bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of a chronic treatment by nisoldipine, a calcium antagonistic dihydropyridine, on arteries of spontaneously hypertensive rats.
Authors: Godfraind T , Kazda S , Wibo M
Published: June 2012

Earlier studies have shown that relaxation in response to several agents is impaired in arteries from spontaneously hypertensive rats (SHR). We had previously reported that SHR aortas present a delayed relaxation when first exposed for 35 minutes to a 100 mM KCl solution and then transferred into physiological solution. The first phase of relaxation appeared similar in SHR and Wistar-Kyoto rat arteries, but the second phase was markedly slowed down in SHR arteries, giving rise to a postcontraction tone. In this study, we found that this postcontraction tone could be demonstrated not only in the aorta but also in the mesenteric artery, was independent of the presence of endothelium, increased with the age of SHR, and disappeared progressively when arterial segments were submitted to successive cycles of KCl depolarization followed by reimmersion in physiological solution. Chronic treatment of SHR with nisoldipine at doses that blocked the development of hypertension and attenuated the concomitant hypertrophy of heart and aorta, or in vitro pretreatment of SHR arteries with nisoldipine, decreased the contractile force developed by arteries in response to KCl depolarization and normalized the subsequent relaxation. [3H] (+)-PN200-110 binding studies on heart and brain homogenates indicated an increase in apparent Kd in nisoldipine-fed rats without significant change in Bmax. Binding data were compatible with the view that occupation of dihydropyridine receptors by nisoldipine after chronic oral administration was responsible for the modifications observed ex vivo in the mechanical activity of arteries. We conclude that the postcontraction tone of SHR arteries was mainly due to an abnormally prolonged activation of calcium channels after transfer of depolarized arteries into the physiological solution and that a labile or slowly releasable factor was probably involved in this phenomenon. We suggest that the antihypertensive action of nisoldipine might be related to the mechanisms involved in the suppression of the postcontraction tone as observed in vitro and that this mode of action could be more important than the vasodilating effect of this drug.
Energetics of isometric force development in control and volume-overload human myocardium. Comparison with animal species.
Authors: Hasenfuss G , Mulieri L A , Blanchard E M , Holubarsch C , Leavitt B J , Ittleman F , Alpert N R
Published: June 2012

Alteration in crossbridge behavior and myocardial performance have been associated with myosin isoenzyme composition in animal models of myocardial hypertrophy or atrophy. In the hypertrophied human heart, myocardial performance is altered without significant changes in myosin isoenzymes. To better understand this discrepancy, isometric heat and force measurements were carried out in 1) control and volume-overload human myocardium, 2) control, pressure-overload, and hyperthyroid rabbit myocardium, and 3) control and hypothyroid rat myocardium. In control human myocardium, peak isometric twitch tension was 44.0 +/- 11.7 mN/mm2, and maximum rate of tension rise was 69.2 +/- 21.0 mN/sec.mm2. In volume-overload human myocardium, peak twitch tension and maximum rate of tension rise were reduced by 55% (p less than 0.05) and 65% (p less than 0.05), respectively. The average force-time integral of the individual crossbridge cycle, calculated by myothermal techniques, was increased by 85% (p less than 0.005) in volume-overload human myocardium. In control and hormonally altered myocardium, both across and within species (control human, control rat, control rabbit, hypothyroid rat, and hyperthyroid rabbit), there was a close relation between the crossbridge force-time integral and the percentage of V3-type myosin isoenzyme in the myocardium. However, hemodynamically altered (volume-overload human and pressure-overload rabbit) myocardium did not follow this relation. Across and within species, there were significant correlations between maximum rate of tension rise and average tension-dependent heat rate (r = 0.97, p less than 0.001) and between maximum rate of tension fall and average tension-independent heat rate (r = 0.82; p less than 0.025). Furthermore, there were close inverse relations between these heat rates and the crossbridge force-time integral. In addition, there was an inverse relation between tension-independent heat and the crossbridge force-time integral. Across and within species total myocardial energy turnover was significantly correlated with the crossbridge force-time integral (relative total heat, r = -0.84, p less than 0.02; relative total-activity related heat, r = -0.88, p less than 0.01). The present findings indicate that 1) factors separate from myosin isoenzymes account for the altered crossbridge cycle in volume-overload human and pressure-overload rabbit myocardium, 2) changes in excitation-contraction coupling processes accompany changes in the crossbridge cycle within and across species, and 3) the force-time integral of the crossbridge cycle is a major determinant of total myocardial energy turnover.
Mechanisms responsible for the heterogeneous coronary microvascular response to nitroglycerin.
Authors: Kurz M A , Lamping K G , Bates J N , Eastham C L , Marcus M L , Harrison D G
Published: June 2012

