Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1985-05-08
1988-08-16
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530324, 530350, A61K 3702, C07K 710
Patent
active
047645040
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to the production and use of polypeptides which are useful as diuretics, natriuretics and vasodilators.
BACKGROUND ART
Most multi-cellular organisms are organized into tissues and organs which perform specialized functions. Thus, a system has evolved to transport materials between them. In higher animals, including mammals, this circulatory system is closed to improve the efficiency of transport. The flow of blood fluid through this closed cardiovascular system requires that the fluid be maintained under pressure and the regulation of the systemic arterial blood pressure reguires a complex interaction of numerous factors including, e.g., fluid volume and vascular elasticity and caliber.
The maintenance of normal extracellular fluid volume depends primarily on the excretion of sodium (natriuresis) and water (diuresis) by the kidneys. This is determined by (1) the rate at which plasma is filtered at the glomerulus (glomerular filtration rate, or GFR) and (2) the degree to which sodium is actively reabsorbed along the renal tubule (with water following passively). The latter process is in part regulated by the adrenal steroid hormone aldosterone. It has been long believed that, in addition to GFR and aldosterone, there must be a "third factor" which also regulates sodium reabsorption. It is now apparent that many of the phenomena which required the postulation of a "third factor" can be explained by the effects of physical forces (e.g. blood pressure, red blood cell concentation and plasma viscosity) on sodium reabsorption. Nonetheless, the search continues for a "natriuretic hormone" which might modulate tubular reabsorption.
There are several candidates for such a hormone, among which are included the natriuretic factor(s) recently isolated from atrial muscle cells. A natriuretic effect has been demonstrated by crude extracts of rat atrial tissue but not ventricular tissue. De Bold, A. J. et al., Life Sciences, 28:89-94 (1981), Garcia, R., Experientia, 38:1071-73 (1982), Currie, M. G. et al., Science 221:71-73 (1983). Various peptides with diuretic and natriuretic properties have been isolated from atrial tissue and sequenced. Flynn, T. G. et al., Biochem. Biophys. Res. Commun. 117:859-865 (1983), Currie, M. G. et al., Science 223:67-69 (1984), Kangawa, K. et al., Biochem. Biophys. Res. Commun. 118:131-139 (1984). The existence of these atrial natriuretic factors strengthens the long-held suspicion that the heart, aside from its obvious influence on renal perfusion, may play an important role in regulating renal sodium and water excretion. Stretching of the atria is known to induce diuresis and natriuresis, and this is possibly mediated by increased release of these factors.
A number of clinically important disease states are characterized by abnormal fluid volume retention. Congestive heart failure, cirrhosis of the liver and the nephrotic syndrome each lead to excessive fluid accumulation on the venous side of the circulation, the presumed common mechanism being under-perfusion of the kidneys leading to a fall in GFR. In addition the reduced renal perfusion stimulates excessive secretion of renin, a proteolytic enzyme whose action in the circulation leads to the formation of angiotensin. Angiotensin is a powerful constrictor of arterioles (which helps to maintain arterial pressure) and also stimulates release of the sodium-retaining hormone aldosterone by the adrenal gland (which further worsens fluid retention). These mechanisms do not, however, fully account for the fluid retention of the so-called "edematous states", and additional factors are likely to be involved. One important possibility is that a relative or absolute deficiency of atrial natriuretic factor, caused either by chronic over-stretching of the atrium (e.g., heart failure) or by inadequate stimulation of the atrium (e.g., cirrhosis and nephrotic syndrome), might contribute to the fluid retention.
An increase in extracellular fluid volume is also thought to contribute to the development of
REFERENCES:
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patent: 4557864 (1985-12-01), Needleman
patent: 4607023 (1986-08-01), Thibault et al.
Biochem. and Biophys. Res. Commun. 859-865, vol. 117, (1983).
Science, vol. 223 (1984) 67-69.
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Biochem. and Biophys. Res. Commun. 131-139, vol. 118 (1984).
The Journal of Histochemistry and Cytochemistry, vol. 26, No. 12 1094-1102 (1978).
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Science, (1983) vol. 221 71-73.
Atlas Steven A.
Johnson Lorin K.
Laragh John H.
Lewicki John A.
McCarthy Brian J.
Biotechnology Research Associates J.V.
Phillips Delbert R.
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