bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrical responses of guinea pig coronary artery to transmural stimulation.
Authors: Keef K D , Kreulen D L
Published: June 2012

Isolated segments of the guinea pig circumflex coronary artery were stimulated transmurally with brief duration (0.05 msec) pulses while recording intracellularly. Resting membrane potential was -60.3 +/- 4.3 mV (n = 66). Transient depolarizations (TDs) graded in amplitude with stimulus intensity were elicited with single stimuli. An action potential of 47 +/- 5 mV was superimposed upon the TD above a threshold membrane potential of -48 +/- 4 mV. Following the spike, a period of slow repolarization requiring 77 +/- 33 seconds was observed. Repetitive stimulation led to summation of TDs and a slow depolarization (less than or equal to 21 mV) that persisted for up to 90 seconds. The TD was reduced in amplitude when the membrane was depolarized with increased [K]o and enhanced when the membrane was hyperpolarized by adding potassium back to a potassium-depleted tissue. Phentolamine (10(-5) M), prazosin (10(-6) M), guanethidine (2 X 10(-5) M), alpha,beta-methylene ATP (2 X 10(-5) M), tetrodotoxin (10(-6) M), and 10-20 mM norepinephrine did not block TDs, action potentials, or slow depolarization. TDs were abolished following cold storage (4 degrees C) for 4 days and significantly reduced in a 2.25-mM CdCl2 solution with 0.25 mM CaCl2. Acetylcholine (10(-8) M to 10(-5) M) produced membrane hyperpolarization and reduced the amplitude of TDs and altered their time course. Atropine (10(-5) M) blocked the effects of acetylcholine but had no effect on the response to nerve stimulation. These observations indicate that TDs exhibit some, but not all, of the properties characteristic of excitatory junction potentials obtained with release of neurotransmitter substances in other vessels. If these TDs are neural events, they must involve a transmitter other than norepinephrine, acetylcholine, or ATP.
Hormonal and cardiac effects of converting enzyme inhibition in rat myocardial infarction.
Authors: Michel J B , Lattion A L , Salzmann J L , Cerol M L , Philippe M , Camilleri J P , Corvol P
Published: June 2012

To explain how converting enzyme inhibition could improve the prognosis in cardiac insufficiency, the effect of converting enzyme inhibition (CEI) by S9490-3 (Perindopril) treatment for 2 months (treated infarctions, n = 18) on hormonal plasma variables and the quantitative and qualitative changes in myocardium were studied in an experimental model of left ventricular infarction in rats (untreated infarctions, n = 18) and compared to a sham-operated control group (n = 15). Induction of myocardial infarction was associated with a transient decrease in blood pressure. CEI treatment maintained a lower blood pressure throughout the experimental period. Plasma renin concentration was not significantly increased in the untreated infarct group (155.4 +/- 136.7 ng AI/ml/hr) as compared to the sham-operated group (47.6 +/- 15.9 ng AI/ml/hr). Plasma aldosterone did not change in the three experimental groups. The plasma level of immunoreactive atrial natriuretic factor increased in the untreated infarct group (185 +/- 245 pg/ml) as compared with the control group (76 +/- 40 pg/ml) and was normalized by CEI (66 +/- 60 pg/ml). Body weight was slightly decreased in both treated and untreated infarct groups, whereas the heart weight was significantly increased in the untreated group (1,540 +/- 310 mg) and normalized by treatment (1,145 +/- 180 mg) as compared with sham-operated controls (1,071 +/- 80 mg). The combined atria and right ventricular mass was significantly increased in the untreated infarct group (660 +/- 210 mg) and decreased by treatment (443 +/- 106 mg) but was not completely normalized (controls, 343 +/- 40 mg). Left ventricular isomyosin profiles were modified by myocardial infarction as compared with controls: V1 form decreased from 62.4 +/- 9.4% in the sham-operated group to 41.6 +/- 13.4% in the infarct group, and the V3 form increased from 13.0 +/- 4.7% in sham-operated animals to 27.4 +/- 11.8% in untreated infarct animals. CEI treatment partially, but significantly, reversed this modification of the isomyosin profile (V1, 53.0 +/- 14.4%; V3, 17.5 +/- 8.0%). Volume density of collagen was significantly increased in the untreated infarct rats (4.14 +/- 0.81% versus 2.68 +/- 0.49% in controls), and this was reversed by treatment (2.95 +/- 0.66%). Messenger RNA encoding for atrial natriuretic factor, measured by dot blot hybridization, was significantly increased in both the atria and the ventricles in the untreated infarct group, and treatment by CEI partially reversed this increase. Thus, myocardial infarction profoundly modified several variables of peripheral circulation and quantitative and qualitative myocardial protein expression.(ABSTRACT TRUNCATED AT 400 WORDS)
Pulmonary vasoconstrictor response to soluble fibrin in isolated lungs: possible role of thromboxane generation.
Authors: Seeger W , Neuhof H , Hall J , Roka L
Published: June 2012

