bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrasting effects of static and pulsatile pressure on carotid baroreceptor activity in dogs.
Authors: Chapleau M W , Abboud F M
Published: June 2012

The purpose of this study was to contrast the effects of static and pulsatile pressure on carotid baroreceptor activity over a wide range of mean arterial pressure. Static and pulsatile pressure were applied to the isolated carotid sinus of dogs anesthetized with chloralose. Recordings were obtained from single baroreceptor units as well as from the whole sinus nerve or a large strand of the nerve. Three observations are reported. First, in single units the pulsatile pressure threshold, which averaged 48 +/- 8 (SEM) mm Hg, was far below the static pressure threshold, which averaged 79 +/- 8 mm Hg (p less than 0.05, n = 15). Thus, pulsatility decreased the threshold by an average of 31 mm Hg in contrast to the minimal or lack of decrease in threshold reported by others in aortic baroreceptors. Second, at moderate arterial pressures a shift from static to pulsatile pressure caused a decrease in single and multiple unit activities. In single units, the decrease approximated 15% (from 42.0 +/- 2.1 to 35.5 +/- 1.9 spikes/sec, p less than 0.05, n = 25). In all units, there was no diastolic nerve activity ("silence") when diastolic pressure was 1 to 10 mm Hg above static pressure threshold; 80% of the units exhibited "diastolic silence" when diastolic pressure was 20-30 mm Hg above threshold and 40% of the units showed silence at diastolic pressures 40-50 mm Hg above threshold. In whole nerve recordings, pulsatility increased activity from 57 +/- 15 to 142 +/- 29 spikes/sec (p less than 0.05) at low mean arterial pressures (50 and 75 mm Hg), as expected from the reduction in pressure threshold noted in single units, and decreased activity by approximately 15% (from 373 +/- 69 to 320 +/- 55 spikes/sec, p less than 0.05, n = 9) at mean arterial pressures of 125 and 150 mm Hg. This decrease in activity with a shift from static to pulsatile pressure at moderate arterial pressures has not been reported previously. Third, the static pressure-activity curve was sigmoid, and its gain peaked sharply at 75-100 mm Hg; in contrast, the pulsatile pressure-activity curve was linear between 25 and 150 mm Hg, and its maximum gain was half the maximum gain during static pressure. These differences between the static pressure-activity curve and the pulsatile pressure-activity curve were noted during both increases and decreases in carotid sinus pressure; both curves exhibited some hysteresis during the decreases in pressure.
A model study of the effects of the discrete cellular structure on electrical propagation in cardiac tissue.
Authors: Rudy Y , Quan W L
Published: June 2012

The effects of the discrete cellular structure on propagation of electrical excitation in cardiac muscle were studied in a one-dimensional fiber model containing a periodic intercalated disk structure. Globally, the macroscopic velocity of propagation follows the behavior associated with propagation in a continuous tissue (except for high values of disk resistance). In addition, the computed spatial extracellular potential along the fiber is a smooth biphasic waveform and does not reflect the underlying discrete cellular structure of the tissue. Other results of the simulations demonstrate the discontinuous nature of propagation and the importance of the structure in arrhythmogenesis. Vmax displays a biphasic behavior as a function of increasing intercalated disk resistance. An initial "paradoxical" increase in Vmax (with a simultaneous decrease in conduction velocity) is followed by a decrease that leads to decremental propagation and conduction block. The time constant of the foot of the action potential (tau foot) increases monotonically with increasing intercalated disk resistance. An increase in the leakage current to extracellular space brings about a significant decrease in the action potential duration and a loss of the plateau. This major effect is accompanied by a relatively smaller decrease in conduction velocity. Collision of two activation wavefronts results in a significant (100%) increase in Vmax and a very small (0.6%) decrease in tau foot.
Accumulation of 5-hydroxytryptamine leads to dysfunction of adrenergic nerves in canine coronary artery following intimal damage in vivo.
Authors: Cohen R A , Zitnay K M , Weisbrod R M
Published: June 2012

Previous in vitro studies have demonstrated that coronary artery adrenergic nerves are a principal site of accumulation of 5-hydroxytryptamine released from aggregating platelets. The purpose of this study was to determine whether 5-hydroxytryptamine is accumulated by adrenergic nerves at sites of endothelial damage and platelet aggregation in vivo. Coronary artery 5-hydroxytryptamine content and response to in vitro adrenergic nerve stimulation were studied in dogs 24 hours following balloon catheter-induced intimal injury. 5-Hydroxytryptamine content was significantly increased in the catheter-damaged arteries, and there was a coincident decrease in the content of norepinephrine. The relaxation caused by acetylcholine was abolished in the catheter-injured arteries, indicating loss of this endothelial cell-mediated function. The normal beta-adrenergic relaxation caused by nerve stimulation was inhibited, and in some cases, contractions resulted; these effects were prevented by serotonergic receptor antagonists. The sensitivity to exogenously added norepinephrine was unchanged, indicating that the changes in the response to nerve stimulation were not due to an altered smooth muscle response to the native neurotransmitter. These observations indicate that following intimal damage, which produces platelet aggregation on the luminal surface of the blood vessel, 5-hydroxytryptamine can assume a transmitter role in coronary artery adrenergic nerves and thereby cause their dysfunction.
Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical.
Authors: Ignarro L J , Byrns R E , Buga G M , Wood K S
Published: June 2012

