA synthesis. bFGF stimulated increased tyrosine phosphorylation of CVEC cellular proteins, including the FGF receptor, which were visible within 1 min of treatment. Concomitant with their effect on DNA synthesis, both compounds exhibited dose-dependent inhibition of tyrosine phosphorylation of intracellular substrates induced by bFGF. A 2-h pretreatment of quiescent CVEC with genistein blocked nuclear translocation but not cytoplasmic internalization of bFGF, whereas the same treatment with methyl 2,5-dihydroxycinnamate inhibited both processes. These results suggest that activation of bFGF receptor tyrosine kinase activity plays a role in nuclear translocation of bFGF and initiation of DNA synthesis in endothelial cells.
Isolated cardiac myocytes are sensitized by hypoxia-reoxygenation to neutrophil-released mediators
Authors: Buerke M. , Weyrich A. S. , Lefer A. M.
Published: December 2017

We exposed isolated rat cardiac myocytes to 20 min of hypoxia followed by 20 min of reoxygenation and observed the effect of supernatants of stimulated neutrophils [polymorphonuclear leukocytes (PMNs)] given at the beginning of reoxygenation. PMN supernatants induced cardiac myocyte injury, which was characterized by a significant (P < 0.01) reduction in cell viability to 53 +/- 3%, vs. 84 +/- 3% in rat myocytes subjected to hypoxia-reoxygenation (H/R) alone. The PMN supernatants also resulted in elevated creatine kinase (CK) activities in the myocyte medium. To examine specific PMN-released mediators that may contribute to this cell death, we studied the effects of hydrogen peroxide (H2O2), elastase, and platelet-activating factor on H/R cardiac myocytes. Incubation of myocytes after hypoxia with 10, 50, and 100 microM H2O2 decreased viability in a concentration-dependent manner (from 83 +/- 2 to 37 +/- 2%; P < 0.01). CK release of H/R myocytes was also significantly increased by 100 microM H2O2 (to 28 +/- 5 from 12 +/- 1% for H/R alone; P < 0.01). Similarly, elastase (5 micrograms/ml) given after hypoxia significantly reduced cardiac myocyte viability during reoxygenation (viability 58 +/- 1 vs. 85 +/- 1% H/R alone; P < 0.05) and increased CK release (to 29 +/- 3 from 11 +/- 1% for H/R alone; P < 0.01), an effect that was abolished by L-680,833, an elastase inhibitor. Unlike H2O2 and elastase, platelet-activating factor had no significant effect on myocyte viability or CK release after H/R.(ABSTRACT TRUNCATED AT 250 WORDS)
Circulatory and metabolic effects of anemia in hyperinsulinemic ovine fetuses
Authors: Papparella A. , Berard D. , Stonestreet B. S.
Published: December 2017

Infants born to women with poorly controlled diabetes mellitus have an increased incidence of perinatal asphyxia, cardiovascular abnormalities, elevated catecholamines, and sudden fetal death. Although hyperinsulinemic fetuses of diabetic women often exhibit polycythemia, they may also develop anemia because of pregnancy- and/or delivery-related complications. Experimental fetal hyperinsulinemia results in cardiovascular changes and a surge in catecholamines. We hypothesized that reductions in fetal O2 availability via anemic hypoxia limits O2 transport and compromises the hemodynamically and metabolically stressed but compensated hyperinsulinemic fetus. Chronically catheterized fetuses receiving insulin (n = 9) or placebo (n = 5) for 48 h were rendered anemic by an isovolemic exchange transfusion. In the hyperinsulinemic state, anemic-hypoxia augmented the insulin-mediated surge in norepinephrine concentration and increases in blood flow to brain, heart, and adrenal glands. Insulin-related increase in the combined ventricular output was sustained during anemia. O2 delivery to the fetus decreased, extraction increased, and O2 uptake did not change. Regional O2 delivery to the brain, kidney, gastrointestinal tract, muscle, fat, pancreas, spleen, and carcass decreased. Hyperinsulinemic ovine fetus exposed to anemic hypoxia demonstrated an accentuated surge in norepinephrine, a sustained increase in the combined ventricular output, preservation of systemic O2 uptake, and compromised regional O2 delivery to certain vascular regions. We conclude that the hyperinsulinemic fetus was able to compensate for anemic hypoxia by increased or sustained regional vascular perfusion.
Mechanical equilibrium determines the fractal fiber architecture of aortic heart valve leaflets
Authors: Peskin C. S. , McQueen D. M.
Published: December 2017

