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

Obese spontaneously hypertensive rats (SHR) develop nephropathy with severe proteinuria, but lean littermates do not develop renal disease. Intrarenal angiotensin has been suggested to contribute to nephropathy in other experimental models. We examined the regulation of angiotensin receptors as a reflection of target tissue response to possible changes in the renin-angiotensin system. We visualized angiotensin receptors in kidneys of 6-8-month-old obese SHR and their lean littermates. Both obese and lean rats were hypertensive as determined by tail-cuff or by direct measurement. Histologic studies showed early glomerular sclerosis in obese but not lean rats. Autoradiographic visualization of angiotensin receptor binding sites in both obese and lean SHR showed glomeruli and medullary rays having the highest levels of binding with additional diffuse labeling in cortex and outer medulla. In obese rats, binding was reduced relative to lean littermates, particularly in the medulla, while intense binding in glomeruli was preserved. Loss of receptors did not reflect tissue damage, since the medulla showed no pathological changes. Biochemical assays of the binding of subtype-selective antagonists to 125I-angiotensin sites in intact sections showed that both losartan-sensitive and PD 123319-sensitive sites were decreased in nephrotic obese rats. We conclude that specific binding sites for angiotensin are decreased in obese SHR with early glomerular sclerosis, suggesting that angiotensin receptors may be regulated by pathogenic processes in this model of renal disease.
Hypertension 1993 Jun
PMID:Renal angiotensin receptor mapping in obese spontaneously hypertensive rats. 850 89

Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2 at 37 degrees C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73 +/- 0.58 micromol/L, EC50) of rings precontracted with the thromboxane A2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 micromol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B2 receptor antagonist Hoe 140 (1 micromol/L) or by 80% with the nonselective Ang II antagonist [Sar1,Thr8]-Ang II (1 micromol/L). In contrast, the selective AT1 or AT2 Ang II antagonists CV 11974 (1 micromol/L), and PD 123319 (1 micromol/L), respectively, were ineffective in inhibiting the Ang-(1-7)-elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 micromol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang-(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B2 bradykinin receptor and a non-AT1, non-AT2, angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.
Hypertension 1996 Mar
PMID:Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. 861 97

We performed studies to further elucidate the mechanisms of angiotensin II (Ang II)-induced angiogenesis of the microvasculature. Rats were placed on a high salt diet (4% NaCl), and Ang II was infused at a subpressor rate (5 ng/kg per minute) for 3 days. Blood pressure was measured daily for 2 control and 3 infusion days. Microvessel density in the cremaster muscle was measured at the end of the infusion. Vessel density in rats that received subpressor Ang II infusion increased by 12.6% compared with rats that received vehicle infusion. When the angiotensin type 2 (AT2) receptor antagonist PD 123319 was coinfused with Ang II, blood pressure was elevated and vessel density increased above that observed with Ang II infusion alone (23% increase). When the AT1 receptor antagonist losartan was coinfused with Ang II, blood pressure was lower than control and vessel density was reduced compared with the Ang II group but was still greater than control (7.8% increase). In this study, Ang II stimulated angiogenesis in the rat cremaster muscle; this effect was enhanced by AT2 antagonism and inhibited by AT1 antagonism. Ang II infusion at a subpressor dose resulted in a pressor response with AT2 antagonism and a depressor response with AT1 antagonism. This suggests that in the microvasculature, the AT1 receptor mediates angiogenesis and vasoconstriction, and the AT2 receptor mediates an inhibition of angiogenesis and vasodilation.
Hypertension 1996 Mar
PMID:Opposing actions of angiotensin II on microvascular growth and arterial blood pressure. 861 37