The objective of this study was to elucidate the close similarity in properties between endothelium-derived relaxing factor (EDRF) and nitric oxide radical (NO). Whenever possible, a comparison was also made between arterial and venous EDRF. In vascular relaxation experiments, acetylcholine and bradykinin were used as endothelium-dependent relaxants of isolated rings of bovine intrapulmonary artery and vein, respectively, and NO was used to relax endothelium-denuded rings. Oxyhemoglobin produced virtually identical concentration-dependent inhibitory effects on both endothelium-dependent and NO-elicited relaxation. Oxyhemoglobin and oxymyoglobin lowered cyclic guanosine monophosphate (cGMP) levels, increased tone in unrubbed artery and vein, and abolished the marked accumulation of vascular cGMP caused both by endothelium-dependent relaxants and by NO. The marked inhibitory effects of oxyhemoglobin on arterial and venous relaxant responses and cGMP accumulation as well as its contractile effects were abolished or reversed by carbon monoxide. These observations indicate that EDRF and NO possess identical properties in their interactions with oxyhemoproteins. Both EDRF from artery and vein and NO activated purified soluble guanylate cyclase by heme-dependent mechanisms, thereby revealing an additional similarity in heme interactions. Spectrophotometric analysis disclosed that the characteristic shift in the Soret peak for hemoglobin produced by NO was also produced by an endothelium-derived factor released from washed aortic endothelial cells by acetylcholine or A23187. Pyrogallol, via the action of superoxide anion, markedly inhibited the spectral shifts, relaxant effects, and cGMP accumulating actions produced by both EDRF and NO. Superoxide dismutase enhanced the relaxant and cGMP accumulating effects of both EDRF and NO. Thus, EDRF and NO are inactivated by superoxide in a closely similar manner. We conclude, therefore, that EDRF from artery and vein is either NO or a chemically related radical species.
Acute hypertension selectively potentiates constrictor responses of large coronary arteries to serotonin by altering endothelial function in vivo.
Authors: Lamping K G , Dole W P
Published: June 2012

We tested the hypothesis that acute coronary artery hypertension may damage vascular endothelium and alter vasomotor responses to humoral agents. We examined effects of intracoronary infusion of the endothelium-dependent agent serotonin and two endothelium-independent agents, angiotensin II and methoxamine, on large coronary artery diameter in the blood perfused dog heart. Responses were examined before and 30 minutes after brief periods of coronary hypertension (200 mm Hg for 10 seconds to 15 minutes). In open-chest anesthetized dogs, the left anterior descending coronary artery was perfused at constant pressure. Coronary diameter (D) was measured with piezoelectric crystals. At a control perfusion pressure of 80 mm Hg, serotonin produced dose-dependent constriction of the large coronary artery (mean +/- SEM; delta D = -22 +/- 10 microns at 5 micrograms/min; -108 +/- 50 microns at 50 micrograms/min). Increasing perfusion pressure to 200 mm Hg increased flow 515 +/- 79% and coronary diameter 509 +/- 9 microns. After 15 minutes of hypertension, when coronary diameter had returned to baseline values, the constriction of the large artery to serotonin was potentiated (delta D = -89 +/- 33 microns at 5 micrograms/min; -207 +/- 45 microns at 50 micrograms/min; p less than 0.05). Hypertension for 1-5 minutes potentiated constrictor responses of large coronary arteries for at least 2 1/2 hours. Removal of endothelium prevented effects of hypertension on constrictor responses of large arteries to serotonin. Hypertension did not alter constrictor responses to angiotension II (1 and 2.5 micrograms/min) or methoxamine (50 and 100 micrograms/min) or the dilator response to acetylcholine (40 micrograms/min). Acute hypertension altered endothelial morphology. There were small endothelial craters following 10 seconds of hypertension, and disruption of endothelial junctions with leukocyte adherence following 1-15 minutes of hypertension. We conclude that acute hypertension alters constrictor responses of large coronary arteries to serotonin by impairing endothelial function and not by directly affecting vascular smooth muscle. These effects of acute hypertension on vascular reactivity are selective in that they do not involve non-endothelium-dependent agents or the endothelium-dependent agent, acetylcholine. The effect of hypertension also persists long after pressure is restored to normotensive levels.
Transient outward current prominent in canine ventricular epicardium but not endocardium.
Authors: Litovsky S H , Antzelevitch C
Published: June 2012

Previous studies have denied the presence of a transient outward current (Ito) in ventricular myocardium of dog, sheep, and calf. Using conventional microelectrode techniques, we provide evidence for a significant contribution of Ito to epicardial, but not endocardial, activity of canine ventricular myocardium. The epicardial action potential when compared with that of endocardium shows a smaller phase 0 amplitude, a much more prominent phase 1, and a phase 2 amplitude that is greater than that of phase 0. Epicardial action potentials, unlike those of endocardium, display a "spike and dome" morphology that becomes progressively more accentuated at slower stimulation rates. Using the restitution of phase 1 amplitude as a marker for the process responsible for the spike and dome phenomenon, we were able to delineate two exponential components: 1) a slow component that recovers with a time constant of 350-570 msec and 2) a fast component with a time constant of 41-85 msec. The slow component was largely abolished by 1-5 mM 4-aminopyridine, an Ito blocker. The fast component was diminished by 4-aminopyridine, but it was also inhibited by ryanodine and by Sr2+ replacement of Ca2+, which are interventions known to inhibit the Ca2+-activated component of Ito. Following 4-aminopyridine and Sr2+ or ryanodine treatment, the epicardial responses more closely resembled those of endocardium. In summary, the data demonstrate a marked heterogeneity of active membrane properties in canine ventricular muscle. These observations may aid in understanding the basis for rate-dependent changes in the T wave of the ECG, supernormal conduction in ventricular muscle, the greater sensitivity of epicardium to ischemia, and the rate dependence of some cardiac arrhythmias.
Abnormalities of dynamic ventricular shape change in patients with aortic and mitral valvular regurgitation: assessment by Fourier shape analysis and global geometric indexes.
Authors: Kass D A , Traill T A , Keating M , Altieri P I , Maughan W L
Published: June 2012

