摘要:

The role of anions in the initiation of ischemia- and reperfusion-induced arrhythmias is unknown. We examined the antiarrhythmic effects of isotonic substitution of extracellular Cl−with NO3−by using the rat Langendorff preparation (n =12 per group). During 30 minutes of regional ischemia, the incidence of ventricular fibrillation (VF) was reduced from 50% in hearts perfused with control solution (containing a Cl−:NO3−ratio of 100:0) to 25%, 0% (p<0.05), 0% (p<0.05), and 0% (p<0.05) by perfusion with solution containing Cl−:NO3−ratios of 75:25, 50:50, 25:75, and 0:100, respectively. The incidence of reperfusion-induced VF was also reduced from 58% to 25%, 8% (p<0.05), 8% (p<0.05), and 0% o(p<0.05), respectively. Similar effects were produced in hearts reperfused after briefer durations of ischemia (10 or 15 minutes). Substitution of NO3−for Cl−also facilitated spontaneous termination of VF. Heart rate and occluded zone size were not affected by anion manipulation. Coronary flow was affected by NO3−, but changes did not correlate with arrhythmias. During ischemia, electrocardiographic changes indicative of class III activity (widening of the ventricular complex) were produced by anion substitution. These changes occurred selectively in the ischemic tissue with no significant influence before ischemia onset. However, the relation between this effect and arrhythmia reduction was not linear and a cause-effect relation is therefore unlikely. In separate groups of hearts (n= 12 per group), switching from 100:0 to 0:100 Cl−:NO3−solution or vice versa 10 seconds after coronary occlusion or just before reperfusion demonstrated that 1) protection against ischemia-induced VF resulted partly from an action in the ischemic zone and partly from an action in the nonischemic zone, and 2) protection against reperfusion-induced VF resulted principally from an action occurring during reperfusion and within the reperfused tissue. To assess whether benefit was offset by deleterious effects on contractile function in nonischemic tissue, we constructed Starling curves in isolated rat hearts. The 0:100 Cl−: NO3−solution had no effect on compliance or contractility at physiological end-diastolic pressures but reduced the slope of the peak systolic pressure-volume relation by ∼20% as end-diastolic pressure was increased above 10 mm Hg. In conclusion, anions appear to play a hitherto unrecognized role in arrhythmogenesis in ischemia and reperfusion. Manipulation of anion homeostasis may represent a novel target for antiarrhythmic drug development.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

This article examines the role of innervation in regulating expression of acetylcholinesterase (AchE), butyrylcholinesterase (BuchE), and the muscarinic acetylcholine receptor (mAchR) in avian heart. Two distinct approaches are taken. The first approach examines the relation between the onsets of parasympathetic and sympathetic innervation and the appearance of AchE and BuchE. All molecular forms of AchE and BuchE are present in early embryonic chick heart well before the onset of parasympathetic and sympathetic innervation. These molecular forms are characterized by sedimentation coefficients of 4.5S, 11S, 15S, and 19S. With further development, the amounts of AchE fall; the reductions in AchE parallel the onset of functional parasympathetic innervation. The amounts of BuchE increase progressively throughout embryonic development, independent of autonomic innervation, and in mature chick heart predominate over the much less abundant amounts of AchE. The 15S and 19S forms of AchE in heart are lost during early embryogenesis but reappear in skeletal muscle during later embryogenesis. The second approach examines the influence of vagotomy and sympathetic denervation of 8-day-old chick myocardium on expression of the molecular forms of AchE, BuchE, mAchR, and β-adrenergic receptors. The amounts of AchE and BuchE molecular forms in avian heart are not measurably influenced by bilateral vagotomy for a duration of 4 days, unilateral vagotomy for a duration of 25 days, or sympathetic denervation. A measurable upregulation is observed in muscarinic receptors (35–46%) after vagotomy but not sympathectomy and in β-adrenergic receptors (29%) after sympathectomy but not vagotomy. In all cases, results in atria and ventricles are nearly identical. The present results indicate that expression of AchE in the myocardium is unique and different from that in skeletal muscle and not directly linked with autonomic innervation.