The blood coagulation system is activated regularly in severe forms of shock, polytrauma, and sepsis. Arising thrombin cleaves the fibrinopeptides A and B from fibrinogen, and it generates monomers of fibrin, which are initially kept in solution by the remaining excess fibrinogen. The effects of soluble fibrin (fibrin monomer/oligomer-fibrinogen complexes) and fibrinopeptides A and B were investigated in blood-free perfused, isolated rabbit lungs. Urea Tris buffer-dissolved fibrin monomers were injected into the pulmonary artery in the presence of circulating excess fibrinogen. In doses above 5 mg, the monomers consistently provoked a sharp rise in pulmonary artery pressure, which was followed by an elevated pressure plateau. Changing to fresh perfusate devoid of soluble fibrin did not restore the pressure to baseline, and a second administration of the soluble fibrin caused a pressor response larger than the first. Only a modest increase in lung weight (less than 2 g) was observed, and lung inflation pressure was not altered. The pressor responses were accompanied by a rapid release of thromboxane A2 and a more delayed release of prostaglandin I2 into the perfusion fluid. A significant correlation between the height of the fibrin-induced pressure rise and the amount of thromboxane release was noted. Inhibition of cyclooxygenase (indomethacin) suppressed the generation of both prostanoids, whereas inhibition of thromboxane synthetase (OKY-046 and imidazole) selectively blocked the liberation of thromboxane. All three inhibitors caused an immediate decline in pulmonary artery pressure, which had been previously elevated due to administration of soluble fibrin, and markedly reduced the pressor response evoked by a subsequent fibrin application in the same lung.(ABSTRACT TRUNCATED AT 250 WORDS)
Mechanism of action and systemic and regional hemodynamics of the potassium channel activator BRL34915 and its enantiomers.
Authors: Hof R P , Quast U , Cook N S , Blarer S
Published: June 2012

BRL34915 (BRL) is a vasodilator with a novel structure. Its mechanism of action, its effects on depolarization-induced and receptor-mediated blood vessel contraction, and its hemodynamic effects were investigated. In the rat portal vein, BRL inhibited spontaneous mechanical activity [IC50 0.013 +/- 0.001 microM (mean +/- SEM) for (-)-BRL], the initial effect being a reduced frequency of contraction. At higher concentrations, the spontaneous contractions were abolished and 86Rb+ efflux was increased. These results suggest that BRL preferentially acts on the pacemaker cells, the K+ channels in other cells being activated only at higher BRL concentrations in this vessel. In experiments on the rabbit aorta, (-)-BRL shifted the KCl concentration-response curve to the right and noncompetitively inhibited responses to angiotensin II. A concentration of 3 microM (-)-BRL reduced maximal angiotensin II contractions by around 50%, higher concentrations having little further effect. This inhibition of angiotensin II contractions is notably greater than that seen with Ca2+ antagonists in this vessel. In anesthetized rabbits, (-)-BRL was a peripheral vasodilator at doses of 3-30 micrograms/kg, but it had no relevant effects on heart rate and myocardial contractile force. This suggests tissue selectivity of this compound or this mechanism of action. BRL preferentially dilated the coronary, gastrointestinal, and cerebral vessels but not those of the kidneys or skeletal muscle as measured with tracer microspheres. This profile of activity is different from that of calcium antagonists or nonspecific vasodilators like dihydralazine. All effects were stereoselective, the (-)-enantiomer being 100 to 200 times more active than the (+)-enantiomer.
Alternans of action potential duration after abrupt shortening of cycle length: differences between dog Purkinje and ventricular muscle fibers.
Authors: Saitoh H , Bailey J C , Surawicz B
Published: June 2012

The purpose of this study was to determine whether the alternans of action potential duration (APD) occurring in Purkinje and ventricular muscle fibers after an abrupt shortening of cycle length can be explained by the two factors controlling the cycle length-dependent APD changes (i.e., restitution and memory effect). Action potentials were recorded simultaneously from dog Purkinje fibers and ventricular muscle fibers using conventional microelectrode techniques. APD change during alternans was dependent on the preceding diastolic interval in the same manner as during restitution in Purkinje fibers but not in ventricular muscle fibers. The course of memory change was not affected by the presence of alternans in either fiber type. In Purkinje fibers, APD alternans was attenuated by a Ca2+ channel blocker, nisoldipine (2 X 10(-6) M), and augmented by a Ca2+ channel agonist, Bay K 8644 (3 X 10(-8) M). These effects were attributed to the changes in the kinetics and the amplitude of restitution. In ventricular muscle fibers, APD alternans was always preceded and accompanied by alternans of action potential shape. Alternans of both action potential shape and APD was suppressed by nisoldipine (2 X 10(-6) M) and attenuated by Bay K 8644 (3 X 10(-8) M). These results show that in Purkinje fibers, APD during alternans can be explained by restitution and memory effect. However, in ventricular muscle fibers, the mechanism of APD alternans is linked to factors controlling action potential shape. These findings are compatible with the hypothesis that APD alternans in Purkinje fibers depends on the differences in the recovery of membrane currents generated by the preceding action potential and in ventricular muscle fibers on the differences in the concentration and/or handling of intracellular calcium.
Acute pulmonary vasoconstriction and thromboxane release during protamine reversal of heparin anticoagulation in awake sheep. Evidence for the role of reactive oxygen metabolites following nonimmunological complement activation.
Authors: Morel D R , Lowenstein E , Nguyenduy T , Robinson D R , Repine J E , Chenoweth D E , Zapol W M
Published: June 2012