The normal cardiac cycle is associated with dynamic changes in left ventricular shape, which can be disturbed in disease states. To assess the influences of diastolic volume, percent ejected volume, and abnormalities of acute or chronic systolic loading on general and detailed chamber geometry, we studied dynamic shape change recorded by x-ray contrast ventriculography in both normal patients and those with aortic (AR) or mitral (MR) valve regurgitation. While both lesions increased diastolic volume, the character of load throughout ejection differed markedly. Detailed cavity geometry was assessed by a Fourier analysis technique and general shape by eccentricity and circularity indexes. Normal hearts, showed increased systolic elongation by all indexes. AR patients displayed a similar rise in eccentricity during ejection; however, the extent of shape change when measured by Fourier and circular indexes was reduced. In contrast, MR patients displayed enhanced systolic shape change, particularly in chamber elongation. Neither simple eccentricity of circular indexes adequately differentiated these shape abnormalities, whereas detailed Fourier geometric analysis precisely characterized the abnormalities of shape change in these two diseases. Relations between the extent of shape change and ejected volume for each patient group revealed significantly more systolic deformation with a different shape versus volume relation for the MR hearts as compared with AR and controls. Thus, while dynamic left ventricular shape is certainly influenced by the extent of volume change, it also varies independently from volume related to the specific nature of loading during ejection.
Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs.
Authors: Rensma P L , Allessie M A , Lammers W J , Bonke F I , Schalij M J
Published: June 2012

We calculated the wavelength of the atrial impulse in chronically instrumented conscious dogs by measuring both conduction velocity and refractory period: wavelength = refractory period X conduction velocity. Implantation of multiple stimulating and recording electrodes allowed wavelength determination at four different areas: the right and left parts of Bachmann's bundle and the free walls of the right and left atria. During programmed electrical stimulation, three types of arrhythmias were observed: rapid repetitive responses, atrial flutter, and atrial fibrillation. During normal rhythm, the wavelength of the atrial impulse varied between 14 and 18 cm. Premature beats had a shorter wavelength, depending on the degree of prematurity. Premature beats that evoked rapid repetitive responses showed a critical shortening of the wavelength below 12.3 cm. Episodes of atrial flutter were induced at a wavelength below 9.7 cm, while fibrillation occurred at wavelengths shorter than 7.8 cm. We correlated the induction of these arrhythmias with the values of refractory period, conduction velocity, and wavelength during control and during administration of several drugs. Intravenous administration of acetylcholine shortened the wavelength by 30-40%, mainly because of refractory period shortening. Both propafenone and lidocaine had strong but opposite effects on refractoriness and conduction and, consequently, little effect on the wavelength. Quinidine markedly prolonged the refractory period, but prolongation of wavelength was less because of a simultaneous decrease in conduction velocity. d-Sotalol also increased refractory period, but because it had no appreciable effect on conduction velocity, this drug was the most effective in prolongation of wavelength. Linear discriminant analysis of the data showed that the refractory period and the conduction velocity each were poor parameters to predict the occurrence of the different arrhythmias (predictive value 48% and 38%, respectively). The combination of both properties, however, as expressed in the wavelength, was a more reliable index that predicted the induction of the different arrhythmias correctly in 75% of the cases. We conclude that the wavelength is a useful parameter for evaluating antiarrhythmic drugs.
Changes in substrate metabolism and effects of excess fatty acids in reperfused myocardium.
Authors: Liedtke A J , DeMaison L , Eggleston A M , Cohen L M , Nellis S H
Published: June 2012

The purpose of these studies was to characterize the rates of fatty acid oxidation in reperfused myocardium and test the influence of excess fatty acids (FA) on mechanical function in the extracorporeally perfused, working swine heart model. Seventeen animals were prepared. Eight were untreated (LOW FA group; serum FA averaged 0.55 +/- 0.07 mumol/ml) and nine received a constant infusion of 10% Intralipid with heparin to raise serum FA to about 1.4 +/- 0.21 mumol/ml (HIGH FA group). Coronary flow in both groups was held at aerobic levels for an equilibrium period of 40 minutes, acutely reduced regionally in the anterior descending circulation by 60% for 45 minutes, and acutely restored to aerobic levels for 60-minute reflow. Appreciable mechanical depression (-47 delta% from aerobic values; p less than 0.01) during reperfusion was noted in both groups. This was associated with modest reductions in myocardial oxygen consumption (p less than 0.05) and losses of total tissue carnitine stores (p at least less than 0.02). Reperfused myocardium showed a strong preference for and aerobic use of FA during reflow such that 14CO2 production from labeled palmitate exceeded preischemic levels (+89 delta% in LOW FA hearts; +111 delta% in HIGH FA hearts). This suggested relative preservation of restoration of certain elements in mitochondrial function during reflow. The findings argue for uncoupling between substrate metabolism and energy production, accelerated but useless energy drainage, or some impairment between energy transfer and function of contractile proteins as possible explanations for the persistent depression of mechanical function (stunning) during reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
A model for early afterdepolarizations: induction with the Ca2+ channel agonist Bay K 8644.
Authors: January C T , Riddle J M , Salata J J
Published: June 2012

