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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to correlate the development of the renin angiotensin system (RAS) in the kidney of the rat with the development of genetic hypertension. Immature (1-week-old) and adult (12-week-old) normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive kidney rats (SHR) were used for quantification of angiotensin II (ANG II) receptors and angiotensin converting enzyme (ACE) binding sites using quantitative autoradiography. In both neonatal and adult animals of either strain, ANG II receptors were of AT1 subtype. In all kidney areas of 1-week-old rats. ANG II receptor density was higher in SHR than WKY. Binding density increased with age in WKY rats; thus, in the glomeruli and the outer stripe of the outer medulla of 12-week-old WKY, binding was significantly higher than that present in age-matched SHR. [125I]351A binding to ACE was highest in the outer medulla and not detectable in glomeruli. In 1-week-old rats, binding to ACE was higher in WKY than in SHR strain. No differences in ACE binding were found between adult SHR and WKY rats, with the exception of the inner stripe of the outer medulla, where no binding was detected in SHR. Our results support the hypothesis that the RAS in kidney is developmentally regulated and is involved in the development and maintenance of genetic hypertension in SHR.
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PMID:Kidney angiotensin II receptors and converting enzyme in neonatal and adult Wistar-Kyoto and spontaneously hypertensive rats. 771 70

In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.
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PMID:The renin-angiotensin system and vascular hypertrophy. 883 52

The aim of this study was to compare the effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II (AII) AT1-receptor blockade, and dihydropyridine calcium antagonism on hypertrophy and on vascular albumin permeability in kidney, heart, and mesenteric artery in a model combining genetic hypertension and diabetes mellitus. Diabetes mellitus was induced by streptozotocin in 8-week-old spontaneously hypertensive rats. The animals were randomized to receive no treatment, the angiotensin converting enzyme inhibitor ramipril, the AII AT1-receptor blocker valsartan, or the dihydropyridine calcium antagonist lacidipine for 3 weeks. Vascular albumin permeability was measured as the tissue content of intravenously injected Evans blue dye (EB) in kidney, heart, and mesenteric artery and the tissue/plasma EB ratio was calculated. Systolic blood pressure was reduced by all three antihypertensive regimens. Glycemic control was similar in all diabetic groups. Kidney hypertrophy was not affected by any of the antihypertensive drugs. Hypertrophy of the mesenteric artery was enhanced by lacidipine but was not affected by ramipril or valsartan. Relative heart weight was also increased by lacidipine. Vascular albumin permeability, expressed as EB content in micrograms/gram dry weight or as tissue/plasma EB ratio, was higher in the kidneys of lacidipine-treated rats than in any other group of diabetic rats. There was a positive correlation between kidney weight/body weight and kidney/plasma EB ratio in the diabetic rats. These findings indicate that the dihydropyridine calcium antagonist lacidipine is associated with an unfavorable effect on vascular hypertrophy and on vascular albumin permeability in the kidneys in rats with hypertension and diabetes mellitus. Furthermore, there seems to be a coupling in the diabetic kidney between hypertrophy and increased vascular albumin permeability.
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PMID:Vascular hypertrophy and albumin permeability in a rat model combining hypertension and diabetes mellitus. Effects of calcium antagonism, angiotensin converting enzyme inhibition, and angiotensin II-AT1-receptor blockade. 887 46

The purpose of the present study was to determine the role of endogenous angiotensin II in exaggerated tubuloglomerular feedback (TGF) in young euvolemic spontaneously hypertensive rats (SHR). TGF was characterized by measuring proximal tubular stop-flow pressure (Psf) responses to loop of Henle perfusion before and during losartan infusion in 7-wk-old SHR and Wistar-Kyoto rats (WKY). In the control period, TGF responses were exaggerated in SHR compared with WKY. This was evidenced by a larger flow-induced maximum decrease in Psf (19 vs. 13 mmHg), lower turning point (8 vs.12 nl/min), and higher reactivity (-6.4 vs. -3.0 mmHg.nl-1.min-1) in SHR. Losartan (DuP-753) was infused into the renal artery to antagonize angiotensin AT1 receptors in the experimental period. This was verified by losartan inhibiting > 90% of the decrease in whole kidney and superficial cortical blood flow produced by exogenous angiotensin II in both strains. Losartan infusion significantly attenuated TGF activity in SHR but not in WKY. In SHR losartan reduced the maximum Psf response (from 19 to 10 mmHg) and increased the turning point (from 8 to 11 nl/min). SHR values during losartan administration were similar to those obtained in WKY. WKY values were unaffected by losartan. The lack of change in maximum TGF responses after losartan treatment was not unique to WKY, inasmuch as similar results were obtained in euvolemic Munich-Wistar rats (-2.0 +/- 0.7 and -1.1 +/- 1.0 mmHg vs. -8.4 +/- 0.7 mmHg in SHR). Thus angiotensin II does not appear to play an essential role in basal TGF activity during euvolemia in normotensive animals when there is minimal stimulation of the renin-angiotensin system. In contrast, our observations indicate that the exaggerated TGF in young euvolemic SHR represents a functional resetting that is dependent on angiotensin II and losartan-sensitive AT1 receptors during the development of genetic hypertension.
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PMID:Exaggerated tubuloglomerular feedback activity in genetic hypertension is mediated by ANG II and AT1 receptors. 892 35

