bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of adrenoceptors and [3H]nitrendipine receptors of porcine vascular smooth muscle: differences between coronary artery and aorta.
Authors: Nishimura J , Kanaide H , Nakamura M
Published: June 2012

Characteristics of the bindings of [3H](-)dihydroalprenolol, [125I](-)iodocyanopindolol, [3H]prazosin, [3H]yohimbine, and [3H]nitrendipine to porcine coronary membranes were investigated and the results compared with studies of porcine aortic membranes. In the equilibrium binding study carried out in sarcolemma-enriched fractions, there were no major differences in the Kd values of these radioligands between coronary artery and aorta. However, the densities of beta-, alpha 1-, and alpha 2-adrenoceptors and [3H]nitrendipine receptors of coronary artery were 258, 12, 12, and 561 fmol/mg protein, respectively, while those of aorta were 37, 525, 1,000, and 215 fmol/mg protein. beta-Adrenergic agonists competed with [3H](-)dihydroalprenolol binding sites in coronary artery, the order of potency being (-)isoproterenol greater than (-)norepinephrine greater than (-)epinephrine greater than (+)isoproterenol. In case of aorta, the order was (-)isoproterenol greater than (-)epinephrine greater than (-)norepinephrine. The competition by (+/-)bisoprolol (beta 1-selective antagonist) and ICI 118,551 (beta 2-selective antagonist) for [125I](-)iodocyanopindolol binding sites in coronary artery resulted in nonlinear Hofstee plots (beta 1:beta 2 = 90%:10%). In case of aorta, linear Hofstee plots were obtained. From these results, we conclude that coronary beta-receptors in pigs are predominantly of beta 1-type, while those of aorta are of beta 2-type; regarding the relative population of adrenoceptors, coronary artery is beta-dominant (beta/alpha = 11), while aorta is alpha-dominant (beta/alpha = 0.02); compared with alpha-adrenoceptors, coronary artery has a greater number of [3H]nitrendipine binding sites (nitrendipine/alpha-adrenoceptor = 23) than aorta (nitrendipine/alpha-adrenoceptor = 0.14).
Cultured human vascular smooth muscle cells with functional thromboxane A2 receptors: measurement of U46619-induced 45calcium efflux.
Authors: Dorn G W , Sens D , Chaikhouni A , Mais D , Halushka P V
Published: June 2012

Thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) are potent vasoconstrictors whose contractile effects are mediated by increases in cellular calcium. Stable analogues of these compounds have shown calcium ionophore activity at high concentrations. To determine if effects of TXA2/PGH2 analogues on 45Ca2+ fluxes are receptor mediated, the effects of the stable TXA2/PGH2 mimetic U46619 and the TXA2/PGH2 receptor antagonist I-PTA-OH on 45Ca/+ fluxes in cultured human vascular smooth muscle cells were studied. The smooth muscle cells were cultured from human saphenous vein explants, and they retained the morphologic and immunologic characteristics of vascular smooth muscle cells. U46619 stimulated 45Ca2+ efflux in a dose-dependent manner with an EC50 of 398 +/- 26 nM (n = 4). The maximal 45Ca2+ efflux in response to U46619 (5 microM) was significantly greater (p = 0.006) than the 45Ca2+ efflux induced by KCl (40 mM). I-PTA-OH inhibited the U46619-induced 45Ca2+ efflux but had no effect on KCl-induced 45Ca2+ efflux. These results suggest that the effects of U46619 in increasing vascular smooth muscle cell calcium efflux are receptor mediated. Furthermore, vascular smooth muscle cells with functional TXA2/PGH2 receptors were cultured from human saphenous veins and provide a potentially useful in vitro system for the further study of TXA2/PGH2 receptor-mediated phenomena in human vascular tissue.
Arrhythmic activity in reoxygenated guinea pig papillary muscles and ventricular cells.
Authors: Hayashi H , Ponnambalam C , McDonald T F
Published: June 2012

Aftercontractions, delayed afterdepolarizations, and automaticity occurred in guinea pig papillary muscles that were reoxygenated after hypoxic conditioning. The emergence of dysfunction was dependent on the severity of hypoxic conditioning and on stimulation during reoxygenation. After 60 minutes of substrate-free hypoxia, reoxygenation induced automaticity in a high proportion of stimulated muscles; the automaticity appeared within 1 minute and lasted for 10-20 minutes. After similar conditioning, muscles reoxygenated for 7-15 minutes were stimulated at various cycle lengths. The incidence of automaticity and the amplitudes of delayed events had W-shaped dependencies on cycle length (200-1,000 msec), whereas coupling intervals had M-shaped dependencies. In ventricular myocytes that displayed automaticity after reoxygenation, extrasystolic upstrokes arose smoothly from delayed afterdepolarizations that reached threshold. In tissue, extrasystolic upstrokes usually rose sharply from delayed afterdepolarizations that were distinctly subthreshold. Thus, threshold was reached elsewhere in the tissue. Further evidence of electrical heterogeneity was obtained from surface mapping of delayed-afterdepolarization amplitude in reoxygenated muscle. There were no detectable aftercontractions, delayed afterdepolarizations, or signs of automaticity in quiescent reoxygenated muscles or in stimulated reoxygenated muscles that were treated with 1 microM ryanodine. We conclude that the dysfunction precipitated by reoxygenation is due to synchronized spontaneous releases of calcium from overloaded sarcoplasmic reticulum.
Selective antagonism of hormone-induced vasoconstriction by synthetic atrial natriuretic factor in the rat microcirculation.
Authors: Proctor K G , Bealer S L
Published: June 2012

