Antagonism of novel inotropic agents at A1 adenosine receptors and m-cholinoceptors in human myocardium

Summary The effects of the new inotropic agents saterinone, sulmazole, UD-CG 212.C1 and milrinone at A₁ adenosine receptors and m-cholinoceptors were evaluated in human myocardium from patients with heart failure. At A₁ adenosine receptors, all compounds inhibited ³H-DPCPX-binding to ventricular membrane preparations at micromolar concentrations. As judged from the K_i-values, the rank order of potency was saterinone > sulmazole > UD-CG 212.C1 > milrinone. The new inotropic agents also displaced the binding of ³H-QNB at m-cholinoceptors. Except for saterinone, the concentration ranges of mean K_i-values were considerably higher at m-cholinoceptors than at A₁ adenosine receptors. The rank order of potency was saterinone > sulmazole > UD-CG 212.Cl > milrinone. Competition of the A₁ adenosine receptor agonist R-PIA to ³H-DPCPX-binding showed a biphasic curve with a shallow slope (Hill coefficient n_H = 0.63) and revealed two affinity states of the A₁ adenosine receptor. In the presence of guanine nucleotides [Gpp(NH)p], the competition curve showed one low affinity class of binding sites and was shifted to the right. In contrast, the competition curves of the new inotropic agents were characterized by a monophasic, steeper slope (mean Hill coefficient n_H = 0.98). Guanine nucleotides had no effect. Similar results were obtained with saterinone and carbachol at m-cholinoceptors. Competition with carbachol revealed three affinity states of the m-cholinoceptor, the superhigh affinity binding was reversed by Gpp(NH)p. Competition with saterinone revealed one class of binding sites which was not influenced by Gpp(NH)p. Accordingly, in isolated, electrically driven human atrial trabeculae, the negative inotropic effect of adenosine was antagonized concentration-dependently by saterinone, sulmazole and UD-CG 212.Cl. Similarly the negative inotropic effect of carbachol was antagonized concentration-dependently by saterinone. It is concluded that the new inotropic agents bind to A₁ adenosine receptors and that their interaction is of antagonist nature. This mechanism might contribute to their capacity to enhance force of contraction by stimulation of cAMP-formation in addition to phosphodiesterase inhibition. The effects of saterinone may be partially due to antagonism at m-cholinoceptors. This is presumably not the case with the other inotropic agents studied given their low affinity for this receptor.Send offprint requests to M. Böhm at the above addressSupported by the Deutsche Forschungsgemeinschaft     

Bicarbon valve - European multicenter clinical evaluation

Objective: Fifteen collaborating centers in eight countries present their pooled experience with the new Bicarbon™ bileaflet valve. Methods: Between 4/90 and 4/96, 1351 patients, 806 males and 545 females, aged 10 to 83, mean 58.4±12.4, underwent valve implantation. Operations: AVR, 726; MVR, 475; DVR, 150. Additional procedures: CABG, 211; TV repair, 64; other, 152. Results: Mortality: 67 early (seven valve related) and 56 late (40 valve related). Valve thrombosis: six obstructive, three non-obstructive; embolism: nine major cerebral, 37 other. Major bleeding: 29. Hemolysis: two clinically significant. Non-structural dysfunction: 24 paravalvular leaks, one leaflet interference. No structural failure! Endocarditis: 24. Reoperation 48: 22 non-structural dysfunctions, 14 endocarditis, seven thrombosis and embolism, five other. Estimated 5-year freedom from valve-related deaths is 97.2% for AVR and 92.4% for MVR; 4-year freedom from valve related deaths for DVR is 90.5%. Mean calculated NYHA improvement is 1.24. Conclusions: The Bicarbon mechanical prosthesis is well designed, durable, has good hemodynamic features and an acceptably low incidence of complications.     