Nitroglycerin dilates large (greater than or equal to 100 microns) but not small coronary arterial microvessels, and a putative metabolite of nitroglycerin, S-nitroso-L-cysteine, has been shown in vitro to dilate both large and small coronary microvessels. Based on this evidence, we tested the hypothesis that the lack of response of small coronary microvessels was due to an inability of small coronary microvessels to convert nitroglycerin into its vasoactive metabolite and examined possible explanations for this phenomenon. We studied left ventricular epicardial microvessels in vivo using video microscopy and stroboscopic epi-illumination in anesthetized, open-chest dogs. Diameters were determined while the epicardium was suffused with nitroglycerin, S-nitroso-L-cysteine, or S-nitroso-D-cysteine (all 10 microM) and nitroglycerin in the presence of L- or D-cysteine (100 microM). None of the agents affected systemic hemodynamics. Nitroglycerin dilated large arterioles (20 +/- 2%) but not small arterioles (1 +/- 1%). Both S-nitroso-L-cysteine and S-nitroso-D-cysteine were potent dilators of all size classes of microvessels. Concomitant application of L-cysteine and nitroglycerin evoked dilation in small microvessels (22 +/- 4%, p less than 0.5 versus nitroglycerin alone) and larger microvessels (27 +/- 6%, p = NS versus nitroglycerin alone). D-Cysteine did not alter the microvascular response to nitroglycerin in either small (7 +/- 4%, p = NS versus nitroglycerin alone) or large (18 +/- 3%, p = NS versus nitroglycerin alone) microvessels. Neither L-cysteine nor D-cysteine had a direct effect on microvascular diameter. These findings suggest that 1) sulfhydryl groups are required for the conversion of nitroglycerin to its vasoactive metabolite; 2) the interaction between nitroglycerin and sulfhydryl residues is a stereospecific process, indicating either an intracellular mechanism or a membrane-associated enzymatic reaction; and 3) a lack of available sulfhydryl groups may be responsible for the lack of response of small coronary arterioles to nitroglycerin.
Fasting in vivo delays myocardial cell damage after brief periods of ischemia in the isolated working rat heart.
Authors: Schneider C A , Taegtmeyer H
Published: June 2012

To assess the effects of fasting on recovery of function and exogenous glucose metabolism after 15 minutes of total ischemia, we perfused isolated working rat hearts from fed and fasted animals. Hearts were perfused in a recirculating system with bicarbonate buffer containing glucose (10 mM). Mechanical performance, release of marker proteins for ischemic membrane damage (lactate dehydrogenase, myoglobin, citrate synthase), and the concentrations of lactate and glucose in the perfusion medium were measured serially. Tissue metabolites were also measured. Fasting raised the myocardial glycogen content by 25%. Cardiac performance of perfused hearts from fed and fasted animals was the same during the preischemic and the post-ischemic period. The time of return of function to preischemic values was significantly less in hearts from fasted rats (2.3 versus 7.8 minutes, p less than 0.025). The release of cytosolic and mitochondrial marker proteins was significantly lower in hearts from fasted rats than in hearts from fed rats. Glucose metabolic rates during control and reperfusion were unchanged for hearts from fasted rats, but decreased for hearts from fed rats during reperfusion. The adenine nucleotide content at the end of ischemia was higher in hearts from fasted animals than in hearts from fed animals. We conclude that increasing glycogen levels prior to ischemia improves recovery of function, lessens membrane damage, and prevents loss of adenine nucleotides.
Antiarrhythmic actions of the ATP-regulated K+ current activated by pinacidil.
Authors: Spinelli W , Sorota S , Siegal M , Hoffman B F
Published: June 2012

We tested the hypothesis that a selective increase in membrane current, as contrasted with the decreases in currents caused by most antiarrhythmic agents, would be an effective antiarrhythmic intervention. We studied models of early afterdepolarizations (EADs), delayed afterdepolarizations (DADs), and abnormal automaticity in single canine ventricular myocytes using intracellular microelectrodes or patch electrodes. EADs were induced by injected current, Bay K 8644 (0.5-1 microM), or ketanserin (1.0 microM); DADs were induced by ouabain intoxication (2 x 10(-7) M); and abnormal automaticity was induced by exposure to barium (0.25 mM). To increase outward K+ current, we used pinacidil and the protein kinase C activator 4 beta-phorbol 12,13-dibutyrate (PDBu). Under control conditions, 10-100 microM pinacidil caused a concentration-dependent and reversible decrease in action potential duration and an increase in steady-state outward current; both effects were blocked by glibenclamide and thus presumably reflected changes in the ATP-regulated potassium current. Pinacidil increased the current required to induce EADs and abolished EADs caused by Bay K 8644 or ketanserin. After exposure of myocytes to ouabain, pinacidil caused a decrease in action potential duration and diminished or abolished DADs. Finally, pinacidil arrested abnormal automaticity caused by Ba2+. PDBu (30 nM) shortened action potential duration without altering plateau amplitude in some of the myocytes. In these cells the depolarizing current needed to produce an EAD was increased by over 70%; outward potassium current tails were also increased, an effect consistent with an increase of the repolarizing potassium current (IK). These findings show that each of the mechanisms for abnormal impulse generation can be effectively antagonized by an increase in outward current and suggest to us that selective augmentation of a repolarizing current, possibly IK, might be a reasonable antiarrhythmic intervention.
Inhibitors of cytochrome P-450 attenuate the myogenic response of dog renal arcuate arteries.
Authors: Kauser K , Clark J E , Masters B S , Ortiz de Montellano P R , Ma Y H , Harder D R , Roman R J
Published: June 2012

