Method for treating cardiac dysfunction and pharmaceutical compo

Details Method for treating cardiac dysfunction and pharmaceutical compo Method for treating cardiac dysfunction and pharmaceutical compo

1996-08-05

1999-07-27

Schenkman, Leonard

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

514 39, 514 40, 514 41, 514674, A61K 3113, A61K 3170

Patent

active

059290390

DESCRIPTION:

BRIEF SUMMARY
The present invention relates generally to a method for, and pharmaceutical compositions useful in, the prophylaxis and/or treatment of cardiac dysfunction in a mammal by the administration of an effective amount of an agent capable of blocking or inhibiting the effect or release of inositol(1,4,5)trisphosphate in cardiac tissue.
Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description.
Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
The phosphatidylinositol (PtdIns) turnover pathway is a complex signal transduction system that mediates a diverse range of neurotransmitter and hormone induced responses in a great variety of cells (1). The pathway usually involves the receptor mediated hydrolysis of a membrane phospholipid phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P.sub.2) by a specific phospholipase C (PLC) causing the release of two well described second messengers sn-1,2-diacylglycerol (DAG) and inositol(1,4,5)trisphosphate, hereinafter denoted as Ins(1,4,5)P.sub.3. DAG activates protein kinase C (PKC) and Ins(1,4,5)P.sub.3 releases calcium from specific intracellular stores. The two arms of the pathway either separately or in concert, control a wide range of cellular responses including contraction, secretion and mitogenesis (2). Ins(1,4,5)P.sub.3 is metabolised rapidly within the cell by dephosphorylation via Ins(1,4)P.sub.2 to Ins(4)P.sub.1 and by phosphorylation to Ins(1,3,4,5)P.sub.4, which is further metabolised to produce a wide range of inositol phosphate isomers (FIG. 1). Ins(1,3,4,5)P.sub.4 itself has been suggested to have a role in calcium sequestration (3) and roles for other inositol phosphates have been suggested (4).
The PtdIns pathway in the heart is activated by .alpha..sub.1 -adrenergic and muscarinic receptors, endothelin and stretch (5). Compared with non-muscle tissues, the heart is insensitive to Ins(1,4,5)P.sub.3 in terms of calcium release (6), with the addition of high concentrations of Ins(1,4,5)P.sub.3 causing a slow leakage of calcium rather than the rapid release seen in most cells (7). In addition, Ins(1,4,5)P.sub.3 enhances calcium oscillations which are associated with the development of arrhythmias (8, 9), but not calcium induced-calcium release, the mechanism involved in excitation-contraction coupling.
The present inventors have previously reported that PtdIns turnover pathway in the heart differs from that described in non-muscle cells. In heart, detectable, indicating reduced Ins(1,4,5)P.sub.3 kinase activity (10). More recent studies have shown that little Ins(1,4,5)P.sub.3 is released and metabolised either by phosphorylation or dephosphorylation and that most of the accumulated inositol phopshates derive from Ins(1,4)P.sub.2 rather than Ins(1,4,5)P.sub.3 (11). These findings suggest that Ins(1,4,5)P.sub.3 does not play a major role in the healthy heart.
However, there is evidence that the PtdIns pathway and Ins(1,4,5)P.sub.3 may be more important under pathological conditions such as myocardial ischaemia and reperfusion. .alpha..sub.1 -Adrenoceptor stimulation, which is associated with inositol phosphate release, is capable of inducing arrhythmias both ventricular tachycardia (VT) and ventricular fibrillations (VF) during both ischaemia and reperfusion. Such responses are not observed under normoxic conditions. Ischaemia has been reported to increase .alpha..sub.1 -adrenoceptor density in a number of myocardial preparations (12) as well as increasing responsiveness to noradrenaline stimulation (13). Reperfusion of ischaemic myocardium, is associated with large calcium accumulations, apparently associated with .alpha..sub.1 -adrenoceptor stimulation (14). These calcium accumulations have been implicate

REFERENCES:
Casti et al. (1975) "Changes in specific radioactivity and levels of free nucleotides and polyamines in infarcted and borderline tissue of reperfused dog heart" Chemical Abstracts 83: 364, 16179n.
Natanson et al, Am. J. Physiol, 259(5, Pt. 2) (Abstract), 1990.
Voorn et al, J. Infect. Dis., 163(3) 640-3 (Abstract), 1991.
Ramos et al, Antimicrob. Agents Chem Other 36(9) 1864-9 (Abstract), 1992.

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