bluuebunny/crossref_metadata_2025 huggingface dataset:
Topology and dimensions of pig coronary capillary network
Authors: Kassab G. S. , Fung Y. C.
Published: December 2017

To provide a morphometric basis for any mathematical modeling of the coronary vasculature, data on the network of coronary capillary blood vessels and the topology of the arteriolar supply and venular drainage relative to the capillaries are presented. The diameters, lengths, and branching patterns of the coronary capillary blood vessels in the right and left ventricles of four pigs were measured. The locations of the coronary arterioles and venules were identified, topological maps were constructed, and the mean functional length of capillaries connecting an arteriole to an adjacent venule was measured. The vasculature was fixed by perfusing the coronary vessels with a catalyzed polymer. After the polymer hardened, plugs of the myocardium were removed, sectioned, dehydrated, and cleared to render the capillary network visible in a light microscope. The capillaries then were traced by optical sectioning. We designated the capillaries as blood vessels of order number zero; we further designated the capillaries as those fed directly by arterioles (C0a), those drained directly into venules (C0v), and those capillary vessels connected to C0a and C0v. The capillaries are connected in patterns identified as Y, T, H, or hairpin and anastomosed through capillary cross-connections (Ccc). The Ccc vessels may connect adjacent capillaries or capillaries originating from different arterioles. The connection among the capillaries, arteries, and veins is presented in terms of a connectivity matrix. Combining the present data with those for the arterial and venous trees, we have obtained a complete set of statistical data of all the blood vessels of the heart of the pig. Such a data set will serve as the basis of coronary hemodynamics.
Myosin heavy chain regulation and myocyte contractile depression after LV hypertrophy in aortic-banded mice
Authors: Dorn G. W. , Robbins J. , Ball N. , Walsh R. A.
Published: December 2017

Using an adult mouse aortic-banded model of pressure-overload hypertrophy and isolated cardiomyocyte mechanics studies, we examined the hypothesis that contractile depression is due to altered cardiac contractile proteins rather than changes in left ventricular (LV) geometry, loading, or the extracellular matrix. FVB mice were banded at the transverse aortic arch or sham operated and studied after 7 days. In nine animals the gradient across the aortic band averaged 47 +/- 4 mmHg. Compared with sham-operated controls, banded animals had increased LV weight-to-body weight ratio (2.8 +/- 0.1 and 3.5 +/- 0.1, respectively; P = 0.035). Left ventricles from additional age-matched groups of mice that underwent identical surgical procedures were examined for altered transcriptional control of myosin heavy chains (MHCs). beta-MHC protein content increased (15 +/- 2%) vs. shams (3.8 +/- 2%; P = 0.004). Dot blots of LV RNA showed a corresponding increase in beta-MHC transcripts in banded animals (15.8 +/- 2%) vs. controls (5.7 +/- 2%; P = 0.012). Contractile performance was assessed using enzymatically disaggregated isolated LV myocytes paced at 0.5 Hz. There was no difference in percentage myocyte shortening between banded (8.6 +/- 0.5%) and control (9.1 +/- 0.5%) animals. However, maximal velocity of contraction was depressed after aortic banding (129 +/- 11 vs. 233 +/- 28 microns/s; P = 0.007), as was velocity of relaxation (105 +/- 11 vs. 188 +/- 22 microns/s; P = 0.007). These results suggest that depressed myocyte contractility after induction of pressure-overload hypertrophy in aortic-banded mice may be, in part, a consequence of transcriptional upregulation of the beta-MHC.
Contrasting effects of propionate and propionyl-L-carnitine on energy-linked processes in ischemic hearts
Authors: Di Lisa F. , Menabo R. , Barbato R. , Siliprandi N.
Published: December 2017

Propionyl-L-carnitine, unlike L-carnitine, is known to improve myocardial function and metabolism altered during the course of ischemia-reperfusion. In this study, the effect of propionyl-L-carnitine has been compared with that of propionate and carnitine on the performance of rat hearts perfused with a glucose-containing medium either under normoxia, ischemia, or postischemic reperfusion. In the postischemic phase, contractile parameters were partially restored both in the control and in the propionate plus carnitine-treated hearts, were markedly impaired by propionate, and were fully recovered by propionyl-L-carnitine. In addition, propionyl-L-carnitine, but not propionate, reduced the functional decay of mitochondria prepared from the ischemic hearts. Even in normoxic conditions propionate, unlike propionyl-L-carnitine, caused a drastic reduction of free CoA and L-carnitine. The concomitant increase in lactate production and decrease in ATP content might be explained by the inhibition of pyruvate dehydrogenase caused by the accumulation of propionyl-CoA. Indeed, when pyruvate was the only oxidizable substrate, propionate induced a gradual decrease in developed pressure, which was largely prevented by L-carnitine. The protective effect of propionyl-L-carnitine may be a consequence of the anaplerotic utilization of propionate in the presence of an optimal amount of ATP and free L-carnitine.
Effect of increased whole blood viscosity on regional blood flows in chronically hypoxemic lambs
Authors: Dalinghaus M. , Knoester H. , Gratama J. W. , Van der Meer J. , Zijlstra W. G. , Kuipers J. R.
Published: December 2017