The role of cytochrome P-450 in the myogenic response of isolated, perfused renal arcuate arteries of dogs to elevations in transmural pressure was examined. The phospholipase A2 inhibitor oleyloxyethylphosphorylcholine (1 and 10 microM) inhibited the greater than threefold increase in active wall tension in these arteries after an elevation in perfusion pressure from 80 to 160 mm Hg. Inhibition of cyclooxygenase activity with indomethacin (1 or 10 microM) had no effect on this response. The cytochrome P-450 inhibitors ketoconazole (10 and 100 microM) and beta-diethyl-aminoethyldiphenylpropylacetate (SKF 525A, 10 and 100 microM) also inhibited the myogenic response. At a pressure of 160 mm Hg, SKF 525A (10 microM) and ketoconazole (100 microM) reduced active wall tension in renal arteries by approximately 70%. Partial inhibition of the myogenic response was obtained after perfusion of the vessels with mechanism-based inhibitors of P-450, 1-aminobenzotriazole (75 microM) and 12-hydroxy-16-heptadecynoic acid (20 microM). The thromboxane receptor antagonist SQ 29,548 (1 or 10 microM) had no effect on the pressure-induced increase in active wall tension in renal arteries. Arachidonic acid (50 microM) constricted isolated perfused renal arteries and potentiated the myogenic response in the presence of indomethacin. This response was completely reversed by ketoconazole (100 microM) or SKF 525A (100 microM). Microsomes (1 mg/ml) prepared from small renal arteries (200-500 microns) and incubated with [1-14C]arachidonic acid (0.5 mu Ci, 50 microM) produced a metabolite that coeluted with 20-hydroxyeicosatetraenoic acid (20-HETE) during reversed-phase high-performance liquid chromatography. The formation of this product was inhibited by both ketoconazole and SKF 525A at concentrations of 10 and 100 microM. These results are consistent with the involvement of the vasoconstrictor 20-HETE and other cytochrome P-450 metabolites of endogenous fatty acids in the myogenic response.
Intracellular calcium transients in myocardium from spontaneously hypertensive rats during the transition to heart failure.
Authors: Bing O H , Brooks W W , Conrad C H , Sen S , Perreault C L , Morgan J P
Published: June 2012

To investigate the mechanism of impaired myocardial function after long-term pressure overload, we studied cardiac muscle mechanical contraction and intracellular calcium transients using the bioluminescent indicator aequorin. Left ventricular papillary muscle preparations were examined from three groups of rats: 1) aging spontaneously hypertensive rats (SHR) with clinical and pathological evidence suggesting heart failure (SHR-F group), 2) age-matched SHRs with no evidence of heart failure (SHR-NF group), and 3) age-matched normotensive Wistar-Kyoto rats (WKY group). Isometric force development was depressed in both SHR groups relative to the WKY group. Resting [Ca2+]i was lower in the SHR-F group, and the time to peak [Ca2+]i was prolonged in this group. The relative increases in peak [Ca2+]i with the inotropic interventions of increased [Ca2+]o and the addition of isoproterenol were similar among groups. Although inotropy increased in all groups with increased [Ca2+]o, after isoproterenol, inotropy increased only in the WKY group. Thus, in SHR myocardium, [Ca2+]i increased after isoproterenol, but inotropy failed to increase. Myosin isozymes were shifted toward the V3 isoform in both SHR groups; the V3 isoform was virtually 100% in papillary muscles from the SHR-F group. These changes may reflect events directly contributing to the development of heart failure or represent adaptive changes to chronic pressure overload and heart failure.
Myocardial angiogenesis and coronary perfusion in left ventricular pressure-overload hypertrophy in the young lamb. Evidence for inhibition with chronic protamine administration.
Authors: Flanagan M F , Fujii A M , Colan S D , Flanagan R G , Lock J E
Published: June 2012

In contrast to young growing animals, pressure-overload hypertrophy in adults is frequently associated with diminished myocardial capillary density and maximal coronary flow per gram. To determine the role of angiogenesis in maintaining perfusion capacity in the hypertrophying heart, the angiogenesis inhibitor protamine sulfate was administered to young lambs during the development of left ventricular (LV) pressure-overload hypertrophy. Baseline and maximum (adenosine) myocardial perfusion was measured in four groups of chronically instrumented 10-week-old lambs subjected to 1) ascending aortic bands since the age of 4 weeks (LVH group, n = 10), 2) sham operation at the age of 4 weeks (SHAM group, n = 8), 3) aortic bands and twice daily injections of protamine since the age of 4 weeks (LVH + P group, n = 9), 4) sham operation and injection of protamine (SHAM + P group, n = 8). Capillary density was measured postmortem. Peak LV pressure and the LV/body weight ratio were similarly increased in LVH and LVH + P compared with sham-operated lambs (p less than 0.001). In LVH lambs, LV capillary number increased by 32% compared with sham-operated lambs (p less than 0.05), and capillary density, coronary flow reserve, and minimal coronary resistance remained normal. In contrast, LVH + P lambs had no significant increase over SHAM lambs in LV capillaries and total maximum coronary flow. The LVH + P lambs had lower LV subendomyocardial capillary density and higher minimal coronary resistance per gram (p less than 0.05 versus LVH lambs). Right ventricular capillary density and minimal resistance were similar in all groups. These findings support the hypotheses that myocardial angiogenesis with pressure-overload hypertrophy is important in maintaining maximal LV coronary flow in the young and that impairment of angiogenesis results in diminished coronary flow capacity.
Effect of norepinephrine and heart rate on intracellular sodium activity and membrane potential in beating guinea pig ventricular muscle.
Authors: Wilde A A , Kléber A G
Published: June 2012

