bluuebunny/crossref_metadata_2025 huggingface dataset:
Adenosine release by the isolated guinea pig heart in response to isoproterenol, acetylcholine, and acidosis: the minimal role of vascular endothelium.
Authors: Bardenheuer H , Whelton B , Sparks H V
Published: June 2012

The objective of this study was to determine the contribution of endothelial cells to adenosine appearing in venous effluent of isolated perfused guinea pig hearts. The adenine nucleotide pool of endothelial cells was selectively labelled by infusing 3H-adenosine (5 X 10(-8) M) into the heart for 30 minutes. Selective labelling of the endothelial adenine nucleotides was confirmed by measuring the relative specific activities of the nucleotides of coronary endothelial cells (removed from the heart by enzyme treatment). Endothelial ATP, ADP, and AMP had relative specific activities that were 49, 25, and 7 times higher, respectively, than their nucleotide counterparts in total myocardial tissue. Isoproterenol increased the release of both total adenosine and radioactive adenosine, but the relative specific activity of venous adenosine decreased dramatically. Acetylcholine, at a concentration that caused no change in left ventricular pressure but caused a decrease in coronary vascular resistance, increased the release of total adenosine. However, both radioactive adenosine release and the relative specific activity of venous effluent adenosine were decreased with acetylcholine. Infusion of hydrochloric acid caused a sustained reduction in left ventricular pressure and coronary vascular resistance. Total adenosine release fell within one minute and remained reduced during HCl. Radioactive adenosine release was elevated at 15 seconds but fell below control values at 2 minutes and remained reduced during steady-state acidosis. We conclude that the majority of the adenosine released in response to isoproterenol and acetylcholine originates from an unlabelled compartment, most likely the myocytes. Acidosis results in decreased release of adenosine from both the labelled endothelium and the unlabelled cells in the heart.(ABSTRACT TRUNCATED AT 250 WORDS)
Stimulation of phosphatidylinositol metabolism in the isolated, perfused rat heart.
Authors: Woodcock E A , White L B , Smith A I , McLeod J K
Published: June 2012

Receptor-stimulated phosphatidylinositol turnover has been studied in isolated, perfused, [3H]inositol-labelled rat hearts by measuring accumulation of inositol phosphates in the presence of lithium chloride. Inositol phosphate accumulation was stimulated by norepinephrine (3 X 10(-5) M) and carbachol (10(-3) M), the increases averaging from 931 +/- 59 (n = 6, mean +/- SEM, cpm/g heart) to 4,165 +/- 609 (n = 6, p less than 0.01) for norepinephrine and to 1,853 +/- 354 (n = 6, p less than 0.05) for carbachol. The norepinephrine stimulation was antagonized by prazosin (10(-7) M) but not by propranolol (10(-7) M), indicating mediation via alpha 1-adrenoceptors. The carbachol stimulation was antagonized by atropine (10(-7) M). The stimulation by norepinephrine was significantly higher in right atria (837 +/- 151 to 6,614 +/- 1,210, n = 6, cpm/g tissue) than in other regions of the heart. Both norepinephrine and carbachol stimulated the formation of inositol monophosphate, inositol bisphosphate, and inositol trisphosphate with norepinephrine stimulation being detected as early as 15 seconds. Furthermore, the inositol trisphosphate was identified as the -1,4,5 isomer by anion exchange high-performance liquid chromatography. These data are consistent with the hydrolysis of phosphatidylinositol-(4,5)-bisphosphate yielding inositol-(1,4,5)-trisphosphate. Inositol-(1,3,4)-trisphosphate was not detected in heart preparations, suggesting unusual metabolism of inositol-(1,4,5)-trisphosphate in heart tissue.
Group B streptococcal sepsis in the piglet: effects of fluid therapy on venous return, organ edema, and organ blood flow.
Authors: Bressack M A , Morton N S , Hortop J
Published: June 2012

We investigated the physiologic effects of normal saline versus 5% albuminated saline fluid resuscitation on 10-12-day-old piglets infected with group B streptococci for four hours. After intravenously receiving 1 X 10(10) bacteria/kg over 45 minutes, one group was untreated while the two fluid-treated groups received enough intravenous fluid to maintain the baseline cardiac output. An increase in the resistance to venous blood return was the major limitation to cardiac output. The resistance nearly quadrupled in the untreated piglets as shown by a 50% decrease in cardiac output with a nearly doubling of the driving pressure for venous return (mean circulatory pressure was normal and atrial pressures decreased by 70%). In both fluid-treated groups, resistance doubled as shown by an unchanged cardiac output with a doubling of the driving pressure (mean circulatory pressure increased by 50%) and atrial pressures remained at baseline). Blood volume was 9% below control in the untreated group and 13% above control in both fluid-treated groups. Much more crystalloid (155 ml/kg) than colloid (58 ml/kg) was necessary to maintain baseline cardiac output; this resulted in a 36% decrease in the plasma protein oncotic pressure of the former group and a 15% increase in the oncotic pressure of the latter group. Organ edema formation (ileum, pancreas, kidney, adrenal gland, lung) occurred only in the saline-treated animals. We conclude that increased resistance to venous return was the primary cause of shock in our model and that this can be effectively treated by giving enough intravenous fluid to elevate the mean circulatory pressure. However, if the plasma protein oncotic pressure is also lowered (saline group), organ edema results.
Metaiodobenzylguanidine [131I] scintigraphy detects impaired myocardial sympathetic neuronal transport function of canine mechanical-overload heart failure.
Authors: Rabinovitch M A , Rose C P , Rouleau J L , Chartrand C , Wieland D M , Lepanto L , Legault F , Suissa S , Rosenthall L , Burgess J H
Published: June 2012

