Antiarrhythmic actions of tedisamil: Studies in rats and primates

Tedisamil is a new bradycardic agent, previously shown to block transient outward and delayed rectifier potassium currents in cardiac tissue [1,2]. In the present study tedisamil caused bradycardia and Q-Tc widening in rats and primates. Q-Tc widening is indicative of class III antiarrhythmic actions. In keeping with this, tedisamil had antiarrhythmic activity against electrical and ischemia-induced arrhythmias in rats. In rats, 0.5–4 mg/kg IV tedisamil caused parallel and dose-related increases in action-potential duration, Q-Tc interval, and refractory period; and decreases in maximum ventricular following frequency. In primates after 0.5–2.0 mg/kg IV, findings were similar for indices of Q-T widening and decreases in maximum ventricular following frequency. Tedisamil did not change QRS width, nor did it increase threshold currents for capture of ventricles, nor for fibrillo-flutter at doses below 4 mg/kg in rats. These findings were consistent with the lack of significant sodium-channel blockade. However, upon increasing the dose to 4 mg/kg, ventricular fibrillo-flutter could not be induced in rats by electrical stimulation; instead, only ventricular tachycardias with slow rates occurred. Ischemia-induced ventricular fibrillation was reduced in a dose-related manner by tedisamil in rats. The overall incidence of ischemia-induced ventricular tachycardia was not markedly reduced, but rates during tachycardic episodes were lower. When pacing was used to overcome tedisamil-induced bradycardia, antiarrhythmic actions during ischemia were more pronounced. These findings are consistent with the hypothesis that tedisamil increased refractoriness, which resulted in extended path lengths for reentry circuits and slower rates during episodes of ventricular tachycardia. High doses of tedisamil increased path lengths so much that the multiple reentry circuits of fibrillation could no longer occur. The limited study in primates suggests similar mechanisms could occur in humans.     

Usefulness of different myocardial sampling zones for the postmortem diagnosis of myocardial infarction

Summary The diagnosis of myocardial infarction requires the use of a group of tests that are very efficient, quick and inexpensive. Another important consideration is the choice of myocardial sampling zones, especially in cases of differential diagnosis between a cardiac injury secondary to a trauma or violent asphyxia and others, secondary to myocardial infarction. The aim of this work was to choose, through discriminant analysis, the most useful zones of cardiac tissue for the quantification of free fatty acids and free carnitine and for the performance of the K/Na quotient, as biochemical parameters for the postmortem diagnosis of myocardial infarction. According to the discriminant analysis performed, seven zones of cardiac tissue are necessary to achieve a differential diagnosis among myocardial infarction, other natural deaths, and violent deaths with a 71.9% efficacy. Greater diagnostic efficacy was found (78.1%) for differentiating between natural deaths and violent deaths. Offprint requests to: E. Lachica     

Haemodynamic effects of atropine during halothane or isoflurane anaesthesia in infants and small children