Early afterdepolarizations (EADs) are one mechanism proposed to cause certain cardiac arrhythmias. We studied the effect of the Ca2+ channel agonist Bay K 8644 (1 x 10(-8) to 5 x 10(-5) M) on normally polarized sheep and canine cardiac Purkinje fiber short segments. EADs occurred with higher Bay K 8644 concentrations and had an average take-off potential of -34 mV. The initiation of EADs was preceded by lengthening of action potential duration and flattening of the plateau. Induction of EADs with Bay K 8644 was enhanced by low stimulation frequencies, lowering of [K]o, addition of tetraethylammonium chloride, or application of depolarizing constant current pulses during the plateau. EADs were abolished by increasing stimulation frequency, raising [K]o, the addition of tetrodotoxin, lidocaine, ethmozin, verapamil, and nitrendipine, or application of repolarizing constant current pulses. Using current pulses to modify the action potential plateau, a steep inverse relationship was found between the EAD peak voltage and its take-off potential, and EADs could be initiated over only a narrow range of take-off potentials. Thus, interventions that suppressed EADs shortened action potential duration or shifted the plateau away from the voltage range needed to initiate EADs. These observations suggest that mechanisms dependent on both time and voltage underlie EADs, and provide a unifying hypothesis for the induction of the EADs. We propose that induction of EADs requires 1) lengthening of action potential duration within a plateau voltage range where 2) recovery from inactivation and reactivation of an inward current possibly carried through Ca2+ channels can occur.
Atrial natriuretic factor regulates the calcium current in frog isolated cardiac cells.
Authors: Gisbert M P , Fischmeister R
Published: June 2012

The effect of external application of synthetic atrial natriuretic factor (ANF) on calcium current (ICa) was studied in single cells isolated from frog ventricle using the whole-cell patch-clamp technique. Rat atriopeptin III (APIII) and 3-28 ANF rat (rANF) had negligible effects on basal ICa at concentrations up to 200 nM. However, when ICa was increased by isoprenaline, both peptides had significant inhibitory effects. rANF (3 nM) decreased isoprenaline-elevated ICa by an average of 33% after 3-5 minutes. APIII was slightly less effective than rANF. The effects of rANF and APIII were dose-dependent in a complex manner: one stimulatory and two different inhibitory effects were observed, one being responsible for an irreversible rundown of ICa. The effects of ANF were not blocked by atropine and desensitization of the cells to isoprenaline did not play a significant role in the response to ANF. When ICa was elevated by intracellular perfusion with cyclic adenosine 3',5'-monophosphate, added to the patch electrode solution or using a perfused pipette, rANF or APIII had less inhibitory effect, and no rundown of ICa was observed. It is proposed that adenylate cyclase may be one of several mechanisms by which ANF regulates ICa.
Thromboxane synthetase inhibitors reduce infarct size by a platelet-dependent, aspirin-sensitive mechanism.
Authors: Mullane K M , Fornabaio D
Published: June 2012

Platelets are suggested to exacerbate ischemia-induced myocardial injury, which has led to the study of various antiplatelet therapies including thromboxane synthetase inhibitors (TXSI). Two such agents, benzylimidazole and OKY-046, reduce infarct size commensurate with a diminution in serum thromboxane B2 formation in anesthetized dogs subjected to 90 minutes of coronary artery occlusion followed by 5 hours of reperfusion. In contrast, platelet depletion with specific antiserum does not reduce infarct size but prevents the cardioprotection afforded by the TXSI. Platelet-derived prostaglandin endoperoxides (PGG2 and PGH2), which cannot be converted to thromboxane A2 in the inhibited platelet, can be transformed to PGE2 and PGD2 in plasma and to PGI2 by the blood vessel wall. These prostaglandins are considered "cardioprotective." Consequently, a low dose of aspirin (3-5 mg/kg) given 24 hours before coronary occlusion was used to selectively block the platelet cyclooxygenase enzyme. Aspirin, by itself, does not reduce infarct size, but it suppresses the myocardial salvage induced by OKY-046. Thus, TXSI reduce infarct size by platelet-dependent, aspirin-sensitive mechanism that depends on the redirection of platelet-derived PGG2 and PGH2 to protective metabolites, rather than inhibition of thromboxane A2 per se. Moreover, myocardial salvage induced by the TXSI is accompanied by a reduction in neutrophil accumulation in the myocardium, as indicated by the levels of the neutrophil-specific myeloperoxidase enzyme. Platelet depletion or pretreatment with aspirin prevents the TXSI-induced suppression of neutrophil accumulation. Consequently, it is proposed that the prostaglandin-mediated protective effects of TXSI can be resolved, at least in part, in terms of a braking action on neutrophil activation to prevent leukocyte-dependent tissue injury.
Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium.
Authors: Weber K T , Janicki J S , Shroff S G , Pick R , Chen R M , Bashey R I
Published: June 2012