In heart failure secondary to chronic mechanical overload, cardiac sympathetic neurons demonstrate depressed catecholamine synthetic and transport function. To assess the potential of sympathetic neuronal imaging for detection of depressed transport function, serial scintigrams were acquired after the intravenous administration of metaiodobenzylguanidine [131I] to 13 normal dogs, 3 autotransplanted (denervated) dogs, 5 dogs with left ventricular failure, and 5 dogs with compensated left ventricular hypertrophy due to a surgical arteriovenous shunt. Nine dogs were killed at 14 hours postinjection for determination of metaiodobenzylguanidine [131I] and endogenous norepinephrine content in left atrium, left ventricle, liver, and spleen. By 4 hours postinjection, autotransplanted dogs had a 39% reduction in mean left ventricular tracer accumulation, reflecting an absent intraneuronal tracer pool. Failure dogs demonstrated an accelerated early mean left ventricular tracer efflux rate (26.0%/hour versus 13.7%/hour in normals), reflecting a disproportionately increased extraneuronal tracer pool. They also showed reduced late left ventricular and left atrial concentrations of tracer, consistent with a reduced intraneuronal tracer pool. By contrast, compensated hypertrophy dogs demonstrated a normal early mean left ventricular tracer efflux rate (16.4%/hour) and essentially normal late left ventricular and left atrial concentrations of tracer. Metaiodobenzylguanidine [131I] scintigraphic findings reflect the integrity of the cardiac sympathetic neuronal transport system in canine mechanical-overload heart failure. Metaiodobenzylguanidine [123I] scintigraphy should be explored as a means of early detection of mechanical-overload heart failure in patients.
Cytosolic calcium staircase in cultured myocardial cells.
Authors: Lee H C , Clusin W T
Published: June 2012

To elucidate the mechanism of the tension staircase, chick embryonic myocardial cell aggregates were loaded with the fluorescent cytosolic calcium indicator, indo 1. Fluctuations in indo 1 fluorescence were compared with recordings of cell edge movement during spontaneous beating and during stimulation by intracellular current pulses. Indo 1-loaded aggregates exhibit fluorescence transients during each transmembrane action potential. The rising phase of the transients is rapid, but the decaying phase is slow (several hundred msec) and is similar in time course to the pandiastolic relaxation seen in the optical recordings of cell edge movement. Acceleration of beat frequency by brief depolarizing current pulses produces an ascending staircase in both edge movement and systolic [Ca2+]i. There is a similar staircase in the diastolic [Ca2+]i, which is also reflected by diastolic cell edge movement. The existence of a diastolic [Ca2+]i staircase may provide new insight into the mechanism of the force-frequency relation in the heart.
Characterization of beta 1- and beta 2-adrenoceptor subtypes in the rat atrioventricular node by quantitative autoradiography.
Authors: Saito K , Kurihara M , Cruciani R , Potter W Z , Saavedra J M
Published: June 2012

We characterized beta-adrenoceptor subtypes in the atrioventricular node of the rat heart by quantitative autoradiography. Consecutive 16-microns-thick sections from single rat hearts containing the atrioventricular node were incubated with increasing concentrations of [125I]iodocyanopindolol. After exposure to [3H]Ultrofilm, optical densities corresponding to the atrioventricular node were determined by computerized densitometry after comparison with [125I]standards. The computer program LIGAND was used for analysis of receptor subtypes. Delineation of beta-adrenoceptor subtypes was achieved by incubating consecutive tissue sections with 50 pM [125I]iodocyanopindolol in the presence of increasing concentrations of the beta 1-selective antagonist atenolol or the beta 2-selective antagonist ICI 118,551. The atrioventricular node contains a higher concentration of beta-adrenoceptors than the adjacent interventricular septum. We estimated that the proportions of beta 1- and beta 2-adrenoceptors in the atrioventricular node were about 56% and 44% of the total binding capacity respectively.
Ventricular atrial natriuretic factor in the cardiomyopathic hamster model of congestive heart failure.
Authors: Franch H A , Dixon R A , Blaine E H , Siegl P K
Published: June 2012

Cardiac atria are thought to be the principle source of plasma atrial natriuretic factor (ANF), a potent natriuretic and diuretic peptide. Whether other ANF production sites are recruited in disease states exhibiting elevated plasma ANF levels is not known. Accordingly, in the cardiomyopathic hamster, an animal model of congestive heart failure with high circulating levels of ANF, contribution of ventricular tissue to total cardiac ANF production and storage was investigated. Measurements were made of immunoreactive ANF in plasma and in atrial and ventricular extracts as well as ANF mRNA levels in the atria and ventricles from normal and cardiomyopathic golden Syrian hamsters. Plasma ANF levels were higher in cardiomyopathic than in control animals. The atrial concentration of ANF (per milligram atrial weight) was 50% and 83% lower in moderate and severe congestive heart failure, respectively, when compared with controls, while atrial ANF mRNA content of cardiomyopathic hamsters was not significantly different from normal hamsters. The ventricular concentration of ANF was 3 times and 7 times higher in animals in moderate and severe heart failure when compared with controls. In severe heart failure, ventricular ANF accounted for 23% of total cardiac stores of ANF. Ventricular ANF mRNA levels were 7 times and 13 times higher in hamsters in moderate and severe heart failure as compared with control animals. Therefore, significant increases in both ANF content and ANF mRNA in ventricles of hamsters in moderate to severe heart failure suggest that the ventricle could be an important source of ANF in congestive heart failure.
In vivo effect of methylene blue on endothelium-dependent and endothelium-independent dilations of brain microvessels in mice.
Authors: Watanabe M , Rosenblum W I , Nelson G H
Published: June 2012