The effect of 3 microM norepinephrine (NE) on intracellular sodium activity (aiNa) and resting membrane potential was studied by continuous intracellular recordings with a conventional and an ion-selective microelectrode. The electrodes were impaled simultaneously in small (diameter, 0.3 mm) superfused trabeculae of the beating guinea pig ventricle at 37 degrees C. In the absence of NE, changes of the beating rate produced an increase of aiNa by 1.5 +/- 0.17 mM (from 0 to 1 Hz) and 1.9 +/- 0.47 mM (from 0 to 2 Hz). In the presence of NE, there was a very small significant increase of aiNa during constant stimulation (1 Hz) and at at [K+]o of 4.7 and 11.5 mM. After 7 minutes of exposure, aiNa increased by 0.5 +/- 0.19 mM (mean +/- SEM, n = 4) at [K+]o of 4.7 mM and by 0.5 +/- 0.22 (n = 6) at [K+]o of 11.5 mM. Resting membrane potential became more positive by 1 mV at both levels of [K+]o. The effect of NE became also clearly manifest from the configurational changes of action potentials (profound increase in plateau height and duration). Stimulation of the Na(+)-K+ pump by NE became manifest from the changes of resting membrane potential and aiNa after abrupt cessation of stimulation. The magnitude and the rate of the decrease in aiNa and the initial rate of hyperpolarization were significantly greater in the presence of NE than in its absence.(ABSTRACT TRUNCATED AT 250 WORDS)
Neointima formation impairs endothelial muscarinic receptors while enhancing prostacyclin-mediated responses in the rabbit carotid artery.
Authors: De Meyer G R , Bult H , Van Hoydonck A E , Jordaens F H , Buyssens N , Herman A G
Published: June 2012

The purpose of this study was to determine whether the generation of a neointima, an early step in the development of atherosclerosis, affects endothelium-dependent or -independent vasodilation. The neointima was induced, within 7 days, by positioning a nonocclusive silicone collar around one carotid artery in rabbits. After 1, 2, 7, or 14 days segments were cut from the collar-surrounded region of this artery as well as from the sham-operated contralateral artery and were used for isometric tension recording or for bioassay of nitric oxide (NO). The acetylcholine-induced release of NO was significantly reduced at 7 days. The tension recordings suggested that this already occurred at the earliest stages of neointima formation. Neither the capacity of the endothelial cells to form NO in response to the calcium ionophore A23187 nor the capacity of the underlying smooth muscle cells to relax in response to sources of exogenous NO (3-morpholinosydnonimine and nitroglycerin) was affected by the neointima. Therefore, the impaired endothelium-dependent relaxations to acetylcholine are presumably due to a defect at the level of the endothelial muscarinic receptors. The presence of a fully developed neointima did not alter the responsiveness to isoproterenol and forskolin but enhanced prostacyclin-mediated responses (assessed by iloprost and 13-hydroxyoctadecadienoic acid). These results illustrate selective alterations of endothelial and smooth muscle cell function in intima generation before fatty streak formation.
Simulation of high-resolution QRS complex using a ventricular model with a fractal conduction system. Effects of ischemia on high-frequency QRS potentials.
Authors: Abboud S , Berenfeld O , Sadeh D
Published: June 2012

Recent studies have analyzed the high-fidelity surface electrocardiographic signal, and efforts have been made to increase the diagnostic sensitivity of the electrocardiogram by observing its high-frequency components. It was found that the high-frequency (150-250-Hz) electrocardiogram appears to detect evidence of transient ischemia with greater sensitivity than visual inspection of the surface electrocardiogram. A finite-element three-dimensional model of the ventricles with a self-similar (fractal) conduction system has been introduced as a bridge to the understanding of electrocardiographic phenomena related to high-frequency potentials. The model was activated, and the dipole potential generated by adjacent activated and resting cells was calculated to obtain a high-resolution QRS complex. Normal and ischemic activation processes was stimulated by regional reduction in conduction velocity. It was found that although the resulted low-frequency QRS complex was not significantly altered from normal conditions, the high-frequency components exhibited morphological changes similar to the ones observed during animal experiments and human studies. Based on the results obtained from the model, it can be concluded that these morphological changes can be attributed to a slowing of conduction velocity in the region of ischemia and that the model is adequate for meeting the challenges imposed by the requirements of high-frequency methods applied in clinical cardiology.
Prolongation of repolarization time by electric field stimulation with monophasic and biphasic shocks in open-chest dogs.
Authors: Zhou X H , Knisley S B , Wolf P D , Rollins D L , Smith W M , Ideker R E
Published: June 2012

Recent studies suggest that 1) electrically induced fibrillation and defibrillation involve prolongation of refractoriness by the shock in addition to stimulation and 2) biphasic waveforms are more efficient for defibrillation than are comparable monophasic waveforms. The purpose of this study was to compare prolongation of action potential duration at 50% repolarization by monophasic and biphasic shocks during paced rhythm. A floating glass microelectrode was used to record intracellularly from the anterior right ventricular epicardium in seven open-chest dogs. After 10 S1 beats paced at an interval of 350 msec, 5-msec and 2.5-msec monophasic shocks and biphasic shocks, with each phase of 2.5 msec, were given via mesh electrodes on either side of the microelectrode. The shock strength was adjusted so that the shock field, measured from eight extracellular electrodes encircling the microelectrode, was about 5 V/cm. Monophasic and biphasic S2 shocks were given starting with an S1-S2 interval of 120 msec, which was increased in 5-msec steps until an action potential was produced by the S2 shock. Both monophasic and biphasic 5 V/cm shock fields caused significant prolongation of action potential duration. The prolongation of action potential duration increased as the S1-S2 interval increased. This prolongation occurred at shorter S1-S2 intervals for 5-msec monophasic shocks than for biphasic shocks.
Impaired diastolic function and coronary reserve in genetic hypertension. Role of interstitial fibrosis and medial thickening of intramyocardial coronary arteries.
Authors: Brilla C G , Janicki J S , Weber K T
Published: June 2012