Cardiac muscle is tethered within a fibrillar collagen matrix that serves to maximize force generation. In the human pressure-overloaded, hypertrophied left ventricle, collagen concentration is known to be increased; however, the structural and biochemical remodeling of collagen and its relation to cell necrosis and myocardial mechanics is less clear. Accordingly, this study was undertaken in a nonhuman primate model of left ventricular hypertrophy caused by gradual onset experimental hypertension. The amount of collagen, its light microscopic features, and proportions of collagen types I, III, and V were determined together with diastolic and systolic mechanics of the intact ventricle during the evolutionary, early, and late phases of established left ventricular hypertrophy (4, 35, and 88 weeks, respectively). In comparison to controls, we found 1) increased collagen at 4 weeks, as well as a greater proportion of type III, in the absence of myocyte necrosis; 2) collagen septae were thick and dense at 35 weeks, while the proportion of types I and III had converted to control; 3) necrosis was evident at 88 weeks, and the structural remodeling and proportion of collagen types I and III reflected the extent of scar formation; and 4) unlike diastolic myocardial stiffness, which was unchanged at 4, 35, or 88 weeks, the systolic stress-strain relation of the myocardium was altered in either a beneficial or detrimental manner in accordance with structural remodeling of collagen and scar formation. Thus, early in left ventricular hypertrophy, reactive fibrosis and collagen remodeling occur in the absence of necrosis while, later on, reparative fibrosis is present.(ABSTRACT TRUNCATED AT 250 WORDS)
Phorbol ester increases the dihydropyridine-sensitive calcium conductance in a vascular smooth muscle cell line.
Authors: Fish R D , Sperti G , Colucci W S , Clapham D E
Published: June 2012

In vascular smooth muscle, phorbol esters cause a slowly developing contraction and an associated transmembrane calcium flux, both of which are inhibited by dihydropyridine calcium channel antagonists. In the A7r5 cultured vascular cell line, we used the whole-cell voltage-clamp technique to identify voltage-dependent calcium conductances and investigate the effect of phorbol esters on that conductance having characteristic dihydropyridine sensitivity (slowly inactivating, high-threshold, "L-type"). With barium as the charge carrier, large-amplitude (100-800 pA) inward currents of two types were characterized by their kinetics and voltage dependence. With holding potential--80 mV, a rapidly inactivating, low-threshold current ("T-type") was activated by depolarizations above-40 mV and was maximal at -10 mV. With holding potential -30 mV, this component was inactivated, and a second slowly inactivating, high-threshold current was activated above -10 mV and was maximal at +10 to +20 mV. These currents are similar to the T-type and L-type currents previously described in vascular smooth muscle cells. When added to the bath, the active phorbol ester, 12-O-tetradecanoyl phorbol-13-acetate (100 nM) increased the slowly inactivating (L-type) current by 32 +/- 20% (n = 8, +/- SD). Phorbol-12,13-dibutyrate (100 nM) caused a similar effect, but the inactive phorbol, 4-alpha-phorbol (100 nM), did not. We conclude that at least two distinct calcium conductances are expressed in A7r5 vascular smooth muscle cells, and that the dihydropyridine-sensitive calcium conductance is acutely modulated by phorbol esters, presumably acting through stimulation of protein kinase C. Such modulation may play a role in increasing transmembrane calcium influx mediated by agonist-receptor interactions that lead to activation of protein kinase C and may help to sustain or amplify calcium-dependent cell responses.
Mechanism of ventricular vulnerability to single premature stimuli in open-chest dogs.
Authors: Chen P S , Wolf P D , Dixon E G , Danieley N D , Frazier D W , Smith W M , Ideker R E
Published: June 2012

To determine the mechanism of ventricular vulnerability to electrical stimulation, we simultaneously recorded from 120 transmural electrodes in a 35 X 20 X 5-mm portion of right ventricular infundibulum in seven dogs. Baseline pacing (S1) was performed from outside the mapped region followed by single premature stimulation (S2) of increasing strength at the center of the mapped region. In five of six episodes of ventricular fibrillation and 26 of 30 episodes of repetitive responses, complete reentrant pathways were observed. Earliest activation following S2 was not at the site of S2 stimulation but was at a point between the S1 and S2 sites of stimulation. Activation spread away from the early site toward the opposite side of the mapped region around the sides of an arc of block near the S2 site to form a "figure-of-eight." The activation fronts coalesced to activate the region around the S2 site last and, if the difference in times between activation at the early site and near the S2 site was large, reentered the tissue toward the S1 site. Ventricular refractory periods were determined in four dogs following S1 pacing; the regions with the greatest nonuniformity in the dispersion of refractoriness were not the regions of unidirectional block after S2 stimulation. Thus, 1) ventricular fibrillation and repetitive responses induced electrically with S1 and S2 stimuli at different ventricular sites arise by figure-of-eight reentry, 2) this reentry is caused by the ability of S2 stimulation both to prolong refractoriness near the S2 site and to initiate a propagated response in the region between the S1 and S2 sites, and 3) a nonuniform dispersion of refractoriness is not crucial for the electrical induction of reentry leading to ventricular fibrillation or repetitive responses when S1 and S2 stimuli are given at different locations on the right ventricular outflow tract.
Passive properties of canine left ventricle: diastolic stiffness and restoring forces.
Authors: Nikolić S , Yellin E L , Tamura K , Vetter H , Tamura T , Meisner J S , Frater R W
Published: June 2012