Synthetic atrial natriuretic factor (ANF) was either added to suffusate solutions (30 nM) or infused into the jugular vein (0.1 nanomol/min/100 g) of anesthetized rats. Steady-state blood flow was calculated from arteriolar diameter and red blood cell velocity measurements using video microscopy in the intestinal or skeletal muscle microcirculation. Arterioles demonstrated spontaneous vasomotor tone by dilating to topical adenosine, but topical or intravenous ANF did not cause vasodilation. Either angiotensin, norepinephrine, or vasopressin was added to the suffusates in the presence or absence of a cyclooxygenase inhibitor (30 microM, meclofenamate or indomethacin) because each agonist is known to stimulate vasoactive prostanoid synthesis. In the intestine, angiotensin (500 nM) caused 40 +/- 2% blood flow decreases during intravenous saline but only 23 +/- 6% during intravenous ANF. Angiotensin (162 nM) and a cyclooxygenase inhibitor caused 19 +/- 4% blood flow decreases but only 8 +/- 5% decreases with cyclooxygenase inhibitor and topical ANF. In contrast, norepinephrine (2-5 microM) caused vasoconstriction that was not altered by topical or intravenous ANF, either alone or in combination with cyclooxygenase inhibitors. In the spinotrapezius muscle, angiotensin (1-2 nM) plus a cyclooxygenase inhibitor caused 40-60% blood flow decreases but only 20-30% decreases during intravenous or topical ANF. Topical or intravenous ANF did not alter the vasoconstriction evoked by arginine vasopressin (0.5-1.0 nM) or by norepinephrine (40-230 nM). Thus, supraphysiologic concentrations of ANF produced no direct vasodilation in the intestinal or skeletal muscle microcirculation.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardio-renal-endocrine dynamics during stepwise infusion of physiologic and pharmacologic concentrations of atrial natriuretic factor in the dog.
Authors: Zimmerman R S , Schirger J A , Edwards B S , Schwab T R , Heublein D M , Burnett J C
Published: June 2012

Infusion of alpha-human atrial natriuretic factor (alpha-h-ANF) into pentobarbital anesthetized dogs (n = 10) at 0.0025, 0.005, 0.01, and 0.3 micrograms/kg/min was performed to differentiate the physiologic actions of atrial natriuretic factor from its pharmacologic actions. The lowest doses of atrial natriuretic factor infusion resulted in circulating levels that were previously produced by 0-10% saline volume expansion. At the lowest infusion rate, circulating ANF increased 31 +/- 3 pg/ml, resulting in a significant increase in absolute sodium excretion, fractional excretion of sodium, and fractional excretion of lithium, and a significant decrease in urine osmolality. A greater change in circulating atrial natriuretic factor (96 +/- 12 pg/ml) was required to significantly decrease right atrial pressure, cardiac output, and plasma renin activity, and to increase systemic vascular resistance and total and fractional excretion of potassium. The highest dose of atrial natriuretic factor infused was required to decrease arterial pressure and renal vascular resistance. The present study demonstrates that atrial natriuretic factor is natriuretic and diuretic at physiologic concentrations; at low concentrations, atrial natriuretic factor appears to decrease the whole kidney proximal tubular reabsorption of sodium and does not affect glomerular filtration rate; a greater (but physiologic) change in circulating atrial natriuretic factor is required to significantly decrease cardiac output, cardiac filling pressure, and plasma renin activity than is required to significantly increase sodium excretion; and a decrease in systemic arterial pressure and vascular resistance does not occur at physiologic concentrations of atrial natriuretic factor.
Instantaneous pressure-volume relation of the ejecting canine left atrium.
Authors: Alexander J , Sunagawa K , Chang N , Sagawa K
Published: June 2012

To characterize the pump function of the left atrium, we determined the instantaneous pressure-volume relation of the isolated supported left atrium. A physiologic after-loading system for the low-pressure atrium was created by coupling it to a real-time computer-simulated ventricle and a simulated venous impedance network via a volume servo-pump. In 10 atria loaded with such systems, multiple isochronal sets of pressure-volume data were collected from many ejecting or isovolumic contractions obtained under a constant inotropic state, and the time-varying elastance, E(t), as well as the volume-axis intercepts, VO(t), were calculated. E(t) is the ensemble of slopes, and VO(t), the volume-axis intercepts resulting from the linear regression of instantaneous pressure on instantaneous volume at multiple instants throughout the cardiac cycle. The systolic portion of the left atrial E(t) was insensitive to loading conditions, as was VO(t), which, in addition, proved to be similar to the right atrial and right ventricular VO(t) waveforms in its time dependence. These results indicate that E(t) and VO(t) adequately represent the instantaneous pressure-volume relation of the left atrium in systole irrespective of the mode of contraction. Whatever the underlying mechanism might be, the load insensitivity and similarity of the basic shape of the left atrial E(t) among different atria suggests that the characterization reflects fundamental features of left atrial contraction.
Nonobstructive left ventricular ejection pressure gradients in man.
Authors: Pasipoularides A , Murgo J P , Miller J W , Craig W E
Published: June 2012