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Aggregating platelets release factors that act in a local paracrine manner to alter vascular tone. The purpose of the present study was to explore the possibility that factors released from aggregating platelets may alter the sensitivity of arterial baroreceptors. Baroreceptor activity was recorded from the vascularly isolated carotid sinus of rabbits anesthetized with sodium pentobarbital. The carotid sinus was filled with oxygenated Krebs-Henseleit buffer and distended with slow ramp increases in nonpulsatile pressure. Sensitivity of baroreceptors to increased pressure was determined before and during intraluminal exposure of the sinus to washed human platelets suspended in Krebs' buffer. Platelets activated with thrombin (0.4 units/ml) decreased baroreceptor activity and the slope of the pressure-activity curve significantly (n=6). The platelet-induced decrease in baroreceptor sensitivity was related to the duration of exposure to platelets with no change in baroreceptor activity after 4 minutes and a progressive decrease in activity over the next 12 minutes. The slope of the pressure-nerve activity relation averaged 1.26±0.08 %/mm Hg during control and decreased to 0.97±0.22, 0.80±0.19, and 0.53±0.15 %/mm Hg after 12–16 minutes of exposure to 107, 108, and 3–6×108activated platelets/ml, respectively (p<0.05). Baroreceptor sensitivity was restored after removal of platelets from the carotid sinus. Thrombin alone had no effect on baroreceptor sensitivity. Activated platelets did not alter the carotid pressure-diameter relation, suggesting a direct inhibitory effect on baroreceptors. The slope of the pressure-activity curve and maximum baroreceptor activity were not decreased by the stable thromboxane analogue U46619, serotonin, or ADP. We conclude that an as-yet-unidentified factor released from aggregating platelets acts in a paracrine manner to decrease baroreceptor sensitivity. We speculate that in pathological states such as atherosclerosis platelets aggregating in carotid sinuses may contribute to decreased baroreceptor sensitivity and trigger reflex sympathetic activation with potential deleterious effects (vasospasm and hypertension).

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Transmembrane electrical activity was recorded from endocardium and epicardium of isolated segments of guinea pig right ventricular free walls. An electrocardiogram was recorded by electrodes at opposite ends of the tissue bath. Endocardium was stimulated. Tissues were exposed to “ischemic” conditions (e.g., acidosis, hyperkalemia, hypoxia, and lactate) for 15 minutes and then were reperfused with “normal” Tyrode's solution. Arrhythmias with characteristics of transmural reentry occurred in ischemic conditions and early reperfusion in 30% and 70% of 20 control hearts, respectively. Arrhythmias were associated with prolongation of transmural conduction time (CT) and abbreviation of endocardial effective refractory period. Verapamil significantly suppressed reperfusion arrhythmias at 0.1–1.0 μM but not at 3.0 μM. Verapamil also significantly decreased the incidence of arrhythmias during ischemic conditions at 0.5 μM but significantly promoted ischemic arrhythmias at 3.0 μM. Action potential duration and effective refractory period were not altered by verapamil during ischemic conditions or reperfusion. However, at 0.1–1.0 μM, verapamil prevented or attenuated prolongation of transmural CT by ischemic conditions and reperfusion. Transmural CT was further prolonged at 3 μM verapamil. In epicardial slices, 1 μM verapamil shortened CT transverse to fiber orientation during reperfusion but had no effect on longitudinal CT. Our results indicate that verapamil may suppress arrhythmias through differential effects on CT transverse and longitudinal to fiber orientation in anisotropic ventricular tissues and thus by specifically improving transmural conduction.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The endothelium-dependent vascular relaxation to acetylcholine (ACh) in spontaneously hypertensive rats (SHR) may be impaired because of an imbalance of endothelium-derived relaxing factor and contracting factor. However, the role of the endothelium-dependent hyperpolarization remains undetermined. We examined the ACh-induced hyperpolarization and its contribution to relaxation in arteries of SHR. Membrane potentials were recorded from the mesenteric artery trunk of 6–8-month-old male SHR and also Wistar-Kyoto (WKY) rats. Endothelium-dependent hyperpolarization to ACh was unaffected byNG-nitro-l-arginine, indomethacin, or glibenclamide; was reduced by tetraethylammonium or high K+solution; and was enhanced by low K+solution or methylene blue, thereby indicating that hyperpolarization is not mediated by nitric oxide (endothelium-derived relaxing factor) but is presumably mediated by a hyperpolarizing factor and is due to an opening of K+channels that probably differ from the ATP-sensitive ones. Hyperpolarizations to ACh were markedly reduced in SHR compared with findings in WKY rats (maximum, 8±1 versus 17±1 mV). In addition, under conditions of depolarization with norepinephrine (10−5M), the ACh-induced hyperpolarization was even less and transient in SHR, while it was large and sustained in WKY rats (6±1 versus 29±2 mV). Endothelium-dependent relaxations to ACh in arterial rings precontracted with 10−5M norepinephrine were far less in SHR than in WKY rats, even in the presence of indomethacin. Furthermore, high K+solution showed smaller inhibitory effects on the relaxations in SHR than in WKY rats. Endothelium-independent hyperpolarizations and relaxations to cromakalim, a K+channel opener, were similar between SHR and WKY rats. It would thus appear that the endothelium-dependent hyperpolarization to ACh is reduced in SHR and this would, in part, account for the impaired relaxation to ACh in SHR mesenteric arteries.