Left ventricular (LV) diastolic pressure-volume (P-V) relations arise from a complex interplay of active decay of force (i.e., relaxation), passive elastic myocardial properties, and time-varying inflow across the mitral orifice. This study was designed to quantify the passive properties of the intact ventricle and the effects of elastic recoil by separating filling from relaxation with a method of LV volume clamping with a remote-controlled mitral valve. Eleven open-chest fentanyl-anesthetized dogs were instrumented with aortic and mitral flow probes, LV and left atrium micromanometers, and a remote-controlled mitral valve. We prevented complete (end-systolic volume clamping) or partial filling at different times in diastole. The ventricle thus relaxed completely at different volumes, and we generated P-V coordinates for the passive ventricle that included negative, as well as positive, values of pressure. We then estimated ventricular volumes from ventricular weight in eight dogs, using regression equations based on data in the literature, to determine the equilibrium volume (V0), that is, volume at zero transmural pressure, in the working ventricle. We abandoned the traditional exponential approach and characterized by the P-V relation with a logarithmic approach that included maximum LV volume (Vm), minimum volume (Vd), and stiffness parameters (Sp and Sn) for the positive (p) and negative (n) phases: Pp = -Sp In[(Vm - V)/(Vm - V0)] and Pn = Sn In[(V - Vd)/(V0 - Vd)]. With this formulation, the chamber compliance, dP/dV, is normalized by the LV operating volume, and Sp and Sn are size-independent chamber stiffness parameters with the units of stress. In eight ventricles with LV weight = 131 +/- 20 g, Vm = 116 +/- 18 ml, V0 = 37 +/- 6 ml, and Vd = 13 +/- 2 ml, stiffness Sp = 14.6 mm Hg and Sn = 5.1 mm Hg were determined from the slopes of the log-linearized equations. Also, the duration of LV relaxation is increased by the process of ventricular filling (161 +/- 31 msec, filling versus 108 +/- 36 msec, nonfilling, measured from dP/dtmin, p less than 0.0001). We conclude that volume clamping is a useful method of studying restoring forces and that the logarithmic approach is conceptually and quantitatively useful in characterizing the passive properties of the intact ventricle.
Sensitivity of left ventricular end-systolic pressure-volume relation to type of loading intervention in dogs.
Authors: Baan J , Van der Velde E T
Published: June 2012

The influence of different types of loading intervention on the resulting end-systolic pressure-volume relation (ESPVR) of the left ventricle in situ was investigated in anesthetized open-chest dogs. Left ventricular volume was measured by conductance catheter and pressure was measured by tip-micromanometer. Two loading interventions were applied: a pressure intervention (INp) by gradually occluding the descending aorta and a volume intervention (INv) by rapidly infusing 180 ml blood into the vena cava. The pressure-volume loops during an intervention always showed a linear ESPVR, the slope of which, Ees, was calculated. Possible method-related artifacts were assessed and could be excluded. Results from 16 dogs show that Ees(INp) was always larger (1.37 +/- 0.45 kPa/ml) than Ees(INv) (0.73 +/- 0.32 kPa/ml) (p less than 0.001). This difference was enhanced by beta-blockade through metoprolol. The same phenomenon was found for the slope (SdPV) of the relation between dP/dtmax and end-diastolic volume: SdPV(INp) = 45.17 +/- 22.63 kPa/ml/sec and SdPV(INv) = 20.55 +/- 11.13 kPa/ml/sec. In seven dogs, a right heart bypass was performed to study the influence of stroke volume on the ESPVR by applying a pressure intervention under three conditions: with constant end-diastolic volume (decreasing stroke volume), Ees = 2.27 +/- 0.79 kPa/ml; with constant stroke volume, Ees = 1.59 +/- 0.51 kPa/ml; and with increasing stroke volume (and increasing end-diastolic volume), Ees = 1.36 +/- 0.49 kPa/ml. Analysis of variance revealed a statistically significant relation between Ees and stroke volume (p less than 0.01). From the right heart bypass experiments, we conclude that shortening-related deactivation plays a role in the observed behavior of the ESPVR. However, the results from the series with intact circulation indicate that aortic occlusion has an additional effect on the slope of the ESPVR, leading to increased myocardial inotropism, perhaps mediated through a peripheral stimulus in response to decreased perfusion.
Formation of S-adenosylhomocysteine in the heart. I: An index of free intracellular adenosine.
Authors: Deussen A , Borst M , Schrader J
Published: June 2012

To assess the concentration of free intracellular adenosine in the heart the kinetic properties of cytosolic S-adenosylhomocysteine (SAH) hydrolase were utilized at elevated levels of L-homocysteine (adenosine + L-homocysteine in equilibrium with SAH + H2O). Global hypoxia was induced in the isolated perfused guinea pig heart by graded reduction of perfusion medium PO2 in the presence of saturating concentrations of homocysteine (0.2-1.0 mM). Reduction of PO2 from 660 to 165 mm Hg increased the steady-state concentration of total tissue adenosine from 2.0 +/- 0.2 to 2.8 +/- 0.2 nmoles/g, while the rate of SAH formation increased linearly from 0.22 +/- 0.03 to 2.50 +/- 0.13 nmoles/min/g. When adenosine was exogenously applied at a concentration of 100 microM together with homocysteine (1 mM), SAH accumulation rates were much greater: 23.34 +/- 3.31 and 42.11 +/- 1.73 nmoles/min/g with normoxic (95% O2) and hypoxic (30% O2) perfusion, respectively. The apparent Km and Vmax values for SAH-hydrolase in vivo were estimated to be 20 microM and 59 nmoles/min/g wet wt, respectively. Since the relation between SAH formation and adenosine in the physiological concentration range is linear, the measured rate of SAH accumulation during normoxia and hypoxia permitted the calculation of the free intracellular adenosine level, which was 0.061 nmoles/g (0.08 microM) in the normoxic heart. With hypoxia (PO2 165 mm Hg), this value increased to 1.57 nmoles/g (2.0 microM). Free intracellular adenosine closely correlated with the hypoxia-induced changes in coronary flow. The data reveal that measurement of the rate of SAH accumulation during homocysteine infusion can be used for sensitive assessment of free intracellular adenosine levels. Assuming that the intracellular adenosine concentration equals that in the interstitial space, the results furthermore indicate that the degree of intracellular adenosine formation during hypoxic perfusion is quantitatively sufficient to account for most of the observed increases in coronary flow.
Formation of S-adenosylhomocysteine in the heart. II: A sensitive index for regional myocardial underperfusion.
Authors: Deussen A , Borst M , Kroll K , Schrader J
Published: June 2012