Simultaneous intraventricular pressure gradients and ejection flow patterns were measured by a multisensor catheter in 6 patients with normal left ventricular function and no valve abnormalities, at rest and in exercise. Peak measured intraventricular pressure gradients were attained very early in ejection, amounted to 6.7 +/- 1.9 (SD) mm Hg at rest, and were intensified to 13.0 +/- 2.3 mm Hg during submaximal supine bicycle exercise. The augmentation of the gradients during exercise was associated with a pronounced accentuation of the flow acceleration and flow at the instant of peak gradient. A peak flow, the intraventricular gradients amounted to 5.4 +/- 1.7 mm Hg at rest and 10.0 +/- 1.8 mm Hg during submaximal exercise. The exercise-induced enhancement of the measured intraventricular pressure difference at the time of peak flow was underlain by an accentuation of the peak flow itself. A semiempirical fluid dynamic model for ejection was applied to the pressure gradient and simultaneous outflow rate and acceleration data to identify the contributions by local and convective acceleration effects to the instantaneous intraventricular gradient values. The peak intraventricular pressure gradient, which is attained very early in ejection, is mostly accounted for by local acceleration effects (85 +/- 5% of the total). Conversely, at peak flow only convective acceleration effects are responsible for the measured pressure gradient. Thus, when inertial effects are augmented, as in exercise and other hyperdynamic states, the intrinsic component of the total left ventricular systolic load can be substantial, even with no outflow tract or valve abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)
Dietary treatment of atherosclerosis abolishes hyperresponsiveness to serotonin: implications for vasospasm.
Authors: Heistad D D , Mark A L , Marcus M L , Piegors D J , Armstrong M L
Published: June 2012

Diet-induced atherosclerosis in primates impairs vasodilator responses and greatly potentiates vasoconstrictor responses to serotonin. Serotonin may play an important role in the pathogenesis of vasospasm. In diet-induced regression of atherosclerosis, intimal lesions are reduced, but maximal vasodilator responses do not improve, perhaps because of vascular fibrosis. Our goal was to determine whether dietary treatment of atherosclerosis reverses the augmented vasoconstrictor responses to serotonin and thus might reduce susceptibility to vasospasm. Normal cynomolgus monkeys, atherosclerotic monkeys, and atherosclerotic monkeys that were given a normal (regression) diet for 18 months were studied. Morphometric studies indicated that the regression diet reduced lesions in the iliac and femoral artery since intimal area was reduced by about 50%. In the hind limb perfused at constant flow, residual resistance during maximal vasodilatation produced by infusion of adenosine tended to be greater in atherosclerotic monkeys than in normals and failed to improve in regression monkeys. In contrast, vasoconstrictor responses to serotonin were greatly potentiated in atherosclerotic monkeys and were restored to normal in regression monkeys. Serotonin (20 micrograms i.a.) decreased hind limb resistance (in mm Hg/ml/min) 0.34 +/- 0.06 (mean +/- SE) in normal monkeys, increased resistance 0.58 +/- 0.17 in atherosclerotic monkeys (p less than 0.05 vs. normal), and decreased resistance 0.70 +/- 0.15 in regression monkeys (p less than 0.05 vs. atherosclerotic). Thus, dietary treatment of atherosclerosis abolishes augmented vasoconstrictor responses to serotonin. It is proposed that treatment of atherosclerosis may be beneficial, even when vasodilator responses fail to improve, by reducing susceptibility to serotonin-induced vasospasm.
Reentrant and nonreentrant mechanisms contribute to arrhythmogenesis during early myocardial ischemia: results using three-dimensional mapping.
Authors: Pogwizd S M , Corr P B
Published: June 2012

The present study assessed the mechanisms responsible for the initiation and maintenance of premature ventricular complexes (PVCs) and ventricular tachycardia (VT) during early ischemia using a unique computerized mapping system capable of recording simultaneously from 232 individual intramural sites. In the chloralose-anesthetized cat, during normal sinus rhythm prior to ischemia, ventricular activation was rapid with a total activation time of 25 +/- 2 msec. Five minutes after occlusion of the left anterior descending (LAD) coronary artery, activation was delayed during sinus rhythm (64 +/- 6 msec) (p less than 0.001 vs. control) and was characterized by slow conduction in the same plane and block in both the same plane and in the endocardial-to-epicardial direction. In 76% of cases (16 of 21), initiation of single PVCs and the first beat of VT occurred through intramural reentry. In all but one case, initiation occurred in the subendocardium, adjacent to the site of delayed subendocardial and midmyocardial activation of the preceding sinus beat. The activation time of the sinus beat preceding the PVC or VT was significantly prolonged (149 +/- 7 msec, p less than 0.001 vs. sinus beats during ischemia not followed by a PVC or VT) with most of the delayed activity occurring in the subendocardium and midmyocardium, a finding that would not have been apparent by epicardial mapping alone. The length of the reentrant pathway ranged from 1.8-3.0 cm. Marked delay was a necessary, but not a sufficient, condition for reentry to occur since, in some cases, delays as large as 220 msec was found without initiation of reentry or the occurrence of nonreentrant PVCs or VT. Maintenance of VT by intramural reentry arose in either the subendocardium or the subepicardium and was primarily dependent on the continued presence of marked transmural delay (159 +/- 8 msec). In contrast, in 24% of cases (5 of 21), initiation of the first beat of VT arose in either the subendocardium or subepicardium by a mechanism other than reentry as evidenced by the lack of intervening electrical activity between the end of the preceding sinus beat and the initiation of the ectopic beat. The preceding sinus beat was characterized by delay (129 +/- 12 msec) comparable to that of sinus beats preceding reentrant ectopic beats (p = NS), but the marked delay was distant from the site of nonreentrant initiation. Ventricular tachycardia could be initiated by one mechanism (reentrant or nonreentrant) and maintained or terminated by another mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)
Tumor-promoting phorbol esters inhibit cardiac functions and induce redistribution of protein kinase C in perfused beating rat heart.
Authors: Yuan S H , Sunahara F A , Sen A K
Published: June 2012

