Specific bradycardic agents--a novel pharmacological class?

Abstract

Data have been reviewed and presented which suggest that substances from two different chemical groups, congeners of alinidine and falipamil, respectively, can be described as representatives of a novel and distinct pharmacological class: specific bradycardic agents (SBAs). They are characterized by a slowing of the sinus rate within physiological limits as the prominent cardiovascular effect. Involvement of alpha-adrenoceptors, beta-adrenoceptors and cholinergic receptors as mediators of the bradycardic effects have been excluded. Experiments in isolated atrial preparations suggested that drugs of the same type as alinidine or as falipamil have a similar mode of rate lowering action which is different from that of Ca-channel blockers: low external Ca2+ increased and low Na+ as well as high K+ decreased the bradycardic effect of SBA; verapamil behaved in the opposite way. Combination of different SBAs did not result in excessive additive rate-lowering effects; in contrast, addition of verapamil to maximally acting concentrations of SBAs resulted in a further significant reduction in rate. SBAs were much more potent in reducing spontaneous sinus rate than in reducing BaCl2 induced automaticity, whereas Ca-channel blockers behaved in the opposite way. Differences in the cardiovascular profile against other drugs with rate lowering effects have been pointed out: beta-adrenoceptor blocking agents more markedly decrease contractility and Ca-channel blocking agents more markedly decrease contractility, slow down AV conduction and have vasorelaxing properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the two enantiomers, S‐16257‐2 and S‐16260‐2, of a new bradycardic agent on guinea‐pig isolated cardiac preparations

“…Specific bradycardic agents represent a new approach in the management of angina pectoris with depressed left ventricular function (Kobinger & Lillie, 1987;Guth, 1991). They block sinus tachycardia and markedly attenuate exercise-induced increases in heart rate at concentrations at which they have no direct effects on the inotropic state or vascular tone (Kobinger & Lillie, 1987; Guth, 1991;O'Brien et al, 1992).…”

“…They block sinus tachycardia and markedly attenuate exercise-induced increases in heart rate at concentrations at which they have no direct effects on the inotropic state or vascular tone (Kobinger & Lillie, 1987; Guth, 1991;O'Brien et al, 1992). The precise mechanism of action of these agents is still uncertain even when in rabbit sinoatrial node cells the bradycardic effect of zatebradine has been attributed to a frequency-dependent inhibition of the hyperpolarizing-activated current (If) (Goethals et al, 1993).…”

Population Pharmacokinetic Data Analysis of Cilobradine, an If Channel Blocker

“…In spite of their known clinical efficacy in the treatment of ischemic heart disease, certain side effects such as negative inotropism and hypotensive effects impairing ischemic status may limit their use (5). The so-called specific bradycardic agents represent a new class of compounds developed to selectively reduce heart rate with little if any effect on other cardiovascular parameters (6)(7)(8). They reversibly block the cardiac pacemaker current (also called the Bfunny current,Î f ) passing through the hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel (I f channel) (9), resulting in a reduced slope of the diastolic depolarisation of the pacemaking cells of the sinoatrial node.…”

Synthesis and Pharmacological Evaluation of 2-(3-Piperidyl)-1,2,3,4-tetrahydroisoquinoline Derivatives as Specific Bradycardic Agents.

“…7) Such agents induce sinus bradycardia at concentrations that are devoid of additional haemodynamic effects. [8][9][10][11] Specific bradycardic agents have been shown to act by reducing the heart's demand for oxygen and by increasing the diastolic period which in turn induces increases in the subendocardial blood flow.…”