In this work, the structure of the aortic valve is derived from its function, which (in the closed-valve configuration) is to support a uniform pressure load. It is assumed that this load is transferred to the aortic wall by a one-parameter family of fibers under tension. The equation of equilibrium for this fiber structure turns out to be equivalent to the equation of motion of vortex lines in the self-induction approximation. The method of Buttke (J. Comput. Phys. 76:301–326, 1988) is used to solve these equations and, hence, to determine the fiber architecture of the aortic leaflets. Because of a singularity at the center of the aortic valve, the computed fiber architecture has a fractal character with increasing complexity at progressively smaller scales. The computed fiber architecture resembles the branching braided structure of the collagen fibers that support the real aortic valve.
Measurement of left ventricular volume in normal and volume-overloaded canine hearts
Authors: Gaynor J. W. , Feneley M. P. , Gall S. A. , Maier G. W. , Kisslo J. A. , Davis J. W. , Rankin J. S. , Glower D. D.
Published: December 2017

Serial studies of adaptation to aortic regurgitation (AR) were undertaken to determine whether sonomicrometry and echocardiography could be combined to measure changes in left ventricular (LV) cavitary volume (Vlv) and wall mass using the geometric formula [Vlv = K pi b2 alpha--wall volume], where K is a constant depending on the geometric model and a and be are epicardial major- and minor-axis diameters, respectively. Postmortem studies were performed in six normal dogs and in nine with AR; ultrasonic ventricular dimensions were measured as Vlv was varied with an intracavitary balloon. Three models were tested: 1) ellipsoid (model I; K = 1/6), 2) cylinder-ellipsoid (model II; K = 5/24), and 3) cylinder (model III; K = 1/4). The slope of the relationship between calculated Vlv and balloon volume varied between models (I, 0.71 +/- 0.11; II, 0.89 +/- 0.14; III, 1.07 +/- 0.17), and empiric determination of K to produce a slope of 1.0 resulted in a value of 0.26 +/- 0.04, not significantly different from the cylindrical model. Serial measurements of LV dimensions in 10 chronically instrumented conscious dogs revealed no significant change in end-diastolic or end-ejection LV shape after up to 16 wk of AR. Sonomicrometry and echocardiography can be integrated using a cylindrical geometric model to accurately estimate changes in end-diastolic or end-ejection Vlv during chronic volume overload.
Glibenclamide prevents coronary vasodilation induced by beta 1-adrenoceptor stimulation in dogs
Authors: Narishige T. , Egashira K. , Akatsuka Y. , Imamura Y. , Takahashi T. , Kasuya H. , Takeshita A.
Published: December 2017

This study aimed to determine whether a putative ATP-sensitive K(+)-channel blocker, glibenclamide (Glb), prevents metabolic coronary vasodilation associated with increased myocardial oxygen consumption (MVO2) caused by beta 1-adrenoceptor stimulation in anesthetized open-chest dogs. Isoproterenol (Iso) was infused selectively into the left circumflex coronary artery before and after Glb. Coronary blood flow (CBF) by an electromagnetic flowmeter, regional myocardial function by sonomicrometers, and left ventricular and arterial pressures were continuously measured. An intracoronary infusion of Iso (10 ng.kg-1 x min-1) resulted in the sustained increase in CBF as well as in the myocardial inotropic and chronotropic state. Glb (10, 30, and 100 micrograms/min ic) attenuated the Iso-induced increase in CBF in a dose-dependent manner, whereas inotropic and chronotropic responses to Iso were not affected by Glb. After beta 1-blockade with bisoprolol (0.3 mg/kg), which completely inhibited inotropic and chronotropic responses to Iso, the Iso-induced increase in CBF, presumably mediated by vascular beta 2-receptor stimulation, was not affected by Glb. Intracoronary denopamine (0.1 microgram.kg-1 x min-1), a beta 1-selective agonist, increased CBF, which was almost completely abolished by Glb. The increases in MVO2 induced by Iso or denopamine were similar before and after Glb, indicating that attenuation of the Iso- or denopamine-induced increase in CBF by Glb did not result from the decrease in MVO2. These results indicate that Glb prevented the increase in CBF associated with increased MVO2 caused by beta 1-adrenoceptor stimulation. It is suggested that ATP-sensitive K+ channels may play an important role in metabolic coronary vasodilation in dogs.
Endothelium-dependent relaxation by angiotensin-converting enzyme inhibitors in canine femoral arteries
Authors: Moroi M. , Akatsuka N. , Fukazawa M. , Hara K. , Ishikawa M. , Aikawa J. , Namiki A. , Yamaguchi T.
Published: December 2017

