Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effective diuresis requires both sufficient glomerular filtrate and adequate delivery of the diuretic drug to the lumen of the renal tubule. Diuretics will not "force open" the kidney. Diuretics that work primarily in the proximal tubule include osmotic diuretics (e.g., mannitol), diuretics that interfere with the adenyl cyclase system (e.g., xanthines), and those which inhibit carbonic anhydrase (e.g., acetazolamide). Some thiazide and thiazide-like diuretics have a secondary site of action in the proximal tubule based on either carbonic anhydrase inhibition or other mechanisms, such as inhibition of sodium phosphate reabsorption. The diuretics that work primarily in the medullary diluting segment of the loop of Henle, furosemide and ethacrynic acid, block the active reabsorption of chloride and interfere with the tubular reabsorption of free water. The exact mechanism remains unknown. These diuretics tend to have a "high ceiling," to be potent and rapidly acting, and to have a short duration of effect. They are excellent for the treatment of severe fluid overload or pulmonary edema but are not ideal for the treatment of uncomplicated hypertension. Furosemide is a sulfonamide derivative; ethacrynic acid can be used in patients who are allergic to sulfa drugs. Diuretics that work primarily in the cortical diluting segment include the thiazides and thiazide-like drugs. They inhibit sodium transport by an undetermined mechanism. Most of them seem to reach a dose-response plateau beyond which little additional effect is gained by increasing the dose. Most of them appear to lose efficacy as the glomerular filtration rate decreases, except for metolazone and indapamide. The thiazides are most commonly used to treat hypertension. Diuretics that work primarily in the distal tubule and collecting tubule include the aldosterone inhibitor spironolactone and two drugs that impair tubular reabsorption of sodium by direct action, triamterene and amiloride. These drugs are primarily used for their potassium-sparing effect.
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PMID:Insights into intrarenal sites and mechanisms of action of diuretic agents. 686 1

Renal prostaglandins are gaining increasing recognition as important modulators of hemodynamics and excretory function in the mammalian kidney. Synthesis of these unsaturated fatty acids from arachidonate precursors is closely regulated by intrarenal factors, and circulating angiotensin II, catecholamines, arginine vasopressin and bradykinin. Endogenous prostaglandins exert little influence on renal blood flow and glomerular filtration rate in the basal state, but inhibition of arachidonate metabolism when renal perfusion is impaired causes marked alterations in these parameters. Renal salt and water excretion is modified by the effects of prostaglandins on glomerular filtration rate, proximal tubule fluid reabsorption, medullary solute gradients, and the intrinsic water and ion reabsorptive properties of distal nephron segments. Prostaglandins also mediate renin release under basal conditions and in response to intravascular volume depletion. Abnormalities of renal prostaglandins are evident in various clinical disorders of renal function including hypertension, ureteral obstruction, Bartter syndrome, hypokalemic nephropathy and drug-induced disorders of water metabolism. Appropriate clinical use of nonsteroidal anti-inflammatory agents requires consideration of the potential renal consequences of inhibiting prostaglandin biosynthesis.
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PMID:Arachidonic acid metabolism, prostaglandins and the kidney. 703 31

Kidneys were samples from male spontaneously hypertensive rats (SHR) and normotensive rats (WKY) in four groups. Renal tissues were examined in 64 rats: 6 SHR and 6 WKY rats 8 and 16 weeks of age and 10 SHR and 10 WKY rats 32 and 64 weeks of age. Tissue samples were fixed, processed, and stained by routine histologic procedures. The parietal layer of Bowman's capsule in 100-115 renal corpuscles from right to left kidney sections was classified as squamous or cuboidal epithelium. The cuboidal epithelium was similar in structure to that of the proximal tubule. Quantitative information from right and left kidneys was pooled, because the data did not differ significantly. The percentages of renal corpuscles with proximal tubule-like epithelium present at the parietal layer of Bowman's capsule in the SHR was 13%, 35%, 44%, and 81% at 8, 16, 32, and 64 weeks, respectively. In WKY rats the values were 4%, 0.5%, 5%, and 13% at 8, 16, 32, and 64 weeks, respectively. The increase in the percentage of renal corpuscles with proximal tubule-like epithelium in SHR Bowman's capsules suggest an association between this tissue and hypertension. The modified layer of Bowman's capsule may be a response to an increase in blood pressure, may have some role in the etiology of hypertension, or may be irrelevant to hypertension.
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PMID:Proximal-tubule-like epithelium in Bowman's capsule in spontaneously hypertensive rats. Changes with age. 706 26