Left ventricular hypertrophy (LVH) in rats with genetic hypertension is accompanied by abnormal myocardial diastolic stiffness and impaired coronary reserve. Whether these functional defects are related to a structural remodeling of the myocardium that includes an interstitial and perivascular fibrosis, myocyte hypertrophy, and medial thickening of intramyocardial coronary arteries is uncertain. To address these issues, 14-week-old male spontaneously hypertensive rats with established hypertension and LVH were treated with low-dose (SLO group: 2.5 mg/kg/day, n = 11) or high-dose (SHI group: 20 mg/kg/day, n = 9) oral lisinopril for 12 weeks to sustain hypertension and LVH or to normalize arterial pressure and myocardial mass, respectively. When SHI and SLO groups were compared with age- and sex-matched 26-week-old untreated spontaneously hypertensive rats (n = 11) and normotensive Wistar-Kyoto rats (n = 9), we found 1) normalization of blood pressure (p less than 0.005) and complete regression of LVH (p less than 0.005) in the SHI group and no significant blood pressure or LVH reduction in the SLO group, 2) complete regression of morphometrically determined myocardial interstitial and perivascular fibrosis in SHI and SLO groups (p less than 0.025) associated with normalization of diastolic stiffness, measured in the isolated heart (p less than 0.025), and 3) regression of medial wall thickening of intramyocardial coronary arteries only in the SHI group (P less than 0.005), accompanied by a normalization of coronary vasodilator reserve to adenosine (p less than 0.005). Thus, interstitial fibrosis and not LVH is responsible for abnormal myocardial diastolic stiffness, whereas medical wall thickening of intramyocardial resistance vessels, influenced by arterial pressure, is associated with impaired coronary reserve.
Stimulation of fibroblast collagen and total protein formation by an endothelial cell-derived factor.
Authors: Villanueva A G , Farber H W , Rounds S , Goldstein R H
Published: June 2012

We investigated the effect of medium conditioned by bovine aortic endothelial cells on collagen accumulation and total protein formation by human embryonic fibroblasts or bovine smooth muscle cells in cultures. The conditioned medium at a 1:10 dilution induced a twofold increase in collagen and total protein accumulation in fibroblast cultures. At low concentration (1:50 dilution), the conditioned medium stimulated collagen accumulation preferentially; at high concentration (1:10 dilution), overall protein synthesis also was increased. The increase in type I collagen accumulation was associated with an increase in the steady-state level of alpha 1 (I) mRNA for collagen. The conditioned medium increased the production of types I and III collagen without affecting the proportion of collagen types in both fibroblast and smooth muscle cell cultures. Partial purification of the endothelial cell-derived factor disclosed it to be a heat-stable protein with an apparent molecular weight of 8-10 kDa. The stimulation of protein formation by this substance was not inhibited by antibodies against transforming growth factor-beta or the insulinlike growth factor I receptor. The partially purified factor stimulated protein production without affecting fibroblast proliferation. This endothelial cell-derived protein may play a role in the remodeling of vascular connective tissue by stimulating collagen synthesis.
Arachidonic acid elicits endothelium-dependent release from the rabbit aorta of a constrictor prostanoid resembling prostaglandin endoperoxides.
Authors: Pagano P J , Lin L , Sessa W C , Nasjletti A
Published: June 2012

This study was designed to investigate the mediator(s) of endothelium-dependent arterial constrictor responses evoked by arachidonic acid in vitro. A segment of descending rabbit thoracic aorta was isolated and perfused (1-2 ml/min) with oxygenated Krebs' bicarbonate buffer. Changes in the vascular smooth muscle-contracting activity of the aortic effluent were detected by superfusion bioassay using either strips of rabbit aorta or rings of dog saphenous vein, both denuded of endothelium and exposed to indomethacin (10 microM). Arachidonic acid (5-50 micrograms) injected into the inflow of the perfused aorta caused a dose-related increase in the vascular smooth muscle-contracting activity of the aortic effluent, whereas arachidonic acid added directly into the aortic effluent did not. The arachidonic acid-induced elevation of vascular smooth muscle-contracting activity in the aortic effluent was not apparent when indomethacin (10 microM) was added to the aortic inflow to inhibit cyclooxygenase, when the endothelium of the perfused aorta was removed by rubbing, or when the thromboxane A2/prostaglandin H2 receptors of the vascular tissues used for bioassay were blocked with an antagonist (1 microM SQ29548), and was unaffected when an inhibitor of thromboxane synthase (10 microM CGS 13080) was added to the aortic inflow. This effect of arachidonic acid was accompanied by release of prostaglandin H2 (measured as prostaglandin F2 alpha after reduction with SnCl2) in amounts sufficient to elicit contraction of the vascular tissues used for bioassay and was attenuated when a reducing agent (2 mM FeCl2) that converts prostaglandin H2 to 12-heptadecatrienoic acid was added to the aortic effluent. Collectively, these observations suggest that arachidonic acid stimulates endothelium-dependent release from the perfused aorta of a prostanoid that contracts vascular smooth muscle via interaction with thromboxane A2/prostaglandin H2 receptors. The study also suggests that the prostanoid responsible for the vascular smooth muscle-contracting activity of the aortic effluent is a prostaglandin endoperoxide(s) rather than thromboxane A2.
Intrarenal hemodynamics in patients with essential hypertension.
Authors: Kimura G , Imanishi M , Sanai T , Kawano Y , Kojima S , Yoshida K , Abe H , Ashida T , Yoshimi H , Kawamura M
Published: June 2012