The effects of angiotensin-converting enzyme (ACE) inhibitors on vascular reactivity were investigated using isolated canine femoral arteries with and without endothelium. N-N-(S)-1-carboxy-3-phenylpropyl-L-alanyl-N-(indan-2-yl)glycine (M-1; an active metabolite of delapril, a nonsulfhydryl ACE inhibitor) and captopril (a sulfhydryl ACE inhibitor, 10(-8) to 10(-5) M) relaxed in a dose-dependent manner canine femoral arterial rings precontracted with prostaglandin F2 alpha in the presence of endothelium only. The endothelium-dependent relaxations by M-1 and captopril were completely blocked by methylene blue, an inhibitor of soluble guanylate cyclase; NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis; and oxyhemoglobin, an inactivator of nitric oxide; they were partially blocked by aspirin, an inhibitor of cyclooxygenase and were enhanced by superoxide dismutase, a radical scavenger. The inhibitory effect of L-NMMA on the relaxations by M-1 and captopril were reversed by a high dose of L-arginine. Moreover, a bradykinin antagonist partially inhibited these relaxations. These results suggest that endothelium-dependent relaxations by M-1 and captopril in canine femoral arteries are mediated through the release of both prostanoids and endothelium-derived nitric oxide via endogenous bradykinin.
Defective endothelium-mediated control of coronary circulation in conscious dogs after heart failure
Authors: Wang J. , Seyedi N. , Xu X. B. , Wolin M. S. , Hintze T. H.
Published: December 2017

The goal of this study was to determine whether coronary endothelial function was altered after pacing-induced heart failure in conscious dogs. Fourteen mongrel dogs were chronically instrumented for measurements of systemic hemodynamics, left circumflex coronary artery diameter (CD) and blood flow, and for left ventricular pacing for 4 wk. Heart failure developed during this pacing regimen and was characterized by a significant reduction in arterial pressure, an increase in left atrial pressure, a resting tachycardia, a depression of left ventricular dP/dt to isoproterenol injection, a significant reduction of the slope of the end-systolic pressure-diameter relationship, and all of the characteristic clinical signs. During heart failure, the dilation of CD after release of a brief coronary artery occlusion, acetylcholine, and arachidonic acid was attenuated, whereas prostaglandin (PG) I2- and nitroglycerin-induced dilations of CD were unchanged. The coronary blood flow responses to occlusion, acetylcholine, and nitroglycerin were depressed, but not to PG. Large coronary arteries and microvessels were isolated from normal and failing hearts. Both isolated large coronary arteries and microvessels from failing hearts produced significantly less nitrite, the immediate metabolite of nitric oxide in aqueous solution, than those of normal hearts. Thus endothelium-mediated control of the coronary circulation was depressed during heart failure. A decrease in the production of nitric oxide-endothelium-derived relaxing factor was most likely responsible for this depression.
Enhanced postischemic dysfunction selective to subendocardium in conscious dogs with LV hypertrophy
Authors: Hasebe N. , Shen Y. T. , Kiuchi K. , Hittinger L. , Bishop S. P. , Vatner S. F.
Published: December 2017

The effects of a 15-min coronary arterial occlusion (CAO) and reperfusion (CAR) for 24 h were compared in 11 normal dogs and in 13 conscious dogs with left ventricular (LV) hypertrophy (H) induced by ascending aortic banding, which increased the LV weight-to-body weight ratio by 69%. The dogs were studied 2–4 wk after recovery from instrumentation for measurement of global LV dynamics and regional wall motion. During CAO, heart rate and LV end-diastolic pressure increased similarly in both groups; however, LV systolic pressure decreased (-38 +/- 6 mmHg; P < 0.01) only in LVH. At 1 h of CAR, all measurements of systemic hemodynamics and global LV function returned to baseline levels in normal dogs; however, sustained depression (P < 0.01) in LV systolic pressure (-18 +/- 4 mmHg) and mean velocity of circumferential fiber shortening corrected for heart rate (-0.17 +/- 0.06) were observed in LVH. The recovery in regional myocardial dysfunction was significantly prolonged in the subendocardium (Endo) of LVH, e.g., at 1 h of CAR, Endo wall thickening was depressed more in dogs with LVH compared with normal dogs (-69 +/- 3% vs. -53 +/- 5%; P < 0.01), but not in the subepicardium (Epi). Coronary flow reserve, assessed by intravenous adenosine, was depressed in Endo of LVH compared with normal dogs, but not altered further by CAR. In conclusion, myocardial stunning after a brief period of CAO in dogs with LVH was not enhanced in Epi but was modestly increased in Endo. This regional dysfunction was, however, sufficiently powerful to induce modest impairment of global LV function.
Neural modulation of ventriculoarterial coupling in conscious dogs
Authors: Asanoi H. , Ishizaka S. , Kameyama T. , Sasayama S.
Published: December 2017

