Alinidine as a model of the mode of action of specific bradycardic agents on SA node activity

Ginneken, A. C. G. Van; Bouman, L. N.; Jongsma, Habo J.; Duivenvoorden, J J; Opthof, T.; W, Giles

doi:10.1093/eurheartj/8.suppl_l.25

Cited by 11 publications

(3 citation statements)

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“…In recent years the pacemaker current "i;' (or "i,," (4,52). Inhibition of if current in sheep Purkinje fibers by UL-FS 49 or falipamil was also recently described by Van Bogaert and Goethals (51).…”

Section: Inhibition Ofrhe Pacemaker Current "If"mentioning

confidence: 83%

“…UL-FS 49 (1.12 pmol/L) was described to delay atrial discharge rate as well as to decrease diastolic depolarization rate in leading pacemaker cells of rabbit sinoatrial node preparations ( Fig. 3) (52). In rabbit sinus nodal preparations, falipamil ( 10 pmol/L) reduced spontaneous discharge and diastolic depolarization rates, slowed down the upstroke, and prolonged the duration of action potential.…”

Section: Isolated Preparationsmentioning

confidence: 90%

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Falipamil (AQ‐A 39) and UL‐FS 49

Kobinger¹,

Lillie²

1988

Cardiovascular Drug Reviews

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In patients with diminished myocardial oxygen supply, decrease in oxygen consumption is a desirable therapeutic goal. This goal can be achieved by decreasing heart rate, myocardial contractility and tension development (46). For a patient with a rigid narrowing of coronary arteries, the expected benefit of heart rate decrease (bradycardia) is even more obvious. Bradycardia is mainly due to a prolongation of diastole, which allows better perfusion of myocardium.Heart rate, which is usually controlled by the sinus node, can be reduced indirectly by drugs that interfere with the activity of the autonomic nervous system (e.g. by padrenoceptor antagonists, certain veratrum alkaloids) or directly at the pacemaker cells of the sinoatrial node. The term "specific bradycardic agents" (SBA) has been proposed for drugs which decrease heart rate by a direct effect on pacemaker cells of sinus node and at concentrations or doses that are smaller than those which elicit other cardiovascular or pharmacological effects (23,28). Two groups of substances with different chemical structures have been found to fit this definition. Alinidine, chemically related to clonidine was reviewed previously (25). The benzolactame-derivative falipamil (AQ-A 39) will be described here together with its congener UL-FS 49, which is a more potent and a more specific representative of this class of SBA. There is, however, less information available on UL-FS 49 than on falipamil. The available data on falipamil will be used, therefore, in this paper for characterization of this novel class of drugs.Falipamil and UL-FS 49 were discovered during evaluation of antiarrhythmic properties of compounds with verapamil-like structures. Falipamil was found to have a pronounced heart rate lowering effect. Subsequently, its pharmacological profile was differentiated from that of antiarrhythmics (7,24). ( 1 ,3,4,5-tetrahydro-7,8-dimethoxy-3- [3-[ [2-( 3,4-dimethoxyphenyl) ethylJmethylimino]propyl]-2H-3-benzazepin-2-on-hydrochlo~de) was synthetized by M. Reiffen and falipamil (AQ-A 39; 5,6-dimethoxy-2-[3[[a-(3,4-dimethoxy)-phenylethyl]methylamino]propyl]phtalimidine-hydrochloride) by W. Eberlein, both from research laboratories of Dr. Karl Thomae GmbH, Biberach an der Riss, FRG. CHEMISTRY UL-FS 49

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Section: Inhibition Ofrhe Pacemaker Current "If"mentioning

confidence: 83%

Section: Isolated Preparationsmentioning

confidence: 90%

Falipamil (AQ‐A 39) and UL‐FS 49

Kobinger¹,

Lillie²

1988

Cardiovascular Drug Reviews

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“…Der negativ chronotrope Effekt war bei -100 mV schwächer als bei -60 mV [183]. Der negativ chronotrope Effekt war bei -100 mV schwächer als bei -60 mV [183].…”

Section: Chemische Struktur Alinidin (St 567) Gehört Als N-allyl-deriunclassified

Selektive If-Kanal-Hemmung: eine Alternative in der Behandlung der koronaren Herzkrankheit?

Schipke

Büter

Hohlfeld

et al. 2006

Herz

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Several clinical studies demonstrate the importance of the heart rate for the cardiovascular morbidity and mortality. Over the last 50 years, some thought has been given to those substances that selectively reduce the heart rate. It is now recognized that I(f) ion channels of the sinus node play a major role in the automatism and modulation of the heart rate. Substances that selectively reduce the heart rate should decrease myocardial oxygen consumption and increase oxygen delivery via the prolonged diastolic coronary perfusion. Direct inotropic effects, however, are unlikely. In principle, anti-anginal and anti-ischemic effects of specific bradycardic substances can be expected. The clinical experience with some of the former bradycardic substances has not been sufficiently convincing. The more recent ivabradine (Procoralan presents an exception to this, as it successfully completed a clinical program for the treatment of chronically stable angina pectoris. In this review article, specific bradycardic substances (= I(f) channel inhibitors) are presented together with the corresponding experimental and clinical studies. The studies were selected against the background of the efficacy of I(f) channel inhibitors in the therapy of cardiovascular disease. As only ivabradine has completed a study on 5,000 patients, the discussion on that particular I(f) channel inhibitor is somewhat extensive. In addition, prospective possibilities and limitations of bradycardic substances are presented.

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