Dahl described a strain of rats with genetically controlled propensities for hypertension. Chronic excess salt feeding increased blood pressure in sensitive (s) rats, whereas resistant rats (R) remain normotensive. We tested the pressure natriuretic function (urinary sodium excretion versus perfusion pressure) in isolated kidneys perfused with a cellular medium: in sodium-restricted normotensive sensitive (S0) and resistant (R0) animals; in sensitive rats receiving a high-salt diet for 3 weeks (S3): and in both S and R animals exposed to excess sodium for 7 weeks (R7 and S7). The aim of these studies was to determine if a preset alteration of the pressure natriuretic function might be present in S animals prior to the development of hypertension. Systolic blood pressure in S0, S3, and S7 animals were 123 +/- 4, 136 +/- 2, and 162 +/- 4 mm Hg, respectively, whereas that of R0 and R7 were 121 +/- 5 and 126 +/- 5 mm Hg. An increase of the perfusion pressure of isolated kidneys from 105 to 185 mm Hg in stepwise fashion resulted in a pressure natriuresis whose slope was similar in R0 and S0 animals. Of interest was that the pressure natriuretic function slope of kidneys from R0 (low sodium) and R7 (high sodium) rats was as predicted by the Guyton system analysis of normal blood pressure control Micropuncture of the proximal nephrons demonstrated that the origin of the natriuresis resulted from a site beyond the accessible proximal tubule. Results from S7 kidneys contrasted with all others in that the natriuretic response was depressed (P less than 0.01), which resulted from significantly lower filtration rates at higher perfusion pressures. We concluded (1) in normal R rats, the pressure natriuretic function is that predicted by the Guyton hypothesis, (2) Dahl S animals have no preset abnormality of this function until hypertension is present for some time, and (3) a depression of the pressure natriuretic function may aggravate hypertension in S rats once high blood pressure has persisted.
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PMID:Pressure natriuresis in isolated kidneys from hypertension-prone and hypertension-resistant rats (Dahl rats). 721 56

The SA gene was initially identified by differential hybridisation because of its higher expression in the kidney of the spontaneously hypertensive rat (SHR) compared with the normotensive Wistar-Kyoto rat. In subsequent studies, the allele of the SA gene from the SHR and several other genetically hypertensive strains was found to cosegregate with increased blood pressure in F2 progeny derived from crosses with normotensive rats. The increased expression of the SA gene in the kidney of the SHR occurs early, before the rapid rise in blood pressure in this model, is genotype-dependent and localised to the proximal tubule. Although the functions of its protein product remain to be elucidated, these findings raise the exciting possibilities that: (i) SA represents a major component of an important novel system regulating blood pressure, and (ii) it underlies a primary renal mechanism predisposing to hypertension.
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PMID:SA gene and hypertension. 747 35

The characterization and cloning of constitutive and inducible nitric oxide (NO)-synthesizing enzymes and the development of specific inhibitors of the L-arginine NO pathway have provided powerful tools to define the role of NO in renal physiology and pathophysiology. There is increasing evidence that endothelium-derived NO is tonically synthesized within the kidney and that NO plays a crucial role in the regulation of renal hemodynamics and excretory function. Bradykinin and acetylcholine induce renal vasodilation by increasing NO synthesis, which in turn leads to enhancement of diuresis and natriuresis. The blockade of basal NO synthesis has been shown to result in decreases of renal blood flow and sodium excretion. These effects are partly mediated by an interaction between NO and the renin angiotensin system. Intrarenal inhibition of NO synthesis leads to reduction of sodium excretory responses to changes in renal arterial pressure without an effect on renal autoregulation, suggesting that NO exerts a permissive or a mediatory role in pressure natriuresis. Nitric oxide released from the macula densa may modulate tubuloglomerular feedback response by affecting afferent arteriolar constriction. Nitric oxide produced in the proximal tubule possibly mediates the effects of angiotensin on tubular reabsorption. In the collecting duct, an NO-dependent inhibition of solute transport is suggested. The L-arginine NO pathway is also active in the glomerulus. Under pathologic conditions such as glomerulonephritis, NO generation is markedly enhanced due to the induction of NO synthase, which is mainly derived from infiltrating macrophages. An implication of NO in the mechanism of proteinuria, thrombosis mesangial proliferation, and leukocyte infiltration is considered. In summary, the data presented on NO and renal function have an obvious clinical implication. A role for NO in glomerular pathology has been established. Nitric oxide is the only vasodilator that closely corresponds to the characteristics of essential hypertension. Using chronic NO blockade, models of systemic hypertension will provide new insights into mechanisms of the development of high blood pressure.
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PMID:Nitric oxide in the kidney: synthesis, localization, and function. 751 25