To investigate the role of autonomic reflexes in stroke-work optimization, we studied ventriculoarterial coupling in unanesthetized dogs with the autonomic system intact and blocked. Ventricular contractility was quantified by the slope of the end-systolic pressure-volume relation, ventricular elastance (Ees). Arterial system properties were quantified by the ratio of end-systolic pressure to stroke volume, arterial elastance (Ea). The coupling between left ventricle and arterial system was expressed by the Ea-to-Ees ratio. Changes in arterial blood pressure during nitroprusside or angiotensin II infusion were used to elicit reflex-mediated influences on ventriculoarterial coupling. With the autonomic system intact, Ees doubled during nitroprusside infusion while Ea remained unchanged due to reactive vasoconstrictor forces and tachycardia. Consequently, the Ea-to-Ees ratio fell 50% from baseline. Angiotensin II infusion increased Ea 46% but did not significantly change Ees, resulting in a 26% increase in the Ea-to-Ees ratio. In contrast to ventriculoarterial coupling, stroke work was insensitive to changes in afterload, remaining close to its theoretical maximum. After autonomic blockade, Ees tended to decrease during nitroprusside and increased during angiotensin II infusion in parallel with changes in Ea, so that the Ea-to-Ees ratio did not change from baseline as much as it did with the autonomic system intact. Again, the left ventricle maintained nearly 90% of its maximal stroke work. Thus, over a wide range of afterload, stroke work was kept near its theoretical maximum, independent of autonomic neural regulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of metoprolol on left ventricular function in rats with myocardial infarction
Authors: Cherng W. J. , Liang C. S. , Hood W. B.
Published: December 2017

To study the effect of beta-receptor-blocking agents in an animal model of left ventricular (LV) dysfunction, we measured LV performance in vivo and in vitro in 69 rats with or without metoprolol (M) treatment 3 wk after left coronary arterial ligation or sham operation. Rats were divided into six groups including control (C) and M noninfarct (C-N and M-N), C and M small infarct (C-S and M-S), and C and M large infarct (C-L and M-L). LV function was measured as slope of change in systolic vs. diastolic pressure (pressure-function curve) during pressor response after administration of a bolus of phenylephrine (5 micrograms/kg i.v.). Reduction of LV function was noted in C-L compared with C-N and C-S (slope of pressure-function curve 3.3 +/- 0.3 vs. 11.0 +/- 1.9 and 11.9 +/- 2.3, respectively) and in M-L compared with M-N and M-S rats (slope of 5.5 +/- 1.4 vs. 11.3 +/- 2.0 and 12.1 +/- 1.4, respectively). There was no significant difference between C and M rats, although there was a trend toward partial correction of the pressure-function curves in M-L compared with C-L rats. In muscle bath preparations the uninfarcted LV posterior papillary muscle from shams and rats with small infarcts showed a dose-related increase in peak rate of tension development with isoproterenol stimulation, but this response was lacking in both C-L and M-L. Tissue assays showed no change in beta-receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)
Platelet-activating factor modulates microvascular transport by stimulation of protein kinase C
Authors: Kobayashi I. , Kim D. , Hobson R. W. , Duran W. N.
Published: December 2017

To investigate the possible involvement of protein kinase C (PKC) in platelet-activating factor (PAF)-stimulated microvascular responses, PKC inhibitors, sphingosine (SPH), 1-(5-isoquino-linylsulfonyl)-3-methylpiperazine (iso H-7), and calphostin C, were applied topically to the hamster cheek pouch, and PAF-elicited changes in microvascular permselectivity and arteriolar constriction were evaluated. Pretreatment with 10(-6) M SPH, 10(-5) M SPH, or 10(-10) M iso H-7 significantly reduced 10(-7) M PAF-induced increase in fluorescein isothiocyanate-Dextran 150 clearance (2,677.3 +/- 397.3, 2,985.3 +/- 350.7, and 2,689.3 +/- 256.0 vs. 4,784.0 +/- 474.7 nl.60 min-1.g-1, respectively). Calphostin C at 10(-7) M attenuated 10(-8) M PAF-induced increase in clearance (2,156.9 +/- 353.3 vs. 3,841.6 +/- 260.9 nl.60 min-1.g-1). Permeability changes were also measured by integrated optical intensity (IOI). Pretreatment with 10(-6) M SPH, 10(-5) M SPH, or 10(-10) M iso H-7 attenuated the maximal increment in IOI induced by 10(-7) M PAF (2,024.0 +/- 364.4, 1,690.0 +/- 525.2, and 2,432.8 +/- 655.3 vs. 4,255.9 +/- 695.6 U, respectively). Direct stimulation of PKC by phorbol dibutyrate increased clearance in dose-dependent fashion. Similarly, activation of PKC with phorbol myristate acetate increased IOI values. The PAF-induced arteriolar constriction was not blocked by the PKC inhibitors. Our results suggest that PKC represents a biochemical pathway involved in the PAF modulation of microvascular permeability but not of arteriolar constriction.
Gastrointestinal hemodynamics during compensation for hemorrhage and measurement of Pmcf
Authors: Rothe C. F. , Maass-Moreno R.
Published: December 2017