In this study, two-dimensional and pulsed Doppler echocardiography were used to measure cardiovascular changes before and after IV atropine in 31 infants and small children during halothane (n = 15) or isoflurane (n = 16) anaesthesia. Prior to induction of anaesthesia heart rate (HR), mean blood pressure (MBP), and two0dimensional echocardiographic dimensions of the left ventricle and pulmonary artery bloodflow velocity were measured by pulsed Doppler echocardiography. Cardiovascular measurements were repeated while anaesthesia was maintained at 1.5 MAC halothane (n = 15) or isoflurane (n = 16). Atropine 0.02 mg·kg⁻¹ IV was then administered and two minutes later, a third set of cardiovascular data was obtained. Heart rate decreased during halothane anaesthesia but did not change significantly during isoflurane anaesthesia. Mean blood pressure, cardiac output (CO) and stroke volume (SV) decreased similarly during 1.5 MAC halothane or isoflurane anaesthesia. Ejection fraction (EF) decreased and left ventricular end-diastolic volume (LVEDV) increased significantly in bothgroups, but decreases in EF (32 ± 5 percentvs18 ± 5 per cent) and increases in LVEDV (18 ± 7 per cent vs7 ± 5 per cent) were significantly greater during halothane than during isoflurane anaesthesia. Following atropine, HR increased more in the patients maintained with halothane (31 ± 6 per cent), than during isoflurane anaesthesia (18 ± 5 per cent). Atropine increased CO in both groups of patients, but SV and EF remained unchanged. When compared with awake values, HR increased similarly and significantly (18 ± 4 per cent) following atropine in both groups, and CO returned to control levels. Halothane decreased EF and increased LVEDV more than isoflurane at 1.5 MAC end— expired anaesthetic levels. Atropine did not diminish the myocardial depression produced by halothane or isoflurane. The increase in CO following atropine during halothane and isoflurane anaesthesia in infants and small children is the result of increases in HR alone. Nous avons utilisé un appareil à échocardiographie bi-dimensionnelle couplé à un Doppler pulsé chez des bébés et de jeunes enfants pour évaluer l’impact hémodynamique de l’halothane (n = 15) et de l’isoflurane (n = 16) et la modification possible de ces effets par l’atropine. Nous avons mesure la frequence cardiaque (FC), la pression artérielle moyenne (PAM), la dimension de la cavité ventriculaire gauche (par écho bi-dimensionnelle) et la vélocité du flot sanguin pulmonaire (par Doppler) et ce, en trois occasions soit avant l’induction, après l’instauration de 1.5 MAC d’halothane ou d’isoflurane et finalement, deux minutes après l’injection IV de 0.02 mg·kg⁻¹ d’atropine. On ne nota une baisse de la frequence cardiaque qu’avec l’halothane tandis que la PAM, le débit cardiaque (DC) et le volume d’éjection (VE) diminuaient autant avec l’un ou l’autre anesthésique. La diminution de la fraction d’éjection (FE) et l’augmentation du volume télédiastolique du ventricule gauche (VTDVG) significatives pour les deux groupes, étaienl plus marqué avec l’halothane qu’avec l’isoflurane: FE 32 ± 5 pour cent vs18 ±5 pour cent; VTDVG 18 ± 7 pour cent vs 7 ± 5 pour cent. Avec l’atropine, la FC monta plus dans le groupe halothane (31 ± 6 pour cent) que dans le groupe isoflurane (18 ± 5 pour cent), le DC augmentant dans les deux groupes, alors que le VE et la FE demeuraient inchangés. Comparée aux mesures pré-induction, l’atropine amenait une hausse significative de la FC, semblable dans les deux groupes (18 ± 4 pour cent) et restaurait le DC. Donc, chez les bebes et les jeunes enfants, a 1.5 MAC, l’halothane diminue la FE et augmente le VTDVG plus que ne le fait l’isoflurane. L’atropine ne modifie pas la depression myocardique et elle ne restaure le DC que par une hausse de la FC.

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Supported by PHS Grant No. 8507300 from the College of Medicine, University of Iowa Hospital, Iowa City, IA.     

Mechanism of adenosine 3′,5′-monophosphate (cAMP)-induced increase in Ca2+ uptake by the sarcoplasmic reticulum in functionally skinned myocardial fibers

The increased rate of Ca²⁺ uptake and ATPase activity in isolated cardiac sarcoplasmic reticulum (SR) by adenosine 3,5-monophosphate (cAMP) has been shown to be activated by a cAMP-dependent protein kinase (cAMP kinase). Functionally skinned myocardial fiber preparations were used to study the mechanisms of cAMP action on the SR at the same time that tension was monitored. cAMP effects were studied on Ca²⁺-activated tension of the contractile proteins, and on Ca²⁺ uptake and release from the SR using caffeine-induced tension transients. Neither cyclic AMP (0.1–5 M) nor the catalytic subunit of cAMP kinase (0.1–1 M) (PK-C) significantly changed either the maximal or the submaximal Ca²⁺-activated tension. The areas of the tension transients were unchanged when cAMP was present in the releasing solution (release phase), and were significantly increased up to a mean of about 80% when cAMP or PK-C was present in the Ca²⁺ loading solutions (uptake phase). The increased tension transient was blocked by the heat-stable inhibitor of cAMP kinase. We conclude that cAMP-induced increases in Ca²⁺ uptake by the SR could play an important role in the positive inotropic effect. cAMP kinase could thus play a crucial role in the regulation of myocardial contractility.     