1. Recent evidence indicates that cardiac hypertrophy induced by pressure overload is associated with a decrease in sarcoplasmic reticulum (SR) Ca2+ -ATPase of myocytes, which may contribute to a diastolic dysfunction of the heart by causing intracellular Ca2+ overload. To elucidate whether or not this is also the case in genetic hypertension, we examined cardiac mRNA levels of SR Ca2+ ATPase in 11 week old spontaneously hypertensive rats (SHR) by northern blot analysis. 2. Furthermore, to test the effects of short-term inhibition of the renin-angiotensin system on its expression, we treated 10 week old SHR with angiotensin-converting enzyme inhibitors (alacepril and imidapril) or an AT1 receptor antagonist (SC-52458) for 7 days. 3. Though the left ventricular weight of SHR was significantly higher than that of Wistar-Kyoto (WKY) rats (277 +/- 6 vs 237 +/- 4 mg/100 g bodyweight, respectively, P < 0.05), the level of SR Ca2+ -ATPase mRNA showed no difference between SHR and WKY at this age. 4. Moreover, the aforementioned three drugs did not at all affect the SR Ca2+ -ATPase expression of SHR. 5. Thus, the expression of SR Ca2+ -ATPase was not down-regulated in the heart of 11 week old SHR, and seemed not to be mediated by angiotensin AT1 receptor at this age. Since some evidence on pressure-overloaded cardiac hypertrophy indicate that the decrease in SR Ca2+ -ATPase expression occur in prominent hypertrophy and in the failured heart, further studies on cardiac SR Ca2+ -ATPase expression in more aged SHR will be required.
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PMID:Expression of sarcoplasmic reticulum Ca2+ -ATPase mRNA in the hypertrophied heart of young spontaneously hypertensive rats. 907 67

The influence of chronic angiotensin AT1 receptor blockade by specific antibody on the development of genetic hypertension was studied in young spontaneously hypertensive rats (SHR). The immunization of 4-week-old SHR with a small part of the angiotensin AT1 receptor molecule attenuated the development of hypertension in these animals. After five subcutaneous injections of the antigen both systolic and diastolic blood pressures were significantly lower (p < 0.005) in immunized SHR compared to sham-immunized SHR. No effect on blood pressure was seen in immunized Wistar-Kyoto control rats. We conclude that renin-angiotensin system might be partially involved in the development of hypertension in young spontaneously hypertensive rats because it can be attenuated by a specific antibody raised against a part of the angiotensin AT1 receptor.
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PMID:Blockade of AT1 receptors by specific antibody attenuated hypertension development in young spontaneously hypertensive rats. 908 80

The structure and function of small arteries of different vascular beds in spontaneously hypertensive rats (SHRs) are altered relative to Wistar-Kyoto (WKY) control rats, and these differences may be blunted under treatment with angiotensin-converting enzyme inhibitors. To determine whether this effect of angiotensin-converting enzyme inhibitors was caused by the interruption of the renin-angiotensin system, our experiments were conducted with an AT1 angiotensin-receptor antagonist to evaluate its ability to induce regression of hypertrophy of resistance arteries in SHRs. The result of treatment of SHRs with losartan, an orally active selective angiotensin AT1 receptor antagonist was examined at a low (20 mg/kg/day) and a high (60 mg/kg/day) oral dose in SHRs once blood pressure had been elevated for some time. SHRs were treated for 12 weeks with losartan. Blood pressure was significantly reduced by losartan treatment from 210 +/- 2 mm Hg in untreated SHRs to 181 +/- 1 mm Hg (low dose) and 156 +/- 4 mm Hg (high dose) (p < 0.01). Cardiac and aortic hypertrophy were dose-dependently reduced in treated SHRs. Coronary, renal, mesenteric, and femoral small arteries (luminal diameter, 200-250 microm) studied on an isometric wire myograph and pressurized mesenteric small arteries examined under isobaric conditions exhibited significant hypertrophy and inward remodeling in SHRs in comparison to WKY rats. Losartan treatment resulted in a dose-dependent reduction in the media thickness and mediato-lumen ratio in small arteries from the four vascular beds studied on the wire myograph and in pressurized mesenteric small arteries. Endothelium-dependent relaxation studied in pressurized arteries was enhanced, and acetylcholine-induced endothelium-dependent contractions studied on the wire myograph were abolished in losartan-treated SHRs relative to untreated SHRs. In WKY rats, treatment had no effect. These results demonstrate that treatment with the selective angiotensin II receptor antagonist losartan, even at doses that reduce blood pressure only moderately, induces regression of cardiovascular hypertrophy and of endothelial dysfunction in genetic hypertension in the rat.
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PMID:Effect of AT1 angiotensin-receptor blockade on structure and function of small arteries in SHR. 926 24