To quantify the degree of autonomic reflex control of the gastrointestinal vasculature, we studied the responses to a 10-ml/kg hemorrhage or transfusion and autonomic blockade in fentanyl- and pentobarbital-anesthetized dogs. The active total blood volume was estimated by indocyanine green dilution. Transfusion and hemorrhage did not significantly change gastrointestinal vascular compliance [1.82 +/- 0.68 (SD) ml/mmHg], but autonomic blockade with hexamethonium and atropine increased it by 0.57 +/- 0.37 ml/mmHg. Neither hemorrhage nor autonomic blockade significantly changed gastrointestinal vascular resistance from its control value of 10.8 +/- 4 mmHg.ml-1.min.kg body wt, but transfusion reduced it by 3.0 +/- 1.2 mmHg.ml-1.min.kg body wt. The ratio of gastrointestinal vascular resistance to total peripheral resistance was not significantly changed, however. We conclude that vascular compliance and resistance of the gastrointestinal bed are minimally influenced by the autonomic nervous system under the conditions studied. Portal pressure and flow measurements (transit-time ultrasound) during the above maneuvers were also combined with estimations of mean circulatory filling pressure (Pmcf) to test the hypothesis that, when the heart is stopped to measure Pmcf, portal pressure equals central venous pressure (Pcv) and hence that portal flow is zero. Seven seconds after the heart was stopped, portal venous pressure (Ppv) remained 0.83 +/- 0.78 mmHg higher than Pcv and portal flow decreased to only 25% of its control value. However, gastrointestinal compliance times (Ppv-Pcv), an estimate of the extra distending volume, was only 0.07 +/- 0.07 ml/kg body wt. Thus we conclude that the error in estimating Pmcf, given this (Ppv-Pcv) difference, is physiologically insignificant.
In vivo monitoring of norepinephrine and .OH generation on myocardial ischemic injury by dialysis technique
Authors: Obata T. , Hosokawa H. , Yamanaka Y.
Published: December 2017

We applied in vivo microdialysis techniques in examining the relation between norepinephrine and free radical generation on myocardial ischemic injury. We designed the microdialysis probe holding system, which includes loose fixation of the tube and synchronization of the movement of the heart and the probe. The heart was subjected to myocardiac ischemia for 15 min by occlusion of rat left anterior descending coronary artery. We confirmed typical changes in the electrocardiogram. The hydroxyl free radical (.OH) reacts with salicylate and generates 2, 3- and 2,5-dihydroxybenzoic acid (DHBA), which can be measured electrochemically in picomole quantity by a high-performance liquid chromatographic-electrochemical procedure. After probe implantation, the norepinephrine concentration of dialysate decreased over the first 120 min and then reached an almost steady-state level of 0.15 +/- 0.02 nmol/ml. However, when the heart was reperfused, the levels of norepinephrine and 2,3- and 2,5-DHBA were elevated. In vivo microdialysis techniques permit monitoring of norepinephrine levels and free radical generation in myocardial ischemic injury.
Prior episode of anoxia attenuates vasorelaxation in response to subsequent episode of anoxia
Authors: Yang B. C. , Mehta J. L.
Published: December 2017

To examine the effect of a prior episode of anoxia on subsequent anoxia-mediated vasorelaxation, norepinephrine-precontracted endothelium-intact rat aortic rings were first exposed to anoxia (95% N2-5% CO2 for 5, 15, or 30 min) then to normoxia (95% O2-5% CO2 for 15 min). These rings were exposed again to anoxia for 30 min. First exposure of rings to anoxia for 30 min resulted in 77 +/- 4% decrease in tone (vasorelaxation), whereas second exposure resulted in only 10 +/- 4% relaxation (n = 11, P < 0.001 vs. relaxation during first exposure). First exposure of rings to anoxia for 5 or 15 min also diminished relaxation to 59 +/- 3 and 19 +/- 8%, respectively, on second exposure to anoxia (both P < 0.01 vs. relaxation during 1st anoxia). Attenuation of vasorelaxation by prior episode of anoxia was not affected by treatment of rings with indomethacin (10(-5) M), the Ca2+ channel blocker felodipine (10(-6) M), the superoxide anion scavenger superoxide dismutase (100 micrograms/ml), or adenosine A1 and A2 blockers (each 10(-6) M). To examine the role of intact functional endothelium in attenuation of vasorelaxation during second anoxic exposure, rings were deendothelialized and treated with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 10(-4) M) or the guanylate cyclase inhibitor methylene blue (MB; 2 x 10(-5) M). In all deendothelialized rings, vasorelaxation during second anoxic exposure was similar to that during first anoxic exposure (100 +/- 0 vs. 98 +/- 3%, P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Changes in myocardial contraction pattern during initial reperfusion
Authors: Rynning S. E. , Birkeland S. , Hexeberg E. , Grong K.
Published: December 2017