Renin gene and angiotensin II AT1 receptor gene expression in the kidneys of normal and of two-kidney/one-clip rats

This study aimed to investigate the inter-relation between the angiotensin II (ANG II) AT₁ receptor and renin gene expression in rat kidneys. To this end, renin mRNA levels and mRNA levels for AT_1a and AT_1b were assayed by RNase protection in the kidneys of normal rats, in animals treated with the AT₁ antagonist losartan and in rats bearing 0.2-mm left renal artery clips for 2 days. In normal rats, we found a negative correlation between renin mRNA levels and AT_1a receptor mRNA levels. Losartan led to a fourfold increase in renin mRNA levels without changing AT₁ receptor mRNA levels. Unilateral renal artery clipping increased renin mRNA levels fourfold in the clipped kidney and suppressed renin mRNA levels in the contralateral kidneys. AT₁ receptor mRNA levels were not changed in the contralateral intact kidneys, but were significantly decreased by 15–25% in the clipped kidneys. Renin mRNA levels were inversely correlated to AT_1a mRNA levels in the clipped, but not in the contralateral, kidneys. Our findings suggest that the systemic activity of the renin angiotensin system has no regulatory influence on renal AT₁ receptor gene expression. Renin mRNA levels in normal and in clipped kidneys appear to be negatively determined by the level of AT_1a receptor gene expression. Thus modulation of AT_1a receptor gene expression could be a pathway for indirect modulation of renin gene expression by ANG II. This conclusion is in agreement with the observation that AT₁ receptor antagonists are powerful stimulators of the renin system.     

Transmural changes in mast cell density in rat heart after infarct induction in vivo

The cardiac distribution of mast cells was investigated after the induction of acute myocardial infarction in the rat. The left anterior descending coronary artery (LAD) was occluded by ligation in the infarct group, whereas in sham rats only a superficial ligature was placed beside the LAD. Rats of both groups were killed at 4, 7, 14, 21, 35, and 85 days following surgery. Hearts were excised and formalin-fixed. Mast cell densities were monitored in subepicardial and subendocardial layers of the left ventricle (LV) in 6 μm thick toluidine blue-stained cross-sections. In control (non-operated) animals, mast cell densities were comparable in the LV subepicardial and subendocardial layers (1·5–2·0 cells per mm²). Following infarction, the mast cell density at the subepicardial site of the infarction gradually increased, reaching a maximum of 25 cells per mm² on day 21, while a non-significant increase was observed at the subendocardial site. In the non-infarcted regions, the mast cell density increased transiently to reach a maximum of 7 cells per mm² on day 35 in the subepicardial layer. Again, changes in mast cell density in the subendocardial layer were non-significant. In the sham group, a gradual increase to 9 cells per mm² on day 21 and a subsequent decrease to 5 cells per mm² on day 85 were observed in the subepicardial layers. These findings indicate a massive accumulation of mast cells in the subepicardial layers of the infarcted region and a small but significant effect of the surgical procedure on cardiac mast cell deposition, especially in the outer layers of the left ventricle.     

Autoradiographic study of DNA synthesis in rats with experimental myocardial infarction

Tritium-labeled thymidine was injected into rats with an experimental myocardial infarct and the number of DNA-synthesizing nuclei was determined in various parts of the heart. Myocardial infarction activated DNA synthesis to some extent in the nuclei of monocytes lying at the periphery of the focus of injury. However, there was no doubt about the extremely low density of labeling in the muscle nucleus. Increasing the dose and giving three injections of thymidine-³H did not increase the number of labeled muscle cell nuclei. Activation of proliferation of the connective tissue cells was observed in all parts of the heart. The number of connective-tissue nuclei synthesizing DNA was increased after 24 h, reached a maximum on the second day, and remained above the control level until the end of the experiment.Central Pathological Anatomical Laboratory, Institute of Human Morphology, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. P. Avtsyn.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 83, No. 5, pp. 612–615, May, 1977.