When protamine (2 mg/kg) was injected intravenously into awake sheep 5 minutes after infusing heparin (200 units/kg), there was transient diffuse pulmonary vasoconstriction with mean pulmonary arterial pressure increasing from 18.0 +/- 0.7 to 43.8 +/- 2.7 mm Hg at 1 minute (x +/- SEM; n = 10). In addition, there was profound leukopenia (36.9 +/- 7.7% of baseline values at 2 minutes) with transpulmonary leukocyte sequestration and transiently elevated plasma concentrations of C3a (from 420 +/- 146 to 1,599 +/- 249 ng/ml; n = 3, p less than 0.01) and thromboxane B2 (from 0.30 +/- 0.05 to 6.3 +/- 2.8 ng/ml; n = 10, p less than 0.0001), without significant increases of plasma 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, leukotrienes, or histamine. Intravenous injection of protamine alone produced no hemodynamic effects and did not increase plasma levels of vasoconstrictor eicosanoids. Intravenous pretreatment with either a cyclooxygenase inhibitor or a hydrogen peroxide scavenger (dimethylthiourea) blocked both the increases of thromboxane levels and the pulmonary vasoconstriction.
Cyclic guanosine monophosphate-enhanced sequestration of Ca2+ by sarcoplasmic reticulum in vascular smooth muscle.
Authors: Twort C H , van Breemen C
Published: June 2012

The purpose of this study was to investigate the effects of the intracellular messenger cyclic GMP (cGMP) on sequestration of cytosolic calcium (Ca2+) into the intracellular Ca2+ store (the sarcoplasmic reticulum) of vascular smooth muscle. Using saponin-skinned primary cultures of rat aortic smooth muscle, we investigated the effect of cGMP on 45Ca uptake in monolayers of cells. The intracellular store was loaded with Ca2+ by exposing the skinned cells to a 45Ca-labeled 1-microM free Ca2+-containing solution for varying durations (0-20 minutes). Addition of 10 microM cGMP to six monolayers increased both the initial Ca2+ uptake at 2 minutes (control, 240 +/- 8 pmol Ca2+/10(6) cells; + cGMP 295 +/- 7; mean +/- SEM; n = 6, p less than 0.01) and the final steady-state uptake reached at 20 minutes (control, 0.96 +/- 0.03 nmol Ca2+/10(6) cells; + cGMP 1.12 +/- 0.03, p less than 0.02). This stimulation of uptake was quantitatively similar to that caused by 10 microM cyclic AMP. It occurred at varying ambient cytosolic Ca2+ concentrations (0.1-1.0 microM Ca2+) and was not further enhanced by addition of 10 microM cGMP-dependent protein kinase. The dose-response of stimulation of Ca2+ uptake with cGMP indicated an ED50 of 5 nM cGMP. The release of Ca2+ from the sarcoplasmic reticulum in response to inositol 1,4,5-trisphosphate or caffeine was unaffected by cGMP. We conclude that the relaxation of vascular smooth muscle with cGMP-producing vasodilators is mediated in part by sequestration of cytosolic Ca2+ by the sarcoplasmic reticulum.
Endothelial-dependent relaxation induced by leukotrienes C4, D4, and E4 in isolated canine arteries.
Authors: Secrest R J , Chapnick B M
Published: June 2012

Leukotriene D4 has been shown to possess the capacity to relax canine superior mesenteric and renal arterial rings in an endothelial-dependent manner. The present study was designed to determine if the remaining peptidoleukotrienes, leukotrienes C4 and E4, share this property. In addition, influences of atropine and of inhibitors of cyclooxygenase and lipoxygenase activities on relaxation produced by leukotriene D4 and acetylcholine were determined to characterize further leukotriene D4-induced relaxation and to compare these properties with those of acetylcholine. Vasomotor tone was measured with isometric force transducers. Following induction of tone with norepinephrine, leukotriene C4 and acetylcholine produced concentration-dependent relaxation of renal and superior mesenteric arterial rings in which the endothelium was intact. Only minimal decreases in tone were produced in response to leukotriene E4. Neither acetylcholine nor leukotriene C4 altered tone after endothelium had been intentionally disrupted. Nitroglycerin relaxed rings both before and after rubbing the endothelium. These results demonstrate that, similar to leukotriene D4, leukotriene C4 possesses the capacity to produce endothelial-dependent relaxation in canine renal and superior mesenteric arteries. Relaxation of the superior mesenteric artery produced in response to acetylcholine, but not leukotriene D4, was inhibited in presence of atropine. Incubation of the rings with meclofenamate had no effect on relaxation induced by either acetylcholine or leukotriene D4. Thus, it appears that endothelial-dependent relaxation induced by leukotriene D4 is neither dependent on muscarinic receptor activation nor related to generation of cyclooxygenase metabolites of arachidonic acid. In contrast, 5,8,11,14-eicosatetraynoic acid and nordihydroguaiaretic acid attenuated relaxation in response to leukotriene D4 and acetylcholine, suggesting that lipoxygenase-derived products may participate in leukotriene D4-induced as well as acetylcholine-induced relaxation.
Differences in response of myosin isozyme transition of ordinary and specialized myocardium to overload.
Authors: Nomoto K , Komuro I , Kuro-o M , Tsuchimochi H , Takaku F , Machii K , Yazaki Y
Published: June 2012

To investigate the response of myosin isozyme transition in specialized myocardium to cardiac overload, we examined immunohistochemically the distribution of myosin isozymes in sinus node cells of overloaded canine atria, using the monoclonal antibodies CMA19 and HMC14, which are specific for atrial myosin heavy chain (alpha-HC) and ventricular myosin heavy chain (beta-HC), respectively. Overloading in canine right atria was induced by artificial tricuspid valve regurgitation and pulmonary stenosis. Right atrial mean pressure rose to 15-20 mm Hg (n = 4) 2 months after surgery. In the working myocardium, cardiac overload caused redistribution of myosin isozymes, alpha-HC to beta-HC. Compared with the normal right atria, fewer myocytes were labeled with CMA19, but more were labeled with HMC14. However, the reactivity of sinus node cells with CMA19 and HMC14 was not changed between normal and overloaded right atria, indicating no redistribution of myosin heavy chain isozymes, alpha-HC to beta-HC. These results suggest that isozymes in myosin heavy chains in the specialized myocardium are protected from overload effects by their firm cytoskeletal framework or other mechanisms.
Evidence that dopaminergic innervation is not involved in the vasodilatation of cat superior mesenteric arterial bed: the role of beta-adrenoceptors and circulating catecholamines.
Authors: Lonart G , Gyorgy L , Doda M , Vizi E S
Published: June 2012