Arterioles on the surface of the mouse brain were observed by in vivo TV microscopy. Four dilators were topically applied to relax the vessels in vivo. Two of the dilators were acetylcholine and bradykinin, whose action in this vascular bed is dependent upon production of endothelium-dependent relaxing factors. The other two dilators were sodium nitroprusside and 8-bromo-cGMP, whose action is not endothelium dependent. The dilations by acetylcholine, bradykinin, and nitroprusside were significantly depressed by 10(-4) M methylene blue applied topically for 7 minutes prior to application of the dilators. The inhibitory effect was reversible, was greatest against acetylcholine, and was least against nitroprusside. These data parallel reports of methylene blue's action against these dilators when applied to large blood vessels in vitro. Our data appear to be the first microvascular data and the first in vivo data showing this effect. The data thus suggest that the mechanisms underlying dilation of cerebral arterioles and large extracerebral vessels are similar. The literature accounts for the effect of methylene blue on the basis of its action as an inhibitor of guanylate cyclase. Our data, including the failure of methylene blue to alter dilation by 8-bromo-cGMP, are in keeping with this hypothesis and with current beliefs that guanylate cyclase and cGMP have a central role in vasodilation. The data do not rule out the possibility that methylene blue has an additional action in the case of acetylcholine and inactivates the endothelium-dependent relaxing factor for that dilator.
Transmural differences in sympathetic coronary constriction during exercise in the presence of coronary stenosis.
Authors: Chilian W M , Ackell P H
Published: June 2012

The goal of this study was to determine the effect of sympathetic neural activation on the transmural distribution of myocardial perfusion distal to a flow-limiting coronary artery stenosis. Treadmill exercise in conscious dogs was used as a physiological stimulus to activate the sympathetic nervous system. In the experimental model, the anterior region of the circumflex artery was innervated, but the posterior circumflex region was treated with phenol to produce regional sympathectomy within the stenotic territory. Myocardial perfusion to innervated and sympathectomized left ventricular regions was measured before and after inflation of the occluder to reduce distal coronary pressure to 45 mm Hg. Measurements were obtained during control conditions with the animal standing on the treadmill, during inflation of the occluder with the animal standing, during exercise alone, during exercise with beta-adrenergic blockade, and during exercise with combined alpha- and beta-adrenergic blockade. Exercise (6 km/hr) resulted in a marked increase in heart rate from 128 +/- 9 (standing) to 218 +/- 7 beats/min. beta-Adrenergic blockade blunted the tachycardia during exercise (146 +/- 6 beats/min). Under control conditions (while standing), there were no differences in myocardial perfusion between the innervated and sympathectomized regions, 187 +/- 26 and 181 +/- 24 ml.min-1.100 g-1, respectively. During exercise or in combination with beta-adrenergic blockade, subepicardial perfusion was significantly less (18-25%) in the innervated stenotic region than that in the sympathectomized stenotic region. In contrast, subendocardial perfusion was significantly greater in the innervated stenotic region (17-26%) than that in the sympathectomized stenotic region. The subendocardial-to-subepicardial blood flow ratio during exercise was 0.60 +/- 0.08 in the innervated stenotic region and 0.42 +/- 0.07 in the sympathectomized stenotic region (p less than 0.05). During exercise with beta-adrenergic blockade, the endocardial-to-epicardial blood flow ratios in the innervated and sympathectomized stenotic regions were 0.47 +/- 0.09 and 0.37 +/- 0.07, respectively (p less than 0.05). These differences were abolished during alpha- and beta-adrenergic blockade. These data indicate that alpha-adrenergic coronary constriction distal to a flow-limiting stenosis facilitates redistribution of blood flow toward the subendocardium. This redistribution was produced by alpha-adrenergic constriction in the outer layers of the left ventricle.
Sodium-lithium exchange in sarcolemmal vesicles from canine superior mesenteric artery.
Authors: Kahn A M , Allen J C , Cragoe E J , Zimmer R , Shelat H
Published: June 2012

Exchange of intracellular sodium for extracellular lithium readily occurs in vascular smooth muscle, but the mechanism of this exchange is not known. These studies examined whether a sodium-lithium countertransport system was present in the cell membrane of vascular smooth muscle. A sarcolemmal-enriched vesicle preparation was obtained from canine superior mesenteric artery via a magnesium aggregation and differential centrifugation technique. An outwardly directed gradient for lithium stimulated 22Na uptake by the vesicles, and an inwardly directed gradient for lithium stimulated 22Na efflux. These effects were not due to an alteration in membrane potential, and sodium uptake was not stimulated by lithium in the absence of a gradient for lithium. The lithium gradient-stimulated component of sodium uptake was not affected by a change in membrane potential and was insensitive to ouabain. Both sodium-lithium exchange and sodium-proton exchange in sarcolemmal-enriched vesicles were inhibited by two compounds that inhibit the sodium-lithium countertransport system in red cells, phloretin and quinidine. Ethylisopropylamiloride also inhibited both sodium-lithium exchange and sodium-proton exchange in the vesicles. In support of the possibility that sarcolemmal sodium-lithium exchange and sodium-proton exchange are mediated by a single cation exchange mechanism with affinity for sodium, lithium, and protons, we found that an inwardly directed sodium or lithium gradient stimulated proton efflux, and that the stimulation of sodium efflux by external lithium or protons was not additive. It is concluded from these studies that sarcolemmal vesicles from canine superior mesenteric artery contain an electroneutral, phloretin, quinidine, and ethylisopropylamiloride inhibitable sodium-lithium exchange transport system.(ABSTRACT TRUNCATED AT 250 WORDS)
Vasoconstrictor effects of platelet-activating factor in the hamster cheek pouch microcirculation: dose-related relations and pathways of action.
Authors: Dillon P K , Ritter A B , Durán W N
Published: June 2012