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The intracellular events and specifically the role of protein kinase C-mediated protein phosphorylation, after α-adrenergic receptor stimulation of the heart, are not well understood. We examined the phosphorylation of sarcolemmal, sarcoplasmic reticular, myofibrillar, and cytosolic proteins in perfused beating rabbit hearts on activation of protein kinase C by phenylephrine. Perfusion of rabbit hearts with phenylephrine was associated with a positive inotropic response, which was dose and time dependent. Maximal stimulation (1.54-fold increase in +dP/dt) was obtained with 10 μM phenylephrine at 4 minutes. Examination of the activity levels of protein kinase C in these hearts revealed a redistribution of this activity from the cytosolic to the membranous fraction, suggesting the activation of this enzyme in vivo. Prazosin, an α1-adrenergic antagonist, prevented the increase in the inotropy and the redistribution of protein kinase C activity mediated by phenylephrine. Examination of the degree of phosphorylation of membranous, myofibrillar, and cytosolic proteins revealed that activation of protein kinase C in vivo was associated with increased phosphorylation of a 15-kd sarcolemmal protein and a 28-kd cytosolic protein. There were no increases in the degree of phosphorylation of phospholamban in the sarcoplasmic reticulum and of troponin I, troponin T, and C protein in the myofibrils, although these proteins were found to be substrates for protein kinase C in vitro. These findings provide evidence that protein kinase C is activated in response to α-adrenergic stimulation and that activation is associated with increased phosphorylation of a 15-kd sarcolemmal protein and a 28-kd cytosolic protein in the myocardium.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

An isoproterenol-induced chloride current has been detected in ventricular myocytes from guinea pig and rabbit but has not been found in canine ventricular cells. This investigation was undertaken to determine whether canine atrial cells possessed such a current. Steady-state currents were examined with potassium currents blocked by cesium. In whole-cell patch-clamp experiments, an isoproterenol-induced chloride current could not be detected shortly after patch rupture. However, whole-cell current in the absence of isoproterenol increased over time after patch rupture. The spontaneously activating steady-state current was outwardly rectifying with a reversal potential of approximately −25 mV. The current that developed over time was sensitive to variation in extracellular chloride concentration and was partially blocked by anthracene-9-carboxylic acid. Isoproterenol could enhance the amplitude of this current once it developed. Although isosmotic pipette filling and extracellular solutions were used, cell swelling was found to be the cause of the increase in whole-cell conductance that was observed during whole-cell patch-clamp experiments. The development of the current and the associated cell swelling could be prevented with the addition of 50–75 mM mannitol to the extracellular solution. The current could be observed in perforated patch recordings with nystatin when extracellular osmolarity was low (221 mosm/kg) but not when the extracellular solution was isosmotic (293 mosm/kg). Cardiac chloride currents have the potential to depolarize the resting membrane potential and cause abnormal automaticity. Chloride currents can also decrease the refractory period through a reduction in action potential duration. The presence of a swelling-induced chloride current could be of importance for understanding cardiac electrical activity during pathological states that are associated with myocardial swelling.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

In human heart failure the positive inotropic and cAMP-elevating effects of both β-adrenoceptor agonists and phosphodiesterase inhibitors are diminished. This has been explained at least in part by an increase in the inhibitory signal-transducing G protein (Gi) and unchanged stimulatory G protein (Gs). In the present study we determined the mRNA expression pattern of the α subunits of Gi-1, Gi-2, Gi-3, and Gsin myocardial tissue samples of patients undergoing heart transplantation. Northern blot analysis of total RNA extracted from left ventricles with32P-labeled cDNAs demonstrated expression of Giα-2, Giα-3, and Gsα. mRNA. In contrast, Giα-1mRNA was not detectable. To investigate whether the increased ratio of Gi/Gsmight be due to altered gene expression, we compared mRNA levels of Giα-2, Giα-3, and Gsαin left ventricular myocardium from failing hearts with idiopathic dilated cardiomyopathy (n=8) and ischemic cardiomyopathy (n=6) and from nonfailing hearts from transplant donors (n=8). Compared with nonfailing control hearts, the Giα-2mRNA was increased by 75±26% (p<0.05) in idiopathic dilated cardiomyopathy hearts and 90±26% (p<0.05) in ischemic cardiomyopathy hearts. Giα.3and GsαmRNA levels were similar in the three groups. The results suggest that as in other mammalian species, Giα-2and Giα-3, mRNA are the predominant GiαmRNA subtypes in human ventricular myocardium. An upregulation of Giα-2but not of Giα-3mRNA probably underlies the increase in Giαprotein and might thus be involved in the pathophysiological process leading to reduced responsiveness to cAMP-increasing agents in end-stage heart failure.