In chronic hypoxemia blood flow and oxygen supply to vital organs are maintained, but to nonvital organs they are decreased. We measured organ blood flows (microspheres) and whole blood viscosity in 10 chronically hypoxemic lambs, with an atrial septal defect and pulmonary stenosis, and in 8 control lambs. Vascular hindrance (resistance/viscosity) was calculated to determine to what extent the effect of increased blood viscosity on organ blood flow was compensated for by a decrease in vascular tone. Arterial oxygen saturation was decreased (68 +/- 10 vs. 91 +/- 3%, P < 0.001), and both hemoglobin concentration (145 +/- 10 vs. 109 +/- 9 g/l, P < 0.05) and blood viscosity (4.4 +/- 0.6 vs. 3.6 +/- 0.6 mPa.s, P < 0.05) were increased in hypoxemic lambs. Systemic blood flow, oxygen supply, oxygen uptake, and blood pressures were not significantly different between hypoxemic and control lambs. Myocardial and cerebral blood flow was maintained in hypoxemic lambs, whereas renal, gastrointestinal, splenic, and thyroidal blood flows were at least 30% lower. Vascular hindrance was significantly decreased in the myocardium and tended to be lower in the brain of hypoxemic lambs, but in all other organs it was similar to that in control lambs. It is concluded that blood flow is redistributed in chronic hypoxemia in lambs; myocardial and cerebral blood flow is maintained, whereas blood flow to splanchnic organs, the kidneys, and the thyroids is decreased. The decreased blood flow to organs is a consequence of the increased whole blood viscosity.
Effects of acidosis on Na+/Ca2+ exchange and consequences for relaxation in guinea pig cardiac myocytes
Authors: Terracciano C. M. , MacLeod K. T.
Published: December 2017

We investigated the effect of intracellular acidosis (imposed by NH4Cl prepulses) on the relaxation and decline in intracellular Ca2+ (using indo 1 fluorescence) of isolated cardiac myocytes from the guinea pig. Acidosis produced a decrease in contraction and a prolongation of the fluorescence transient. The rate of decline in fluorescence after a rapid-cooling contracture was slower in acidosis compared with control. The decline in fluorescence after a rapid-cooling contracture in the presence of 10 mM caffeine was greatly slowed during acidosis, suggesting that Na+/Ca2+ exchange is affected. We recorded indo 1 fluorescence and the transient inward current in voltage-clamped cells on rapid application of 10 mM caffeine under control conditions and in acidosis. The amplitude of the transient increase in fluorescence was reduced in acidosis and the decline in fluorescence slowed. The current showed no difference in amplitude in acidosis, but the time to 50% recovery was increased by 57%. When amiloride or ethylisopropylamiloride was present, no differences in the current were found between control and acidosis, and the times to 50% recovery were similar. We conclude that intracellular acidosis slows Ca2+ efflux via Na+/Ca2+ exchange because of an increase in intracellular Na+ due to enhanced Na+/H+ exchange activity.
Segmental heterogeneity of NO-mediated pulmonary vasodilation in rats
Authors: Eichinger M. R. , Walker B. R.
Published: December 2017

Nitric oxide (NO) is known to elicit vasodilation in the preconstricted rat lung. However, the sites of dilation within the pulmonary vasculature remain unknown. We hypothesized that donated NO would dilate all areas of constriction within the pulmonary vasculature, whereas receptor-mediated, NO-induced dilations would correspond to regional binding of agents. Isolated lungs from male Sprague-Dawley rats were perfused at constant flow with physiological saline solution. Pulmonary arterial and pulmonary venous pressures were monitored, while pulmonary microvascular pressures were estimated by vascular occlusion. Lungs were constricted with U-46619, and upon development of a stable degree of vasoconstriction, the NO donor sodium nitroprusside or the endothelium-dependent dilators A23187, arginine vasopressin, or ATP were administered. U-46619 caused constriction of both arterial and venous segments. Administration of sodium nitroprusside and the calcium ionophore A23187 elicited similar dilation of preconstricted arterial and venous segments. Arginine vasopressin significantly dilated both arterial and venous segments, with a greater reversal of venous resistance. In contrast, ATP significantly reduced arterial resistance more than venous. These results demonstrate that donated NO uniformly dilates all constricted regions of the pulmonary vasculature. However, receptor-mediated, endothelium-dependent dilators display characteristic heterogeneities in the sites of decreased pulmonary vascular resistance.
Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts
Authors: Allard M. F. , Schonekess B. O. , Henning S. L. , English D. R. , Lopaschuk G. D.
Published: December 2017

The contribution of glycolysis and oxidative metabolism to ATP production was determined in isolated working hypertrophied hearts perfused with Krebs-Henseleit buffer containing 3% albumin, 0.4 mM palmitate, 0.5 mM lactate, and 11 mM glucose. Glycolysis and glucose oxidation were directly measured by perfusing hearts with [5–3H/U-14C]glucose and by measuring 3H2O and 14CO2 production, respectively. Palmitate and lactate oxidation were determined by simultaneous measurement of 3H2O and 14CO2 in hearts perfused with [9,10–3H]palmitate and [U-14C]lactate. At low workloads (60 mmHg aortic after-load), rates of palmitate oxidation were 47% lower in hypertrophied hearts than in control hearts, but palmitate oxidation remained the primary energy source in both groups, accounting for 55 and 69% of total ATP production, respectively. The contribution of glycolysis to ATP production was significantly higher in hypertrophied hearts (19%) than in control hearts (7%), whereas that of glucose and lactate oxidation did not differ between groups. During conditions of high work (120 mmHg aortic afterload), the extra ATP production required for mechanical function was obtained primarily from an increase in the oxidation of glucose and lactate in both groups. The contribution of palmitate oxidation to overall ATP production decreased in hypertrophied and control hearts (to 40 and 55% of overall ATP production, respectively) and was no longer significantly depressed in hypertrophied hearts. Glycolysis, on the other hand, was accelerated in control hearts to rates seen in the hypertrophied hearts. Thus a reduced contribution of fatty acid oxidation to energy production in hypertrophied rat hearts is accompanied by a compensatory increase in glycolysis during low work conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in dogs. II. Vagal afferent traffic
Authors: Hurt C. M. , Wang L. , Xu J. , Sterious W. , Pelleg A.
Published: December 2017