Platelet-activating factor (PAF) has been implicated as a potential mediator of inflammatory processes. In this study, we quantified the effects of PAF on vessel diameter in a microvascular bed and investigated the biochemical pathways of this compound. The hamster cheek pouch microcirculation was observed with intravital microscopy. Experiments were video-recorded and analyzed with an image shearing device. Vasoconstriction was the predominant vasomotor response to PAF. PAF (10(-10) -10(-5) M) was applied topically to the pouch for 3 minutes. Arterioles ranging in size from 8 to 15 micron were the most sensitive, and they constricted completely in response to PAF 10(-7) and 10(-5) M. Arterioles 21-40 micron in diameter constricted to 12-17% of control after PAF at 10(-7) and 10(-5) M, respectively; they reopened to about 70% of their control value after a few minutes and remained near that size throughout the experiment. Arterioles 41-60 micron in diameter constricted to about 20% control size in response to 10(-7) and 10(-5) M PAF, and by the end of the experiment, these vessels had returned to about 90% control size. To determine the pathways of PAF actions, inhibitors of the arachidonic acid cascade and receptor blockers were used. Dexamethasone, indomethacin, OKY-046 (a thromboxane A2 synthetase inhibitor), and kadsurenone (a PAF-receptor blocker) blocked the vasoconstrictor response to PAF. Our experiments demonstrate that PAF-produced arteriolar constriction in a microvascular bed is 1) dose-related, 2) dependent upon vessel size, 3) largely due to thromboxane A2 activity, and 4) mediated by PAF-receptor interactions.
Morphometric evidence for non-pressure-related arterial wall thickening in hypertension.
Authors: Liu J L , Bishop S P , Overbeck H W
Published: June 2012

To investigate the relation of pressure and vascular wall thickening in hypertension, we coarcted the abdominal aorta upstream to the renal arteries in 14 rats. Sham-coarcted (n = 16) and two-kidney, one-clip (Goldblatt) hypertensive rats (n = 13) served as controls. Tail, femoral, and carotid arterial pressures rose (p less than 0.01) in the two-kidney, one-clip hypertensives; only carotid pressure rose (p less than 0.01) in the coarcted rats, tail and femoral pressures remaining normal (p greater than 0.25). Thus, the hindquarters of the coarcted rats remained normotensive. Four to six weeks after surgery we perfusion-fixed vascular tissues of the hindquarters, including kidneys, with formalin at in vivo levels of pressure. Glycol methacrylate-embedded tissues were sectioned at 1 micron thickness and vessels quantitatively evaluated. The outer medial and lumen perimeters of abdominal aorta, femoral artery, and renal arterioles were measured; from these measurements, vessel outer and lumen diameters, medial thickness, medial area, and medial thickness-to-lumen radius ratios were calculated. Compared with sham-coarcted rats, abdominal aorta, femoral arteries, and renal arterioles less than 61 microns outer diameter in rats with coarctation and Goldblatt hypertension had significantly increased (up to +100%) medial area, medial thickness, and medial thickness-to-lumen radius ratios. In general, magnitudes of abnormalities were similar in Goldblatt and coarcted rats. Renal arterioles greater than 60 microns outside diameter in Goldblatt hypertensive, but not coarcted, rats also were thickened. These results indicate that vascular wall thickening occurs in conduit arteries and smaller renal arterioles in the normotensive hindquarters of coarcted rats, providing morphometric evidence for non-pressure-related mechanisms involved in vascular growth in this form of hypertension.
Quinidine delays IK activation in guinea pig ventricular myocytes.
Authors: Roden D M , Bennett P B , Snyders D J , Balser J R , Hondeghem L M
Published: June 2012

A major action of the antiarrhythmic agent quinidine is prolongation of cardiac repolarization. In these experiments, the time-dependent effects of quinidine on the delayed rectifier potassium current, IK, a current contributing to cardiac repolarization, were investigated in acutely disaggregated guinea pig ventricular myocytes using the whole-cell recording configuration of the patch-clamp method. The effect of quinidine on IK was dependent on the duration of depolarization. After long (2,000 msec) pulses, IK was reduced by 30 +/- 27% (SD; n = 8, paired) by 10 microM quinidine; in contrast, after short (100 msec) pulses, the drug decreased IK 65 +/- 35% (p less than 0.05). This effect was found both in paired experiments as well as when quinidine-pretreated cells were compared to non-pretreated cells. Quinidine significantly delayed IK activation (9 +/- 20 msec at baseline vs. 44 +/- 25 msec in drug, p less than 0.05), but did not alter the subsequent time course of activation (time constant 659 +/- 118 msec). These findings are consistent with the hypothesis that quinidine promotes occupancy of a channel state from which opening does not occur.
Effect of nitroglycerin on aortic impedance, diameter, and pulse-wave velocity.
Authors: Latson T W , Hunter W C , Katoh N , Sagawa K
Published: June 2012