In the presence of phentolamine, stimulation of the cat splanchnic nerve decreased the resistance of the superior mesenteric arterial bed. This effect was not significantly influenced by sulpiride. Sulpiride, in the presence of phentolamine, did not inhibit the decrease in resistance in animals pretreated with guanethidine but propranolol or ablation of the adrenal glands prevented the effect of stimulation. These results are not compatible with the assumption that dopamine released from dopaminergic nerves is involved in the vasodilatation but do provide evidence for the role of beta-adrenoceptors and circulating catecholamines in the vasodilatation of mesenteric vessels.
Localization of angiotensinogen messenger RNA in rat aorta.
Authors: Cassis L A , Lynch K R , Peach M J
Published: June 2012

The distribution of angiotensinogen messenger (mRNA) was determined in the rat aorta. Other investigators have demonstrated the presence of angiotensinogen mRNA in whole rat aorta; however, its precise location in the blood vessel wall has not been defined. When various layers of the vessel wall were separated by dissection or cell dispersion, angiotensinogen mRNA levels were greatest in the periaortic adipose tissue. Angiotensinogen mRNA was present in very small levels in the adventitia, with no detectable levels in the muscle layer. In addition to periaortic adipose tissue, angiotensinogen mRNA was also present in the interscapular brown fat pad of the rat. The high levels of angiotensinogen mRNA in periaortic brown adipose tissue suggests that angiotensin may be synthesized there and responses may exist in this tissue or adjacent sympathetic nerve terminals.
Transmural activations and stimulus potentials in three-dimensional anisotropic canine myocardium.
Authors: Frazier D W , Krassowska W , Chen P S , Wolf P D , Danieley N D , Smith W M , Ideker R E
Published: June 2012

Epicardial and endocardial pacing are widely used, yet little is known about the three-dimensional distribution of potentials generated by the pacing stimulus or the spread of activation from these pacing sites. In six open-chest dogs, simultaneous recordings were made from 120 transmural electrodes in 40 plunge electrodes within a 35 X 20 X 5-mm portion of the right ventricular outflow tract during epicardial and endocardial pacing at a strength of twice diastolic threshold and at 1 mA. The magnitude of extracellular potentials generated by the stimulus and the activation times were compared in regions proximal (less than 10-12 mm) and distal to the pacing site. Local fiber orientation was histologically determined at each recording electrode. For endocardial pacing, endocardial potentials were larger than epicardial potentials only in the proximal region (p less than 0.001); while in the distal region, epicardial potentials were larger (p less than 0.001), and endocardial activation occurred earlier than epicardial activation for both regions (p less than 0.001). For epicardial pacing, epicardial potentials were larger than endocardial potentials in both regions (p less than 0.001), and epicardial activation occurred earlier only in the proximal region (p less than 0.02), while endocardial activation occurred before epicardial activation in the distal region (p less than 0.01). In planes of recording electrodes parallel to the epicardium and endocardium, the initial isochrones were elliptical with the major axes of the ellipses along the mean fiber orientation between the pacing site and recording plane rather than along the local fiber orientation in the recording plane. Thus, the ellipses in each plane rotated with respect to each other so that in three dimensions the activation front was helicoid, yet the twist of the helix was less than that of the corresponding transmural rotation of fibers. For pacing from the right ventricular outflow tract, we conclude that beyond 10-12 mm from endocardial and epicardial pacing sites epicardial stimulus potentials in both cases are larger than endocardial potentials because of resistivity differences inside and outside the heart wall and activation in both cases is primarily endocardial to epicardial because of rapid endocardial conduction, and we conclude that the initial spread of activation is helicoid and determined by transmural fiber direction.
Neuronal sodium homoeostatis and axoplasmic amine concentration determine calcium-independent noradrenaline release in normoxic and ischemic rat heart.
Authors: Schömig A , Kurz T , Richardt G , Schömig E
Published: June 2012

Calcium-independent noradrenaline release was studied in the isolated perfused rat heart under conditions of normoxia, cyanide intoxication, and ischemia. The release of endogenous noradrenaline and dihydroxyphenylglycol were determined by high-performance liquid chromatography. The release of dihydroxyphenylglycol, the main neuronal noradrenaline metabolite, was used as an indicator of the free axoplasmic amine concentration. When storage function of neuronal vesicles was disturbed by Ro 4-1284 or trimethyltin, high dihydroxyphenylglycol release was observed without concomitant overflow of noradrenaline. If, however, these agents were combined with inhibition of Na+K+-ATPase or with veratridine-induced entry of sodium into the neuron, both dihydroxyphenylglycol and noradrenaline were released. Noradrenaline release was independent of extracellular calcium and was suppressed by blockade of neuronal catecholamine uptake (uptake1), indicating nonexocytotic noradrenaline liberation from the sympathetic nerve ending. This release critically depended on two conditions: 1) increased cytoplasmic concentrations of noradrenaline within the sympathetic neuron and 2) intraneuronal sodium accumulation. Both conditions together were required to induce noradrenaline efflux across the plasma membrane using the uptake1 carrier in reverse of its normal transport direction. A disturbed energy status of the sympathetic neuron, induced by cyanide intoxication or ischemia, likewise caused calcium-independent noradrenaline release by interfering with both vesicular storage function and neuronal sodium homoeostatis. Again, release was sensitive to uptake1 blockade. Since neuronal sodium accumulation was the rate-limiting step, release was further accelerated when residual Na+,K+-ATPase activity was inhibited. Na+-H+ exchange was identified as the predominant pathway of sodium entry into the sympathetic nerve ending in ischemia, and its inhibition by amiloride and ethylisopropylamiloride markedly suppressed ischemia-induced noradrenaline release.
Acceleration of the wavefront of myocardial necrosis by chronic hypertension and left ventricular hypertrophy in dogs.
Authors: Dellsperger K C , Clothier J L , Hartnett J A , Haun L M , Marcus M L
Published: June 2012