Activation of protein kinase C has been implicated in the regulation of a variety of cellular reactions. Although we, and others, have found protein kinase C and its substrate proteins to be present in both membrane and cytosolic fractions in the heart, the physiologic role of this kinase in the regulation of cardiac functions remains unknown. In the present study, we found that in isolated perfused rat heart, administration of phorbol esters 4 beta-phorbol 12,13-dibutyrate(PDBu) and 12-0-tetradecanoylphorbol 13-acetate(TPA), which are specific activators of protein kinase C, produced marked dose-dependent negative changes in inotropy and chronotropy. A dose-dependent decrease in coronary flow was also observed. The diacylglycerol analogues, 1,2-oleoylacetyl-glycerol and 1,2-dioctanoylglycerol, produced similar effects as the active phorbol esters on these isolated perfused hearts. An inactive analogue of phorbol ester, 4 alpha-phorbol, failed to produce any effect. Protein kinase C activity in both membrane and cytosolic fractions prepared from rat heart could be activated by TPA and PDBu at the same concentration range as used in the experiments with perfused hearts. Following perfusion of the hearts with PDBu, a rapid translocation of protein kinase C from cytosolic to membrane fractions was also observed. Our findings provide the first direct evidence that protein kinase C may play a potentially important role in the regulation of cardiac functions.
Platelet-activating factor effects on bovine pulmonary artery endothelial cells.
Authors: Grigorian G Y , Ryan U S
Published: June 2012

Endothelial cells (ECs) were isolated from bovine pulmonary artery and maintained in long-term culture. On reaching confluency, ECs formed a characteristic "cobblestone" monolayer. One hour after addition of 1 nM platelet-activating factor (PAF) to the growth medium, ECs underwent dramatic changes in shape from their normal polygonal morphology to more elongated spindle-shaped forms. More pronounced effects were evident in the presence of 0.1 nM phorbol-12-myristate-13-acetate (PMA), a potent activator of C kinase. It was found that at concentrations from 10(-11)-10(-7) M, PAF stimulates the phosphoinositide turnover in EC. The half-maximal activation in the release of inositol phosphates was at 10(-9) M. This finding suggested that an increase in intracellular Ca2+ concentration and activation of protein kinase C were involved in the mechanism of action of PAF on EC. The metabolic responses of EC were evaluated by measuring the activity of beta-adrenergic receptor-coupled adenylate cyclase (AC) in a crude membrane fraction and by assay of prostacyclin and thromboxane released by cultured EC. AC from control membranes was activated by isoproterenol in a dose-dependent manner (EC50 = 30 nM) from 0.8-5.5 pmol cAMP/min/mg protein. If the membranes were isolated after preincubation of ECs with 1 nM PAF or 0.1 nM PMA, the AC activity was decreased by 70 and 90%, respectively; in both cases, affinity for isoproterenol was lowered threefold (EC50 = 100 nM). Our data suggest that PAF interaction with EC leads to an apparent beta-adrenergic receptor desensitization that probably acts via a phosphorylation mechanism involving C kinase.(ABSTRACT TRUNCATED AT 250 WORDS)
A receptor for type I antiarrhythmic drugs associated with rat cardiac sodium channels.
Authors: Sheldon R S , Cannon N J , Duff H J
Published: June 2012

We assessed the effects of type I antiarrhythmic drugs on the binding of ligands to receptors on voltage-sensitive sodium channels of rat cardiac myocytes. The radioligand was [3H]batrachotoxinin A 20 alpha-benzoate ([3H]BTXB), a toxin that binds to the sodium channel. The 8 drugs tested inhibited [3H]BTXB binding in a dose-dependent fashion with IC50 values from 1.34 microM for O-demethylencainide to 811 microM for procainamide. A log-log plot of IC50 versus mean therapeutic serum concentration yielded a regression line with slope of 1.17 and r of 0.95. Scatchard analysis of [3H]BTXB binding showed that lidocaine reduced the maximal binding without altering the KD for [3H]BTXB binding, indicating allosteric inhibition. The inhibition by lidocaine of [3H]BTXB binding was reversible within 30 minutes when the samples were diluted from 390 to 39 microM lidocaine. In other studies, the stereoisomers of tocainide were shown to have a threefold to fourfold difference in IC50 for inhibition of [3H]BTXB binding. The binding of antiarrhythmic drugs to this site is saturable, reversible, and stereospecific and occurs at pharmacologically relevant concentrations with similar rank order of potency in vivo and in vitro. This suggests that binding at this site relates to pharmacologic activity.
Release of endothelium-derived relaxing factor from freshly harvested porcine endothelial cells.
Authors: Hartmann A , Saeed M , Bing R J
Published: June 2012

