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

We investigated the release of endothelin-1 (ET) from rat mesenteric arteries to clarify its pathophysiological role in the sustained hypertension of spontaneously hypertensive rats (SHR) following nephrectomy and the regulatory mechanism of the ET release which might be modified by vascular angiotensins and bradykinins. Nephrectomy increased the plasma level of ET and enhanced the ET release in both SHR and Wistar-Kyoto rats (WKY). CV-11974, an angiotensin II receptor antagonist, did not affect the ET release from arteries of nephrectomized rats. On the contrary, infusion of captopril, a converting enzyme inhibitor, further enhanced the ET release in both intact and nephrectomized rats. These findings suggest that the release of ET from mesenteric arteries may be regulated by bradykinins, but not by angiotensins. This pressor substance does not contribute to the sustained hypertension because the enhanced production of ET observed in both SHR and WKY. However, there is a possibility that the exaggerated responsiveness of vascular ET may in part account for local vascular tone and vascular remodeling in renal dysfunction.
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PMID:Augmentation by converting enzyme inhibition of accelerated endothelin release from rat mesenteric arteries following nephrectomy. 803 18

Angiotensin II receptor binding sites in type 1 interstitial cells in the inner stripe of the outer medulla are readily labeled in vitro by the radioligand but not in vivo after systemic radioligand administration. In anesthetized rats, we investigated if reduced vascular delivery due to angiotensin II-induced renal vasoconstriction or, alternatively, prior occupancy of these sites by endogenous angiotensins modulates angiotensin II subtype 1 receptor binding to renal medullary interstitial cells in vivo using electron microscopic autoradiography. Using 125I-angiotensin II, administered systemically, as a radioligand, binding in control rats occurred predominantly in the glomeruli and proximal tubules, while only low binding was observed in the inner stripe of the outer medulla. Pretreatment of rats with unlabeled [Sar1,Ile8]angiotensin II or with the angiotensin II subtype 1 receptor antagonist losartan before receiving the radioligand completely abolished binding to all sites. Renal vasodilatation induced by sodium nitroprusside or use of the radiolabeled antagonist analogue 125I-[Sar1,Ile8]angiotensin II did not alter binding to the inner stripe. In contrast, chronic salt loading or inhibition of angiotensin-converting enzyme by perindopril significantly increased binding not only to the cortical sites but also to the sites in the inner stripe of the outer medulla. Electron microscopic autoradiographs of the inner stripe detected binding in the interstitial cells only in rats treated with chronic salt loading or perindopril. These results suggest that endogenous angiotensins may modulate binding of circulating angiotensin II to the interstitial cells in vivo, and these angiotensin II receptor-bearing cells are more likely to be more responsive to interstitial angiotensin II than to the circulating hormone.
Hypertension 1994 Jun
PMID:In vivo occupancy of angiotensin II subtype 1 receptors in rat renal medullary interstitial cells. 820 14

The aim of this study was to determine whether angiotensin receptor subtypes play a role in angiotensin clearance from plasma. Angiotensin metabolic clearance rate was measured in rats by the constant infusion method. Increasing doses of angiotensin II were infused for 15 minutes, and blood was sampled for angiotensin II. The type 1 angiotensin II receptor antagonist losartan decreased the apparent metabolic clearance rate by > 50% at low-dose infusion, suggesting that type 1 angiotensin II receptors are involved in angiotensin II clearance from plasma. At higher angiotensin infusion rates, the-metabolic clearance rate of angiotensin was unaffected. To dissect the contribution of renin-generated angiotensin, additional experiments were performed in nephrectomized rats. In anephric rats, angiotensin clearance was unaffected by type 1 angiotensin II receptor inhibition. In contrast, the type 2 angiotensin II receptor ligand PD123319 in intact rats caused a > 50% increase in metabolic clearance rate of angiotensin at higher infusion rates (P < .05). In anephric rats, the type 2 angiotensin II receptor ligand alone or combined with type 1 receptor inhibition was without effect on the metabolic clearance rate or the T1/2 for angiotensin disappearance. These data argue against a role for type 1 or 2 angiotensin II receptors as clearance receptors. Increased clearance of angiotensin by type 2 receptor blockade in the presence but not the absence of kidneys suggests an alternative renal mechanism by which selective type 2 ligands may alter angiotensin effects.
Hypertension 1994 Jun
PMID:Effects of angiotensin receptor subtype inhibitors on plasma angiotensin clearance. 820 17

