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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Canrenone, a metabolic product of spironolactone, which competes with ouabain for binding to Na-K-ATPase at the digitalis receptor site and by itself inhibits Na-K-ATPase, was administered intramuscularly to reduced renal mass-saline drinking hypertensive and reduced renal mass-distilled water drinking normotensive rats for 8 days. Reduced renal mass-saline hypertension in the rat, is a low renin, volume expanded form of hypertension. Rats with this type of hypertension have been shown to have depressed arterial Na-K pump activity and increased Na-K pump inhibitory activity in their plasma. Canrenone treatment caused a progressive decrease in blood pressure in the hypertensive rats and this was associated with normalization of Na-K pump activity in arteries. Water and salt intake and excretion did not change. On the other hand, canrenone progressively increased blood pressure in the normotensive rats and this was associated with positive inotropy in isolated papillary muscles. These findings suggest that the depressed pump activity and the pump inhibitor play a role in reduced renal mass-saline hypertension in the rat and that the rise in blood pressure in the normotensive rats probably reflects canrenone's ability, by itself, to inhibit Na-K-ATPase.
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PMID:Effects of canrenone on blood pressure in rats with reduced renal mass. 215 66

Recent studies in essential hypertensive patients and rats with genetic hypertension strongly suggested that the development of primary hypertension takes place by a transient and chronic "cascade" of events (i) excess Na+ intake, (ii) secretion of natriuretic factors, (iii) abnormal cells Na+ homeostasis in the vascular wall, due to the presence of inherited abnormalities in different Na+ transport systems, and (iv) increase in cytosolic free Ca2+ content and catecholamines. Canrenone, an antihypertensive drug, behaves like a partial agonist at the digitalis-receptor site of the Na+, K+ pump. We observed here that (i) a 4 hr preincubation of human red cells with this compound increases its antagonistic properties against ouabain, (ii) in cultured smooth muscle cells, canrenone counterbalances the increase in cytosolic free Ca2+ induced by ouabain, and (iii) in a model of experimental hypertension with increased endogenous "ouabain-like" factors (rats with reduced renal mass), the administration of canrenone tends to normalize Na+, K+-pump activity and decrease blood pressure.
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PMID:Involvement of natriuretic hormones and Na+ transport in the antihypertensive action of canrenone. 242 26

Anatagonists to angiotensin, catecholamines, aldosterone, and vasopressin have long been used to help determine agonist roles in hypertension. We here call attention to a possible extension of this approach to detect, evaluate, and treat vascular sodium transport defects in hypertension. Two basic types of transport defects have been identified in the blood vessels of hypertensive animals, increased sodium permeability and decreased sodium pump activity. Intravenous injection of 6-iodo-amiloride, a sodium channel blocker and vasodilator, produces an immediate and sustained decrease in blood pressure in two genetic models of hypertension characterized by increased permeability of the vascular smooth muscle cell membrane to sodium (Okamoto spontaneously hypertensive rat, Dahl salt sensitive rat), whereas it produces only a transient fall in arterial pressure in two renal models of hypertension having normal sodium permeability in vascular smooth muscle cells (reduced renal mass-saline rat, one-kidney, one clip rat). Canrenone, a metabolic product of spironolactone which can compete with oubain for binding to Na+,K+-ATPase at the digitalis receptor site, decreases blood pressure in a low renin, volume expanded model of hypertension which has been shown to have depressed sodium pump activity in arteries and increased sodium pump inhibitor in plasma (reduced renal mass-saline rat) but has no effect on blood pressure in a genetic model of hypertension which has been shown to have increased sodium pump activity secondary to increased sodium permeability (spontaneously hypertensive rat). Thus, a sodium channel blocker and a competitor to ouabain binding can detect and determine the functional significance of sodium transport defects in the blood vessels of intact hypertensive animals. Studies in red and white blood cells suggest that similar defects may exist in the blood vessels of hypertensive humans. Thus, this approach, probing for vascular transport defects in the intact animal, may ultimately also be useful in the clinical setting.
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PMID:Pharmacologic agents for the in vivo detection of vascular sodium transport defects in hypertension. 244 62

It has been proposed that peripheral resistance can be increased by ouabain-like factors that are able to increase cell sodium and thereby cell calcium. Canrenone has been reported to be a partial agonist of ouabain. The effect of canrenone was investigated in rats with reduced renal mass (RRM) showing evidence of excess circulating ouabain-like factors. Wistar rats were uninephrectomized, 30% of the other kidney was removed, and they were given a 0.8% NaCl solution to drink. Half of them received 60 mg/kg per day of canrenone orally for 26 days. In RRM, the following indices of a ouabain-like activity were found: erythrocyte Na+K(+)-pump activity was decreased by 39% (P < 0.001), sodium content increased by 12% (P < 0.01), net erythrocyte sodium extrusion in plasma decreased by 20% (P < 0.01), and plasma digoxin equivalents increased by 62% (P < 0.02). Canrenone increased the IC50 for ouabain from 1.05 to 2.16 x 10(-4) mol/l (P < 0.05) in erythrocytes. In RRM with systolic blood pressure of 165 mmHg, acute administration of canrenone decreased blood pressure by 36 mmHg. Chronic administration blunted the blood pressure rise by 12, 26 and 21 mmHg at days 5, 14 and 26, respectively (P < 0.05). Haematocrit was markedly reduced in RRM (33%) and much less when treated with canrenone (37.5%). In conclusion, in contrast with spontaneously hypertensive rats, RRM hypertension is a model where a ouabain-like factor is present and in which canrenone reduces blood pressure. The hypotensive effect of canrenone may be related to a competition with ouabain-like factors.
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PMID:Hypotensive action of canrenone in a model of hypertension where ouabain-like factors are present. 285 27