Previous studies have shown that hypertension and left ventricular hypertrophy (HT-LVH) increase completed infarct size. Myocardial infarction progresses in a wavefront of myocardial necrosis from the subendocardium to the subepicardium. We tested two hypotheses: First, HT-LVH accelerates the wavefront of myocardial necrosis when compared with normotensive animals; and second, lowering of arterial pressure by infusing nitroprusside 1 hour after coronary artery occlusion exerts a salutary effect on infarct size. To test these hypotheses, systemic hypertension (mean aortic pressure = 141 +/- 3 mm Hg) and left ventricular hypertrophy (18% increase in left ventricular mass) were induced in dogs using a single-kidney, single-clip model. Seventeen adult mongrel dogs were used as controls. We measured mean aortic pressure, heart rate, left atrial pressure, and myocardial perfusion (microspheres) in several groups of normal and HT-LVH awake dogs. In two groups (normal and HT-LVH), 1 hour of circumflex coronary artery occlusion was followed by 4 hours of reperfusion. In two additional groups (normal and HT-LVH), 3 hours of circumflex coronary artery occlusion was followed by 90 minutes of reperfusion. In another group with HT-LVH, nitroprusside was infused to reduce mean arterial pressure to 100 mm Hg beginning 1 hour after occlusion and was continued for the duration of reperfusion period (HT-LVH + N). Infarct size was assessed using triphenyltetrazolium chloride stain and risk area was determined using postmortem barium angiography. Fifteen of 17 (88%) control animals survived coronary artery occlusion, whereas only 17 of 42 (40%) dogs with HT-LVH survived coronary occlusion (p less than 0.05). Infarct-to-risk ratios in the various layers of the left ventricular wall were determined for survivors in all groups. After 1 hour of coronary occlusion more than twice as much mid-wall and epicardium was infarcted in the HT-LVH group compared with the control group. After 3 hours of coronary occlusion significantly more endocardium, mid-wall, and epicardium was infarcted in the dogs with HT-LVH. In the nitroprusside-treated HT-LVH dogs, the infarct sizes were similar to control animals. From these data we conclude: 1) the rate of infarction is accelerated in animals with HT-LVH; 2) nitroprusside infused 1 hour after coronary artery occlusion and continued throughout the reperfusion period exerts beneficial effect on infarct size when compared with control animals; and 3) acute coronary artery occlusion in animals with HT-LVH is associated with significantly greater mortality when compared with control animals.
Certain beta-blockers can decrease beta-adrenergic receptor number: I. Acute reduction in receptor number by tertatolol and bopindolol.
Authors: De Blasi A , Fratelli M , Marasco O
Published: June 2012

We have previously reported that a potent new beta-blocker, tertatolol, when given at therapeutic doses to healthy volunteers, rapidly reduced the number of human mononuclear leukocyte beta-receptors. In the present study, the mechanism of receptor regulation by beta-antagonists incubated with target cells in vitro was investigated. Two different cell types (human mononuclear leukocytes and S49 murine lymphoma cells) were used, and beta-adrenergic receptors were measured using either the hydrophilic ligand 3H-CGP 12177 (specific for surface receptors) or lipophilic 125I-pindolol (which measures total receptors). In a comparison between beta-blockers, tertatolol and bopindolol, but not propranolol and pindolol, were found to rapidly (1 hour at 37 degrees C) reduce the number of beta-adrenergic receptors. This was paralleled by a reduction in isoproterenol-stimulated cyclic AMP accumulation. The reduction in receptors was the same whether surface or total receptors were measured; thus, it was not due to receptor sequestration. This effect was not caused by partial agonist activity (bopindolol is a weak partial agonist); in parallel experiments, tertatolol and bopindolol, but not pindolol (potent partial agonist) and isoproterenol (full agonist), reduced beta-adrenergic receptors. Finally, this effect was not due to irreversible binding: the receptor reduction induced by the irreversible blocker bromo-acetyl-alprenolol-methane (BAAM) was stable for several hours, while the effect of tertatolol and bopindolol was slowly reversed over the same time course. We suggest that tertatolol and bopindolol have two effects on beta-adrenergic receptors: they bind competitively, and then they modify the receptors so that they are no longer available for binding by ligands or catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)
Hemodynamic responses to atrial natriuretic factor in nephrectomized rabbits: attenuation of the circulatory consequences of acute volume expansion.
Authors: Volpe M , Vecchione F , Cuocolo A , Lembo G , Pignalosa S , Condorelli M , Trimarco B
Published: June 2012