Extracellular ATP can act on chemosensitive vagal C-fiber nerve terminals in the lungs, thereby eliciting a pulmonary-cardiac depressor reflex. Previous studies have shown a right vagal dominance in afferent traffic elicited by intra-right atrial ATP. To elucidate the mechanism of this phenomenon, the following hypotheses were tested in a canine model. 1) Intra-right and intra-left pulmonary ATP elicit neural afferent traffic, which travels via the right and left vagus nerves, respectively. 2) Intra-right vs. intra-left pulmonary ATP causes similar suppression of sinus node automaticity. Data obtained in this study support both hypotheses and suggest that right vagal dominance in afferent neural traffic elicited by ATP is probably due to the action of ATP and/or its metabolites on nonpulmonary tissues.
Thyroid hormone effects on intracellular calcium and inotropic responses of rat ventricular myocardium
Authors: Bing O. H. , Hague N. L. , Perreault C. L. , Conrad C. H. , Brooks W. W. , Sen S. , Morgan J. P.
Published: December 2017

To examine the mechanisms by which thyroid hormone modulates the inotropic state of rat myocardium, we studied the effects of thyroid state on isolated rat left ventricular papillary muscle function and intracellular calcium transients in the baseline state and in response to calcium and isoproterenol. Marked differences in contractile state of papillary muscles from hypothyroid and thyroid hormone-treated rats seen under baseline conditions (1.0 mM bath calcium, 30 degrees C, stimulation rate 12/min) do not appear to be due to differences in intracellular calcium concentration ([Ca2+]i) or to changes in myofilament calcium sensitivity but correlate with shifts in myosin isozyme distribution. In response to superimposed inotropic interventions (calcium, 0.625-5.0 mM, or isoproterenol, 10(-8)-10(-6) M), myocardial thyroid state modulates peak [Ca2+]i and inotropy, both of which are increased in thyroid hormone-treated relative to hypothyroid myocardium. The change in inotropy appears to be proportional to peak [Ca2+]i, whether mediated directly by calcium or as a result of beta-adrenergic stimulation. Thus, whereas baseline differences between hypothyroid and thyroid hormone-treated myocardium appear to be due to differences in myosin isozymes and presumed changes in adenosinetriphosphatase activity and cross-bridge cycling, superimposed inotropic responses appear to be mediated by changes in [Ca2+]i.
Microvascular volume changes induced by exercise, heat exposure, or endotoxin injection
Authors: Lee J. S.
Published: December 2017

The microcirculation as a blood reservoir for volume compensation and the microvascular volume change (MVC) as a means of blood volume regulation are investigated. The density equations of LaForte et al. [Am. J. Physiol. 262 (Heart Circ. Physiol. 31): H190-H199, 1992] are modified to assess the MVC and volume of fluid restitution from changes in systemic hematocrit and plasma protein concentration induced by maximal exercise. It is estimated that exercise causes an MVC that is 5.6% of total blood volume (Vb) to counter the effect of plasma volume loss at 9.4% of Vb. A similar analysis of the result for 120 min of heat exposure indicates that the plasma volume decreases by 8.1% of Vb while the microcirculation constricts to produce an MVC that is 7.9% of Vb, with a net result of insignificant change in the macrovascular volume. Analysis of endotoxin injection to splenectomized dogs indicates that the microvascular dilation and plasma volume decrease combine to decrease the macrovascular volume by 31%, which may lead to the endotoxin shock. I conclude from these findings and the results of lower body negative pressure suction and cyclic hemorrhage that MVC could alter macrovascular filling to change cardiovascular function. It is also shown that the use of systemic hematocrit change as the sole determinant of plasma volume change could be erroneous.
Baroreflexes influence autoregulation of cerebral blood flow during hypertension
Authors: Talman W. T. , Dragon D. N. , Ohta H.
Published: December 2017

Cerebral blood flow (CBF) is autoregulated at mean arterial pressures (MAP) ranging from approximately 50 to 150 mmHg. When MAP exceeds the upper limit, autoregulation breaks through, vasodilatation occurs, and CBF increases rapidly. Earlier studies have shown that the arterial baroreflex does not influence autoregulation. However, CBF may rise to a lesser degree during abrupt hypertension immediately after interruption of the baroreceptor reflex than it would at comparable levels of blood pressure in intact animals. Generally this shift of the breakthrough point has been attributed to an increase in sympathetic nerve activity immediately after sinoaortic denervation. We hypothesized that denervation of arterial baroreceptors would blunt vasodilatation during slow controlled increases of arterial pressure, and we sought to determine whether sympathetic nerves contributed to regulation of CBF during hypertension in baroreceptor-denervated animals. Thirty-eight rats were studied to determine whether sinoaortic denervation affected autoregulation or breakthrough during acute hypertension. In five intact rats, when arterial pressure was raised by phenylephrine to 155 +/- 4 mmHg, cerebrovascular resistance fell by 60% and CBF increased by 434%. After interruption of the baroreflex in six rats, such dramatic increases in CBF with breakthrough did not occur despite greater increases in MAP (to 185 +/- 2 mmHg). Similar results were obtained when arterial pressure was raised by infusion of arginine vasopressin in four intact and three denervated rats. The effects of baroreceptor reflex interruption were not significantly affected by bilateral removal of the superior cervical ganglia. Rates of rise of MAP and increases of pulse pressure were equivalent between groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Testosterone increases thromboxane A2 receptor density and responsiveness in rat aortas and platelets
Authors: Matsuda K. , Ruff A. , Morinelli T. A. , Mathur R. S. , Halushka P. V.
Published: December 2017

