UMLS:C0085580 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0085580 (essential hypertension)
14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human essential hypertension is a polygenic disease whose phenotypic expression is modulated by the environment. Though the kidney could play a major role in the initiation and maintainment of hypertension, many questions remain open. Rat models of primary hypertension provided the substantial information with experiments on kidney cross-transplantation showing that at least a portion of hypertension could be transplanted with the kidney in all strains where such experiment has been carried out. Data consistent with those of rats have also been obtained in humans. Many abnormalities in kidney function and cell membrane on transport have been described in hypertensive rats and humans but the logical sequence of events going from a genetic-molecular abnormality to a cellular abnormality which causes hypertension via a modification of kidney function is difficult to prove. We established this sequence in Milan hypertensive rats using a variety of experimental techniques such as the study of isolated kidney and renal cell function, cell membrane ion transport, cross-immunisation with membrane proteins, molecular biology, genetic crosses and manipulation. Such study led to the identification of a polymorphism in the cytoskeletal protein adducin and to the demonstration of its role in blood pressure control. Recently, alpha-adducin variants have been associated to both human primary hypertension and salt sensitive hypertension. Finally, recent findings strongly support the hypothesis that adducin variants may affect kidney function by modulating the overall capacity of the tubular epithelial cells to transport ions through both a modification in the assembly of actin cytoskeleton, and a modulation of sodium pump activity.
...
PMID:Renal genetic mechanisms of essential hypertension. 937 22

Accumulated evidence has suggested that several sodium pump inhibitors, similar to cardiotonic steroids, are present in the human body. Ouabain-like factor, the most appealing candidate, has been found to be increased with high sodium intake and hypervolaemia, and in essential hypertension, mineralocorticoid hypertension, and pregnancy-induced hypertension. Furthermore, blocking the action of ouabain-like factor with digibind or a novel anti-ouabain agent lowers blood pressure in several models of hypertension. Several important questions remain, however, before it can be concluded that ouabain-like factor is indeed involved in the regulation of sodium homeostasis and blood pressure.
...
PMID:Ouabain-like factor. 952 22

Three lines of evidence led to our suggestion in 1976 that sodium pump inhibitors are involved in volume expanded hypertension. These were 1) pressor activity of low renin hypertensive blood 2) natriuretic and sodium pump inhibiting activities of volume expanded blood and 3) potassium vasoactivity which was blocked by ouabain and suppressed potassium vasodilatation, myocardial Na-K-ATPase, and artery, vein and WBC sodium pumps in low renin hypertension. This led to bioassay of plasma from acutely volume expanded dogs and from dogs with one-kidney, one wrapped hypertension for sodium pump inhibiting activity that acts on arteries. Positive results were reported in 1980. The assay was also positive in rats with one-kidney, one clip and reduced renal mass hypertension (but not in rats with spontaneous or salt sensitive hypertension) and in humans with acute volume expansion and low renin essential hypertension (but not in humans with normal renin hypertension). Thus the inhibitor which acts on the sodium pump in arteries appears to be present only in low renin hypertension.
...
PMID:Role of ouabain-like factors and Na-K-ATPase inhibitors in hypertension--some old and recent findings. 968 6

The human circulation contains four readily distinguishable biologically active inhibitors of the sodium pump that appear to be endogenous to mammals. Of these, one has been purified to homogeneity and by numerous chromatographic, mass spectral, biochemical, and physiological analyses has been shown to be a novel steroidal isomer of ouabain in which the location and orientation of two or more steroidal hydroxyl groups differ. The human endogenous "ouabain" (EO) is a high affinity reversible inhibitor of the pump with inotropic and vasopressor activity. Circulating levels of EO depend upon the adrenal cortex and metabolic events preceding and following pregnenolone formation are involved in EO biosynthesis. Within the adrenal gland, the stimulus-secretion mechanisms for EO secretion are distinct from those for aldosterone highlighting different regulation. Among Caucasians with essential hypertension, 30-45% have elevated circulating levels of EO. Sustained elevation of plasma ouabain in rats induces chronic hypertension with characteristics similar to those in patients and whose severity is determined by inherited factors and renal function. In conclusion, at least one of the mammalian counterparts to the cardiac glycosides is a novel steroidal isomer of ouabain. The isomer is secreted by the adrenal cortex, and augments cardiovascular function. The observation of this entity in the human circulation, the demonstration of its biosynthesis, and the existence of specific receptors suggest to us that EO is a novel adrenocortical hormone and may be part of a broader family of novel mammalian steroids that regulate the sodium pump and other processes.
...
PMID:Observations on the nature, biosynthesis, secretion and significance of endogenous ouabain. 968 8