Rate of accumulation of myocardial S-adenosylhomocysteine (SAH) was used in an open-chest dog preparation as an index of free cytosolic adenosine levels. Following 30 minutes of coronary artery ligation and infusion of L-homocysteine thiolactone (10 mumol/kg/min i.v.) SAH levels increased from 1.3 (control) to 3.3 nmoles/g in the nonischemic and to values over 100 nmoles/g in the ischemic region. Compared with regional myocardial blood flow the enhanced rate of SAH accumulation was strictly confined to the ischemic area. As long as blood flow was 0.6-1.2 ml/min/g, SAH levels remained unchanged. However, they steeply increased when regional myocardial blood flow decreased below 60% of control. Tissue levels of adenine nucleotides, adenosine, and lactate were not significantly affected in the flow range of 0.4-0.6 ml/min/g but rate of SAH accumulation was enhanced by 400%. In the nonischemic myocardium, SAH accumulation was 60% higher in the subendocardium than in the subepicardium. Decreasing coronary perfusion pressure from 110 to 60, 45, and 35 mm Hg was associated with an exponential increase in coronary venous adenosine release only when perfusion pressure was below 60 mm Hg. Transmural mapping of SAH revealed that at 110 mm Hg SAH was homogeneously distributed, while at a perfusion pressure of 60 mm Hg SAH accumulation was enhanced only in the subendocardial layers. Decreasing perfusion pressure further to 40 and 30 mm Hg not only enhanced subendocardial SAH levels to 120 and 170 nmoles/g, respectively, but also considerably steepened the transmural gradient of SAH. SAH-hydrolase exhibited a broad pH-optimum and its activity in different parts of ventricular myocardium was identical. Our findings provide evidence that 1) measurement of SAH accumulation is a sensitive metabolic index for the assessment of regional myocardial ischemia, 2) significant formation of SAH occurs only when regional myocardial blood flow is less than 0.6 ml/min/g, and 3) transmural SAH gradient, a measure of free cytosolic adenosine, and coronary venous adenosine release significantly increase only when the autoregulatory reserve is exhausted.
QTU prolongation and polymorphic ventricular tachyarrhythmias due to bradycardia-dependent early afterdepolarizations. Afterdepolarizations and ventricular arrhythmias.
Authors: el-Sherif N , Zeiler R H , Craelius W , Gough W B , Henkin R
Published: June 2012

Polymorphic ventricular tachyarrhythmias occurred spontaneously during bradycardia in dogs given the inotropic polypeptide anthopleurin-A (AP-A). The arrhythmia was investigated in in vitro and in vivo experiments. In in vitro experiments, AP-A (50 micrograms/l) produced bradycardia-dependent prolongation of action potential duration that was more pronounced in Purkinje than in muscle fibers. Only Purkinje fibers developed early afterdepolarizations (EAD) and triggered activity. These effects could be abolished by rapid pacing, lidocaine (4 mg/l), or tetrodotoxin (1 mg/l). In vivo experiments were conducted in anesthetized healthy dogs with simultaneous recording of surface ECG, monophasic action potentials from the endocardial and epicardial surface of the left ventricle by contact electrode catheter technique, and transmembrane action potentials from the epicardial surface of the left ventricle with a floating microelectrode technique. AP-A in a dose comparable to that used in vitro (4 micrograms/kg, i.v. bolus) resulted in bradycardia-dependent marked prolongation of both monophasic and transmembrane action potentials. An EAD gradually appeared on both recordings but was more marked in endocardial monophasic action potentials. Eventually, a premature ventricular depolarization arose from or very close to the peak of the EAD. The prolongation of action potentials was associated with similar prolongation of the QTU interval in surface ECG, and in some experiments, the EAD corresponded to a distinct prominent U wave. A ventricular premature depolarization arose from the U or TU complex and initiated polymorphic ventricular tachyarrhythmias that terminated spontaneously or degenerated into ventricular fibrillation. These effects were reversed by rapid pacing or lidocaine (1 mg/kg). The present study provides evidence in support of the hypothesis that AP-A-induced ventricular tachyarrhythmias are due to bradycardia-dependent EAD and triggered activity.
Altered minimal coronary resistance to antegrade reflow after chronic coronary artery occlusion in swine.
Authors: Roth D M , White F C , Bloor C M
Published: June 2012