Testosterone has been implicated as a risk factor for cardiovascular diseases. Thromboxane (Tx) A2 is an important pathophysiological mediator for thrombotic vascular diseases. This study investigated the effects of testosterone on platelet and vascular TxA2 receptors. Male rats were treated with either testosterone cypionate for 2 wk, sham operated, castrated, or castrated and treated with testosterone cypionate for 2 wk. Treatment of intact rats with testosterone significantly (P < 0.001) increased the TxA2 receptor density in platelets from 25.4 +/- 3.2 to 42.9 +/- 4.2 fmol/mg protein (P < 0.005, n = 17) and in aortic membranes from 48.7 +/- 1.7 to 86.1 +/- 6.1 fmol/mg protein, n = 9. The threshold concentration of the TxA2 mimetic, [1S-(1 alpha, 2 beta(5Z),3 alpha(1E,3R*)4 alpha)]-7-[3-(3-hydroxy-4- (4'-iodophenoxy)-1-butenyl)-7-oxabicyclo[2.21]heptan-2-yl]-5 -heptenoic acid (I-BOP), to induce platelet aggregation was significantly (P < 0.01) decreased from 0.45 +/- 0.16 nM, n = 7, in the control rats to 0.07 +/- 0.01 nM, n = 13, in the testosterone-treated rats. Testosterone treatment resulted in a significantly (P < 0.05) greater maximum aortic contractile response to the TxA2 mimetic, U-46619, compared with intact rats. Castration resulted in a significant (P < 0.01) decrease in aortic TxA2 receptor density from 51.7 +/- 3.7 to 27.3 +/- 5.3 fmol/mg protein, which was significantly reversed by testosterone treatment (89.2 +/- 7.1 fmol/mg protein; n = 4). Castration resulted in a significantly (P < 0.05) lower maximal aortic contractile response that was reversed by treatment with testosterone. Castration did not significantly change platelet TxA2 receptor density.(ABSTRACT TRUNCATED AT 250 WORDS)
Ca-dependent facilitation of cardiac Ca current is due to Ca-calmodulin-dependent protein kinase
Authors: Yuan W. , Bers D. M.
Published: December 2017

Repetitive membrane potential (Em) depolarization from -90 to 0 mV in rabbit and ferret ventricular myocytes induces a facilitation or "staircase" of Ca current (ICa), which is Ca (not Em) dependent and takes several seconds to accumulate and dissipate. That is, ICa at the tenth pulse at 1-2 Hz exceeds that at the first pulse (I10 > I1). The ICa staircase was completely abolished by dialysis with either of two inhibitory peptides of Ca-calmodulin-dependent protein kinase (CaMKII) CaMKII(290-309) and CaMKII(273-302)], implicating this kinase. Inclusion of ATP gamma S in the patch pipette gradually increased ICa but also abolished the staircase implicating phosphorylation. KN-62, a nonpeptide CaMKII inhibitor, reversed the ICa staircase (I1 > I10). However, this effect of KN-62 was largely attributed to a slower recovery from inactivation and a gating shift to more negative Em (not seen with CaMKII peptides). Similar results were obtained with H-89 and staurosporine (inhibitors of adenosine 3',5'-cyclic monophosphate and phospholipid-/Ca-dependent protein kinase, respectively). The reversal of the ICa staircase with H-89 and KN-62 could be prevented by more negative interpulse Em or elevation of extracellular [Ca] (which could counteract changes in channel gating due to a reduction in internal negative surface potential). That is, these kinase inhibitors might decrease phosphorylation at the inner membrane surface. In approximately 30% of the cells studied with H-89 and staurosporine the characteristic kinetic difference in ICa inactivation (faster at I1 than I10) was also diminished. This might be due to a relatively nonspecific inhibition of the same protein kinase inhibited by the CaMKII peptides. We conclude that the Ca-dependent ICa facilitation is due to activation of CaMKII and phosphorylation of a site on or near the Ca channel. KN-62, H-89, and staurosporine shifted ICa gating to more negative potentials and slowed recovery from inactivation, effects that could be due to reduction in phosphorylation at the inner membrane surface. Thus the reversal of the ICa staircase by KN-62, H-89, and staurosporine may not be Ca channel specific.
Pressure-flow analysis of portal vein and hepatic artery interactions in porcine liver
Authors: Ayuse T. , Brienza N. , O'Donnell C. P. , Robotham J. L.
Published: December 2017

Interactions between the hepatic arterial and portal venous circulations were investigated in nine intact and eight isolated perfused porcine livers. Pressure-flow (P-Q) relationships were obtained in either the portal vein or hepatic artery with constant baseline or low flow in the other bed and a stable hepatic venous pressure (Phv). The slope was obtained by linear regression analysis of the P-Q relationship, and effective back pressure (Pback) was obtained from the pressure intercept for the portal vein and the measured zero-flow pressure for the hepatic artery. The Pback in the hepatic artery (13.4 +/- 1.5 mmHg) and the portal vein (4.6 +/- 0.3 mmHg) were higher than Phv (P < 0.05). Reducing portal vein flow (Qpv) produced an increase in hepatic artery flow (Qha) (P < 0.05) due only to a decrease in slope (P < 0.05). Decreasing Qha caused an identical change in Pback of the portal vein (P < 0.05) in the intact and isolated liver preparations. A change in Qpv alters the hepatic arterial resistance upstream from the site of a constant arterial Pback. Changes in total flow through the common sinusoidal compartment appear to alter the Pback of the portal vein via hydraulic mechanisms.
Metformin decreases plasma insulin levels and systolic blood pressure in spontaneously hypertensive rats
Authors: Verma S. , Bhanot S. , McNeill J. H.
Published: December 2017

