Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest the presence of local angiotensin generating system in the kidney. By using in situ hybridization technique, mRNA for angiotensinogen has been shown to be present in the proximal tubule. In the present study, we have attempted to examine the production of angiotensinogen and renin-like activity by the proximal convoluted (PCT) and straight (PST) tubular cells. PCT and PST cells were obtained from microdissected rabbit proximal tubules and cultured in vitro. Angiotensinogen and renin-like activity were quantitated in culture media and cell lysates. It was found that PCT culture medium contained both angiotensinogen and renin-like activity, whereas only angiotensinogen was detected in PST culture medium. Support for de novo synthesis is provided by the observation that both angiotensinogen and renin-like activity in PCT culture medium increased in a time-dependent and hormone-sensitive manner in defined serum-free medium. These results thus demonstrate the actual production of angiotensinogen and renin-like activity by proximal tubular cells, and indicate that these locally synthesized components may contribute to the regulation of angiotensin generation in renal proximal tubule.
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PMID:Production of angiotensinogen and renin-like activity by rabbit proximal tubular cells in culture. 206 10

The search for endogenous digitalis led to the isolation of ouabain from blood adrenals and hypothalamus. Additional cardiotonic steroids of the cardenolid and bufadienolide type seem to circulate in blood. Adrenal cortical cells in tissue culture release ouabain upon addition of angiotensin 11. Ouabain in blood is increased in 50% of Caucasians with low renin hypertension. Analogous to other steroid hormones, cardiotonic steroid hormones in blood are bound to a specific cardiac glycoside binding globulin. Since ouabain induced growth of myocytes in tissue culture, this effect probably mediates by partial inhibition of the sodium pump and consecutive rise of intracellular Ca2+ the thickening of the wall of arteries and myocardium. PST 2238, an antagonist of cardiac glycoside function at the sodium pump, leads in rats under prolonged therapy to a decrease of hypertension. The finding of ouabain as a new adrenal hormone of the Na+ metabolism and of ouabain antagonists opens new possibilities of therapy of hypertension and congestive heart failure.
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PMID:Endogenous cardiotonic steroids. 1135 1

The search for endogenous digitalis has led to the isolation of ouabain as well as several additional cardiotonic steroids of the cardenolide and bufadienolide type from blood, adrenals, and hypothalamus. The concentration of endogenous ouabain is elevated in blood upon increased Na(+) uptake, hypoxia, and physical exercise. Changes in blood levels of ouabain upon physical exercise occur rapidly. Adrenal cortical cells in tissue culture release ouabain upon addition of angiotensin II and epinephrine, and it is thought that ouabain is released from adrenal cortex in vivo. Ouabain levels in blood are elevated in 50% of Caucasians with low-renin hypertension. Infusion over several weeks of low concentrations of ouabain, but not of digoxin, induces hypertension in rats. A digoxin-like compound, which has been isolated from human urine and adrenals, as well various other endogenous cardiac glycosides may counterbalance their actions within a regulatory framework of water and salt metabolism. Marinobufagenin, for instance, whose concentration is increased after cardiac infarction, may show natriuretic properties because it inhibits the alpha1 isoform of Na(+)/K(+)-ATPase, the main sodium pump isoform of the kidney, much better than other sodium pump isoforms. In analogy to other steroid hormones, cardiotonic steroid hormones in blood are bound to a specific cardiac glycoside binding globulin. The discovery of ouabain as a new adrenal hormone affecting Na(+) metabolism and the development of the new ouabain antagonist PST 2238 allows for new possibilities for the therapy of hypertension and congestive heart failure. This will lead in turn to a better understanding of the disease on a physiological and endocrinological level and of the action of ouabain on the cellular level as a signal that is transduced to the plasma membrane as well as to the cell nucleus.
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PMID:Endogenous cardiac glycosides, a new class of steroid hormones. 1202 81

PST 2238 is a new antihypertensive compound that is able to correct the molecular and functional alterations of the renal Na-K pump and the pressor effect associated with either alpha-adducin mutations or high circulating levels of endogenous ouabain (EO) in genetic and experimental rat models. Due to the close relationship between renal Na-K pump function and tubular Na reabsorption, PST 2238 was investigated to determine whether it is endowed with diuretic activity and consequently might trigger alterations of the renin-aldosterone system and the carbohydrate and lipid metabolism often associated with chronic diuretic therapy. In Milan hypertensive (MHS) rats, in which hypertension is genetically associated with alpha-adducin mutation, increased tubular Na reabsorption, and hyperactivation of the renal Na-K pump. PST 2238 reduced blood pressure and normalized the renal Na-K pump activity at oral doses of micro g/kg, but did not induce, either acutely or chronically, any diuretic activity or hormonal or metabolic alterations. In contrast, HCTZ, given to MHS rats orally at 40 mg/kg, although it displayed diuretic activity and reduced the renal Na-K pump activity, did not lower blood pressure and caused hyperactivation of the renin-aldosterone system, hypokaliemia, and hyperglycemia. The findings lead to the conclusion that PST 2238 is a new antihypertensive compound that normalizes the altered function of the renal Na-K pump associated with hypertension in rat models, but that it is devoid of diuretic activity and does not induce the diuretic-associated side effects.
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PMID:PST 2238: a new antihypertensive compound that modulates renal Na-K pump function without diuretic activity in Milan hypertensive rats. 1245 21

The search for an endogenous digitalis has led to the identification of the cardenolides ouabain and digoxin and the bufadienolide marinobufagenin in mammalian tissues and biological fluids. Ouabain's release from adrenal glands is under the control of epinephrine and angiotensin II; hence, its blood concentration changes rapidly on physical exercise. It also is controlled by brain areas sensing cerebrospinal Na+ concentration and apparently the body's K+ content because urinary K+ loss leads to an increase in its plasma concentration as well. Long-term treatment of rats with ouabain results in arterial hypertension, and 50% of Caucasians with low-renin hypertension have increased plasma concentrations of this cardenolide. Levels of digoxin, which is synthesized from acetate in adrenal glands, increase slightly in blood on prolonged exercise. It counteracts the hypertensinogenic action of ouabain in rats, as does the ouabain antagonist PST 2238. The plasma concentration of the bufadienolide marinobufagenin is increased after cardiac infarction. It may show natriuretic properties because it inhibits the alpha1 isoform of Na+/K+-adenosine triphosphatase (ATPase), the main sodium pump isoform of the kidney, much better than other sodium pump isoforms. These effects of endogenous cardiac glycosides are observed at concentrations that do not inhibit the sodium pump. Apparently, Na+/K+-ATPase is used by these steroids as a signal transducer to activate tissue proliferation, heart contractility, arterial hypertension, and natriuresis via various intracellular signaling pathways.
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PMID:Endogenous cardiac glycosides: hormones using the sodium pump as signal transducer. 1613 90