We examined coronary pressure-flow relations after chronic coronary artery occlusion induced by placement of an ameroid occluder on the left circumflex coronary artery in swine. An acute open-chest procedure was performed in nine pigs 27 +/- 2 days (mean +/- SEM) after surgical placement of the ameroid occluder, and in eight nonoperated control pigs. Coronary vascular resistances were measured during maximal coronary vasodilation with adenosine. Minimal coronary resistance was assessed before and after cannulation and extracorporeal perfusion of the left circumflex coronary artery distal to the site of the ameroid occluder in pigs from the ameroid group and in a similar site in control pigs. Minimal coronary resistance to antegrade reflow in the left circumflex region was decreased significantly in ameroid pigs compared with control pigs (0.06 +/- 0.01 vs. 0.26 +/- 0.03 mm Hg.min.100 g/ml, p less than 0.001, respectively). Decreased minimal coronary vascular resistance was present transmurally in the left circumflex region of ameroid pigs. Altered vascular resistance occurred only in myocardium distal to the ameroid occluder since the nonoccluded left anterior descending region in ameroid pigs had minimal coronary resistance similar to that of the same region from control pigs (0.23 +/- 0.03 vs. 0.19 +/- 0.02 mm Hg.min.100 g/ml). Thus altered minimal coronary vascular resistance occurs and probably reflects vascular proliferation and/or vascular alterations which result in an increased total cross-sectional area of the vasculature in the myocardium distal to the occlusion.
Increase in cross-linking of type I and type III collagens associated with volume-overload hypertrophy.
Authors: Iimoto D S , Covell J W , Harper E
Published: June 2012

Types I, III, IV, and V collagen were isolated and characterized from eight normal dog hearts and seven with volume-overload hypertrophy. Animals with volume-overload hypertrophy were killed at a time when left ventricular end-diastolic pressure and stiffness were increased. The collagens were characterized by solubility properties, sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, and enzyme-linked immunosorbent assay. The percentage of collagen obtained from canine left ventricles was decreased from 32.4% in normal hearts to 15.0% in hypertrophied hearts. We attribute this to a diminution in the extractability of types I and III collagen, which fell from 199.5 mg type I/g collagen and 76.4 mg type III/g collagen in normal hearts to 83.5 mg type I/g collagen and 26.4 mg type III/g collagen in hypertrophied hearts. The amount of types IV and V collagen isolated remained constant in both the control and arteriovenous shunt hearts averaging 15.7 mg type IV/g collagen and 32.1 mg type V/g collagen in control hearts and 12.5 mg type IV/g collagen and 28.9 mg type V/g collagen in hypertrophied hearts. The reduction in quantity of types I and III collagen probably reflects a greater degree of cross-linking in these two types of collagen. Cyanogen bromide peptide analysis confirmed that there was an increase of high molecular weight cross-linked peptides from 3.96% in normal samples to 8.88% in hypertrophied samples. We conclude that cross-linking of types I and III collagen increases in volume-overload hypertrophy and that this is associated with a rise in diastolic stiffness.
Calcium current restitution in mammalian ventricular myocytes is modulated by intracellular calcium.
Authors: Tseng G N
Published: June 2012

Restitution of the conventional L-type calcium current (ICa) was studied in dog or guinea pig ventricular myocytes to understand its time course and regulation. Whole-cell ICa free of other overlapping currents was recorded with a suction pipette. The intracellular environment was varied by intracellular dialysis. The properties of ICa were similar in dog and guinea pig ventricular myocytes, except that the amplitude of ICa was larger in the latter (2.2 +/- 0.5 nA in guinea pig cells and 0.9 +/- 0.2 nA in dog cells, n = 8 for both). In both types of cells during restitution a holding voltage (Vh) negative to -50 mV induced a transient increase in ICa above the control level (ICa overshoot). This overshoot was inhibited by substituting barium for calcium, lowering [Ca]0, increasing intracellular calcium buffering capacity, ryanodine (1-2 microM), or caffeine (10 mM). The overshoot peaked 30-100 msec after repolarization from the conditioning depolarization and gradually declined over the following 2-3 seconds. During the overshoot, although the amplitude of ICa was larger its half-time of decay was longer than the control. The maximum overshoot occurred following a conditioning step to plateau voltages and it was decreased by prolonging the conditioning step from 50 to 100 or 500 msec. It is concluded that intracellular calcium regulates restitution of the L-type calcium channels in mammalian ventricular myocytes and that the sarcoplasmic reticulum is involved in this process.
Ischemia induces changes in the level of mRNAs coding for stress protein 71 and creatine kinase M.
Authors: Mehta H B , Popovich B K , Dillmann W H
Published: June 2012

Hyperthermia, hypoxia, and other conditions induce the appearance of heat shock or stress proteins in cells. We have previously shown that in the ischemic dog myocardium the level of a messenger RNA (mRNA) coding for a protein with migration characteristics similar to heat shock/stress protein 71 increases. Using a human heat-shock protein (hHSP) 70 genomic clone and anti-HSP70 antibodies as probes, we demonstrate in this report that heart stress protein (SP) 71 mRNA and its translational products (71 kDa polypeptides) are members of the stress protein family. In rabbit hearts, the ischemia-induced mRNAs translate into three isoforms with different isoelectric points (6.0, 6.1, and 6.15), in contrast to dog heart mRNA that translates into a protein with a pI of 5.8. The levels of SP71 mRNA in the dog and rabbit ischemic myocardium increased by sixfold and 18-fold, respectively. In the same samples, the levels of creatine kinase M mRNA decreased by about 40%, whereas those of myosin heavy chain mRNA remain unaltered. Our comparative analysis of three different mRNAs indicates that ischemia manifests its effects by differentially changing the levels of specific mRNAs coding for proteins with separate and distinct roles in the cell.