Intrarenal hemodynamics were estimated clinically in essential hypertension. Two-week studies were performed in 30 patients with essential hypertension who were given a regular sodium diet in the first week and a sodium-restricted diet in the second week. Intrarenal hemodynamic parameters such as afferent arteriolar (preglomerular) resistance, efferent arteriolar resistance, and glomerular hydrostatic pressure were calculated from renal clearances and plasma total protein concentration measured on the last day of the regular sodium diet. Calculations were based on Gomez's equations with the assumption that the gross filtration coefficient of glomerular capillaries was normal. The increase in afferent arteriolar resistance (8,100 +/- 500 dyne.sec.cm-5) was significantly correlated with an elevation in mean arterial pressure (120 +/- 2 mm Hg), whereas glomerular pressure (56 +/- 1 mm Hg) and efferent arteriolar resistance (2,500 +/- 100 dyne.sec.cm-5) remained normal. The renal function curve (pressure-natriuresis relation) was drawn by plotting urinary sodium excretion on the y axis as a function of mean arterial pressure on the x axis, both of which were measured on the last 3 days of each week. The extrapolated x intercept (107 +/- 2 mm Hg) of the renal function curve was strongly correlated in a 1:1 fashion with the sum of the arterial pressure drop from the aorta to the renal glomeruli plus the opposing pressures against glomerular filtration at glomeruli (r = 0.7, p less than 0.001) on the regular sodium diet, suggesting that the difference between mean arterial pressure on the regular sodium diet and the extrapolated x intercept represented the effective filtration pressure across the glomerular capillaries on the regular sodium diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Sympathetic stimulation-evoked overflow of norepinephrine and neuropeptide Y from the heart.
Authors: Warner M R , Senanayake P D , Ferrario C M , Levy M N
Published: June 2012

Neuropeptide Y (NPY) and norepinephrine are released together on sympathetic activation. To compare the time courses of NPY and norepinephrine washout from cardiac tissues, we measured the overflow of NPY-like immunoreactivity (NPY-LI) and norepinephrine in coronary sinus blood before, during, and after 3-minute trains of ansae subclaviae stimulation in 13 anesthetized dogs. We also measured vagally induced cardiac cycle length responses before and after ansae stimulation. Ansae stimulation increased NPY-LI and norepinephrine overflow from the heart in a frequency-dependent manner (p less than 0.02). After stimulation of the ansae at 5 and 10 Hz, the peak norepinephrine overflows decayed by 90% within 2 minutes, but the NPY-LI overflows required 17 +/- 11 and 35 +/- 21 minutes, respectively, to decay by 90%. Cardiac vagal effects were inhibited after 5- and 10-Hz ansae stimulations, and the peak inhibitions decayed by 90% after 19 +/- 7 and 39 +/- 16 minutes, respectively. The 90% decay times of the NPY-LI overflows were longer (p less than 0.003) than those of the norepinephrine overflows but did not differ significantly (p greater than 0.4) from the 90% decay times of the inhibition of vagal effects. We characterized NPY-LI in coronary sinus and arterial plasma by reversed-phase high-performance liquid chromatography. Before ansae stimulation, the main peak of NPY-LI in the plasma had a retention time similar to that of the oxidized human NPY-(1-36) standard. During ansae stimulation, however, there was a substantial increase in the peak of NPY-LI that eluted in a position similar to that of the monoxidized human NPY-(1-36) standard. These data support the hypothesis that neurally released NPY mediates the sympathetically evoked inhibition of vagal effects and indicate that the time course of removal of NPY from the heart differs substantially from that of norepinephrine. Moreover, under basal conditions, most NPY in the circulation is present in the oxidized form or as a fragment of the 36-amino-acid peptide. In contrast, cardiac sympathetic stimulation evokes the overflow of monoxidized NPY-(1-36) into the coronary sinus plasma.
Catecholamine release from bovine adrenal chromaffin cells during anoxia or metabolic inhibition.
Authors: Dry K L , Phillips J H , Dart A M
Published: June 2012