The effects of an intravenous infusion of 1 microgram/kg/min nitroglycerin were studied on systemic arterial properties in nine acutely instrumented dogs. Aortic impedance and pulse-wave velocity were calculated from measured pressure and flow signals collected during random ventricular pacing. Central aortic diameter was simultaneously determined with ultrasonic dimension crystals. Mean blood pressure was maintained constant to avoid the confounding effects of passive, pressure-induced changes in vascular properties. Nitroglycerin both reduced the amplitude of peripheral vascular reflections and delayed the return of these reflections to the aortic root. This reflection delay was manifested as a consistent leftward shift in both impedance modulus and phase. The magnitude of this reflection delay could not be entirely accounted for on the basis of the measured changes in average pulse-wave velocity along the aorta.
Microvascular changes in the heart during chronic arterial hypertension.
Authors: Laine G A
Published: June 2012

Changes of myocardial microvascular permeability in chronic renovascular arterial hypertension were studied. Hypertension was induced in dogs utilizing a one-kidney, one-clip Goldblatt model. Systemic arterial pressure, coronary sinus pressure, systemic venous pressure, myocardial lymph flow rate, myocardial interstitial fluid pressure, and the lymph-to-plasma protein concentration ratio for total plasma proteins and for beta-lipoprotein (CL/CP) were determined in control animals and 4-6 weeks following the Goldblatt procedure in hypertensive animals. Control values for the normotensive animals were 123 +/- 17 mm Hg, 7.3 +/- 1.3 mm Hg, 2.5 +/- 2.1 mm Hg, 3.1 +/- 2.1 ml/hr, 14.9 +/- 3.1 mm Hg, 0.82, and 0.33, respectively, while control values for the chronically hypertensive dogs were 160 +/- 20 mm Hg, 7.8 +/- 1.9 mm Hg, 2.9 +/- 2.5 mm Hg, 10.5 +/- 2.5 ml/hr, 24.8 +/- 3.7 mm Hg, 0.87, and 0.31, respectively. Under control conditions, myocardial lymph flow rate was significantly higher in the hypertensive group while no difference could be demonstrated in CL/CP between the two groups. This is indicative of either a change in myocardial microvascular permeability or an increase in microvascular exchange surface area. Coronary sinus pressure was elevated in both groups in order to increase transmicrovascular fluid flux and determine the filtration-independent reflection coefficient (sigma) for each group. Sigma is a surface area-independent indicator of microvascular permeability when determined for specific protein molecules at high transmicrovascular fluid fluxes.(ABSTRACT TRUNCATED AT 250 WORDS)
Protective effects of long-term bradycardial pacing against catecholamine-induced myocardial damage in rabbit hearts.
Authors: Brown M D , Hudlická O
Published: June 2012

A high intravenous dose of norepinephrine (4 micrograms/kg/min for 60 minutes) to New Zealand Red rabbits produced patchy subendocardial damage (estimated stereologically in frozen sections) of about 5% of the heart volume 2 days after application. The damaged areas showed loss of staining for alkaline phosphatase, an enzyme present in normal capillary endothelium. Heart performance (cardiac output index, cardiac work [i.e., cardiac output X mean blood pressure], and dP/dtmax) were significantly lower than in control hearts. Capillary density distribution estimated in nondamaged areas of the left ventricular free wall was inhomogeneous favoring subepicardial regions, while homogeneous transmural distribution was found in control hearts. Bradycardial pacing (reduction of heart rate to 50% of normal) performed for 3-4 weeks prior to norepinephrine administration showed a protective effect against catecholamine damage manifested in a smaller extent of necrosis, in the maintenance of homogeneous transmural capillary distribution in nondamaged areas, and, most importantly, in the maintenance of normal cardiac pump performance at rest and during maximal work in response to acutely administered norepinephrine.
Time course of denervation of efferent sympathetic and vagal nerves after occlusion of the coronary artery in the canine heart.
Authors: Inoue H , Zipes D P
Published: June 2012

To determine the time course of efferent sympathetic denervation after transmural myocardial infarction (TMI) and of efferent vagal denervation after transmural or nontransmural myocardial infarction (NTMI), we measured effective refractory periods (ERP) basal and apical to TMI or NTMI in secobarbital-anesthetized, open-chest dogs. In eight dogs with latex-induced TMI, bilateral ansae subclaviae stimulation shortened ERP at all 45 apical and basal test sites before latex injection. After latex injection, ERP shortening was unchanged at all 15 basal sites but was eliminated (less than or equal to 2 msec shortening) at three apical sites in 5-20 minutes and at 14 of 30 apical sites 30-180 minutes after latex injection. At the remaining 13 apical sites, ERP shortening was not eliminated but attenuated significantly in 5-180 minutes. ERP shortening induced by infused norepinephrine (0.20-0.25 microgram/kg/min) did not differ between basal and apical test sites 3-4 hours after latex injection; that is, no supersensitivity occurred. Of six dogs with TMI produced by ligation of multiple coronary arteries without latex injection, ERP shortening induced by efferent sympathetic neural stimulation was eliminated at 10 apical sites in four dogs over a period of 3 hours. At 14 apical sites that did not show denervation in these six dogs, ERP shortening was unchanged. In seven dogs with latex-induced TMI, bilateral vagal stimulation lengthened ERP at all 40 apical and basal test sites before latex injection. Vagally induced ERP lengthening was unchanged at all 13 basal sites after latex injection. ERP lengthening was eliminated (less than or equal to 1 msec lengthening) at four of 27 apical sites in 5-20 minutes and at 13 apical sites 30-180 minutes after latex injection. At the remaining 10 apical sites, ERP lengthening was not eliminated but decreased significantly 3 hours after latex injection. Of nine dogs with ligation-induced NTMI, five dogs showed elimination of vagally induced ERP lengthening at eight apical sites in 3 hours after ligation. ERP lengthening induced by vagal stimulation was unchanged at all 17 basal sites in nine dogs with NTMI. We conclude that TMI produced by latex injection and ligation of multiple coronary arteries produces heterogeneous loss of efferent sympathetic innervation in noninfarcted apical sites as early as 5-20 minutes after coronary occlusion with more complete denervation occurring over time.(ABSTRACT TRUNCATED AT 400 WORDS)
Atriopeptin III induces early relaxation of isolated mammalian papillary muscle.
Authors: Meulemans A L , Sipido K R , Sys S U , Brutsaert D L
Published: June 2012