We investigated the hemodynamic responses to three doses of atrial natriuretic factor [human atrial natriuretic factor-(99-126)] (ANF) in nephrectomized rabbits anesthetized with ketamine and acepromazine. The influence of the different doses of the peptide on the hemodynamic consequences produced by acute volume expansion (0.9% NaCl, 1.4 ml/kg/min for 60 minutes) was also studied. All three dosages of ANF (0.001, 0.01, and 0.2 micrograms/kg/min for 20 minutes) significantly reduced blood pressure. With the lowest dose, the hypotensive effect was associated with reduction in systemic vascular resistance and no significant change in heart rate, stroke volume, central venous pressure, and hematocrit. In contrast, the intermediate and high doses, which resulted in markedly higher plasma levels, caused a significant decrease in heart rate, central venous pressure, and stroke volume; a slight rise in hematocrit; and no change in systemic vascular resistance. Volume expansion produced by saline infusion in an additional group of nephrectomized rabbits increased central venous pressure and decreased hematocrit. When ANF infusion was associated to volume expansion, each dosage of ANF was able to reduce the rise in central venous pressure, while only the higher dosage attenuated the progressive fall in hematocrit caused by volume expansion. Plasma volume, measured at the end of volume expansion was lower in the group treated with the highest dose of ANF than in the control animals (28.2 +/- 9 vs. 35.1 +/- 3 ml/kg, p less than 0.05). We conclude that 1) ANF induces significant hemodynamic effects independently from its renal action.(ABSTRACT TRUNCATED AT 250 WORDS)
Prenatal and postnatal hydralazine treatment does not prevent renal vessel wall thickening in SHR despite the absence of hypertension.
Authors: Smeda J S , Lee R M , Forrest J B
Published: June 2012

Previous studies in our laboratory have shown that the renal blood vessels of 21-week-old Wistar-Kyoto spontaneously hypertensive rats exhibited thicker vascular walls than age matched Wistar-Kyoto normotensive rats. Morphometric analysis of the relaxed renovasculature revealed an increase in the cross-sectional area of the media, which in most cases was associated with an increase in the number of smooth muscle cell layers. To test if these structural changes occur in the absence of raised blood pressure, hydralazine was administered to spontaneously hypertensive rats and normotensive controls prior to and during pregnancy (100 ml/l drinking water), and to the newborn males up to 21 weeks of age (16.9 mg/kg/day by gavage until weaning followed by 100 mg/l in the drinking water). Treated animals were compared with untreated rats. Treatment prevented hypertension development in spontaneously hypertensive rats but did not alter the structural changes found in untreated animals with hypertension. At 21 weeks of age, hydralazine-treated spontaneously hypertensive rats had similar wall-to-lumen area ratios, medial cross-sectional areas and numbers of medial smooth muscle layers as untreated hypertensive rats while these parameters were greater in treated and untreated spontaneously hypertensive rats than in either treated or untreated normotensive controls. Withdrawal of hydralazine from 26-week-old spontaneously hypertensive rats that had been treated in utero and postnatally and had normal blood pressures throughout life resulted in the rapid onset of hypertension. Our results show that renal vascular wall thickening in spontaneously hypertensive rats occurs in the absence of high blood pressure and therefore is not a secondary effect of raised blood pressure.
A theoretical method for estimating small vessel distensibility in humans.
Authors: Patel D J , Vaishnav R N , Coleman B R , Tearney R J , Cothran L N , Currey C L
Published: June 2012

A simple theoretical approach is presented for estimating vascular distensibility of small blood vessels from noninvasively obtained pressure-flow data in the hand and forearm of human subjects. To the extent that Poiseuille's law applies to blood flow in these vascular beds, conductance (the reciprocal of vascular resistance) can be calculated from these data as the ratio of blood flow to mean arterial pressure. The fourth root of the conductance is proportional to the radius of the vascular bed. The slope of the relation between the logarithm of the radius of the vascular bed and the transmural pressure is proportional to the vascular extensibility (E), which, in turn, for small deformations and constant vascular length, is proportional to the distensibility of small blood vessel. Data obtained from the hands of six hypertensive subjects were compared with that obtained from six normotensive subjects, all with their vascular beds in a maximally dilated state. Also compared were data obtained from four normal subjects with their vascular beds in the resting state and when the beds were maximally dilated. The results indicate that 1) in the hypertensive subjects, the small blood vessels of the maximally dilated vascular bed of the hand are significantly (p less than 0.02) less distensible (E = 0.126 +/- 0.034/mm Hg) than those in the normotensive subjects (E = 0.272 +/- 0.047/mm Hg) and 2) the small blood vessels of the normal forearm at resting levels of vasomotor tone are more distensible (E = 1.00 +/- 0.38/mm Hg) than in the maximally dilated state (E = 0.51 +/- 0.08/mm Hg).
Myoplasmic [Ca2+] determines myosin phosphorylation in agonist-stimulated swine arterial smooth muscle.
Authors: Rembold C M , Murphy R A
Published: June 2012

Our objective was to test the hypotheses that 1) myoplasmic [Ca2+] is the primary determinant of crossbridge phosphorylation and that 2) phosphorylation is the primary determinant of crossbridge interactions with the thin filament in swine carotid arterial smooth muscle. We tested these hypotheses by evaluating the relation between aequorin-estimated myoplasmic [Ca2+], myosin light chain phosphorylation, shortening velocity at zero load (V0), and stress at various times after stimulation with histamine, phenylephrine, and depolarization with KCl. Agonist-induced changes in myoplasmic [Ca2+] were associated with predictable changes in myosin phosphorylation. Depolarization required proportionally higher changes in myoplasmic [Ca2+] for a given change in myosin phosphorylation. The relation between phosphorylation and V0 or steady-state stress was invariant with all tested stimuli. This suggests that Ca2+-dependent crossbridge phosphorylation is the primary determinant of the mechanical response.
Progressive hypoxemia limits left ventricular oxygen consumption and contractility.
Authors: Walley K R , Becker C J , Hogan R A , Teplinsky K , Wood L D
Published: June 2012