To determine the relationship between hyperinsulinemia and hypertension in spontaneously hypertensive rats (SHR), the antihyperglycemic agent metformin was administered to SHR and their Wistar-Kyoto (WKY) controls, and its effects on plasma insulin levels and blood pressure were examined. Five-week-old rats were started on oral metformin treatment (350 mg.kg-1.day-1, which was gradually increased to 500 mg.kg-1.day-1 over a 2-wk period). Metformin treatment caused sustained decreases in plasma insulin levels in the SHR (27.1 +/- 2.3 vs. untreated SHR 53.5 +/- 2.7 microU/ml, P < 0.001) without having any effect in the WKY (30.7 +/- 2.2 vs. untreated WKY 37.8 +/- 1.6 microU/ml, P > 0.05). The treatment did not affect the plasma glucose levels in any group. Metformin treatment also attenuated the increase in systolic blood pressure in the SHR (157 +/- 6.0 vs. untreated SHR 196 +/- 9.0 mmHg, P < 0.001) but had no effect in the WKY (134 +/- 3 vs. untreated WKY 136 +/- 4 mmHg, P > 0.05). Furthermore, raising plasma insulin levels in the metformin-treated SHR to levels that existed in the untreated SHR reversed the effect of metformin on blood pressure (189 +/- 3 vs. untreated SHR 208 +/- 5.0 mmHg, P > 0.05). These findings suggest that either hyperinsulinemia may contribute toward the increase in blood pressure in the SHR or that the underlying mechanism is closely associated with the expression of both these disorders.
Regional changes in myocyte structure in model of canine right atrial hypertrophy
Authors: Dolber P. C. , Bauman R. P. , Rembert J. C. , Greenfield J. C.
Published: December 2017

To investigate regional variation of myocyte response to atrial hypertrophy, control dogs were compared with dogs with right atrial hypertrophy created by induction of tricuspid regurgitation; after 1 yr, right atrial-to-body weight ratio increased 122% over controls. One section from the interatrial band, appendage and nonappendage roofs, and nonappendage side of each atrium of each dog was stained to reveal myocyte outlines and transverse tubules; myocyte cross-sectional areas were measured and transverse tubule prevalence was estimated. In control dogs, interatrial band myocytes were significantly larger and had more transverse tubules than other atrial myocytes. With atrial hypertrophy, right interatrial band myocytes did not increase significantly in size, whereas other right atrial myocytes nearly doubled in size, approaching the size of interatrial band myocytes without approaching the content of transverse tubules. Left atrial myocytes did not increase in size. Thus hypertrophic response of atrial myocytes to hemodynamic stress depends on the region in which the myocytes are found, and atrial hypertrophy does not demand transverse tubule proliferation.
Role of rostral ventrolateral medulla in centrally mediated pressor responses
Authors: Kiely J. M. , Gordon F. J.
Published: December 2017

The region of the rostral ventrolateral medulla (RVLM) plays an important role in central nervous system regulation of cardiovascular function. The initial purpose of these studies was to determine whether synaptic activation of excitatory amino acid (EAA) receptors in the RVLM might mediate central pressor responses. Blockade of EAA receptors in the RVLM with kynurenic acid abolished pressor responses evoked by stimulation of sciatic nerve afferents but had no effect on increases in arterial pressure produced by stimulation of hypothalamic sites. To determine whether synaptic transmission in the RVLM, independent of EAA receptor activation, was a prerequisite for the production of hypothalamic pressor responses, axonal conduction and/or synaptic transmission were pharmacologically interrupted in the RVLM. Blockade of synaptic transmission with muscimol or kainic acid attenuated, but did not eliminate, hypothalamic pressor responses. Concurrent blockade of synaptic and axonal transmission in the RVLM with lidocaine produced the greatest reduction of hypothalamic pressor responses. Collectively, these results suggest that central pressor responses are not uniformly mediated by synaptic activation of neurons within the RVLM. Instead, a combination of synaptic transmission and axonal conduction within and possibly outside the region of the RVLM may be required for the production of many centrally mediated pressor responses.
Mechanisms mediating responsiveness to beta-adrenergic stimulation after coronary reperfusion in conscious dogs
Authors: Kiuchi K. , Shen Y. T. , Vatner S. F. , Vatner D. E.
Published: December 2017

The goal of this study was to assess beta-adrenergic receptor (beta-AR) signaling mechanisms in mediating physiological responses to sympathomimetic amines after 45 min coronary artery occlusion followed by 45 min reperfusion. At this time, isoproterenol (Iso) infusion (0.1 microgram/kg-1.min-1, n = 5) increased percent wall thickening in previously ischemic subendocardium (Endo) more than in nonischemic Endo (12.6 +/- 1.2 vs. 7.2 +/- 0.6%, P < 0.05), whereas forskolin (25 nmol.kg-1.min-1, n = 6) elicited the opposite effect (3.6 +/- 0.6 vs. 10.4 +/- 2.8%, P < 0.05). During Iso and forskolin infusions increases in regional myocardial blood flow in the previously ischemic zone were similar to the nonischemic zone. In all groups, total beta-AR density was depressed in previously ischemic Endo compared with nonischemic Endo (65 +/- 7 vs. 82 +/- 8 fmol/mg, P < 0.05), but the fraction of beta-AR binding agonist with high affinity increased (82 +/- 4 vs. 49 +/- 1%, P < 0.05). The changes in beta-AR were associated with a decrease in Iso-stimulated adenylyl cyclase (22 +/- 8%), a decrease in guanosine 5'-triphosphate (GTP)-stimulatory protein (Gs) (23 +/- 6%), and a decrease in inhibitory G proteins (16 +/- 4%). However, regional Endo functional responsiveness to beta-AR stimulation was enhanced in reperfused myocardium in response to Iso but not to forskolin. Thus the mechanism of increased number of beta-AR binding agonist with high affinity in previously ischemic myocardium predominated over persistent downregulation of total beta-AR density and reductions in Gs and adenylyl cyclase activity and correlated best with the physiological response to beta-AR stimulation. These data may also suggest that Iso exerts an action distal to adenylyl cyclase in previously ischemic myocardium.
Tension production and thin-filament protein isoforms in developing rat myocardium
Authors: Reiser P. J. , Westfall M. V. , Schiaffino S. , Solaro R. J.
Published: December 2017