Atrial natriuretic peptide, released by mammalian atria in response to volume overload, induces vasodilation and natriuresis. In this study, a direct effect on cardiac mechanical performance was demonstrated. Atriopeptin III (10(-9)-10(-7) M) induced early relaxation and decreased peak twitch of isometric and isotonic twitches of isolated papillary muscles of cat and rat, without affecting maximal unloaded velocity of shortening. This effect resembled the effects of dibutyryl cyclic GMP and of sodium nitroprusside on cardiac muscle. The action of atriopeptin III, but not of dibutyryl cyclic GMP or sodium nitroprusside, was abolished by mechanically or chemically damaging the endocardial endothelial surface. Thus, the early relaxation of cardiac muscle induced by atrial natriuretic peptide may be mediated through receptors on the endocardial endothelium.
Effects of metabolic blockade on intracellular calcium concentration in isolated ferret ventricular muscle.
Authors: Smith G L , Allen D G
Published: June 2012

Tension and intracellular free calcium concentration [( Ca2+]i) were measured in isolated ferret papillary muscles. When both anaerobic glycolysis and oxidative phosphorylation were prevented (metabolic blockade), there was a rapid decline of both developed tension and systolic [Ca2+]i signals. Subsequently, resting tension increased, and after a further delay, resting [Ca2+]i also rose. When oxidative metabolism was restarted after a period of metabolic blockade that was sufficient to elevate both resting tension and [Ca2+]i, a variable recovery of mechanical function occurred. In preparations that showed recovery, resting tension declined toward control level, and there was considerable recovery of developed tension. [Ca2+]i initially fell, but it then rose to a level similar to that at the end of the preceding period of metabolic blockade and exhibited large variations in amplitude with frequency components in the range 0.2-1 Hz. This elevated [Ca2+]i gradually declined. Arrhythmias were often present during this recovery period and appeared to be triggered by the spontaneous increases in [Ca2+]i. In preparations that failed to recover, resting tension remained elevated or increased, and developed tension showed little recovery. Such preparations showed larger rises in [Ca2+]i both during and after metabolic blockade, and [Ca2+]i continued to rise when oxidative metabolism was restarted. In experiments in which Na-Ca exchange was inhibited (by replacement of sodium by lithium or by the application of nickel), the rise of [Ca2+]i when oxidative metabolism was restarted was reduced, but recovery of mechanical function was improved. The correlation between elevated [Ca2+]i on reactivation of oxidative metabolism and failure of recovery of mechanical function suggests that elevated [Ca2+]i has a direct role in preventing the recovery of mechanical function.
Velocity of the creatine kinase reaction decreases in postischemic myocardium: a 31P-NMR magnetization transfer study of the isolated ferret heart.
Authors: Neubauer S , Hamman B L , Perry S B , Bittl J A , Ingwall J S
Published: June 2012

Recovery of postischemic function may be limited by energy synthesis by mitochondria, energy transfer via the creatine kinase reaction, or energy utilization at myofibrils. To identify the limiting step, we defined the relations among oxygen consumption, creatine kinase reaction velocity and cardiac performance in myocardium reperfused following mild, moderate, and severe ischemia. Isolated isovolumic ferret hearts were perfused with Krebs-Henseleit buffer at 37 degrees C. After 30 minutes of control, hearts were made ischemic for 20, 40, or 60 minutes and reperfused for 40 minutes. During preischemia, cardiac performance (estimated as the rate-pressure product), was 14.8 x 10(3) mm Hg/min, oxygen consumption was 16.7 mumol/min/g dry weight, and creatine kinase reaction velocity measured by 31P-nuclear magnetic resonance saturation transfer was 12.7 mM/sec. For hearts reperfused after 20, 40, or 60 minutes of ischemia, rate-pressure product was 11.5, 6.5, and 1.1 x 10(3) mm Hg/min; oxygen consumption was 13.5, 14.2, and 6.9 mumol/min/g dry weight; and creatine kinase reaction velocity was 9.6, 5.0, and 2.0 mM/sec, respectively. Thus, with increasing severity of insult, creatine kinase reaction velocity decreased monotonically with performance (r = 0.99). Changes in creatine kinase reaction velocity were predicted from the creatine kinase rate equation (r = 0.99; predicted vs. measured velocity) and can therefore be explained by changes in substrate concentration. Oxygen consumption did not correlate with performance or creatine kinase velocity, consistent with abnormalities in mitochondrial energy production. In all cases, creatine kinase reaction velocity was an order of magnitude faster than the maximal rate of ATP synthesis estimated by oxygen consumption. We conclude that, in postischemic myocardium, creatine kinase reaction velocity decreases in proportion to performance, but high-energy phosphate transfer does not limit availability of high-energy phosphate for contraction.
Delineation of the distribution of beta-adrenergic receptor subtypes in canine myocardium.
Authors: Murphree S S , Saffitz J E
Published: June 2012