1. Experimental hypertension is associated with several functional alterations of vascular endothelium and smooth muscle, but relatively few studies have examined the control of arterial tone in isolated vascular preparations from patients with essential hypertension. Therefore, we compared functional characteristics in vitro of distal ring segments of the mesenteric artery from 17 hypertensive and 22 normotensive humans. 2. Arterial constrictor responses induced by cumulative addition of Ca(2+) in the presence of noradrenaline (NA) were more effectively inhibited by the Ca(2+) entry blocker nifedipine (0.5 nM) in hypertensive than normotensive subjects (by 55.4+/-4.9, n=17 and 35.0+/(-5.2%), n=22, respectively). Also the contractions elicited by high concentrations of KCl were more effectively inhibited by nifedipine in arterial rings from hypertensive than normotensive patients (by 38.9+/(-3.7), n=17 and 20. 2+/(-4.6%), n=22, respectively). However, the concentration-response curves of contractions to NA, serotonin and KCl in the absence of nifedipine were similar between the study groups. 3. The concentration-response curves of endothelium-dependent relaxations to acetylcholine and Ca(2+) ionophore A23187, as well as of endothelium-independent relaxations to the nitric oxide donor nitroprusside, beta-adrenoceptor agonist isoprenaline and K+ channel opener cromakalim did not show any differences between the groups. Moreover, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (0.1 mM) almost abolished the relaxations to acetylcholine and Ca(2+) ionophore in both groups, indicating that these responses were largely mediated by nitric oxide. The function of arterial sodium pump was evaluated by relaxations elicited by the return of K+ upon contractions induced by K+-free solution. The rate of K+-relaxation was similar in hypertensive and normotensive arteries (for all these responses n=20 - 22 in the normotensive and 15 - 17 in the hypertensive group). 4. These results suggest abnormal function of voltage-dependent Ca(2+) channels in arterial smooth muscle of hypertensive patients, whereas vascular responses to endothelium-dependent and -independent vasodilators and classical contractile agents were similar between hypertensive and normotensive subjects. The present findings support the view that blockade of voltage-dependent Ca(2+) channels is an effective means of reducing arterial tone in essential hypertension.
...
PMID:Control of vascular tone in isolated mesenteric arterial segments from hypertensive patients. 1045 33

It is clear that defective renal sodium handling plays an important role in the development of hypertension and that this abnormality could be caused by heterogeneous hereditary factors in the kidney. It is likely that sodium pump inhibitors with or without whole-body autoregulation gradually produce a rise in blood pressure in response to retained body sodium. Accumulated evidence has suggested that several sodium pump inhibitors similar to cardiotonic steroids are present in the human body. Ouabainlike compound (OLC) has been found to be increased with high sodium intake and hypervolemia, and in essential hypertension, mineralocorticoid hypertension, and pregnancy-induced hypertension. Further, blocking the action of OLC with digibind or a novel anti-ouabain agent has been observed to lower blood pressure in several models of experimental and clinical hypertension. The blockade of OLC action may become the basis of novel rational antihypertensive agents and may help to solve the problems still present in the management of hypertensive patients.
...
PMID:Putative roles of ouabainlike compound in hypertension: revisited. 1101 13

Elevated circulating levels of an endogenous ouabain (EO) have been associated with essential hypertension. To investigate structure-activity relationships relevant to blood pressure, we infused either ouabain, ouabagenin, digoxin or digitoxin at 30 microg/kg/day in normal Sprague Dawley rats. After five weeks, the ouabain and ouabagenin infused rats were hypertensive, whereas blood pressures declined below their vehicle controls in rats infused with digoxin or digitoxin. In a second study, mean blood pressures were 118.5+/-1.7 mmHg in rats infused with ouabain (15 microg/kg/day) on day 35 vs. 98.3+/-1.8 and 100.3+/-1.1 mmHg in the digoxin (30 microg/kg/day) and vehicle infused groups (both p<0.005 vs. ouabain), respectively. Plasma and kidney levels of ouabain immunoreactivity were increased 4-8 fold in ouabain infused rats while blood pressure and plasma levels of ouabain returned to normal one week following discontinuation of the steroid infusion. In rats with ouabain-dependent hypertension, secondary infusions of digoxin or digitoxin (30 microg/kg/day) normalized blood pressure even though circulating ouabain remained elevated. In digoxin infused rats, neither blood pressure nor kidney digoxin immunoreactivity was raised whereas plasma digoxin was increased. Collectively, the results show that the hemodynamic effects of these sodium pump inhibitors differ dramatically during prolonged administration and that tissue rather than circulating levels of these agents appear to better explain their effects on blood pressure. These studies suggest that sodium pump inhibition is not the exclusive mediator of the hemodynamic effects of these cardiac glycosides and demonstrate the presence of structure-specific mechanisms that regulate their tissue levels and effects on long-term blood pressure.
...
PMID:Chronic hypertension induced by ouabain but not digoxin in the rat: antihypertensive effect of digoxin and digitoxin. 1101 24