The calcium sensitivity of tension production and the expression of troponin I (TnI) and troponin T (TnT) isoforms in skinned neonatal (7 days after birth) and adult rat myocardium were determined. Isometric tension was measured after activation at a known resting sarcomere length in ventricular trabeculae at adult and, for the first time, neonatal ages. Analysis of the tension-pCa relationships indicates a greater calcium sensitivity (approximately 0.3 pCa units) in neonatal ventricular trabeculae compared with adult trabeculae. The maximal isometric tension-generating ability (i.e., tension-tissue cross-sectional area) is threefold greater in adult compared with neonatal trabeculae. Developmental transitions in TnI and TnT isoform expression in atrial and ventricular tissue were examined simultaneously and were found to be dissimilar. Shifts in the expression of TnT isoforms precede shifts in TnI isoforms in ventricular tissue. The opposite pattern occurs in atrial tissue, with shifts in TnI preceding those in TnT. The results show that the greater calcium sensitivity of neonatal compared with adult rat ventricular tissue is associated with developmental changes in both TnT and TnI isoform expressions. These isoform expression patterns may facilitate myocardial tension production at the neonatal stage, when the tension-generating ability of individual trabeculae is much lower than that in the adult.
L-type calcium current in rod- and spindle-shaped myocytes isolated from rabbit atrioventricular node
Authors: Hancox J. C. , Levi A. J.
Published: December 2017

The atrioventricular node (AVN) is vital to normal cardiac function. The present report describes the properties of L-type calcium current (ICa) in rod- and spindle-shaped myocytes isolated from the rabbit AVN. With depolarizing voltage clamps from a holding potential of -40 mV, a rapidly activating ICa was observed, which peaked at +10 mV in most cells and exhibited a “bell-shaped” current-voltage relation. ICa was abolished by nifedipine (2–20 microM) and cadmium (100–200 microM) and was greatly reduced by manganese (1 mM). At +10 mV, time to peak ICa was 3.3 +/- 0.15 (SE) ms (n = 12) and ICa current density was 9.3 +/- 1.2 pA/pF (n = 9). Steady-state activation and inactivation curves for ICa showed half-maximal activation at -3.6 mV [slope factor (k) = 6.6 mV] and half-maximal inactivation at -25.8 mV (k = 6.5 mV). The time course of decay of ICa during a depolarizing pulse was voltage dependent and biexponential. The time course of recovery of ICa from inactivation was also biexponential (with two time constants tau 1 = 194.7 and tau 2 = 907.4 ms). Under current clamp, spontaneous action potentials from AVN cells were blocked by nifedipine as well as by cadmium, suggesting that L-type ICa was largely responsible for the action potential upstroke.
Hypoxic reperfusion after ischemia in swine does not improve acute brain recovery
Authors: Ulatowski J. A. , Kirsch J. R. , Traystman R. J.
Published: December 2017

We tested the hypothesis that transient hypoxic reperfusion after 15 min of global cerebral ischemia would improve acute recovery of electrical function. We also determined the changes in cerebral blood flow (CBF) and cerebral oxygen consumption (CMRO2) during transient hypoxic reperfusion. Pentobarbital-anesthetized pigs were exposed to cerebral ischemia by raising intracranial pressure to 100 mmHg above arterial pressure with rapid infusion of artificial cerebral spinal fluid into a lateral ventricle. During the reperfusion period, normoxia was maintained at an arterial oxygen partial pressure (PaO2) of 80–120 mmHg for 120 min of reperfusion and hypoxia at a PaO2 of 35–45 mmHg for the first 30 min of reperfusion in another group. The postischemic hypoxia group showed persistent elevation in microsphere-determined CBF at 30 min of reperfusion in all brain regions and lack of delayed hypoperfusion through 120 min of reperfusion. The normoxic group demonstrated transient postischemic hyperemia and hypoperfusion. CMRO2 was not significantly different between groups at any time point. In both groups, the somatosensory-evoked potential amplitude reached only 10% recovery by the end of 120 min of reperfusion. We conclude that hypoxemia during reperfusion after cerebral ischemia in this model does not improve acute brain electrical function and prolongs postischemic hyperemia.
Hemorrhagic hypotension induces arteriolar vasomotion and intermittent capillary perfusion in rat pancreas
Authors: Vollmar B. , Preissler G. , Menger M. D.
Published: December 2017

Hemorrhage-induced intermittent capillary perfusion and its relation to arteriolar vasomotion was studied in rat pancreatic acinar tissue using intravital fluorescence microscopy. During prehemorrhage conditions, microscopic analysis of the pancreatic microcirculation displayed neither arteriolar vasomotion nor intermittency of capillary perfusion (n = 22 animals). Hemorrhage-induced hypotension of 40 mmHg provoked arteriolar vasomotion in 18 of 22 animals and 59 of 115 arterioles studied. The maximum relative amplitude of arteriolar vasomotion was 44 +/- 8% (range 12–81%), and vasomotion frequency averaged 4.73 +/- 0.11 cycles/min. Hemorrhagic hypotension was further accompanied by 1) a decrease of functional capillary density [length of red blood cell-perfused capillaries per area of tissue under investigation (cm/cm2)] from 515 +/- 3 cm-1 at baseline to 386 +/- 3 cm-1 (P < 0.05) and 2) the instantaneous occurrence of intermittency of capillary perfusion in all observation areas (N = 220) of the 22 animals studied. The frequency of intermittency of capillary perfusion (4.72 +/- 0.14 cycles/min) did not differ from the frequency of arteriolar vasomotion, which implies a causal relationship between these two hemorrhage-induced microvascular mechanisms with the probable aim to counteract the decrease of functional capillary density.
Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart
Authors: Hashimoto E. , Ogita T. , Nakaoka T. , Matsuoka R. , Takao A. , Kira Y.
Published: December 2017

