Antagonism of endothelin actions

Details Antagonism of endothelin actions Antagonism of endothelin actions

1998-09-14

2002-06-25

Wang, Andrew (Department: 1635)

Drug, bio-affecting and body treating compositions

Solid synthetic organic polymer as designated organic active...

Polymer from ethylenic monomers only

C424S093200, C514S002600, C514S012200

Reexamination Certificate

active

06410007

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods for down-regulating local endothelin-mediated vasoconstrictor and/or vascular growth activity in “apparently” normal physiological conditions in order to re-establish normal control in specific regions of the circulation which demonstrate pathophysiology. More particularly this invention relates to the administration of agents which antagonize the expression or activity of endothelin for the treatment of abnormalities of specific regions of the vasculature such as in erectile dysfunction in male patients.
BACKGROUND OF INVENTION
Endothelins were first described in 1988 and have been shown to be powerful vasoconstrictors, predominantly found in the vascular endothelium and, since that time, numerous endothelin antagonists and pharmaceutically acceptable salts thereof have been identified and can be obtained commercially (e.g., Sigma, American Peptides). Attention is also directed to U.S. Pat. No. 5,284,828 issued Feb. 8, 1994 to Hemmi et al., U.S. Pat. No. 5,378,715 issued Jan. 3, 1995 to Stein et al. and U.S. Pat. No. 5,382,569 issued Jan. 17, 1995 to Cody et al., which describe in detail the chemical structures of various endothelin antagonists, and to U.S. Pat. No. 5,338,726 issued Aug. 16, 1994 to Shinosaki et al., which describes the chemical structure of endothelin converting enzyme inhibitors, the disclosures of which are incorporated herein by reference. To date, however, antagonists of endothelin have not been approved for therapeutic use, although a number of investigators have postulated that endothelin antagonists could be used for conditions ranging from renal failure, endotoxic shock, asthma, angina, or diabetes to pulmonary hypertension and possibly other indications.
Under normal physiological conditions, endothelin can be found in almost all parts of the circulation at very low levels. In general, in the normal rodent circulation endothelin (ET) is not found in elevated quantities and appears to have minimal effect in the normal regulation of vascular tone, i.e., there is no appreciable decrease in blood pressure when an endothelin antagonist is administered by injection in normal circulation. Further, at present there does not appear to be any evidence suggesting that ET plays a physiological role even in a small portion of the circulation under normal conditions in experimental models. However, it is likely that the circulation may appear normal when in fact a specific region of the circulation reveals pathophysiological changes, such as occurs with erectile dysfunction. Penile erection demands specific local vasodilation and/or inhibition of local vasoconstrictor mechanisms. It is not surprising that findings of elevated levels of endothelin in the blood are not widespread, as the regulation of ET action indicates a release preferentially towards the smooth muscle side, away from the circulation. In addition, it is highly improbable that there would be increased ET found in the circulation resulting from increased activity in a small portion of the circulation. ET is known to have a very short half-life.
It is widely known that administration of nitric oxide (NO) can provoke powerful vasodilator responses. The chronic role of nitric oxide synthase (NOS) as a vasodilator has only been inferred by indirect means, i.e., by removal of the NOS activity. Endogenously, there is much more redundancy in control of vasodilatation. For example, vasodilation can be induced by acetylcholine, bradykinin, adenosine triphosphate (ATP), histamine, vasoactive intestinal polypeptide (VIP), and leukotrienes, amongst others. The actions of these endogenous modulators have been shown to be dependent on the presence of the endothelium, an effect likely mediated by endothelial derived relaxing factor/NO (EDRI/NO) (1,2,3). Other vasodilator mechanisms exist which are not endothelium dependent, such as &bgr;
2
-adrenergic, arial natriuretic peptide (ANP) and certain prostaglandins. The actions of NO appear to be mostly cGMP-mediated via guanylate cydase activation, although other mechanisms have been suggested. Garg and Hassid (1, 2) and others (4,5) demonstrated a difference in the effects of NO-generating vasodilator agents in inhibiting vascular smooth muscle cell growth in culture; however, it is clear that NO can act not only as a vasodilator but also to inhibit vascular growth responses in a number of conditions (6).
In the last several years a large number of studies has demonstrated that decreased NO production using inhibitors of NO synthase (e.g., N
&ohgr;
-nitro-L-arginine-methyl ester or L-NAME) produces dose-dependent hypertension (i.e., L-arginine reversible, and which correlates with decreased cyclic guanosine monophosphate (cGMP)) (7,8,9). Data from Schiffrin's (4,10) and Morton's (11) groups demonstrate that prolonged high dose L-NAME hypertension is associated with hypertrophic changes in the mesenteric vasculature (1 media thickness and 1 media/lumen ratio). Interestingly, Schiffrin's group found that the degree of change in vascular structure was less marked than in other models (2K1C) with equivalent hypertension and of a similar duration. Taken together with the findings of NO development of cardiac hypertrophy and slower vascular changes, current evidence indicates that L-NAME hypertension is quite different from other models. Further, although these findings could suggest a role for NO as a modulator of vascular structure, our recent findings suggest that NO may play a more important inhibitory role in suppressing the activity of the endothelin vasoconstrictor system. The concept of NO suppression of ET expression is further supported by evidence both from Luscher's group in vitro and from the Clozel group (12) in vivo showing that there is increased release of ET from endothelial cells after NOS blockage. These data suggest that exogenous administration of NO synthase antagonists produces a condition wherein the lack of NO appears to be a modulator of ET expression and release. Recent findings, in particular from Schiffrin's group (13,14), in deoxycorticosterone acetate (DOCA)-salt hypertension point to a trophic role for endogenous endothelin in the development of vascular structural changes. They found that there is increased ET-1 gene expression and immunoreactivity in blood vessels, but not in the plasma, of DOCA-salt hypertensive rats, whereas renin angiotensin system (RAS) activity was decreased. There was a substantial development of vascular hypertrophy in the DOCA-salt model which was markedly attenuated by treatment with an ET
A
/ET
B
receptor antagonist. The concept that ET-1 is a vascular trophic factor is further supported by findings in studies with cultured vascular smooth muscle cells showing that addition of endothelin produces a mitogenic response (15), as well as findings in other in vivo studies indicating a role in structural changes associated with pulmonary hypertension (16). ET-1 is approximately 100 times more potent as a vasoconstrictor than Ang II or catecholamines. Interestingly, in the culture studies, although the maximal growth response to ET-1 was less than half of that for Ang II, the combination of ET-1 plus Ang II provoked a greater mitogenic response than either peptide alone. We are not aware of any studies that have assessed the in vivo cardiovascular growth responses to direct endothelin infusion.
An important aspect of the invention derives from the development of a concept which reveals an interrelationship between NO activity and endothelin vasoconstrictor activity, in vivo: specifically, that NO acts primarily as a chronic inhibitor of endothelin-mediated vasoconstriction, and less as a chronic vasodilator. Accordingly, it is proposed that endothelin plays a role in disease conditions associated with impaired NO synthesis, particularly if the pathophysiology is restricted to a specific portion of the circulation; i.e., if the entire circulation were altered, numerous compensatory changes in neurohumoral systems would also occur.
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