A significant release of catecholamines within the heart has been observed during myocardial ischemia. Because this can be markedly inhibited by amine-uptake-blocking agents, it has been suggested that its mechanism is a carrier-mediated efflux from neurons, which is not operative under normal conditions. The present work examined this release process in chromaffin cells isolated from the bovine adrenal medulla, a model system for studying the sympathetic nervous system. Chromaffin cells in primary culture retained normal secretory responses for up to 7 days. Conditions designed to mimic ischemia, that is, anoxia or metabolic inhibition, resulted in a significant release of catecholamines. This release was shown to be independent of extracellular calcium but, in contrast to the release observed in ischemic hearts, was not inhibited by amine-uptake blockers. Electrophoresis with immunoblotting demonstrated that significant levels of the chromaffin granule protein, chromogranin A, were released during metabolic inhibition, indicative of an exocytotic mechanism. However, there was no release of the cytosolic protein, lactate dehydrogenase, indicating that there was no concomitant breakdown of the cell membrane. These results provide evidence for an exocytotic release of catecholamines mediated by the direct action of conditions of metabolic inhibition.
Alterations in myocyte shape and basement membrane attachment with tachycardia-induced heart failure.
Authors: Zellner J L , Spinale F G , Eble D M , Hewett K W , Crawford F A
Published: June 2012

Chronic supraventricular tachycardia (SVT) results in left ventricular (LV) dilatation and dysfunction. However, the underlying mechanisms responsible for LV failure in this setting are not known. LV force production is dependent on the coupling of myocytes to the extracellular matrix, which is mediated through the basement membrane. This study was designed to determine whether alterations in myocyte geometry and basement membrane attachment are associated with LV failure in a pacing-induced model of cardiomyopathy. Echocardiographic measurement of LV function was performed in six pigs after 3 weeks of pacing-induced SVT (240 beats/min) and in eight sham-operated controls. Myocytes from these hearts were isolated, and attachment studies to specific components of the basement membrane were performed using laminin, fibronectin, and collagen IV. The SVT group when compared with the control group showed a significant reduction of LV fractional shortening (14 +/- 2% versus 31 +/- 2%, respectively; p less than 0.05), increased end-diastolic dimension (50 +/- 1 versus 35 +/- 1 mm, respectively; p less than 0.05), and lengthening of isolated myocytes (196 +/- 18 versus 142 +/- 9 microns, respectively; p less than 0.05). Myocyte attachment to laminin (50 micrograms/ml) was significantly decreased at 60 minutes in the SVT group compared with the control group (18.2 +/- 4.5 versus 60.9 +/- 4.5 cells/mm2, respectively; p less than 0.05). Similar reductions in myocyte attachment to fibronectin and collagen IV were observed. Ultrastructural examination of LV sections revealed focal disruptions of the basement membrane-sarcolemmal interface and a reduced number of sarcolemmal festoons in SVT hearts compared with control hearts (0.8 +/- 0.6 versus 2.8 +/- 0.8/4 microns, respectively; p less than 0.05). These alterations in myocyte morphology and basement membrane attachment may contribute to the LV failure associated with chronic SVT. Further, these structural changes may play a significant role in the progression of ventricular dysfunction as well as recovery from chronic SVT.
Acetylcholine-induced coronary vasoconstriction and vasodilation in tranquilized baboons.
Authors: Knight D R , Shen Y T , Young M A , Vatner S F
Published: June 2012

To determine the effects of acetylcholine on the coronary bed in the baboon and whether the effects preceded or followed the action of acetylcholine on ventricular function, eight adult baboons (Papio anubis) were instrumented to measure left ventricular (LV) and mean arterial pressures, LV dP/dt, regional myocardial function, and coronary blood flow. Acetylcholine was injected locally through a catheter positioned in the coronary artery ostium using fluoroscopic guidance in intact sedated baboons. With heart rate held constant, intracoronary acetylcholine (0.5 micrograms/kg) reduced coronary blood flow by 82 +/- 4% from a baseline value of 34 +/- 4 ml/min without a significant change in mean arterial pressure and with a reduction in LV dP/dt of only 12 +/- 3%. The decrease in coronary blood flow occurred before either LV dP/dt or regional myocardial function fell in the region of the heart receiving acetylcholine. After the intense coronary constriction, a later phase characterized by dilation was observed. The changes in coronary blood flow with acetylcholine were unaffected by combined alpha- and beta-adrenoceptor blockades but were abolished by muscarinic blockade. Low doses of acetylcholine elicited only coronary vasodilation. All doses of acetylcholine, administered directly into the iliac artery, also elicited only iliac vasodilation. Intracoronary acetylcholine in conscious dogs also induced only coronary vasodilation, whereas in conscious calves at higher doses, initial vasoconstrictor responses were observed, which also preceded reductions in regional myocardial function. These results suggest that the controversy surrounding the effects of acetylcholine can be reconciled on the basis of species, vascular bed studied, and dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of electrical axis of stimulation on excitation of cardiac muscle cells.
Authors: Tung L , Sliz N , Mulligan M R
Published: June 2012

Orthogonal sequential shock can defibrillate the heart with greater efficacy compared with single shock defibrillation. In this study we tested the hypothesis that cardiac cells have a preferred orientation in their response to excitatory extracellular electric fields, so that orthogonal shocks may stimulate distinct populations of cells. A micropaddle electrode system was used to deliver rectangular pulses for extracellular field stimulation of individual heart cells. We found that single frog and guinea pig ventricular myocytes are excitable with rectangular pulse field stimulation over a wide range of pulse durations, ranging from 10 msec to as little as 20 microseconds. The excitation field strength varies inversely with pulse duration as described by the Weiss-Lapicque equation, although the frog myocytes show a significant "notch" at pulse durations of approximately 1-2 msec, and the guinea pig myocytes are more excitable than predicted for pulse durations of less than 0.2 msec. Every myocyte tested was more excitable when the long axis of the cell was oriented parallel to the stimulating field than when perpendicular to the field. For 2-msec pulses, the difference in field strength was a factor of 5.8 +/- 2.0 (n = 30) for frog and 2.6 +/- 0.5 (n = 23) for guinea pig myocytes. Complete excitation strength-duration curves were obtained in seven frog and 14 guinea pig cells for both parallel and perpendicular cell orientations.(ABSTRACT TRUNCATED AT 250 WORDS)
Fatty acid uptake in normal human myocardium.
Authors: Vyska K , Meyer W , Stremmel W , Notohamiprodjo G , Minami K , Machulla H J , Gleichmann U , Meyer H , Körfer R
Published: June 2012