Vascular endothelial growth factor (VEGF or vascular permeability factor), a direct-acting, endothelial cell-specific mitogen, has been suggested to be involved in development and maintenance of vasculatures in tumor neovascularization and in normal tissues. To investigate possible roles of VEGF in ischemic hearts, we studied induction of VEGF mRNA by ischemia and hypoxia using coronary artery-ligated hearts in vivo and perfused hearts and cultured myocardial cells in vitro. VEGF mRNA was potently induced by ischemia in the heart in vivo. In perfused hearts, maximum expression was rapidly induced (within 30 min) by transient reversible ischemia (5–10 min of ischemia) and lasted at least 3 h. Induction was also caused by hypoxia, which was confirmed in perfused hearts and cultured myocardial cells. These results suggest that induction of VEGF mRNA is upregulated by oxygen deprivation in the heart and that not only infarction but also chronic ischemia in the clinical setting could induce VEGF as a potent angiogenesis factor to stimulate coronary collateral formation.
Effects of cardiac glycosides on myocardial function and energetics in conscious dogs
Authors: Lucke J. C. , Elbeery J. R. , Koutlas T. C. , Gall S. A. , D'Amico T. A. , Maier G. W. , Rankin J. S. , Glower D. D.
Published: December 2017

The physiological effects of intravenous ouabain on left ventricular (LV) systolic function and metabolic-to-mechanical energy transfer were examined in eight conscious dogs. LV pressure and volume were measured using micromanometers and ultrasonic dimension transducers during transient vena caval occlusions under control conditions and after increasing doses of ouabain. Doppler coronary flow and coronary sinus O2 saturations were used to determine arterial-to-coronary sinus O2 content difference and thereby to calculate LV O2 consumption; total mechanical energy was computed as the sum of LV stroke work and the product of end-diastolic volume and LV mean ejection pressure, neglecting LV unstressed cavitary volume. The slope (10(4) erg/ml) of the stroke work vs. end-diastolic volume relationship increased progressively with rising doses of ouabain from 7.0 +/- 1.6 at control to 9.6 +/- 1.7 after ouabain 0.75 mg (P = 0.0002). Regression analysis of LV O2 consumption (mW/cm3) vs. total mechanical energy (mW/cm3) yielded a linear relationship that did not change with 0.75 mg of ouabain (P > 0.4). These data indicate that ouabain possesses a significant positive inotropic effect on the intact left ventricle without a change in energy transfer efficiency or O2 wasting.
In vivo visualization of oxygen transport in microvascular network
Authors: Itoh T. , Yaegashi K. , Kosaka T. , Kinoshita T. , Morimoto T.
Published: December 2017

Oxygen transport from the blood to the tissues is a diffusive process driven by the gradient of oxygen tension (PO2). We developed an oxygen-quenching fluorescent membrane that allowed visualization of the PO2 distribution near the microvessels as optical patterns on the membrane by epifluorescence microscopy. This membrane was highly gas permeable to allow PO2 measurement and was transparent enough to also permit observation of the microcirculation. In combination with a newly devised gastight chamber and a micropositioning system, this membrane technique made it possible to visualize the PO2 distribution in the rat mesenteric microvascular network under well-defined conditions. Our preliminary findings indicate that the oxygen distribution in the microvascular network is heterogeneous and suggest that there is considerable release of oxygen from the arterioles. The time lag of the system for tracking rapid PO2 changes in vitro was shown to be negligible, indicating that dynamic PO2 changes occurring in vivo can also be assessed. This technique should provide a novel tool for the study of oxygen transport and metabolism under normal and abnormal conditions.
Capillary perfusion during ischemia-reperfusion in subcutaneous connective tissue and skin muscle
Authors: Friesenecker B. , Tsai A. G. , Instaglietta M.
Published: December 2017

Ischemia-reperfusion injury was investigated in terms of functional capillary density (FCD), capillary red blood cell velocity (cRBCv), and arteriolar and venular diameter after 4-h ischemia in the unanesthetized hamster skin-fold preparation. Animals in group 1 were studied by transillumination. Group 2 received a bolus injection of fluorescein isothiocyanate (FITC)-dextran (mol wt 150,000) and was studied by transillumination (zone 1) and epi-illumination (zone 2). In group 1, FCD decreased after ischemia (92% of baseline, 30 min), returning to control up to 24 h. cRBCv increased after reperfusion, being 175% of baseline at 24 h. Arterioles and venules dilated for 24 h after reperfusion. In group 2/zone 2, FCD progressively decreased to 11% of control, arteriolar dilation was inhibited, and cRBCv increased 30 min and 2 h after reperfusion. Tissue perfusion index (FCD x cRBCv) increased 158% in group 1 at 24 h, did not change in group 2/zone 1, and was 9% of control at 24 h in group 2/zone 2 (P < or = 0.05). We conclude that increased perfusion is a normal reaction to ischemia-reperfusion injury in this model, and previously observed capillary no reflow is due to FITC-dextran phototoxicity.
Chronic administration of angiotensin II receptor antagonist, TCV-116, in cardiomyopathic hamsters
Authors: Nakamura F. , Nagano M. , Kobayashi R. , Higaki J. , Mikami H. , Kawaguchi N. , Onishi S. , Ogihara T.
Published: December 2017