Decreased R-R variation: A criterium for overdosage of tricyclic psychotropic drugs

Objective Since intoxication with tricyclic antidepressants is common, a supplementary screening method for differentiation between therapeutic and supratherapeutic ranges would be a valuable diagnositc tool, particularly in delirious and unconscious patientsSetting 109 patients treated with amitriptyline, 8 patients treated with doxepin, 10 patients treated with clozapine, and 72 normal control subjects matched for age and sex were tested for heart rate variability while resting.Results Considering time and frequency derived measures, which are rather independent of heart rate, the patients showed significantly decreased heart rate variability parameters (p<0.0001), as compared with the normal subjects. Of the patients presenting delirious symptoms 6 showed coefficients of variation more than 4 standard deviations below the mean control value.Conclusions As heart rate variability can be easily calculated, this measurement is suggested as a useful tool to quickly exclude or support the diagnosis of chronic intoxication with tricyclic antidepressants or clozapine.     

Fear and the startle reflex: Blink modulation and autonomic response patterns in animal and mutilation fearful subjects

The present study was designed to examine the pattern of startle reflex modulation and autonomic responses for individuals high in animal or blood-injury fear when viewing pictures of their feared objects. Sixteen individuals in each fear group and 16 low-fear control individuals viewed 32 color slides depicting fear-relevant, unpleasant but fear-unrelated, neutral, and pleasant scenes. Free viewing times were assessed in a second phase of the procedure as an index of avoidance behavior. Exposure to pictures of feared objects resulted in a consistent startle reflex potentiation and behavioral avoidance in both fear groups. This activation of the basic aversive system was independent of the autonomic pattern of the fear responses, which differed for the high-fear groups. These results suggest that the probe startle response indexes the organism's basic motivational disposition and add new information to the assessment of fear.     

Neuronal dysfunction in heart failure assessed by cardiac 123-iodine metaiodobenzylguanidine scintigraphy

In patients with chronic heart failure, increased sympathetic activity and cardiac sympathetic neuronal dysfunction are present and have been related to unfavourable clinical outcome. Modification of these alterations with the objective to improve prognosis has become an important aim of pharmacological therapy for these patients. A noninvasive technique to assess sympathetic neuronal function at the cardiac level may be valuable in evaluating newly developed therapeutic strategies. 123-iodine metaiodobenzylguanidine can be used visualize cardiac sympathetic nerve function and activity. Single photon emission computerized tomographic is preferred to planar scintigraphy since it does not depend on superposition of other anatomical structures and may allow assessment of regional cardiac 123-iodine metaiodobenzylguanidine uptake. Although the quantitation of cardiac uptake in these tomographic images has several limitations, the use of the left ventricular cavity as a reference, calibrated by the 123-iodine activity in a blood sample drawn at the time of acquisition, may have clinical applications, with respect to the evaluation of therapeutical intervention in patients with heart failure.Abbreviations BS blood sample - CD count density - dP/dt change in pressure over time - [¹²³I] 123-iodine - K_m affinity constant - MIBG metaiodobenzylguanidine - MB_q mega Bequerel - SPECT single photon emission computerized tomography - V_m capacity constant     

心衰患儿红细胞内外钙离子浓度的变化及临床意义 心衰患儿红细胞内外钙离子浓度的变化及临床意义

目的：为了深讨心肌细胞内钙离子浓度的变化与心力衰竭发生的关系。方法：原子吸收分光技术测定红细胞内外Ca2+含量。我们对住院的56例心力衰竭患儿进行了红细胞内及血浆钙离子浓度的测定，并与30例正常小儿对照。结果：心衰患儿红细胞内Ca2+浓度明显升高，血浆Ca2+浓度降低，与对照组相比有非常显著性差异（P＜0．001）。其升高程度与心衰呈正相关（r=0．63，P＜0．01），即心衰越重，心功能越差，红细胞内Ca2+浓度升高亦越明显。而当心衰纠正，心功能恢复后，红细胞内Ca2+浓度则明显下降，血浆Ca2+浓度也恢复正常。而不同病因所致的心衰，其间红细胞内Ca2+浓度升高程度无明显差异。结论：提示钙离子参与了心力衰竭的发生与发展。     

Vasodepressor reactions after orthotopic cardiac transplantation: Relationship to reinnervation status