beta 2-Receptors constitute only 10-30% of the total beta-adrenergic receptors in mammalian ventricular myocardium, but their precise tissue location cannot be determined easily by measuring physiological variables. To delineate the distribution of beta-receptor subtypes in myocytic and vascular components of the heart, we incubated transmural sections of canine left ventricle with [125Iodo]cyanopindolol and selected concentrations of the beta 1-selective antagonist betaxolol or the beta 2-selective antagonist ICI 118,551. Detailed competition binding data were best accounted for by a two-site model in which approximately 75% of total sites were beta 1- and 25% were beta 2-receptors. The relative proportions of beta-receptor subtypes in myocytic and vascular components were assessed autoradiographically by analyzing the density of binding sites in transmural sections incubated with radioligand and subtype-selective displacers. Betaxolol (10(-7) M) reduced the density of radioligand binding sites by 44% in regions composed primarily of ventricular myocytes but by less than 5% in small coronary arterioles. ICI 118,551 (10(-7) M) reduced radioligand binding-site density by 18% in myocytic regions and by 55% in small arterioles. In myocytic regions, these data indicated a subtype composition of approximately 85% beta 1- and 15% beta 2-sites. In contrast, arterioles contained almost exclusively the beta 2-subtype. The diameters of coronary vessels in which beta 2-receptors were found to be selectively increased fell within a narrow range (mean +/- SD, 35 +/- 11 microns; range, 16-55 microns). Small mural arteries and venules did not contain a significantly higher proportion of beta 2-receptors than adjacent myocytic regions.
Protection by beta-blocking agents against free radical-mediated sarcolemmal lipid peroxidation.
Authors: Mak I T , Weglicki W B
Published: June 2012

The effects of beta-blocking and class I antiarrhythmic agents on free radical-mediated sarcolemmal lipid peroxidation were examined. Highly purified canine myocytic sarcolemmal membranes were pretreated with 10-800 microM of selected beta-blocking (propranolol, pindolol, metoprolol, atenolol, or sotalol) and class I (quinidine, lidocaine, procainamide, or diphenylhydantoin) antiarrhythmic agents at 37 degrees C for 10 minutes. Subsequently, a superoxide radical (derived from dihydroxyfumarate) driven, Fe3+-ADP catalyzed free radical generating system was added and incubated for up to 45 minutes. Lipid peroxidation of sarcolemma was determined by malondialdehyde formation. Pretreatment of the membranes with the five beta-blockers resulted in various degrees (20-95%) of inhibition of sarcolemmal peroxidation in a concentration- and time-dependent manner. All the class I agents were less effective (less than 20% inhibition). The order of potency of the beta-blockers was propranolol greater than pindolol greater than metoprolol greater than atenolol greater than sotalol and appeared to relate to their degree of lipophilicity. Propranolol, the most potent agent, achieved half-maximal inhibition of peroxidation at about 100 microM and achieved significance (p less than 0.01) at 20 microM. At pH 6.0, the efficacy of pindolol, metoprolol, atenolol, and sotalol diminished by 30-50% compared to pH 7.2, but the potency of propranolol remained unchanged. Since increased free radical production may occur during myocardial ischemia/reperfusion injury, the above findings suggest that the lipophilic beta-blockers may provide additional antiperoxidative protection of ischemic tissue.
Action potential transfer in cell pairs isolated from adult rat and guinea pig ventricles.
Authors: Weingart R , Maurer P
Published: June 2012

An enzymatic procedure was used to obtain ventricular cells from adult rat and guinea pig hearts. Isolated pairs of cells were selected to study the action potential transfer from cell to cell and determine the resistance of the nexal membrane, rn. For this purpose, each cell of a cell pair was connected to a patch pipette so as to enable whole-cell, tight-seal recording. Normal impulse transmission was observed when rn ranged from 5-265 M omega. In these cases, the action potential in both cells occurred virtually simultaneously. An occasional failure in action potential transfer was seen in cell pairs whose rn had increased to 155-375 M omega. In these cases, the impulse transfer across the nexal membrane occurred with considerable delay. Impulse transfer was completely blocked once rn was larger than 780 M omega. Assuming a single connexon conductance of 100 pS, this would mean that more than 13 connexons are necessary to allow impulse transfer from cell to cell. Two single myocytes, gently pushed together, neither showed electrotonic interaction nor impulse transfer, thus rendering unlikely the possibility of an ephaptic signal transmission.
Nonlinear relation between Vmax and INa in canine cardiac Purkinje cells.
Authors: Sheets M F , Hanck D A , Fozzard H A
Published: June 2012

We studied the relation of the maximal upstroke velocity (Vmax) of action potentials to the peak sodium current (INa) under voltage clamp in single, internally perfused, canine cardiac Purkinje cells under conditions that ensured membrane action potentials due only to INa. Three different methods of altering sodium channel availability were investigated: voltage-dependent inactivation, tetrodotoxin (TTX) block, and use-dependent block by quinidine. Under all three conditions, the relation of Vmax to INa was nonlinear, and no relation was found that would allow prediction of INa results from Vmax measurements. With voltage-dependent inactivation or TTX block, sodium channel availability measured by Vmax was reduced less than availability measured by peak INa, so that Vmax overestimated sodium channel availability. This overestimation of sodium channel availability by Vmax could be attributed to greater sodium channel mobilization during the slowed action potential upstrokes. The overestimation varied with experimental temperature as a consequence of changes in sodium channel kinetics. Vmax also overestimated sodium channel availability during TTX exposure so that the Kd for TTX block was 4.5 micron from Vmax measurements but only 1.6 microM from INa measurements. Use-dependent block of INa by quinidine had a striking voltage-dependent component under voltage clamp that could not be appreciated from action potentials. Consequently, block could be underestimated or overestimated by Vmax measurements. We conclude that Vmax measurements represent a convenient index for INa, but Vmax is not a reliable method for quantitative studies of sodium channel behavior.
C5a decreases regional coronary blood flow and myocardial function in pigs: implications for a granulocyte mechanism.
Authors: Martin S E , Chenoweth D E , Engler R L , Roth D M , Longhurst J C
Published: June 2012