The characteristics of hypercontraction during initial reperfusion were studied in 10 pentobarbitone-anesthetized cats. The left anterior descending coronary artery was occluded for 10 min followed by 1 h of reperfusion, and regional function was assessed by two cross-oriented pairs of sonomicrometers placed in the left ventricular anterior wall. At 1 min of reperfusion (hyperfunctional phase) there was an uniform contraction pattern with 90% recovery of ejection shortening in both circumferential and longitudinal segments. During initial hypercontraction, end-diastolic segment lengths remained unchanged, whereas end-systolic segment lengths decreased transiently. Inotropic stimulation during reperfusion in four additional animals also affected end-systolic lengths more than end-diastolic lengths. This suggests that the initial hyperfunctional phase is due to an inotropic stimulation of the stunned myocardium, most probably caused by intracellular Ca2+ overload. At 5 min of reperfusion a nonuniform contraction pattern had developed with 68% recovery of shortening in circumferential segments vs. 25% in longitudinal segments. The decreased performance in longitudinal segments was paralleled by a delayed start of contraction as well as a decreased velocity of contraction. Because longitudinal segment shortening is a sensitive parameter of subendocardial performance, our results indicate a brief transmural hypercontraction followed by increasing dysfunction (stunning) in the subendocardial layer.
Characterization of pulmonary endothelial charge barrier
Authors: Swanson J. A. , Kern D. F.
Published: December 2017

To clarify the role of charge in protein movement across the pulmonary endothelial barrier, we simultaneously measured the permeability-surface area product (PS) for native [isoelectric point (pI) 4.4-5.1] and cationic (pI 7.2-8.0) albumin in isolated rabbit lungs perfused with and without protamine sulfate. We focused our measurement on the initial (endothelial) barrier by using a technique that is based on the very rapid (3 min) uptake of tracer. This allowed us to distinguish the charge properties of the endothelium separate from other barriers. In control studies, PS was greater for cationic than for native albumin (8.67 +/- 0.93 vs. 2.55 +/- 0.20 x 10(-2) ml.min-1.g dry lung-1). In the presence of 1 mg/ml protamine sulfate, cationic albumin permeability was not different from control (7.34 +/- 0.49 x 10(-2) ml.min-1.g dry lung-1), whereas PS for anionic albumin increased to 8.82 +/- 1.32 x 10(-2) ml.min-1.g dry lung-1. Thus the protamine sulfate eliminated the difference between native and cationic albumin PS. This selective increase in anionic albumin permeability is presumably due to the cation, protamine sulfate, binding to the anionic charges on the endothelium and reducing the anionic charge-charge repulsion. If protamine sulfate had produced a general endothelial injury, the PS for both albumins would have increased. Our results suggest that the normal pulmonary endothelium is an anionic charge barrier restricting the transcapillary movement of negatively charged molecules.
Indomethacin-sensitive CO2 reactivity of cerebral arterioles is restored by vasodilator prostaglandin
Authors: Wagerle L. C. , Degiulio P. A.
Published: December 2017

To investigate the role of vasodilator prostanoids in the CO2-induced relaxation of cerebral arterioles, the present study examined the effect of exogenous prostaglandin (PG) E2 and nonprostanoid vasodilators, adenosine and sodium nitroprusside, on the indomethacin-impaired pial arteriolar response to CO2 in newborn piglets. Reactivity of pial arterioles (52-131 microns diam) was determined using a closed cranial window with intravital microscopy. Cortical prostanoid synthesis was assessed by analyzing for select prostanoids in cerebrospinal fluid sampled from under the cranial window. Inhalation of 7% CO2 caused an elevation of cortical 6-keto-PGF1 alpha and thromboxane (Tx) B2 and increased pial arteriolar diameter by 34 +/- 5%. Two cyclooxygenase inhibitors, indomethacin (5 mg/kg i.v.) and ibuprofen (30 mg/kg i.v.), abolished the CO2-induced elevation of cortical prostanoids. Indomethacin, but not ibuprofen, blocked the CO2-induced increase in pial arteriolar diameter. The indomethacin-impaired vasodilator response to CO2 was restored when PGE2 (0.1-1 microM) was applied topically to the cortical surface. Adenosine (1-100 microM) and sodium nitroprusside (0.5 microM) only partially restored the vasodilator response to CO2. The data suggest that vasodilator prostanoids facilitate cerebrovascular relaxation to CO2 and may play a permissive role in the relaxation response of vascular smooth muscle. The fact that adenosine (adenosine 3',5'-cyclic monophosphate-mediated dilator) and sodium nitroprusside (guanosine 3',5'-cyclic monophosphate-mediated dilator), were partially effective suggests a role for those intracellular signaling pathways. We speculate that receptor activation of intracellular pathways may alter Ca2+ sensitivity of the contractile apparatus in such a way that the relaxation response to CO2 can occur.(ABSTRACT TRUNCATED AT 250 WORDS)
Maximal vascular conductance in right ventricular myocardial circulation
Authors: Vlahakes G. J. , Verrier E. D. , Turley K. , Hoffman J. I.
Published: December 2017