The renin-angiotensin system is considered to be one of the most important hormonal systems in the regulation of blood pressure and body fluid homeostasis. Ever since this system has been demonstrated to be present also in the brain, vast efforts have been made in investigating its central impact and function. The last few years, and especially the development of non-peptidic angiotensin II receptor subtype specific antagonists and the subsequent pharmacological characterization of these subtypes, brought this field of research a large step forward. This progress also might have opened up new avenues of developing highly specific anti-hypertensive drugs and thereby new ways of treating hypertension. This paper intends to provide a summary of the knowledge about the brain renin-angiotensin system accumulated during recent years; an update 1993.
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PMID:The renin-angiotensin system in the brain: an update 1993. 821 May 9

The 'angiotensin system' is expressed at the whole body, organ/tissue and cellular levels through the action of angiotensin II at specific receptors. An appreciation of the full scope of the actions of angiotensin II (endocrine, paracrine and autocrine) has been made possible by the discovery of the non-peptide angiotensin II receptor antagonists, losartan (DuP 753/MK954)(AT1-selective) and PD123177 (AT2-selective). Virtually all of the known effects of angiotensin II are blocked by losartan and designated AT1. Selective AT1 receptor blockade with losartan lowers BP in angiotensin II-dependent models of hypertension, reduces cardiac hypertrophy, improves haemodynamics in models of cardiac failure and reduces the intimal response to vascular injury. AT2 sites have been localised in distinct parts of the brain and in foetal tissue. The functional role of the AT2 sites remains controversial, but possible roles in neuronal ion channel function and collagen metabolism in fibroblasts have been reported. AT1 (losartan-sensitive) receptor subtypes have now been cloned from several rat tissues, suggesting that selective agents of the future may be even more specifically targeted. New perspectives in the control of the angiotensin system continue to evolve rapidly as the new receptor antagonists and molecular biology techniques expand our understanding of angiotensin II.
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PMID:New perspectives in angiotensin system control. 823 85

We investigated the acute and chronic effects of converting enzyme inhibitors (captopril or enalapril) and of angiotensin II receptor blockade (DuP 753) on rapid (30-minute) baroreceptor resetting elicited by a prompt and sustained hypertensive response provoked by aortic constriction. Pressure-nerve activity curves, pressure at 50% of maximal baroreceptor activity, baroreceptor gain (slope of the curve), and systolic threshold pressure for baroreceptor activation were determined as indexes of baroreceptor function. A slight fall in mean arterial pressure after acute treatment with the converting enzyme inhibitor or DuP 753 was accompanied by a partial leftward curve shift, which is associated with a partial threshold shift and increase in gain. A maintained hypertensive stimulus caused a partial rightward curve shift and partial (49% to 56%) threshold shift to hypertensive levels in both acutely treated and control rats. The hypertensive stimulus provoked a partial rightward curve shift and complete (88% to 94%) threshold shift to hypertensive levels in chronically treated rats. The effect of enalapril on baroreceptor function was unaltered by the bradykinin antagonist Hoe 140. These data demonstrate that chronic inhibition of converting enzyme or blockade of angiotensin II receptors facilitates rapid resetting of the baroreceptors to hypertensive levels caused by partial aortic constriction without a change in baroreceptor sensitivity.
Hypertension 1994 Jan
PMID:Chronic converting enzyme inhibition facilitates baroreceptor resetting to hypertensive levels. 828 78

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1993 Sep
PMID:Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects. 834 27

Systemic inhibition of endothelium-derived relaxing factor (EDRF) synthesis leads to acute hypertension and increased peripheral vascular resistance. The changes in vascular resistance are not evenly distributed to all vascular beds. In this study, we compared the renal and femoral hemodynamic responses to EDRF synthesis inhibition. Renal blood flow (RBF) and femoral blood flow (FBF) were assessed in the presence and absence of DuP 753, an angiotensin II receptor antagonist. Inhibition of EDRF synthesis by a bolus dose of Lw-nitroarginine methyl ester (L-NAME) increased blood pressure (BP) by 21 +/- 1 mm Hg (p < 0.001) and decreased RBF by 32 +/- 5% (from 5.9 +/- 0.5 to 3.9 +/- 0.3 ml/min/g kidney weight; p < 0.005) while FBF remained unchanged (9.5 +/- 0.4 versus 9.4 +/- 0.4 ml/min). Renal vascular resistance (RVR) increased by 83 +/- 16% (p < 0.001), compared with only a 24 +/- 6% increase in femoral vascular resistance (FVR; p < 0.005). To eliminate the influence of systemic hypertension, we returned organ perfusion pressure to pre-L-NAME levels by partial aortic constriction. The kidney maintained RBF by decreasing RVR by 8 +/- 2% (p < 0.02), while FBF decreased by 15 +/- 5% (p < 0.01). When rats were pretreated with DuP 753, L-NAME still increased BP by 22 +/- 2 mm Hg, but RVR increased by only 26 +/- 5% (from 13.2 +/- 1.6 to 16.8 +/- 2.7; p < 0.01) and RBF did not change. DuP 753 had no effect on the femoral vascular response to L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal versus femoral hemodynamic response to endothelium-derived relaxing factor synthesis inhibition. 835 52

Drug induced modification of the renin-angiotensin system is of established benefit in the treatment of hypertension and heart failure. The responses to the angiotensin converting enzyme (ACE) inhibitor enalapril (CAS 75847-73-3) have been studied in essential hypertension and normotensive controls. The kinetics and dynamics of enalapril have been characterised in an integrated concentration-effect model to identify factors underlying responsiveness to the ACE inhibitor. In addition models to predict the response to long-term treatment from changes after the first dose have been developed. Enalapril response could be described by a non linear (Emax) model defined by two parameters - the maximum response (Emax) and the drug concentration required to cause 50% of the maximum response (C50). Acute dosing accurately predicted the Emax after 6 weeks treatment. In addition to individual pharmacokinetics, pretreatment blood pressure was the most important determinant of response to enalapril. In caucasian salt-replete essential hypertension neither age nor plasma renin activity were major factors. However, in states of sodium restriction and/or diuretic treatment, the response to enalapril was greatly increased. The angiotensin II receptor antagonist, losartan has been reported to be without effect on blood pressure in salt-replete normals. Salt restriction together with furosemide for 3 days led to dose-related falls in blood pressure in normal subjects after losartan 25-100 mg. Concentration-effect analysis can be used to describe blood pressure responses, to predict the responses to long-term treatment and also to identify quantitatively important factors determining the response in individual patients.
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PMID:Inhibitors of the renin-angiotensin system. Clinical pharmacology studies on kinetics, dynamics and concentration-effect relationships. 849 75

Inhibition of the renin-angiotensin system with angiotensin-converting enzyme inhibitors is well established as a treatment modality for hypertension and congestive heart failure. While converting enzyme inhibitors are well tolerated, they still have some side effects, which rightly or wrongly are attributed to the lack of specificity of the target enzyme for the renin-angiotensin cascade. The attempt is therefore made to inhibit the more specific enzyme renin or to block the angiotensin II receptor. While so far renin inhibitors are generally hampered by insufficient oral bioavailability, potent orally active angiotensin II antagonists are currently in clinical development. Both pharmacologic principles, renin inhibition and angiotensin II antagonism, have been shown to actively reduce blood pressure of hypertensive patients. It remains to be seen whether these newer compounds will be able to replace the converting enzyme inhibitors and exhibit even fewer untoward effects.
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PMID:Inhibitors of the renin-angiotensin system. 849 78


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