Vascular relaxation in rabbit aortic preparations induced by acetylcholine is endothelium-dependent. The nature of the endothelium-derived relaxing factor (EDRF) has not been ascertained because it is very labile (reported half-life 6-50 seconds). To obtain a stable source of EDRF, a system was developed in which the relaxing factor was continuously produced by freshly harvested porcine endothelial cells. Endothelial cells were collected from aortas by exposing the endothelial lining to collagenase 0.1%. Cells were washed and concentrated by repeated centrifugation to obtain a high cell count (7.2 X 10(6) cells/ml). Endothelium-deprived aortic strips from rabbits were incubated in these cells suspended in tissue culture medium and fetal calf serum. The strips were precontracted with histamine. Acetylcholine was added to induce EDRF release. Significant relaxation of endothelium-deprived aortic strips was observed. Superoxide dismutase, an enzyme known to protect EDRF against inactivation, caused further relaxation, which was inhibited by the addition of hemoglobin, an agent known to inhibit the relaxing action of EDRF. Even without the addition of acetylcholine, hemoglobin caused contraction of the denuded aortic strips in suspension of porcine endothelial cells, demonstrating spontaneous EDRF release. Hemoglobin had no effect in cell-free medium. Endothelial-cell-dependent relaxation occurred without attachment of endothelial cells to the endothelium-deprived aortic strips: when the cell suspension was replaced by cell-free medium, relaxation did not occur after acetylcholine. Scanning electron microscopy showed no attachment of endothelial cells to the subendothelial layer. It can be concluded that freshly harvested endothelial cells produce endothelium-derived relaxing factor with an without stimulation by acetylcholine.
Influence of calcium-entry blockade on vasoconstrictor responses in feline mesenteric vascular bed.
Authors: Lippton H L , Armstead W M , Hyman A L , Kadowitz P J
Published: June 2012

The subtypes of postjunctional alpha-adrenoceptors activated by neuronally released and exogenous norepinephrine and the source of calcium used for vasoconstrictor responses were investigated in the feline mesenteric vascular bed. Under constant flow conditions, intra-arterial injections of phenylephrine and UK14304, alpha 1- and alpha 2-adrenoceptor agonists, increased mesenteric arterial perfusion pressure in a dose-related manner. Prazosin, an alpha 1-antagonist, reduced vasoconstrictor responses to phenylephrine without altering responses to UK14304. Yohimbine, an alpha 2-antagonist, reduced responses to UK14304 without altering responses to phenylephrine. The same pattern of blockade was observed in animals pretreated with 6-hydroxydopamine to destroy the integrity of adrenergic terminals. Responses to phenylephrine and UK14304 were reduced by nitrendipine, a calcium-entry blocking agent, and this agent decreased vasoconstrictor responses to sympathetic nerve stimulation, tyramine, and norepinephrine. Responses to sympathetic nerve stimulation were selectively blocked by prazosin, but responses to norepinephrine were selectively blocked by yohimbine. Vasoconstrictor responses to tyramine were reduced by both prazosin and yohimbine. Nitrendipine also reduced responses to angiotensin II, U46619, a prostaglandin endoperoxide analogue, Bay K 8644, and potassium chloride. These data suggest the presence of alpha 1- and postjunctional alpha 2-adrenoceptors and support the hypothesis that norepinephrine released by nerve excitation acts mainly on alpha 1-receptors but that exogenous norepinephrine acts primarily on alpha 2-receptors. However, norepinephrine released by tyramine acts on both receptor subtypes. Nitrendipine inhibited responses to the alpha 1- and alpha 2-adrenoceptor agonists as well as those to nerve released and exogenous norepinephrine, the calcium agonist, Bay K 8644, and to other vasoconstrictor agents. These data suggest that in the feline mesenteric vascular bed, an extracellular source of calcium ions is required for vasoconstriction induced by a variety of mechanisms including activation of alpha 1- and postjunctional alpha 2-adrenoceptors.
Failure of swimming exercise to improve capillarization in cardiac hypertrophy of renal hypertensive rats.
Authors: Rakusan K , Wicker P , Abdul-Samad M , Healy B , Turek Z
Published: June 2012

Female Sprague-Dawley rats were made hypertensive by the two kidney/one clip Goldblatt procedure, while control animals were sham-operated. One week later, half of the animals were subjected to a moderate swimming exercise and the other half remained sedentary. Thus, four experimental groups, each consisting of 14 rats, were formed: control animals that were exercised or kept sedentary and corresponding renal hypertensive animals either exercised or sedentary. In hypertensive rats, a significantly increased left ventricular weight and reduced coronary reserve were found. Cardiac hypertrophy in hypertensive rats was characterized by a lower number of capillaries on a tissue cross-section, larger heterogeneity of the capillary net, and a less uniform orientation of capillaries in space. Total length of capillaries in the hypertrophic hearts increased significantly, but less than the increase in cardiac weight, resulting in reduced capillary length density. Chronic swimming for 2 hr/day for a period of 6 weeks, subsequent to a 4-week acclimation period, did not significantly influence any of the investigated indexes of capillaries from hypertrophic hearts. In the normotensive rats, chronic swimming resulted only in a moderate increase in total capillary length associated with a small increase in the left ventricular weight of similar degree. Thus, chronic exercise in normotensive rats induced a moderate increase in total capillary length per left ventricle, while it did not alleviate impaired capillarization of hypertrophic hearts from hypertensive rats.
Vibrational analysis of bioprosthetic heart valve leaflets using numerical models: effects of leaflet stiffening, calcification, and perforation.
Authors: Hamid M S , Sabbah H N , Stein P D
Published: June 2012