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Capillary-to-fiber geometrical relations constitute an integral component of peripheral gas exchange. Determination of capillary length and surface area density necessitates quantification of capillary orientation (i.e., tortuosity and branching). In skeletal muscle, capillary tortuosity increases in a curvilinear fashion at reduced sarcomere length, and this compensates for decreased capillary density as fiber cross-sectional area increases. To investigate these relations in myocardium, rat hearts were glutaraldehyde perfusion-fixed in calcium- or barium-induced “systole” to provide varying degrees of fiber shortening. Morphometric techniques were used to analyze capillary geometry in subepicardium (EPI) and subendocardium (ENDO) using 1-μm sections cut transverse and longitudinal to the muscle fiber axis. Capillary density on transverse and longitudinal sections, capillary diameter, fiber cross-sectional area, and sarcomere length were determined in each region. Capillary surface density was computed, and values were related to sarcomere length and compared with published data for diastolic hearts. Sarcomere length in systole ranged from 2.06±0.03 to 1.35±0.02 μm (EPI) and from 1.93±0.04 to 1.44±0.04 μm (ENDO). Fiber cross-sectional area (EPI, 344±13 μm2; ENDO, 343±12 μm2) was significantly larger, and capillary density on transverse sections was significantly smaller (EPI, 4,105±318 mm−2; ENDO, 4,145±267 mm−2) than in hearts arrested in diastole. Compared with skeletal muscle, capillary tortuosity was substantially less increased by fiber shortening. Capillary tortuosity and branching did not differ between EPI and ENDO and contributed a maximum of 33% (range, 13–33%) to capillary length density and surface area at a sarcomere length of 1.45±0.04 μm. Compared with diastolic hearts, capillary length density decreased on average by 19.6% (EPI) and 17.7% (ENDO); similarly, capillary surface density decreased 19.9% (EPI) and 13.7% (ENDO). We conclude that, with fiber shortening in the heart, fiber cross-sectional area increases and capillary numerical density decreases as predicted from reduced sarcomere length. Combined with the minimal geometrical changes of the capillary bed at shorter fiber lengths, this results in a lower capillary length and surface area per fiber volume in systole. Consequently, the structural potential for O2diffusion into myocytes is determined, in part, by fiber length.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

We have investigated the effects of electric field stimulation on membrane repolarization in rabbit papillary muscles and assessed the consequences of these effects for the dispersion of intracellular potentials and the production of a propagation wave front or unidirectional block in relatively refractory tissue. The stimuli studied had electric field strength of 0.25–14 V/cm, duration of 2 msec, and field orientation along or across the myocardial fibers. The field strengths to excite the muscles in diastole were 0.68 or 1.23 V/cm for stimuli oriented along or across the fibers, respectively (p<0.01, along versus across). A 2.5-V/cm stimulus given near the end of the action potential (AP) produced either no response or, after increasing the stimulus delay only 2–3 msec, a full response with almost no AP durations that were intermediate. For stimulation along and across the fibers, respectively, given at 70% of the AP duration, a 4-V/cm stimulus produced AP prolongation (measured at 90% repolarization) of 209%, and 4% (p<0.05), an 8-V/cm stimulus produced AP prolongation of 36% and 20% (p<0.05), and a 14-V/cm stimulus produced AP prolongation of 36% and 30% (p=NS). For either orientation, AP prolongation by stimuli of 8 V/cm or 14 V/cm increased gradually as the stimulus delay was increased. The different effects in relatively refractory tissue of stimuli of 2.5 V/cm compared with 8 V/cm can explain the propagation wave front and block that occur with electrically induced functional reentry in the heart. After stimulation with fields below a critical strength (∼5 V/cm), a large intracellular potential difference may occur among cells that are sufficiently recovered to become excited by the stimulus and cells that are not sufficiently recovered to become excited, consistent with the reported propagation wave front where the two groups of cells are closely opposed. After stimulation with fields above the critical strength, differences in intracellular potentials among cells during repolarization may be decreased, and the intracellular potentials may be in a range in which sodium current is inactivated, consistent with the reported absence of a propagation wave front. Thus, the different effects of low and high electric field strengths can account for the “critical point” mechanism for unidirectional block and reentry.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID