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

We have previously demonstrated that loss of renal functional reserve (renal response to protein loading) in two-kidney, one clip Goldblatt hypertension is characterized by no change in glomerular filtration rate or single nephron glomerular filtration rate and decreased absolute proximal tubular reabsorption during glycine administration. Captopril restores proximal reabsorption and renal functional reserve in this condition. Because captopril suppresses angiotensin II generation and increases bradykinin, prostaglandins, and potentially nitric oxide, we have investigated the role of angiotensin II blockade in restoring proximal reabsorption and renal functional reserve by comparing captopril with DuP 753, an angiotensin II receptor antagonist, in Goldblatt rats. One month after clipping, two period micropuncture studies (control and glycine) were performed on the unclipped kidney. Normal rats and three groups of clipped rats were studied: an untreated group (HYP), a group treated with captopril (CEI), and a group treated with DuP 753 (DuP) 5 days before micropuncture. Glycine increased glomerular filtration rate, nephron plasma flow, and single nephron glomerular filtration rate in normal rats. Systemic and glomerular hypertension in HYP rats was associated with loss of renal functional reserve and a decrease in absolute proximal reabsorption during glycine. Captopril and DuP 753 normalized systemic and glomerular capillary pressure and prevented the decrease in proximal reabsorption during glycine; however, only CEI rats increased single nephron glomerular filtration rate and glomerular filtration rate after glycine. In conclusion, abnormal responses of both glomerular and tubular function are responsible for the loss of renal functional reserve in Goldblatt rats. Inhibitory angiotensin II activity is responsible for decreasing proximal reabsorption during glycine; however, factors other than angiotensin II limit the glomerular response to glycine.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 Jun
PMID:Angiotensin II and renal functional reserve in rats with Goldblatt hypertension. 159 82

The pathogenesis of hypertensive glomerular injury is complex, involving both hemodynamic and nonhemodynamic factors. One can therefore confidently predict that a wide variety of disparate therapeutic interventions, pharmacologic and nonpharmacologic, may be effective in arresting or slowing progressive glomerular injury. Based on the experimental and clinical literature available to date, it is clear that glomerular capillary hypertension is an important pathogenetic factor in this disease and that lowering of Pgc with antihypertensive drugs is associated with prevention of glomerular injury. Furthermore, the CEI may have a special renoprotective effect compared to other antihypertensive agents, most likely due to their unique renal hemodynamic actions. Pending the results of well-designed clinical trials, converting enzyme inhibitors represent the antihypertensive agents most likely to arrest the progressive decline in renal function observed in patients with hypertension and chronic renal failure. The calcium channel blockers are effective antihypertensive agents in patients with chronic renal failure, but whether they confer specific renoprotective effects remains uncertain. Since a large number of patients with chronic renal failure require more than one antihypertensive drug for adequate blood pressure control it may be of interest to evaluate the benefits of drug combinations. In this regard, it is possible that a combination of a CEI and a CCB may have complimentary effects in protecting the kidney. The development of these new classes of antihypertensive agents has had a major impact on the treatment of patients with chronic progressive renal failure. Future studies will hopefully clarify the optimal antihypertensive therapeutic regimen and allow us to move closer to the goal of eliminating end-stage renal failure.
 ...
PMID:Antihypertensive therapy and the progression of chronic renal disease. Are there renoprotective drugs? 174 81

Renal functional reserve (renal response to protein loading, RFR) has been suggested as a method to verify the presence of hyperfiltration. This study was designed to evaluate the role of RFR as an indicator of increased glomerular capillary hydrostatic pressure in short-term treated and untreated rats with two-kidney, one-clip Goldblatt hypertension. One month after placing a silver clip, micropuncture studies were performed on the unclipped kidney. Normal rats and three groups of clipped rats [untreated group (HYP), a group treated with captopril (CEI) and a group treated with verapamil (VER) 5 days before the micropuncture studies] were studied. Glomerular hemodynamics and proximal tubular reabsorption were measured in control period and during intravenous administration of glycine (G). In normal rats, G produced afferent and efferent dilation, increases in single nephron plasma flow (SNPF) and single nephron glomerular filtration rate (SNGFR) of 24%. Systemic hypertension in HYP rats was associated with increases in transcapillary pressure gradient (delta P) and SNGFR. In this hyperfiltration state, infusion of G did not modify SNGFR of SNPF defining loss of RFR. The antihypertensive treatment was equally effective in normalizing MAP and delta P in CEI and VER, but only CEI rats responded to G with a 20% increase in SNGFR due to an increase in delta P. The most striking findings were that loss of RFR in both HYP and VER rats was associated with a significant decrease in absolute and proximal fractional reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Renal functional reserve in treated and untreated hypertensive rats. 178 41