The fundamental natural frequency of the closed cusps of porcine bioprosthetic valves, fabricated from the normal leaflets of pig aortic valves, was estimated using a finite element model. Both normal and stiffened leaflets were considered in the vibrational analysis. The effects of conditions that simulated degeneration, such as stiffening, central perforation, a tear, calcium deposits in the commissural attachments, and combinations of these were determined. The primary frequency of vibration of the normal leaflets was within the range of the dominant frequency of the heart sounds determined clinically by spectral analysis of the recorded phonocardiogram. If only one leaflet was stiffened or calcified, there was only a marginal change of frequency. With stiffening and calcification of the commissures of all 3 leaflets, the frequency of vibration increased. Introduction of a tear in a single leaflet of a stiffened and calcified valve markedly reduced the fundamental frequency. In view of the relation between the frequency content of heart sounds and the frequency of valve vibration, this mathematical simulation establishes a possible basis for the observation of a varying dominant frequency of heart sounds in patients with bioprosthetic valves that are in the process of degenerating.
Negative inotropic effects of amrinone in the neonatal piglet heart.
Authors: Ross-Ascuitto N , Ascuitto R , Chen V , Downing S E
Published: June 2012

Cardiac mechanical function and coronary flow (CF) were measured in isovolumically beating hearts from neonatal piglets 0.5 to 12 days of age. The hearts were perfused retrogradely at 70 cm H2O with a recirculating modified Krebs-Henseleit solution containing washed adult pig red cells (hematocrit, 25%). They were electrically paced (180 beats/min), and left ventricular developed pressure (delta P), maximum rate of rise of pressure (dP/dt), CF, and myocardial oxygen consumption were measured. These parameters were found to remain stable for at least 60 minutes. In one group, a single dose of amrinone was added to the perfusate to yield a concentration of 50 micrograms/ml. Within 5 minutes delta P decreased from 104.0 +/- 7.1 to 65.3 +/- 8.6 mm Hg (p less than 0.001), and dP/dt fell from 1,160 +/- 96 to 658 +/- 78 mm Hg/sec (p less than 0.001). In a second group, successive doses of amrinone were added to yield concentrations ranging from 5 to 50 micrograms/ml. There was a progressive decrease in delta P and dP/dt to 66.5 +/- 4.2% and 57.6 +/- 4.8% of initial values, respectively. CF increased progressively from 3.2 +/- 0.2 to 6.8 +/- 0.5 ml/min/g. In 3 experiments, amrinone was washed out after achieving the maximum concentration. Depressed mechanical function reversed and delta P and dP/dt returned to control values in each heart. Additionally, CF decreased from 7.6 +/- 0.3 to 5.0 +/- 0.2 ml/min/g. It is concluded that amrinone has concentration-dependent negative inotropic actions in the neonatal piglet heart. Hence, the drug may not be useful in treating heart failure in the human neonate.
cAMP regulation of myosin ATPase activity in the maturing rat heart.
Authors: Horowits R , Winegrad S
Published: June 2012

Calcium-activated myosin adenosine triphosphatase (ATPase) activity has been measured in sections of rat ventricles that were rapidly frozen to preserve the structure and regulatory state of myosin occurring in vivo. These results were related to myosin isozyme composition measured in ventricles by native gel electrophoresis and by quantitative immunocytochemistry. Both total ATPase activity and percent alpha-heavy chain rapidly rise during the first month following birth. However, ATPase activity remains constant at a high level from 1 to 12 months following birth, even though percent alpha-heavy chain declines during this period. The ATPase activity of V1 myosin was specifically determined using sections in which V3 myosin had been completely inhibited by exposure to alkaline pH in the absence of adenosine 5'-triphosphate (ATP). Relative V1 specific activity, taken as the ratio of V1 ATPase activity to percent alpha-heavy chain, doubles in the first 2.0 months after birth and then remains approximately constant at this higher level until at least 4 months after birth. The specific activity of V1 can be further increased by the addition of adenosine-3',5'-cyclic monophosphate (cAMP). This effect of cAMP is age dependent, increasing threefold between 1 and 2 months following birth and then declining as V1 is replaced by V3.
Acute decrease in left ventricular diastolic chamber distensibility during simulated angina in isolated hearts.
Authors: Isoyama S , Apstein C S , Wexler L F , Grice W N , Lorell B H
Published: June 2012

It is not clear what factors contribute to the prompt and reversible decrease in left ventricular diastolic chamber distensibility during angina pectoris that is induced by an increase in myocardial energy demand due to exercise or pacing tachycardia. To simulate the demand ischemia that occurs clinically during pacing-induced angina, we used isolated, blood-perfused rabbit hearts with restricted coronary flow and increased myocardial energy demand. A constant left ventricular balloon volume model was used to measure left ventricular diastolic chamber distensibility during 6 minutes of low-flow global ischemia, induced by a reduction in coronary perfusion pressure from 100 to 20 mm Hg. To investigate the influence of different levels of myocardial energy demand, the effects of two different heart rates were studied during low-flow global ischemia; pacing tachycardia (6.4 +/- 0.2 Hz, n = 7) was compared with the rabbit's baseline heart rate of 4 Hz (n = 7). Low-flow ischemia caused a marked decrease in contractile function relative to the baseline preischemic state. In the pacing-tachycardia group, myocardial energy demand, as estimated by the rate X systolic pressure product, was significantly greater than in the constant heart-rate group. When tachycardia was imposed during low-flow global ischemia, there was a transient and reversible increase in isovolumic left ventricular end-diastolic pressure from 14 +/- 1 to 25 +/- 4 mm Hg (measured during long diastoles obtained with transient cessation of pacing) in the pacing-tachycardia group, but there was no increase in left ventricular end-diastolic pressure during low flow ischemia in the constant heart-rate group with lower energy demand (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Beneficial effects of iloprost in the stunned canine myocardium.
Authors: Farber N E , Pieper G M , Thomas J P , Gross G J
Published: June 2012