To study the cardiac effects of progressive hypoxemia, we measured the left ventricular end-systolic pressure-volume relation (ESPVR), myocardial oxygen consumption (MVO2), and myocardial oxygen delivery (MQO2) in eight thoracotomized dogs anesthetized with fentanyl and droperidol. We specifically looked for evidence of oxygen supply limitation of MVO2 and depressed contractility (altered ESPVR) during stepwise decreases in inspired oxygen fraction. We hypothesized that the reported relation between MVO2 and left ventricular pressure-volume area (PVA) may hold when inadequate MQO2 determines MVO2, which then may limit PVA, manifested partly as a change in the ESPVR. Initially, as arterial oxygen saturation was decreased from 95 +/- 3% to 64 +/- 14%, coronary blood flow increased so that MQO2 was maintained with no change in myocardial extraction ratio (ERm = MVO2/MQO2). During this first phase, lactate utilization, PVA, and ESPVR did not change. When oxygen saturation was further reduced, coronary blood flow rose no higher and ERm increased, but not enough to maintain MVO2. Lactate consumption decreased and ST segments rose, signaling a change from aerobic metabolism. MVO2 decrease was associated with a fall in PVA, which was due to a fall in blood pressure and a significant depression of the ESPVR. Specifically, the volume intercept of the ESPVR increased in all dogs (6.5-20.1 ml, p less than 0.0001), accounting for two thirds of the increase in end-systolic volume. The slope of the ESPVR decreased during hypoxia (13.3-6.1 mm Hg/ml, p less than 0.02), accounting for only one third of the observed increase in end-systolic volume. We believe that the evidence of anaerobic metabolism, the decrease in PVA, and the depression of the ESPVR demonstrates onset of oxygen supply limitation of MVO2. Our data are consistent with the hypothesis that limited MVO2 may limit PVA. The hypoxic volume intercept alteration of the ESPVR is different from changes in the slope of ESPVR seen with other interventions. This may be analogous to recent observations in isolated muscle that show hypoxic depression in contractility to be different from other interventions.
Loss of selective endothelial cell vasoactive functions caused by hypercholesterolemia in pig coronary arteries.
Authors: Cohen R A , Zitnay K M , Haudenschild C C , Cunningham L D
Published: June 2012

The influence of hypercholesterolemia on the reactivity of coronary arteries was investigated after feeding a high-cholesterol diet to pigs for 9 weeks. After this duration of hypercholesterolemia, the fatty or intimal proliferative changes of atherosclerosis were not yet evident in the coronary arteries by light or electron microscopy. Changes in isometric tension were compared in isolated ring segments of coronary arteries from normal and hypercholesterolemic animals. The endothelium failed to inhibit contractions caused by 5-hydroxytryptamine in coronary arteries from hypercholesterolemic animals, but it did so in normal vessels. In contracted arteries, endothelium-dependent relaxations caused by 5-hydroxytryptamine and substance P were reduced by hypercholesterolemia. In contrast, endothelium-dependent relaxations mediated by norepinephrine acting at alpha 2-adrenoceptors and those caused by the calcium ionophore A23187 were unaffected. Endothelium-independent beta-adrenergic relaxations caused by norepinephrine, as well as those caused by nitroprusside, and papaverine also were unaffected by hypercholesterolemia. The loss of selective endothelial cell receptor-mediated relaxation suggests that it is not the ability of the coronary artery endothelium to elaborate vasodilators, but the initiation of the coronary artery endothelial cell response to 5-hydroxytryptamine and substance P that is affected by hypercholesterolemia. Thus, during hypercholesterolemia, selective endothelial cell dysfunction giving rise to abnormal coronary artery reactivity precedes the onset of coronary artery atherosclerosis.
Rate-dependent effects of hypoxia on internal longitudinal resistance in guinea pig papillary muscles.
Authors: Hiramatsu Y , Buchanan J W , Knisley S B , Gettes L S
Published: June 2012

We have studied the independent and combined effects of 30 minutes' exposure to hypoxia and an increase in stimulation frequency from 0.5 Hz to 3.0 Hz on internal longitudinal resistance (ri) and conduction in guinea pig papillary muscles through the use of the voltage ratio method with air as the external insulator. Increasing stimulation frequency from 0.5 to 3.0 Hz in the presence of O2 caused no significant change in ri. Hypoxia to a level of PO2 = 30 mm Hg caused an increase in ri that averaged 13.7% at a stimulation frequency of 0.5 Hz and 46% at 3.0 Hz. In all experiments, the increase in ri during hypoxia at 3.0 Hz was greater than the increase at 0.5 Hz, but conduction velocity did not change at either rate. These results indicate that hypoxia causes rate-dependent cellular uncoupling but, under the conditions of our experiments, does not cause significant changes in conduction.
Bimodal effect of stimulation on light fluctuation transients monitoring spontaneous sarcoplasmic reticulum calcium release in rat cardiac muscle.
Authors: Kort A A , Lakatta E G
Published: June 2012