Relative 125I-albumin concentration was measured in vivo in the aortic media of sham-operated (n = 10) and hypertensive (two-kidney, one clip) rats, untreated (n = 8) or treated (n = 10) by an angiotensin converting enzyme inhibitor (CEI, Trandolapril). Blood pressure was acutely lowered to a normal level at the time of the experiment in hypertensive rats (n = 7) to separate the direct effect of increased pressure from the effect of pressure-induced structural changes. Relative tissue concentration profiles of labeled albumin across the media were obtained using a serial frozen-sectioning technique. In hypertensive rats, the mean medial albumin concentration decreased by 35% in the ascending arch and 32% in the descending arch (p less than 0.01). When blood pressure was acutely lowered in hypertensive animals, this value decreased further by 56% in the ascending arch, 48% in the descending arch (p less than 0.01), and 22% in the thoracic aorta (p less than 0.05) as compared with controls. The medial thickness in hypertensive rats was significantly increased (more in the ascending arch than in the rest of the aorta). Four-week CEI treatment reversed hypertension and medial thickening, but the mean medial albumin concentration remained significantly lower in the arch (by 36% in the ascending part and 40% in the descending part, p less than 0.01). The collagen content in the thoracic aorta was significantly increased in hypertensive rats (by 40%, p less than 0.01) and remained increased (by 29%, p less than 0.01) after CEI treatment. These results suggested that the hypertension-induced structural changes might reduce the medial distribution volume for albumin, whereas elevated blood pressure per se tended to enhance albumin concentration within the media. However, the net result of chronic hypertension was a reduction of the mean medial albumin concentration. The aortic arch appeared to be more affected than the rest of the aorta. Fiber content, more than medial thickness, might be responsible for the observed differences in albumin concentration. Lowering of blood pressure seemed to be insufficient to restore normal albumin concentration profiles and perhaps those of other macromolecules. This finding may be relevant in evaluating some of the complications associated with hypertension.
 ...
PMID:Reduction of transmural 125I-albumin concentration in rat aortic media by chronic hypertension. 199 51

The multicentre ramipril trial was original in that the CEI was tested at its lowest effective dosage level. More than 80 p. 100 of the patients responded to a single-drug treatment with ramipril 5 mg per day or less. At that dosage level the drug was well tolerated and no severe or serious side-effect was noted. A relation could be demonstrated between the prevalence of cough and the dose of ramipril. The trial was carried out in a population of ambulatory patients with moderate, uncomplicated arterial hypertension (DAP between 95 and 115 mmHg and SAP less than or equal to 200 mmHg). It was conducted according to the "Good Clinical Practice" rules by 102 general practitioners, under their usual conditions of work, and this provided them with experience for further clinical studies of hypertension and with education for the managements of that disease in private practice.
 ...
PMID:[The French ambulatory multicenter trial of Triatec: conclusions of the trial]. 214 99

Antihyertensive drugs are non of the preventive measures aimed at reducing cardiovascular mortality and morbidity. Seen from that angle, their blood pressure lowering effect is necessary but insufficient. Diuretics and beta-blockers prescribed as first-line treatment of moderate arterial hypertension have only partly fulfilled these requirements: they have significantly reduced the incidence of cerebral vascular accidents but have been unable to lower the incidence of coronary disease which is the main cause of death in hypertensive subjects. Because of this failure, the objectives of antihypertensive treatments had to be revised as follows. The first objective is to ensure a satisfactory control of blood pressure with good compliance, which means that the drugs must be well tolerated and easy to take regularly. The second objective os to reduce the rhythmic and metabolic factors of coronary disease. The third objective is to reverse left ventricular hypertrophy and vascular wall hypertrophy. CEI are as effective as diuretics or beta-blockers in controlling blood pressure, but they are better tolerated from the clinical, metabolic and rhythmic points of view and they act effectively on ventricular and vascular hypertrophy. Following this assessment, although CEI have not proved efficient as regards cardiovascular prevention, in 1988 the WHO authorities have decided that they should be used as first-line treatment in moderate arterial hypertension.
 ...
PMID:[The role of converting enzyme inhibitor in the treatment of arterial hypertension]. 214

To assess the renin-angiotensin (RA) dependence of evolving neonatally induced coarctation hypertension (NICH) in inbred pups, we randomized sex-matched littermates to a high dose of converting-enzyme inhibitor (CEI:MK-421) or placebo from the time of neonatal aortic banding (coarcted) vs. no banding (control). In phase 1 studies, pups were examined serially on normal diet (Bagby and Fuchs, Hypertension In press.): chronic CEI lowered systolic blood pressure (BP) equally in coarcted and controls and failed to prevent systolic BP excess in coarcted dogs. In phase 2 studies, the same pups were exposed to a low sodium (LS) diet at 4 mo of age, a time when the untreated NICH model exhibits increased forelimb systolic BP. Measurements of systolic BP, RA components, renal function, and extracellular volume (ECV) were made before and serially during 12 days on the LS diet. Responses of coarcted and control pups to the LS diet were similar, with or without CEI, providing no evidence for exaggerated angiotensin II (ANG II) dependence in evolving NICH. Independently of coarctation status, chronic CEI significantly modified RA and renal functional responses to the LS diet: a greater renin rise but abnormal renin substrate fall, thus no rise in ANG I or ANG I generation rate; a greater rise in creatinine and a trend toward a greater fall in glomerular filtration rate (GFR). Despite these findings compatible with sustained ANG II deficit, chronic CEI unexpectedly failed to impair maintenance of systolic BP during a superimposed LS diet.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Chronic CEI alters effect of low Na+ diet in normal and coarcted pups. I. BP, renin, and GFR. 253 42

To assess angiotensin (ANG II) dependence of evolving neonatally induced coarctation hypertension (NICH) in inbred pups, we randomized sex-matched littermates to high-dose converting enzyme inhibitor (CEI: MK-421, 3 mg/kg) or placebo from the time of neonatal aortic banding (coarcted) vs. no banding (control). During phase 1 studies over 4 mo postbanding during ad libitum Na+ intake (Bagby and Fuchs, Hypertension Dallas in press). CEI failed to prevent evolution of proximal blood pressure (BP) excess or to impair renal function. Phase 2 studies examine, in the same pups, responses to low Na+ (LS) diet superimposed on chronic CEI at 4 mo, timed to allow development of BP increase in untreated NICH. The present report details metabolic handling and balances of Na+, K+, and fluid for 3 days before (normal Na+ intake) and daily for 11 days after initiation of LS diet, a companion paper describes BP, renin-angiotensin (RA), and renal functional responses. In no case did metabolic responses of coarcted pups to LS diet differ from those of controls, whether on CEI or placebo, whereas responses to LS diet and to CEI reveal positive findings of independent interest. LS diet induced expected renal and fecal Na+ conservation, no net effect on K+ balance, and, despite unexpected free-water diuresis, mild hyponatremia. Chronic CEI impaired maximal renal (but not fecal) Na+ conservation during LS diet, caused exaggerated free-water diuresis but no change in fluid balance, and thus, with the larger Na+ deficit, accounted for greater hyponatremia. CEI caused no net effect on K+ balance. Results indicate normal renal handling of fluid, Na+, and K+ in evolving NICH and provide no evidence for selective intrarenal RA activation or exaggerated ANG II dependence. Findings also suggest that, during LS diet, ANG II is 1) essential for maximum renal Na+ conservation and normal free-water handling, and 2) not essential for fecal Na+ and water conservation or for maintenance of normal water and K+ balances. Results are also compatible with a CEI-induced thirst stimulation and/or osmotic insensitivity and with functional vasopressin deficiency during LS diet.
 ...
PMID:Chronic CEI alters effect of low Na+ diet in normal and coarcted pups. II. Na+ and H2O balance. 253 43