Granulocytes cause some of the pathophysiological effects associated with the capillary no-reflow phenomenon during ischemia and in ischemia-reperfusion injury. However, no study has examined the consequences of in vivo granulocyte activation during normal perfusion pressures. In this study, we examined the effects of intracoronary administration of the complement component C5a, which is known to be a potent granulocyte activating factor. Nine open-chest, anesthetized pigs were instrumented to monitor regional coronary blood flow and segment shortening, left ventricular dP/dt, heart rate, and pulmonary artery and aortic blood pressures and to sample arterial and regional coronary venous blood for oxygen content and complete blood counts. Intracoronary infusion of human or porcine C5a in doses ranging from 10 to 500 ng produced a significant reduction in regional coronary blood flow and myocardial function. Although perfusion pressure and heart rate remained constant, venous oxygen content fell, indicating an imbalance between myocardial oxygen supply and demand. In addition, the arteriovenous difference of white blood cells was increased significantly after anaphylatoxin infusion, indicating intravascular trapping in the myocardium. Granulocytes accounted entirely for the differences in leukocyte counts because no significant changes in platelet, lymphocyte, or hematocrit levels were observed. Injection of vehicle alone did not alter any of the monitored variables.(ABSTRACT TRUNCATED AT 250 WORDS)
Potentiation of myocardial salvage by tissue type plasminogen activator in combination with a thromboxane synthetase inhibitor in ischemic cat myocardium.
Authors: Lefer A M , Mentley R , Sun J Z
Published: June 2012

We studied the effects of a thrombolytic agent (t-PA) and a thromboxane synthetase inhibitor (CGS-13080) in a model of myocardial ischemia and reperfusion. Occlusion of the left anterior descending coronary artery for 2 hours followed by 4 hours of reperfusion in anesthetized cats results in a large washout of creatine kinase into the blood (32 +/- 7 IU/mg protein) and an area of necrotic tissue comprising 52 +/- 5% of the area at risk and 9 +/- 0.6% of the left ventricle. Intravenous administration of t-PA (500 IU/kg.min) for 30 minutes alone at reperfusion or infusion of CGS-13080 (500 micrograms/kg.hr) had no effect on washout of creatine kinase or extent of necrotic tissue development. Administration of the same doses of both t-PA and CGS-13080 together markedly attenuated creatine kinase release to 10 +/- 2 IU/mg protein (p less than 0.01) and reduced the area of necrotic tissue to 9 +/- 2% of the area at risk and only 1.3 +/- 0.3% of the left ventricle (p less than 0.001). No significant sustained effects of these agents were observed on mean arterial blood pressure, heart rate, or the pressure rate index in these experiments. Thus, t-PA and CGS-13080 exert synergistic effects in preserving myocardial integrity in cats subjected to acute myocardial ischemia followed by reperfusion. The mechanism of this beneficial effect does not appear to be via reduced myocardial oxygen demand, increased myocardial oxygen supply, or enhanced inhibition of thromboxane A2 formation. The mechanism of this anti-ischemic effect is not clear but may involve a metabolic or a cytoprotective effect.
Effect of intravertebral angiotensin II on cardiac output and its distribution in conscious dogs.
Authors: Quillen E W , Reid I A
Published: June 2012

Intravertebral infusion of angiotensin II (Ang II) increases mean arterial pressure (MAP), but the contribution of cardiac output (CO) and total peripheral resistance (TPR) to this increase is unclear. In the present study, the effects of Ang II infusion on CO and regional blood flow was determined by the microsphere technique in eight conscious, chronically catheterized dogs. Ang II was infused into both vertebral arteries at 0.33 and 1.0 ng/kg/min, and intravenously at 0.66, 2.0 and 5.0 ng/kg/min. Intravertebral infusion of Ang II at 0.33 ng/kg/min increased MAP by increasing CO without changing TPR or peripheral plasma Ang II concentration. MAP also was increased with intravertebral infusion of Ang II at 1.0 ng/kg/min, but this resulted from small increases in both CO and TPR. In contrast, intravenous infusion of Ang II at 2.0 and 5.0 ng/kg/min increased MAP by increasing TPR in association with a decrease in CO. The increase in CO with intravertebral infusion of Ang II at 0.33 ng/kg/min was distributed primarily to the muscles, kidneys, heart, and brain. Intravenous infusion of Ang II at 5.0 ng/kg/min and, to a lesser extent, 2.0 ng/kg/min decreased blood flow to the skin, splanchnic region, and kidneys. These data indicate that the increase in MAP produced by a low intravertebral dose of Ang II results from an increase in CO, which is distributed primarily to the muscle, kidney, heart, and brain. In contrast, the increase in MAP produced by a higher intravertebral dose of Ang II results from increases in CO and TPR. This latter action is apparently due to a peripheral action of Ang II to increase resistance in the skin, splanchnic, and renal circulations.