With acutely increasing right ventricular (RV) hypertension, failure eventually occurs because of RV ischemia. This study examines the effects of RV hypertension on the diastolic right coronary circulation. Conscious dogs instrumented to measure right coronary artery pressure and blood flow were studied after maximal coronary vasodilation with chromonar. Diastolic coronary pressure-flow relations, described by slope (conductance) and zero-flow, pressure axis intercept (Pf = 0), were generated before and during RV hypertension. Diastolic Pf = 0 increased from 11.8 +/- 6.5 to 17.1 +/- 7.1 (means +/- SD, P < 0.01) Torr, with no change in conductance. During RV hypertension, RV diastolic pressure increased. To examine possible mechanisms for the increase in Pf = 0, pressure-flow relations were generated before and after volume loading, without systolic hypertension. Diastolic Pf = 0 increased from 15.5 +/- 3.1 to 20.8 +/- 4.1 Torr, suggesting that changes in Pf = 0 with RV hypertension were mediated by increased filling pressures. Pressure flow relations were derived from mean right coronary flow and RV driving pressure before and during RV hypertension. Under these conditions, Pf = 0 is close to zero; the use of RV driving pressure provides a method for calculating maximal right coronary conductance.
Modulation of autonomic responses in normal and denervated isolated canine atria by substance P
Authors: Priola D. V. , Cao X. , Smith D. C.
Published: December 2017

The experiments were performed to determine whether the neuromodulatory effect of substance P (SP) could be demonstrated in the isolated atrium. Strips from the right (RA) and left atria (LA) of normal (control) and denervated canine hearts were placed in an isolated muscle bath, and isometric muscle tension was measured. Inotropic responses to direct muscarinic stimulation were obtained with 1 x 10(-9) to 1 x 10(-8) M acetylcholine (ACh), and responses to stimulation of the intramyocardial intrinsic cardiac nerves (ICN) were produced with nicotine (Nic), 1.0-10 x 10(-6) M. The same drugs were tested in the presence of 1 x 10(-6) M SP, which had no significant inotropic effects of its own. Responses to ACh were unaffected by SP. The primary negative inotropic response to Nic was greatly attenuated by SP in both control and denervated atria, whereas the secondary positive response in control atria was unaffected. This inhibition was very pronounced in LA but less so in the RA. We conclude that SP appears to modulate the responses of the ICN to nicotinic stimulation in a manner similar to that previously observed in intact animals. This mechanism may provide a means of direct modification of efferent cardiac responses by afferent nerves within the heart itself.
Effects of aging on AV nodal and ventricular beta-adrenergic receptors in the Fischer 344 rat
Authors: Kusumoto F. M. , Lurie K. G. , Dutton J. , Capili H. , Schwartz J. B.
Published: December 2017

The effects of aging on atrioventricular (AV) nodal and right and left ventricular beta-adrenergic receptor (beta-AR) characteristics were studied in Fischer 344 rat hearts using quantitative autoradiography. Twenty-micrometer-thick cardiac sections containing the compact AV node from 16 mature (4-6 mo old) rats, 6 middle-aged (12 mo old) rats, and 16 old (24 mo old) rats were incubated with [125I]iodocyanopindolol, [125I]iodocyanopindolol plus atenolol, or ICI 118551. Saturation experiments revealed a significant age-related decrease in AV nodal beta-AR density (mature: 190 +/- 46, middle-aged: 165 +/- 27, old: 133 +/- 34 amol/mm2; P < 0.01), with no change in affinity (mature: 106 +/- 62, middle-aged: 132 +/- 46, old: 128 +/- 66 pM). No age-related changes in AV nodal beta-AR subtype ratio (55% beta 1, 45% beta 2) or estimated compact AV node volume were detected (mature: 66 +/- 17, old: 65 +/- 23 microns 3). No difference in beta-AR density or affinity was detected between mature and old rats in either left (LV) or right (RV) ventricular tissue (LV, mature: 60 +/- 11, middle-aged: 59 +/- 11, old: 62 +/- 11 amol/mm2; RV, mature: 65 +/- 9, middle-aged: 65 +/- 11, old: 58 +/- 10 amol/mm2). beta-AR subtype ratios for the left ventricle (64% beta 1, 36% beta 2) and right ventricle (63% beta 1, 37% beta 2) did not significantly differ between mature and old rats. To summarize, aging from 4 to 24 mo in the Fischer 344 rat is associated with 1) a decrease in AV nodal beta-AR density with no change in affinity; 2) no change in volume of the compact region of the AV node; 3) no change in beta-AR subtype ratio in the AV node, left ventricle, or right ventricle; and 4) no change in either RV or LV beta-AR density.
Assessment of cardiomyocyte DNA synthesis during hypertrophy in adult mice
Authors: Soonpaa M. H. , Field L. J.
Published: December 2017