Ventricular vagal nerve endings are thought to trigger vasodepressor syncope. Reports of vasodepressor reactions associated with donor bradycardia after cardiac transplantation have led to speculation that vagal reinnervation occurs. We assessed reinnervation status in seven patients 23–36 months (median 24 months) post-transplantation. Heart rate responses to vagal manoeuvres (respiration, Valsalva) and sympathetic stimuli (exercise and injection of tyramine into the coronary artery supplying the sinus node) were measured. All patients underwent 60 min of 60° head-up tilt with foot plate support. During tilt four of the seven had vasodepressor reactions with a fall in mean arterial pressure of 20–90 mmHg. During vasodepression two patients had falls in donor heart rate of 13 and 40% relative to peak heart rate during tilt. These two patients had evidence of functional sympathetic reinnervation. By contrast the two patients without donor bradycardia during vasodepression had only limited or no evidence of sympathetic reinnervation. No patient had consistent evidence of parasympathetic reinnervation as judged by the heart rate response to vagal manoeuvres. Headup tilt can thus produce vasodepressor reactions with donor bradycardia after cardiac transplantation in the absence of consistent evidence of vagal reinnervation. Left ventricular nerve endings may not be the only mediators of tilt-induced vasodepressor reactions in man. Donor bradycardia during vasodepression may reflect sympathetic withdrawal and not vagal reinnervation.     

Effect of external high-frequency oscillation on severe cardiogenic pulmonary edema

Effective gas exchange can be maintained in animals without endotracheal intubation using external high-frequency oscillation (EHFO). The aim of this study was to evaluate the effect of EHFO in patients with respiratory failure due to severe cardiogenic pulmonary edema. Seven patients were ventilated with EHFO for 2h at 60 oscillations·min⁻¹, with a cuiras pressure of 36 cmH₂O (−26 to +10) and an inspiratory to expiratory ratio of 1:1, with EHFO. Blood gas values and hemodynamic parameters were measured. Significant increases were noted in cardiac index (2.3±0.5 to 2.5±0.5 l·m⁻²;P<0.05), stroke volume index (24±7 to 28±8 ml·m⁻²;P<0.05), and arterial O₂ pressure (Pao₂) (70±4 to 95±23 mmHg;P<0.01) without a change in pulmonary artery wedge pressure at 1 h after EHFO. The respiratory rate decreased from 28±3 to 22 ±3 breaths·min⁻¹ at 5 min after the termination of EHFO (P <0.01). Arterial CO₂ pressure (Paco₂) did not, however, decrease. Increased stroke volume without a change in pulmonary artery wedge pressure (preload) suggests either improved inotropic function of the left ventricle or reduced left ventricular afterload with EHFO. The use of EHFO may be effective not only for gas exchange but also for left ventricular function in patients with severe cardiogenic pulmonary edema.     

多巴酚丁胺负荷及运动试验~(99m)Tc-MIBI心肌断层显像与冠状动脉造影的对比研究

比较６９例冠心病患者多巴酚丁胺负荷９９ｍＴｃ甲氧基异丁基异腈（ＭＩＢＩ）心肌断层显像与８２例运动试验９９ｍＴｃＭＩＢＩ心肌断层显像的结果，以探讨它们对冠心病的诊断价值。结果表明：以冠状动脉造影结果为标准，多巴酚丁胺负荷诊断冠心病的敏感性和特异性分别为９１２％和８００％，运动试验分别为８９４％和８２９％。多巴酚丁胺负荷检出冠状动脉病变的敏感性和特异性：左前降支为７８１％和９１３％，回旋支为６６７％和９８２％，右冠状动脉为１００％和８３７％；运动试验分别为７８３％和９１１％，６００％和９６８％，９０９％和８５０％，差异均无显著性（Ｐ＞００５）。提示两者结果相近，对于不能进行运动试验的病人，多巴酚丁胺试验是一种有价值的诊断冠心病的方法。     

Effects of Ethanol on the Contractile Function of the Heart: A Review

Chronic ethanol consumption leads to a number of alterations in the contractile function of the heart and is a leading cause of cardiomyopathy. Ethanol also has an acute negative inotropic effect mediated by direct interaction with cardiac muscle cells, although this action is often masked by indirect actions resulting from enhanced release of catecholamines in vivo. This article reviews the effects of ethanol on the contractile function of the heart. The specific targets affected by ethanol in cardiac muscle cells are discussed in terms of potential mechanisms underlying the depressions of contractility resulting from both acute and chronic actions of ethanol.