We examined whether specific blockade of the renin-angiotensin system is beneficial for the treatment of cardiac dysfunction in heart failure. The angiotensin II type-1 (AT1) receptor antagonist TCV-116 (10 mg.kg-1.day-1) or its vehicle was given orally to UM-X 7.1 cardiomyopathic (CM) and normal Golden Syrian (GS) hamsters for 8 wk. Plasma and cardiac angiotensin II levels were significantly higher in CM than in GS hamsters. The CM heart showed a smaller response of left ventricular (LV) pressure and first derivative of maximal LV pressure (+dP/dtmax) to the elevation of perfusion pressure (from 60 to 120 cmH2O) in Langendorff-perfused than in GS heart. Treatment with TCV-116 did not affect LV function in GS but significantly improved cardiac contractility in CM hamsters. These results suggest that the renin-angiotensin system plays an important role in the development of cardiac dysfunction due to cardiomyopathy. Blockade of this system by the AT1 antagonist TCV-116 appears to be useful in the prevention of heart failure.
Positive inotropic effect of Streptococcus faecalis in isolated cardiac muscle
Authors: Schoemaker I. E. , Sys S. U. , Andries L. J. , Meyers J. M. , Pattyn S. R. , Brutsaert D. L.
Published: December 2017

Infective endocarditis is caused by bacterial colonization of the endocardium. Because endocardium modulates mechanical performance of subjacent myocardium, we studied acute effects of bacteria on isolated cardiac muscle and on the functional role of the endocardium. Bacteria, grown in broth at 37 degrees C, were added at increasing concentrations (10(2) to 10(6) bacteria/ml) to cat papillary muscles in Krebs-Ringer solution (1.25 mM Ca2+, 35 degrees C). The endocardial surface was damaged by exposing muscles to a stream of dry air for 30 s. Streptococcus (Enterococcus) faecalis induced significant increases in total peak isometric twitch tension (TT) and maximal velocity of unloaded shortening (Vmax) and significant decreases in time to TT (TtTT) and time to half isometric twitch tension decline (RT 1/2), both before and after removal of endocardial endothelium. This response could also be elicited with bacterial filtrate, after boiling the filtrate or after extracting the polysaccharides from it with KIO4. Increasing Ca2+ concentrations progressively reduced the response to the filtrate. Propranolol slightly, although not significantly, diminished the effects on TT and Vmax while abolishing the effects on TtTT and on RT 1/2. By contrast, Streptococcus bovis and Staphylococcus aureus did not affect TT or Vmax but induced a slight but significant decrease in TtTT at the highest concentration of bacteria. Accordingly, the filtrate of Strep. faecalis induces a positive inotropic effect. The active component is neither a protein nor a polysaccharide, and its effect may be partly beta-adrenoceptor mediated. Strep. bovis and Staph. aureus have negligible acute effects on contractility.
Asynchrony and ryanodine modulate load-dependent relaxation in the canine left ventricle
Authors: Lew W. Y.
Published: December 2017

Load-dependent relaxation was studied in six anesthetized dogs by inflating an intra-aortic balloon to increase peak left ventricular (LV) pressure by 1–20 mmHg within a single cardiac cycle. A series of timed and graded pressure loads was produced by inflating the balloon either during diastole (early loads) or midsystole (midsystolic pressure loads). The rate of LV pressure fall was measured with the time constant (tau). There was a significant increase in tau with 63 midsystolic pressure load [tau increased 1.4 +/- 0.1% (SE)/mmHg increase in peak LV pressure] but not with 67 early pressure loads (-0.5 +/- 0.1%/mmHg). This difference remained with LV pacing-induced asynchrony (tau increased 1.8 +/- 0.1%/mmHg with 54 midsystolic pressure loads compared with -0.2 +/- 0.1%/mmHg with 56 early pressure loads) and after 5 micrograms/kg of intravenous ryanodine (tau increased 1.0 +/- 0.2%/mmHg with 58 midsystolic pressure loads compared with -0.7 +/- 0.1%/mmHg with 59 early pressure loads). When compared with control, asynchrony significantly augmented and ryanodine significantly attenuated the effects of midsystolic pressure loads. In conclusion, asynchrony and ryanodine modulate the extent of load-dependent relaxation in the intact left ventricle.
Adenosine analogues prevent phorbol ester-induced PKC depletion in porcine coronary artery via A1 receptor
Authors: Marala R. B. , Mustafa S. J.
Published: December 2017

This study was undertaken to determine the adenosine receptor involved in the modulation of protein kinase C (PKC) in porcine coronary artery. Endothelium-denuded arterial rings were incubated with phorbol 12,13-dibutyrate (PDBu) in the presence or absence of adenosine receptor agonists and antagonists for 24 h. After incubation, contractile responses to endothelin-1 (ET-1) were compared in various treatment groups. Arterial rings incubated with PDBu alone failed to produce significant contractions in response to ET-1. (2s)-N6-[2-endo-norbornyl]adenosine (ENBA), an A1-receptor agonist, attenuated the PDBu-induced blunting of the ET-1 contractions. Incubation with ENBA alone elevated ET-1 contractility by about twofold. Inclusion of A1-receptor antagonists completely blocked both effects of ENBA: protection against PDBu and increase in ET-1 contractility. On the contrary, arterial rings incubated with the A2-receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine (CGS-21680) did not show significant alteration of the ET-1 contractility when incubated with CGS-21680 alone or in combination with PDBu. Inclusion of A2-receptor antagonist in combination with CGS-21680 mimicked the effects of ENBA alone, i.e., protected against PDBu and enhanced ET-1 contractions. Measurement of PKC activities in arteries indicated that exposure to ENBA caused a twofold increase in the enzyme activity, whereas exposure to CGS-21680 had no significant effect on PKC activity. Adenosine analogues caused an accumulation of PKC through the activation of A1- but not A2-adenosine receptors. These results indicate that the modulation of PKC by adenosine analogues is mediated through A1-adenosine receptors in the coronary artery.