The ability of cardiomyocytes to synthesize DNA in response to experimentally induced cardiac hypertrophy was assessed in adult mice. Isoproterenol delivered by osmotic minipump implantation in adult C3Heb/FeJ mice resulted in a 46% increase in heart weight and a 19.3% increase in cardiomyocyte area. No DNA synthesis, as assessed by autoradiographic analysis of isolated cardiomyocytes, was observed in control or hypertrophic hearts. A survey of 15 independent inbred strains of mice revealed that ventricular cardiomyocyte nuclear number ranged from 3 to 13% mononucleate, suggesting that cardiomyocyte terminal differentiation is influenced directly or indirectly by genetic background. To determine whether the capacity for reactive DNA synthesis was also subject to genetic regulation, cardiac hypertrophy was induced in the strains of mice comprising the extremes of the nuclear number survey. These data indicate that adult mouse atrial and ventricular cardiomyocytes do not synthesize DNA in response to isoproterenol-induced cardiac hypertrophy.
2-Fluoroadenosine uptake by erythrocytes and endothelial cells studied by 19F-NMR
Authors: Decking U. K. , Alves C. , Spahr R. , Schrader J.
Published: December 2017

Transport and phosphorylation of 2-fluoroadenosine (F-AR) were studied in human erythrocytes and porcine aortic endothelial cells by 19F-nuclear magnetic resonance (NMR) spectroscopy. F-AR (590 microM) added to a human erythrocyte suspension (15% hematocrit) was rapidly incorporated into adenine nucleotides at a rate of 38 nmol.min-1.ml red blood cells-1. Intracellular F-AR could be distinguished from extracellular F-AR due to a chemical shift difference of 0.43 +/- 0.03 ppm (n = 5 experiments). Compared with F-AR, fluoro-ATP purified by high-performance liquid chromatography (HPLC) exhibited a chemical shift of -0.052 ppm, which was too small to differentiate intracellular F-AR and fluoro-ATP in vivo. F-AR uptake was decreased by inhibition of membrane transport with dipyridamole (25 microM) or blockade of adenosine kinase by iodotubercidin (10 microM). The time course of F-AR uptake suggested that the rate-limiting step was not membrane transport but the intracellular phosphorylation by adenosine kinase. In porcine aortic endothelial cells grown on microcarrier beads and perfused within the magnet, there was a linear relation between the F-AR concentration applied (2, 4, 8, or 32 microM) and net uptake measured (27-827 pmol.min-1.mg-1). Intra- and extracellular fluoroadenine compounds were separated by 0.12 ppm, and HPLC analysis confirmed F-AR conversion to fluoroadenine nucleotides. Our findings demonstrate that cellular transport and metabolism of F-AR can be noninvasively studied and analyzed by 19F-NMR.
Vascular contractile potency of endothelin-1 is increased in the presence of monocytes or macrophages
Authors: Magazine H. I. , Andersen T. T. , Bruner C. A. , Malik A. B.
Published: December 2017

Accumulation of inflammatory cells and altered responsiveness to vasoactive mediators are commonly observed events in atherosclerotic vessels. We studied the effect of monocytic cells on endothelin-1 (ET-1)-induced contraction of strips of guinea pig carotid artery. The vascular contractile potency of ET-1 was increased markedly in the presence of human peripheral blood monocytes, guinea pig alveolar macrophages (M phi), and the human monocytic cell line, THP-1. Specific binding of 125I-labeled ET-1 to these cells was detected, and Scatchard analysis indicated a dissociation constant value of approximately 1 nM. In contrast, the human monocytic cell line, U-937, failed to bind 125I-ET-1 and did not alter ET-1 potency, suggesting that the ability of monocytic cells to increase ET-1 potency requires expression of ET receptors. Selective inhibition of ET-1 binding to vascular smooth muscle with BQ-123, an ETA receptor antagonist that does not inhibit ET-1 binding to monocytes, resulted in complete inhibition of vascular contraction. These data indicate that ET-1-induced vasoconstriction may be increased by monocytic cells via stimulation of monocyte endothelin receptors.