Microscopic, myofilament motion caused by spontaneous oscillatory Ca2+ release from the sarcoplasmic reticulum (SR) of unstimulated rat papillary muscles produces scattered light intensity fluctuations (SLIF) in a laser beam scattered by the tissue. SLIF frequency increases with Ca2+ loading of resting muscle. We used novel time-gated SLIF measurements to determine how electrical stimulation (which per se both induces SR Ca2+ release and modulates total cellular Ca2+ loading) affects SLIF. Stimulation of thin rat, right ventricular muscles at 1 Hz in bathing [Ca2+] (Ca0) of 1.5 mM at 29 degrees C abolished SLIF for 5-7 seconds; SLIF then reappeared and monotonically increased for 10-15 seconds to reach the steady resting level. Resting force transients paralleled those of SLIF. The magnitude of depression and time course of recovery of both resting force and SLIF at this Ca0 vary inversely with the rate of prior stimulation and the number of stimuli given. An increase in Ca0 or disablement of the Na-K pump increased both resting SLIF and force; transient stimulation under these conditions (i.e., in a 2.5-5.5-second "diastolic window" after cessation of stimulation) augmented SLIF and force above the resting level. Isoproterenol caused a modest reduction of resting SLIF, but it transiently increased SLIF after stimulation up to 10-fold above the resting level. Nifedipine did not affect resting SLIF but transiently depressed SLIF after stimulation. Ryanodine abolished SLIF both after stimulation and at rest.(ABSTRACT TRUNCATED AT 250 WORDS)
Responsiveness of iliac collateral vessels to constrictor stimuli in atherosclerotic primates.
Authors: Lopez J A , Armstrong M L , Harrison D G , Piegors D J , Heistad D D
Published: June 2012

This study was performed to examine, first, the protective effects and responses of collateral vessels of the hind limb in normal and atherosclerotic monkeys and, second, the effects of chronic arterial occlusion on the development of atherosclerosis. The iliac artery was ligated on one side in cynomolgus monkeys. Sixteen months later, we recorded the pressure gradient across the limb collaterals and measured blood flow with microspheres. Collateral conductance was fivefold greater after chronic ligation of the iliac artery than after acute ligation. Despite dilatation or growth of collateral vessels after chronic ligation, iliac pressure was reduced distal to the ligation. Blood flow to the limb was normal after chronic ligation in both normal and atherosclerotic monkeys. Collateral vessels constricted in response to infusion of phenylephrine and serotonin in normal and atherosclerotic monkeys. Thus, one conclusion of this study is that collateral vessels restore limb blood flow to normal after chronic vascular occlusion in both normal and atherosclerotic monkeys, but the protective effects of collateral vessels may be compromised by vasoconstrictor stimuli. Morphometric measurements indicated that occlusion of the iliac artery reduced proliferation of atherosclerotic intima distal to the occlusion in the cholesterol-fed monkeys. Thus, a second conclusion of this study is that atherosclerosis is attenuated below an arterial occlusion.
Effect of various plasminogen activators on prostacyclin synthesis in cultured vascular cells.
Authors: Kawaguchi H , Yasuda H
Published: June 2012

In this study, we examined the effects of various plasminogen activators on arachidonic acid release and prostacyclin biosynthesis in cultured rat aortic smooth muscle cells and bovine pulmonary artery endothelial cells. Prostacyclin was the major product formed from arachidonic acid in aortic smooth muscle cells and endothelial cells. When intact cells were incubated with streptokinase, one of the plasminogen activators, a significant stimulatory effect on prostacyclin biosynthetic activity in cells was evident without any cellular damage at all concentrations used (1-5,000 units/ml). Streptokinase also caused a marked release of arachidonic acid. However, when it was incubated with cell-free homogenates and [3H]arachidonic acid, it did not show any effects on prostacyclin biosynthesis. The addition of urokinase and tissue-type plasminogen activator had no effect on prostacyclin biosynthesis. Urokinase stimulated the release of arachidonic acid from cells, but it did not show any effect on prostacyclin release at any concentration of urokinase (1-5,000 units/ml). The release of arachidonic acid and the increased prostacyclin synthesis were not observed when tissue-type plasminogen activator was added. These results indicate that, among various plasminogen activators investigated, only streptokinase causes the release of arachidonic acid and prostacyclin. This could be a beneficial effect in thrombolytic therapy.
Lesion of the area postrema region attenuates hypertension in spontaneously hypertensive rats.
Authors: Mangiapane M L , Skoog K M , Rittenhouse P , Blair M L , Sladek C D
Published: June 2012

To determine whether the area postrema contributes to the development of hypertension in spontaneously hypertensive rats (SHR), sham or electrolytic lesions of the area postrema (AP) were made in 4-week-old SHR and Wistar-Kyoto (WKY) controls. From weeks 5 through 16, systolic pressure was measured via tail plethysmography. While blood pressure rose markedly in sham-operated SHR, increases in pressure were small in AP-ablated SHR and similar to those seen in all WKY. Subsequent direct measurements of mean arterial pressure in the same rats showed a significant correlation (r = 0.87, p less than 0.01) with the pressure data acquired via weekly tail-cuff measurement, thereby confirming that hypertension in AP-ablated SHR had indeed been attenuated. Analysis of several hundred computer-acquired measurements of mean arterial pressure from each rat showed that AP ablation shifted the distribution of mean arterial pressure to a lower range in SHR but not WKY. Ablation of the AP also decreased resting heart rate in SHR but not WKY. Suppression of heart rate in response to intravenous phenylephrine was equivalent in sham-operated and AP-ablated rats, suggesting that baroreflex-mediated slowing of heart rate was not impaired. In response to intravenous angiotensin II, suppression of heart rate was similar in sham and AP-ablated SHR, and actually was enhanced in AP-ablated WKY. Histological evaluation of the lesions indicated that visible damage to the adjacent nuclei of the solitary tracts was confined to a small portion of the commissural nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)