Enhanced salt reabsorption by the kidney, which may arise from impaired regulation of proximal tubule Na(+)-K(+)-ATPase activity, has a central role in the pathogenesis of essential hypertension. Guanine nucleotide binding proteins (G proteins) are involved in many regulatory pathways and have been implicated in the regulation of proximal tubule Na(+)-K(+)-adenosinetriphosphatase (ATPase) activity. The present study was designed to evaluate further the regulation of Na(+)-K(+)-ATPase activity by G proteins in proximal tubule suspensions from Wistar-Kyoto rats (WKY) and to determine whether such regulation is abnormal in spontaneously hypertensive rats (SHR). Cholera toxin (CTX) inhibited Na(+)-K(+)-ATPase activity by approximately 40% in WKY but had no effect on Na(+)-K(+)-ATPase activity in SHR. In WKY, pretreatment of tubules with pertussis toxin (PTX), followed by the application of dopamine, inhibited Na(+)-K(+)-ATPase activity significantly, compared with the inhibition produced by dopamine alone. In SHR, dopamine alone did not inhibit Na(+)-K(+)-ATPase activity. However, in the presence of PTX, dopamine inhibited Na(+)-K(+)-ATPase activity significantly. These studies indicate that the renal proximal tubule Na(+)-K(+)-ATPase in WKY is regulated by both a PTX- and CTX-sensitive G protein(s) and that this regulation is abnormal in SHR. Such a defect could cause enhanced sodium reabsorption in SHR and contribute to the pathogenesis of hypertension in this model.
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PMID:Abnormal regulation of renal proximal tubule Na(+)-K(+)-ATPase by G proteins in spontaneously hypertensive rats. 781 Jun 94

Effects of benidipine on urine volume, excretion of electrolytes and renal hemodynamics were investigated in anesthetized spontaneously hypertensive rats (SHR). Benidipine at 3 and 10 micrograms/kg (i.v.) significantly increased urine volume, sodium (Na) and potassium (K) excretion with no change of creatinine clearance (CCRE). The increase in K excretion was relatively slight when compared with that in Na excretion. In another series of experiments, the tubular sites of action of benidipine were determined by the lithium clearance (CLi) technique and the stop-flow method. Benidipine at 3 micrograms/kg (i.v.) increased CLi, decreased creatinine concentration and increased Na concentration in the stop-flow urine from the distal nephron. These results suggest that benidipine produces diuresis and natriuresis by the inhibition of water and Na reabsorption at both the proximal tubule and the distal nephron. Benidipine increased p-aminohippuric acid clearance, but not CCRE, at doses of 3 and 10 micrograms/kg (i.v.), suggesting that benidipine dilates the glomerular efferent arteriole as well as the afferent arteriole. It is, therefore, expected that benidipine does not cause intraglomerular hypertension and has a beneficial effect in progressive renal disease.
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PMID:Effects of benidipine on renal function in anesthetized spontaneously hypertensive rats. 786 71

The study aimed at evaluating an excretion of beta 2-microglobulin with the urine of hypertensive patients. Thirty patients with mild-to-moderate hypertension (diastolic blood pressure 14.26 +/- 0.86 kPa) and 13 patients with severe hypertension (diastolic blood pressure 17.8 +/- 1.7 kPa) were included into the studies. Significantly increased beta 2-microglobulin excretion with the urine was noted in both groups with the highest values in patients with severe blood hypertension. Moreover, significant correlation between tubular reabsorption of beta 2-microglobulin and diastolic blood pressure was noted in both groups. Increased excretion of beta 2-microglobulin in the arterial hypertension may be due to an increased glomerular filtration of this protein and/or decreased reabsorption in proximal tubule.
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PMID:[Excretion of beta-2-microglobulin in hypertension]. 786 87

The sodium pump Na,K-ATPase, a heterodimer of an alpha catalytic subunit and a beta glycoprotein subunit, is regulated by a wide array of hormonal, autocrine, and paracrine factors. Both short-term acute adjustments of activity and long-term adjustments of sodium pump pool size are important determinants of cellular Na,K-ATPase activity. Phosphorylation and dephosphorylation are implicated in the acute regulation of activity. Although there is not yet any direct demonstration of phosphorylation in vivo, in vitro studies on purified enzyme directly demonstrate that phosphorylation decreases Na,K-ATPase activity. In addition, it is likely that phosphorylation of other proteins regulates sodium pump activity and cellular distribution. In regard to long-term regulation, recent demonstration of differential translatability of alpha and beta mRNAs and differential stability of newly synthesized alpha and beta subunits suggests that beta subunit is synthesized in excess over alpha subunit and that the excess is rapidly degraded. The isoform composition of alpha beta heterodimers has been shown to affect enzymatic properties, and tissue-specific heterodimer patterns are emerging from regulation studies. In regard to Na,K-ATPase and hypertension, there is continued interest in the significance of the uncoupling of dopamine inhibition of proximal tubule Na,K-ATPase activity in hypertensive rat strains. The uncoupling has been shown to be specific to the proximal tubule, which has been shown to express DA1 dopamine receptors, and both receptor and postreceptor defects are implicated. Questions remaining include how activation of dopamine receptors is coupled to decreased sodium transporter expression in the proximal tubule (short- and long-term regulation) in normotensive rats, the precise nature of the defect in hypertension, and whether a similar defect is observed in human hypertensive patients.
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PMID:Regulation of Na,K-ATPase activity. 792 15


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