In order to investigate the cardiac effects of antihypertensive therapies in one-clip two-kidney hypertension in rats, we compared the consequences on myosin isoenzyme profile and on left ventricular hypertrophy of two treatments: one was a new converting enzyme inhibitor (S9490), the second a more standard tripletherapy associating clonidine, dihydralazine and furosemide. The two treatments were initiated 4 weeks after clipping and administered during 5 weeks. During the treatment period average systolic blood pressure was 215 +/- 32 mmHg in the hypertensive untreated group (HC2, n = 12) and 144 +/- 13 mm Hg in the CEI group (HT1, n = 13), which is not significantly different from the value found in the sham-operated group (139 +/- 4 mm Hg, C2, n = 13). Blood pressure was lowered only to 173 +/- 18 mm Hg in the group treated with tripletherapy (HT2, n = 12). The left ventricular weight decreased significantly in the CEI-treated group toward values similar to those of the sham-operated animals (2.2 +/- 0.13 mg/g vs. 1.9 +/- 10 mg/g, respectively NS), whereas it did not change in the tripletherapy group when compared to the untreated hypertensive animals despite the fall in blood pressure. In the hypertensive untreated rats the percentage of V1 isoenzyme of cardiac myosin was lower than in the sham-operated group (42.8 +/- 9.0% vs. 57.5 +/- 7.6% P less than .001). In parallel the V3 form of cardiac myosin increased (24.1 +/- 7.4% vs. 15.7 +/- 4.3%, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effect of antihypertensive treatment on the left ventricular isomyosin profile in one-clip, two kidney hypertensive rats. 293 25

Long considered a single clinical entity, essential hypertension is now recognized as a heterogeneous spectrum of pathophysiologic disturbances, based on extensive clinical, pharmacologic and biochemical evidence. Two distinctly different mechanisms for long-term vasoconstriction can be identified and quantified in the spectrum of patients with essential hypertension, although the causes of this group of disorders are still obscure. The first vasoconstrictor mechanism is renin-angiotensin mediated and involves an increase in vascular smooth muscle cytosolic free calcium mobilized from intracellular sites. The degree of activity of this mechanism can be assessed by plasma renin level and/or by the hypotensive response to circulating anti-renin-system drugs (such as CEI inhibitors and beta blockers). The second vasoconstrictor mechanism, on the other hand, is renin-independent. It appears to require antecedent renal sodium retention and to be related to abnormal membrane influx of calcium. A low plasma renin level identifies this kind of vasoconstriction, which is also characterized by a low serum ionized calcium. Low-renin vasoconstriction is correctable by sodium depletion or by calcium channel or alpha adrenergic blockade. Depending on the state of sodium balance, these two vasoconstrictor mechanisms contribute reciprocally to maintenance of arteriolar tone in models of experimental hypertension, normotensive and hypertensive people, and in the vasoconstriction of edematous states, such as congestive heart failure. One of the two mechanisms also sustains diastolic hypertension in the experimental and clinical forms of renovascular hypertension and primary aldosteronism. Thus, both experimentally and clinically, at the polar extremes of the range of plasma renin values, one of the two mechanisms predominates: it is possible that, in the medium range of renin values, both mechanisms contribute to vasoconstriction. In our proposed unifying, analytic model, arteriolar vasoconstriction is associated with increased intracellular calcium and decreased magnesium levels in vascular smooth muscle. In the vasoconstriction consequent to sodium-volume expansion, cytosolic calcium is increased by an increased membrane influx. In renin-mediated vasoconstriction, receptor-operated channels mobilize cytosolic calcium instead from intracellular stores. These interrelationships provide a basis for stratifying hypertensive patients pathophysiologically and for applying simpler, more specific, and more rational therapies. Thus, the array of modern pharmacologic agents can often be rationally directed at one or the other, or both, of these two vasoconstrictor mechanisms.
 ...
PMID:Recognizing and treating two types of long-term vasoconstriction in hypertension. 305 33


1 2 3 Next >>