Elevated levels of an endogenous ouabain circulate in many patients with essential hypertension. However, in contrast to ouabain, digoxin does not induce hypertension. This study investigated the hypothesis that within a single cardiac glycoside, the structural elements that induce hypertension differ from those responsible for high potency as a sodium pump inhibitor. Normal male Sprague-Dawley rats received infusions of vehicle (VEH), rhamnose (RHA), ouabain (OUA), ouabagenin (OGN), dihydro-ouabain (DHO), iso-ouabain (ISO), and a lactone ring opened analog (ORO) at 30 microgram. kg(-1). 24 h(-1) for 5 weeks via subcutaneous osmotic pumps. Cuff pressures were taken weekly. At the end of the study, trunk blood was harvested, extracted by C18 column, and subjected to high-performance liquid chromatography. Fractions were analyzed for OUA, OGN, and DHO by immunoassay. In OUA-, OGN-, and DHO-infused rats, 1 main peak of immunoreactivity corresponding to the infused agent was found. No evidence of in vivo conversion to OUA or DHO was found for any analog except ORO. At 5 weeks, systolic blood pressures in VEH, RHA, OUA, OGN, DHO, ISO, and ORO were 132+/-2.5, 133+/-1.5, 159+/-2.6,* 154+/-4,* 167+/-4,* 171+/-2.2,* and 169+/-2.4* mm Hg, respectively (*P<0.01 versus VEH and RHA, P<0.05 versus OUA). The hypertensinogenic activity was greater than OUA in 3 analogs (DHO, ISO, and ORO) in which the lactone was saturated, conformationally restrained by linkage with the oxygen at C14, or opened, respectively. These compounds were weak inhibitors of dog kidney Na,K-ATPase. Thus, RHA and the unsaturated lactone ring are crucial to the high potency of OUA as an inhibitor of the sodium pump but appear to be unrelated to its ability to induce hypertension. The conclusion that this form of hypertension is mediated primarily by the steroid nucleus suggests also that OUA may have a mechanism of action independent of the sodium pump.
...
PMID:Structure-activity relationships for the hypertensinogenic activity of ouabain: role of the sugar and lactone ring. 1123 Mar 21

Many studies of essential hypertension find evidence of insulin resistance in the same individuals, leading some to postulate a hypertensive role for insulin. However, the mechanisms by which insulin might exert a hypertensive effect are not fully resolved. An endogenous sodium pump inhibitor or digitalis-like factor (DLF) has been proposed as a hypertensive agent and its plasma concentrations are elevated in hypertension and in Type II diabetes, where insulin levels are elevated. Hence, we studied the effect of insulin on DLF using two approaches to achieve hyperinsulinemia. Normotensive men and women underwent a hyperinsulinemic, euglycemic clamp (40 mU/m2/min insulin, 40 mU = 1.6 x 10(-6) g) in which plasma insulin concentration was kept at high, but physiologic levels. Serum DLF (measured as inhibition of [Na,K]ATPase activity) and insulin levels were measured at baseline and every 30 min throughout the 2 hr clamp. Additionally, other subjects underwent an oral glucose tolerance test (OGTT) as a second means of increasing insulin levels. Insulin and DLF levels were measured prior to and hourly for 3 hours after receiving 100 gm of oral glucose. Serum DLF increased significantly during the clamp from a baseline of 4.6 +/- 0.81 to a peak of 8.7 +/- 1.2% inhibition (p=0.001). Comparison of the baseline and peak DLF levels with concomitant plasma insulin levels revealed a significant correlation (R=0.60, p=0.003). During the OGTT, DLF levels rose from a baseline of 2.4 +/- 1.0 to a peak level of 5.0 +/- 0.4%, p = 0.04. These results suggest that DLF, a factor that can cause vascular smooth muscle contraction and potentially influence blood pressure, is increased by hyperinsulinemia and provides a mechanism by which insulin may increase blood pressure.
...
PMID:Digitalis-like factor response to hyperinsulinemia accompanying a euglycemic hyperinsulinemic clamp or oral glucose tolerance test. 1148 94

In the last two decades extensive study has been carried out on the isolation, identification and biosynthesis of the "endogenous digitalis-like compounds" whose physiological and pathophysiological functions are only starting to be understood. Besides ouabain (strophanthin) and digoxin, four further endogenous cardiac glycosides were isolated and identified so far. These compounds are found in almost all mammalian tissues, including blood plasma and urine, but with the highest concentrations in the adrenal gland, pituitary and hypothalamus. De novo biosynthesis of these glycosides occurs in zona fasciculata cells of adrenal glands, precursors such as progesterone, pregnenolone, and rhamnose increase the synthesis of the ouabain-like immunoreactive material. The secretion of these compounds from the adrenocortical cells are controlled by adrenerg mechanisms, as well as via the renin-angiotensin system. The hydrophobic cardiac glycosides are transported in blood as complexes bound to specific binding globulins. The identified endogenous cardiac glycosides fulfill all the postulated criterions of the hormones, so they represent a new class of steroid hormones. The cardiac glycosides influence the active sodium pump, indirectly the intracellular free calcium concentration and therefore exert a positive inotropic effect on cardiac muscle. Furthermore, in physiological concentrations they can regulate the cell growth and protein synthesis inducing activation of intracellular signal pathways. Under pathological conditions, however, when the concentration of these steroids are high, they play a crucial role in the development of different serious illnesses such as essential hypertension as well as congestive heart failure. Further intensive investigations are needed to clarify some contradictory details accumulated during the last few years in this field.
...
PMID:[New steroid hormone family: endogenous cardiac glycosides and their role in physiologic and pathologic conditions]. 1503 19

<< Previous 1 2 3 4 5 6 7 8 9 Next >>