Angiotensin-converting enzyme (ACE) inhibition alone or in combination with the angiotensin type-I receptor (AT1) antagonist losartan augments circulating levels of the bioactive peptide angiotensin-(1-7) [Ang-(1-7)]. Hence, we determined whether Ang-(1-7) contributes to the hypotensive effects produced by the combined administration of lisinopril and losartan in spontaneously hypertensive rats by blocking the peptide's synthesis with either of two structurally different neprilysin inhibitors. Intravenous administration of CGS 24592 (30 mg/kg) to rats in which blood pressure was normalized by 9 days of therapy with lisinopril and losartan elicited an elevation of mean arterial pressure that was sustained throughout the infusion period and for 20 minutes thereafter. The hypertensive response was associated with a 62% reduction in circulating levels of Ang-(1-7) and no change in plasma angiotensin II (Ang II). Intravenous infusion of one other neprilysin inhibitor (SCH 39370, 30 mg/kg) produced an increase in mean blood pressure of a magnitude similar to that found with CGS 24592. Pretreatment with the nonselective antagonist [Sar1,Thr8]-Ang II abolished any additional pressor effects of either neprilysin inhibitor in spontaneously hypertensive rats treated with lisinopril or losartan. However, neither the endothelin A antagonist BQ123 nor the kinin B2 antagonist HOE 140 had an effect on basal blood pressure or altered the pressor or heart rate effects of the neprilysin inhibitors. These data suggest that inhibition of Ang-(1-7) formation in rats exposed to the combined blockade of Ang II production and activity is associated with a reversal of the antihypertensive actions produced by these therapies. Thus, endogenous Ang-(1-7) functions as a vasodilator hormone in this form of genetic hypertension.
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PMID:Angiotensin-(1-7) contributes to the antihypertensive effects of blockade of the renin-angiotensin system. 945 28

Low-voltage-activated T-type Ca2+ channels are present in most excitable tissues including the heart (mainly pacemaker cells), smooth muscle, central and peripheral nervous systems, and endocrine tissues, but also in non-excitable cells, such as osteoblasts, fibroblasts, glial cells, etc. Although they comprise a slightly heterogeneous population, these channels share many defining characteristics: small conductance (< 10 pS), similar Ca2+ and Ba2+ permeabilities, slow deactivation, and a voltage-dependent inactivation rate. In addition, activation at low voltages, rapid inactivation, and blockade by Ni2+ are classical properties of T-type Ca2+ channels, which are less specific. T-type Ca2+ channels are weakly blocked by standard Ca2+ antagonists. Pharmacological blockers are scarce and often lack specificity and/or potency. The physiological modulation of T-type Ca2+ currents is complex: they are enhanced by endothelin-1, angiotensin II (AT1-receptor), ATP, and isoproterenol (cAMP-independent), but are reduced by angiotensin II (AT2-receptor), somatostatin and atrial natriuretic peptide. Norepinephrine enhances these currents in some cells but decreases them in others. T-type Ca2+ currents have many known or suggested physiological and pathophysiological roles in growth (protein synthesis, cell differentiation, and proliferation), neuronal firing regulation, some aspects of genetic hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac rhythm (normal and abnormal), and atherosclerosis. Mibefradil is a new Ca2+ antagonist that is effective in hypertension and angina pectoris. Its favorable pharmacological profile and limited side effects appear to be related to selective block of T-type Ca2+ channels: mibefradil reduces vascular resistance and heart rate without negative inotropy or neurohormonal stimulation, and it also has significant antiproliferative actions.
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PMID:T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. 951 67

Angiotensin II is vasoconstrictor and antinatriuretic; it also stimulates cell growth and proliferation in vascular smooth muscle, resulting in hypertrophy or hyperplasia of conduit and resistance vessels. These actions are mediated through angiotensin II receptors (AT1 subtype), which activate several G-protein-dependent intracellular transduction pathways, such as the phospholipase C, diacylglycerol and inositol trisphosphate the mitogen-activated protein (MAP) kinase pathway, and Janus kinase (JAK)-signal transducers and activators of the transcription (STAT)-mediated pathway. These can all increase the expression of certain proto-oncogenes, particularly c-fos. Angiotensin II also stimulates the activity of certain growth factors, such as platelet-derived growth factor-A-chain and basic fibroblast growth factor. The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy), or DNA synthesis with cell division (hyperplasia). In genetic hypertension, there is either cellular hyperplasia or remodeling, whereas in renovascular hypertension, there is hypertrophy of vascular smooth muscle cells. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries and increase arterial compliance. These properties are also shared by AT1 receptor antagonists. The implications of these findings for morbidity and mortality in hypertension still await rigorous testing in prospective clinical trials.
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PMID:Vascular hypertrophy in hypertension: role of the renin-angiotensin system. 952 May 14


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