The effect of the prostacyclin-mimetic, iloprost, on the reversibly damaged ("stunned") myocardium was studied in barbital-anesthetized, open-chest dogs subjected to 15 minutes of coronary artery occlusion and 3 hours of reperfusion. Regional myocardial segment shortening (%SS) was measured in the subendocardium of nonischemic and ischemic-reperfused areas by sonomicrometry. Iloprost was infused for 30 minutes beginning 15 minutes prior to occlusion (0.05 microgram/kg/min, ILO-LOW, or 0.1 microgram/kg/min, ILO-HIGH) or immediately prior to reperfusion (0.1 microgram/kg/min, ILO-REP). %SS in the ischemic-reperfused region recovered to 3% of pretreatment values in the control (saline-treated) group by 3 hours of reperfusion. In contrast, %SS in the iloprost-treated groups was significantly enhanced versus the control group at all times of reperfusion. At 3 hours of reperfusion, %SS recovered to 43% (ILO-LOW), 58% (ILO-HIGH), and 35% (ILO-REP) of pretreatment values. The beneficial effect on functional recovery was significantly greater when iloprost was administered before occlusion versus immediately prior to reperfusion. Thus, part of the salutory effects of iloprost appear to occur prior to and/or during ischemia. Iloprost did not improve collateral blood flow to the ischemic region or myocardial high energy phosphate content at 3 hours of reperfusion. While iloprost significantly decreased mean arterial pressure during ischemia and early reperfusion, the hypotensive action did not appear to play a role in the amelioration of postischemic dysfunction, as preocclusion treatment with an equihypotensive dose of sodium nitroprusside produced no significant effect on postischemic recovery beyond 5 minutes of reperfusion. Results of in vitro experiments indicated that iloprost had no effect on the xanthine oxidase free-radical generating system including lipid peroxidation. However, iloprost decreased the neutrophil-derived superoxide burst after chemotactic stimulation. This beneficial action may, in part, explain the efficacy of iloprost in enhancing postischemic function of the stunned myocardium.
Nonuniform epicardial activation and repolarization properties of in vivo canine pulmonary conus.
Authors: Burgess M J , Steinhaus B M , Spitzer K W , Ershler P R
Published: June 2012

The relation between nonuniform epicardial activation and ventricular repolarization properties was studied in 14 pentobarbital anesthetized dogs and with a computer model. In 11 dogs, isochrone maps of epicardial activation sequence were constructed from electrograms recorded from the pulmonary conus with 64 electrodes on an 8 X 8 grid with 2-mm electrode separation. The heart was paced from multiple sites on the periphery of the array. Uniformity of epicardial activation was estimated from activation times at test sites and their eight neighboring sites. Acceleration shortened and deceleration prolonged refractory periods. The locations of acceleration and deceleration sites of activation differed during drives from various sites, and differences in uniformity of activation during pairs of drives were correlated to differences in refractory periods (r = 0.76, range 0.59-0.93). In three additional experiments, transmural activation sequence maps were constructed from electrograms recorded from needle-mounted electrodes placed upstream and downstream to epicardial activation delays. Activation proceeded from epicardium to endocardium upstream to the delays and from endocardium to epicardium downstream to the delays. A computer simulation of two-dimensional action potential propagation based on the Beeler-Reuter myocardial membrane model provided insights to the mechanism for the results of the animal experiments. The two-dimensional sheet modeled the transmural anisotropic histology of the canine pulmonary conus and corresponded to previous reports and histology of specimens from five experiments. Simulated activation patterns were similar to those found in the experimental animals. In addition, action potentials were electronically prolonged at sites of deceleration and shortened at sites of acceleration, results comparable to the animal experiments. Our findings demonstrate that the location of areas of nonuniform epicardial activation is dependent on drive site and that nonuniform activation electronically modulates repolarization properties. Therefore it seems likely that the site of origin of ectopic ventricular complexes, especially in ischemic myocardium where activation is nonuniform, could be an important determinant of whether ectopic activity initiates sustained tachyarrhythmias.
Facilitating effect of cold shock on recovery from anoxia-induced contractile depression in isolated rat heart and heart muscle.
Authors: Okada T
Published: June 2012

The effect of rapid cooling on the recovery process from anoxia-induced hypodynamic state was studied in isolated rat ventricular muscle and ventricle. Following 10-15 minutes' perfusion of N2-saturated Krebs solution, the muscle was reoxygenated. When the muscle was rapidly cooled for 10-30 seconds during the early phase of reoxygenation, the rate of recovery from contracture significantly increased (p less than 0.01). Rapid cooling was also effective on the recovery from contracture induced by superfusion of Krebs solution with lowered sodium chloride concentration, but it did not affect the recovery from rigor induced by CN-. In the recovery from sustained anoxia (60 minutes), cooling facilitated reattainment of tension development and reduction in contracture tension. Similarly, in whole heart, 2-3 episodes of rapid cooling for about 60 seconds significantly accelerated the recovery of pressure development after 30 minutes of anoxia. At 60 minutes after reoxygenation, pressure development in hearts that were reoxygenated without rapid cooling was 29.8 +/- 26.9% (mean +/- SD) of pressure developed before anoxia. This value increased to 93.8 +/- 27.5% following recurrent rapid cooling (p less than 0.001). At the same time, rapid cooling prevented any significant elevation in resting tension (development of oxygen paradox). These results indicate that excess intracellular calcium ions were removed by rapid cooling. This relief of the myocardium from calcium overload is believed to improve mitochondrial function and result in facilitated recovery of contractile activity.
Pharmacologic treatment of hyperlipidemia reduces glomerular injury in rat 5/6 nephrectomy model of chronic renal failure.
Authors: Kasiske B L , O'Donnell M P , Garvis W J , Keane W F
Published: June 2012