Increasing evidence has accumulated for rapid nongenomic steroid actions in various cell systems and, more recently, for rapid aldosterone effects on the Na(+)-H+ antiport in human mononuclear leukocytes. The aim of the present study was to demonstrate a rapid, nongenomic aldosterone action in rat vascular smooth muscle cells as a key effector cell in cardiovascular regulation. Basal 22Na+ influx in quiescent vascular smooth muscle cells was 22.1 +/- 1.9 nmol/mg protein per minute (mean +/- SEM, n = 9). Aldosterone (1 nmol/L) stimulated influx to 28.6 +/- 1.5 nmol/mg protein per minute after 4 minutes (n = 9, P < .05), with a half-maximal effect between 0.1 and 0.5 nmol/L; the effects were inhibited by ethylisopropylamiloride, the specific inhibitor of the Na(+)-H+ exchanger, demonstrating the involvement of this transport system in rapid effects of aldosterone. Hydrocortisone (1 mumol/L) was ineffective, and fludrocortisone and deoxycorticosterone increased influx with half-maximal effects at approximately 0.5 nmol/L. Canrenone, a classic antagonist of aldosterone action, did not inhibit stimulation by aldosterone at a 1000-fold excess concentration. Aldosterone significantly stimulated intracellular inositol 1,4,5-trisphosphate levels (P < .05) after 30 seconds; the inhibitors of phospholipase C, neomycin and U-73122, inhibited aldosterone-stimulated Na+ influx and increase of intracellular inositol 1,4,5-trisphosphate. The rapid stimulation of sodium transport in vascular smooth muscle cells and the pharmacological characteristics of this effect are clearly incompatible with the classic, genomic pathway of steroid action and represent further evidence for nongenomic effects of aldosterone.
Hypertension 1995 Jan
PMID:Rapid effects of aldosterone on sodium transport in vascular smooth muscle cells. 784 42

Spironolactone, a competitive aldosterone receptor antagonist (ARA), has traditionally been the treatment of first choice in idiopathic hyperaldosteronism (IHA) and for preoperative management of aldosterone producing adenoma (APA). Spironolactone is partially absorbed, is extensively metabolized mainly by the liver and its therapeutic properties are attributable to active metabolite canrenone. At therapeutic doses of 25 to 400 mg per day, spironolactone effectively controls blood pressure and hypokalemia in the majority of cases. Endocrine side effect are often associated and mainly consist of gynecomastia, decreased libido and impotence in man and menstrual irregularities in women. Canrenone and the K+ salt of canrenoate are also in clinical use: they avoid the formation of intermediate products with anti-androgenic and progestational actions, resulting in a decreased incidence of side effects. Furthermore, a relatively new selective ARA compound (eplerenone) with reduced affinity for androgen and progesterone receptors, is currently undergoing clinical trials. In essential hypertension aldosterone can contribute to hypertension and increases the incidence of myocardial hypertrophy and cardiovascular events. On the other hand, inhibition of Renin-Angiotensin-Aldosterone System (RAAS) is associated with a decrease in blood pressure, with a regression of left ventricular hypertrophy and a reduction of target organ damage. Thus, ARA have been proposed as complementary treatment associated to ACE inhibitors and angiotensin receptor antagonists. Aldosterone is also known to play an important role in pathophysiolgy of congestive heart failure (CHF). In vitro and in vivo evidences suggest that aldosterone promotes myocardial fibrosis. This effect reflects direct, extra-epithelial actions of aldosterone via cardiac MR which are counteracted by ARAs in animal models. The RAAS is chronically activated in CHF. Non potassium-sparing diuretics further stimulate the RAAS and cause hypokalemia. Thus, use of ARAs in CHF was first proposed to correct potassium and magnesium depletion. At present ARAs are indicated in the management of primary hyperaldosteronism, in oedematous conditions in patients with CHF, in cirrhosis of the liver accompanied by oedema and ascites, in essential hypertension and in hypokalemic states. Its indication as adjunctive therapy of heart failure is currently under investigation. In fact, it is well known that even high doses of ACE inhibitors may not completely suppress the RAAS; aldosterone 'escape' may occur through non angiotensin II dependent mechanisms. Addition of spironolactone to an ACE inhibitor causes marked diuresis and symptomatic improvement. During the last few years, the RALES study (Randomized Aldactone Evaluation Study) was organized to explore the efficacy of combination therapy with spironolactone and ACE inhibitor in patients with CHF, class III or IV NYHA. The study was stopped 18 months early because the results were so statistically and clinically significant that it would be unethical to continue the trial. It is reported a 30 percent decrease in mortality and hospitalisation for cardiac causes in spironolactone-treated group vs placebo group.
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PMID:Aldosterone antagonists in hypertension and heart failure. 1079 May 93

Canrenone is a derivative of spironolactone with lower antiandrogen activity. The drug is used only in few countries and can block all the side effects of aldosterone (ALDO). The drug is effective even in the presence of normal concentrations of ALDO. Mineralcorticoid receptor antagonists block the inflammatory activity of ALDO at the level of target tissues as heart, vessels and mononuclear leukocytes. Canrenone reduces the progression of insulin resistance and of microalbuminuria in type 2 diabetes and other related diseases. Both canrenone and hydrochlorothiazide can enhance the effect of treatment with ACE inhibitors and angiotensin II receptor blockers on microalbuminuria, but ALDO receptor blockers are more active. This different action is due to the fact that only canrenone blocks mineralocorticoid receptors. Serum potassium and renal function should be monitored before and during the treatment. ALDO receptor blockers are recommended in addition to polytherapy for resistant hypertension, but there are no studies on the effect of the drug as first-choice therapy.
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PMID:Aldosterone receptor blockers spironolactone and canrenone: two multivalent drugs. 2461 54