Fatty acid binding protein has been found in rat aortic endothelial cell membrane. It has been identified to be a 40-kDa protein that corresponds to a 40-kDa fatty acid binding protein with high affinity for a variety of long chain fatty acids isolated from rat heart myocytes. It is proposed that this endothelial membrane fatty acid binding protein might mediate the myocardial uptake of fatty acids. For evaluation of this hypothesis in vivo, influx kinetics of tracer-labeled fatty acids was examined in 15 normal subjects by scintigraphic techniques. Variation of the plasma fatty acid concentration and plasma perfusion rate has been achieved by modulation of nutrition state and exercise conditions. The clinical results suggest that the myocardial fatty acid influx rate is saturable by increasing fatty acid plasma concentration as well as by increasing plasma flow. For analysis of these data, functional relations describing fatty acid transport from plasma into myocardial tissue in the presence and absence of an "unstirred layer" were developed. The fitting of these relations to experimental data indicate that the free fatty acid influx into myocardial tissue reveals the criteria of a reaction on a capillary surface in the vicinity of flowing plasma but not of a reaction in extravascular space or in an unstirred layer and that the fatty acid influx into normal myocardium is a saturable process that is characterized by the quantity corresponding to the Michaelis-Menten constant, Km, and the maximal velocity, Vmax, 0.24 +/- 0.024 mumol/g and 0.37 +/- 0.013 mumol/g(g.min), respectively. These data are compatible with a nondiffusional uptake process mediated by the initial interaction of fatty acids with the 40-kDa membrane fatty acid binding protein of cardiac endothelial cells.
Evolution of rhythms during periodic stimulation of embryonic chick heart cell aggregates.
Authors: Zeng W Z , Glass L , Shrier A
Published: June 2012

During periodic stimulation of spontaneously beating chick heart cell aggregates, there is often an evolution of coupling patterns between the stimulator and the aggregate action potential. For example, at rapid stimulation frequencies, a rhythm that is initially 1:1 (stimulus frequency:aggregate frequency) can evolve to other rhythms such as 5:4 and 4:3. Time-dependent effects generated during periodic stimulation are characterized by three types of experiments to determine 1) the effect of periodic stimulation on the intrinsic cardiac beat rate (overdrive suppression), 2) the effect of periodic stimulation on the phase resetting properties of the aggregate, and 3) the time-dependent changes in the coupling patterns between the stimulator and the aggregate during periodic stimulation. The protocols involved variations in the duration and rate of periodic stimulation. A mathematical model is developed in the form of a two-dimensional finite difference equation based on the data from experiments 1 and 2. The model is used to predict the data generated by experiment 3. There is good correspondence with the experiments in that the theory reproduces complex transitions between various rhythms and displays irregular rhythms similar to those observed experimentally. These results have implications for the evolution of cardiac arrhythmias such as atrioventricular heart block and modulated parasystole.
Troponin T isoform expression in humans. A comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle.
Authors: Anderson P A , Malouf N N , Oakeley A E , Pagani E D , Allen P D
Published: June 2012

The expression of troponin (Tn) T, a thin-filament regulatory protein, was examined in left ventricular myocardium from normal and from failing adult human hearts. The differences in isoform expression between normal and failing myocardium led us to examine the ontogenic expression of TnT in human striated muscle. Left ventricular samples were obtained from patients with severe heart failure undergoing cardiac transplantation and normal adult organ donors. Fetal muscle was obtained from aborted fetuses after 14-15 weeks of gestation, and adult skeletal muscle was obtained from surgical biopsies. Western blots of normal and failing adult heart proteins demonstrated that two isoforms, TnT1 and TnT2, are expressed in different amounts, with TnT2 being significantly greater in failing hearts (p less than 0.004). Western blots of two-dimensional gels of these proteins resolved two predominant spots of both TnT1 and TnT2 and several minor TnT species. Alkaline phosphatase treatment converted the two major spots of each isoform into the single more basic spots. A comparison of the ATPase activities and the TnT2 percentage of total TnT in individual failing and normal adult hearts demonstrated an inverse and negative relation (r = 0.7, p less than 0.02). In the fetal heart, four TnT isoforms were found, two of which had the same electrophoretic mobilities as the adult cardiac isoforms TnT1 and TnT2. Fetal skeletal muscle expressed two of the four fetal cardiac TnT isoforms, one of which comigrated with adult cardiac TnT1. These cardiac isoforms were expressed in low abundance in fetal skeletal muscle relative to seven fast skeletal muscle TnT isoforms. No cardiac isoforms were present in adult skeletal muscle. Because many etiologies caused heart failure in the transplant patients, we propose that the disease-associated increased expression of the TnT isoform TnT2 is an adaptation to the heart failure state and a partial recapitulation of the fetal expression of cardiac TnT isoforms.