The role of lipid abnormalities in the pathogenesis of focal glomerulosclerosis was investigated in the rat remnant kidney model of chronic renal failure. Rats subjected to right nephrectomy and two-thirds segmental infarction of the left kidney (5/6 nephrectomy) were treated for 10 weeks with the lipid-lowering agent clofibric acid. Both serum cholesterol and urine albumin excretion were significantly reduced by clofibric acid. At 10 weeks, the percent of glomeruli with focal glomerulosclerosis was 5 +/- 2% in clofibric acid-treated and 24 +/- 5% in untreated 5/6 nephrectomy rats (p less than 0.01). Inulin clearance was greater in clofibric acid-treated than in untreated 5/6 nephrectomy rats (0.28 +/- 0.02 versus 0.22 +/- 0.02 ml/min 100 g body wt, p less than 0.05). Body weight, kidney weight, and systemic blood pressure were not significantly altered by clofibric acid. Micropuncture studies, performed in separate groups of clofibric acid-treated and untreated 5/6 nephrectomy rats, demonstrated elevated single nephron glomerular filtration rates and glomerular capillary pressures 4 weeks after surgery. However, clofibric acid did not significantly alter single nephron glomerular filtration rates (95 +/- 2.1 nl/min in treated versus 97.0 +/- 6.2 nl/min in untreated, p greater than 0.05) or glomerular capillary pressures (56.6 +/- 1.5 mm Hg in treated versus 57.8 +/- 0.8 mm Hg in untreated, p greater than 0.05) in 5/6 nephrectomy rats. In a separate set of experiments, 5/6 nephrectomy rats were treated with the specific cholesterol synthesis inhibitor, mevinolin. Mevinolin improved serum lipid levels and reduced albuminuria in 5/6 nephrectomy rats without causing significant alterations in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Intracoronary alpha 2-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise.
Authors: Seitelberger R , Guth B D , Heusch G , Lee J D , Katayama K , Ross J
Published: June 2012

Studies on the role of alpha-adrenergic constrictor tone in the coronary vascular bed during ischemia were performed in dogs running on a treadmill. The animals were instrumented with a left ventricular pressure transducer, and regional systolic wall thickening (%WTh) was assessed by sonomicrometry in the anterior and posterior walls of the left ventricle. An intracoronary catheter was implanted chronically in the circumflex coronary artery, and a hydraulic cuff was placed proximally around the artery. After beta-adrenergic blockade with propranolol (0.8 mg/kg i.v.), acute stenosis of the coronary artery was performed during running in five dogs to induce severe regional myocardial dysfunction in the posterior wall. Intracoronary infusion of the selective alpha 2-adrenergic blocking agent idazoxan (80 micrograms/kg) improved %WTh in the ischemic region from 5.1 +/- 1.6 to 10.8 +/- 2.8% (p less than 0.05), without any significant effect on the anterior wall. Blood flow to the subendocardium of the posterior wall (radioactive microspheres) increased from 0.17 +/- 0.05 to 0.45 +/- 0.30 (ml/min)/g (p less than 0.05). It is concluded that in exercising dogs subjected to beta-adrenergic blockade, significant postjunctional alpha 2-adrenergic receptor-mediated coronary vasoconstriction exists, even during severe ischemia. Regional alpha 2-adrenergic receptor blockade can reduce regional ischemia and improve contractile function by attenuating exercise-induced sympathetic vasoconstriction in this conscious animal model.
Adrenaline increases the rate of cycling of crossbridges in rat cardiac muscle as measured by pseudo-random binary noise-modulated perturbation analysis.
Authors: Hoh J F , Rossmanith G H , Kwan L J , Hamilton A M
Published: June 2012

The mechanism of action of adrenaline on cardiac contractility in rat papillary muscles containing V1 and V3 isomyosins was analyzed during barium-activated contractures at 25 degrees C by frequency domain analysis using pseudo-random binary noise-modulated perturbations. The analysis characterizes a frequency (fmin) at which dynamic stiffness of a muscle is a minimum, a parameter that reflects the rate of cycling of crossbridges. We have previously shown that fmin for V1- and V3-containing papillary muscles were 2.1 +/- 0.2 Hz (mean +/- SD) (n = 10) and 1.1 +/- 0.2 Hz (n = 8), respectively, and that these values were independent of the level of activation. The present study's goal was to determine whether the inotropic action of adrenaline was associated with an increased rate of crossbridge cycling. The results show that a saturating dose of adrenaline increased fmin in V1 hearts by 49 +/- 2% (n = 11). The action on V3 hearts was significantly less; the increase in fmin was 26 +/- 2% (n = 6). The increase in fmin for V1 hearts was shown to be sensitive to the beta-blocking agent propranolol. These results suggest that adrenaline significantly increases the rate of crossbridge cycling by a beta-receptor-mediated mechanism. We conclude that the increased contractility of the heart in the presence of adrenaline arises not only from more complete activation of the contractile proteins but also from the increased rate at which each crossbridge can transduce energy.