We determined the effects of angiotensin II (Ang II) on cytosolic free calcium concentrations ([Ca2+]i) in the absence and presence of the selective angiotensin subtype 1 (AT1) receptor antagonist losartan or the selective AT2 antagonist PD 123319 in cultured neonatal rat atrial and ventricular cardiomyocytes. We also Ang II receptor density, affinity, and mRNA expression. [Ca2+]i was measured in single cells microphotometrically and by fluorescent digital imaging with fura 2 methodology. Receptor parameters were assessed by competitive binding studies with 125I-[Sar1,Ile8]Ang II in the presence of increasing concentrations of [Sar1,Ile8]Ang II, losartan, and PD 123319. AT1 receptor (types AT1A and AT1B) mRNA abundance was measured by reverse transcription-polymerase chain reaction. Ang II produced concentration-dependent increases in [Ca2+]i values in atrial and ventricular cells were similar but Ang II (10-9 mol/L)-induced [Ca2+]i changes were significantly greater in atrial compared with ventricular cells Ang II responses were blocked by losartan (10-7 mol/L) but not PD 123319 (10-7 mol/L). Binding studies demonstrated a single class of high-affinity. Ang II binding sites on cardiomyocyte membranes (Kd = 0.71 +/- 0.11 mumol/L). 125I-[Sar1,Ile8]Ang II was displaced by losartan but not by PD 123319. AT1 receptor mRNA was detected by reverse transcription-polymerase chain reaction in cells from atria and ventricles. In atrial cardiomyocytes, both AT1A and AT1B receptor genes were expressed, whereas in ventricular cardiomyocytes, only the AT1A receptor gene was expressed. These data demonstrate that neonatal cardiomyocytes possess Ang II receptors of the AT1 receptor subtype that are linked to [Ca2+]i signaling pathways. The different Ang II-induced [Ca2+]i responses between atrial and ventricular cells may be related to differences in the distribution of AT1 receptor subtype subvariants.
Hypertension 1996 May
PMID:Cytosolic calcium changes induced by angiotensin II in neonatal rat atrial and ventricular cardiomyocytes are mediated via angiotensin II subtype 1 receptors. 862 Dec 1

The intrarenal renin-angiotensin system (RAS) contributes to the increased renal vascular resistance and reactivity observed in spontaneously hypertensive rats (SHR) and to the pathogenesis of high blood pressure (BP). Thus, we decided to characterize angiotensin II (ANG II) receptors in the renal arteries and glomeruli of 16-week-old SHR and their age-matched, normotensive Wistar-Kyoto (WKY) controls. SHR had significantly higher BP (153 +/- 4 v 96 +/- 10 mmHg) and heart weight (440 +/- 5 v 327 +/- 4 g/100 g body weight) than WKY rats. There was no difference in plasma renin activity between strains. Radioligand binding assays using non-peptide antagonists for AT1 (losartan) and AT2 (PD 123319) showed that renal preglomerular microvessels and glomeruli expressed a single receptor population (AT1) for ANG II. AT1 density tended to be lower in glomeruli of SHR compared to WKY (377 +/- 45 v 555 +/- 74 fmol/mg protein), but was significantly higher in preglomerular vessels (93 +/- 7 v 57 +/- 1 fmol/mg protein). No difference in receptor affinity was found in either preparation. Isolated kidney perfusion revealed that at low flow (3-10 ml/min), perfusion pressure was similar in both strains; however, at higher flow levels, SHR showed higher reactivity and less compliance than their controls. In addition, SHR presented a higher renal vascular reactivity to ANG II (but not to arterenol) than WKY rats. Thus, upregulation of ANG II receptors in the renal vasculature may mediate the hyperreactivity to ANG II observed in SHR kidney.
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PMID:Characterization and hemodynamic implications of renal vascular angiotensin II receptors in SHR. 872 67

Angiotensin II (Ang II) is both a vasoactive and a potent growth-promoting factor for vascular smooth muscle cells. Little is known about the in vivo contribution of AT1 and AT2 receptor activation to the biological action of Ang II. Therefore, we investigated the effect of AT1 or AT2 subtype receptor chronic blockade by losartan or PD123319 on the vascular hypertrophy in rats with Ang II-induced hypertension. Normotensive rats received for 3 wk subcutaneous infusions of Ang II (120 ng/kg per min), or Ang II + PD 123319 (30 mg/kg per d), or Ang II + losartan (10 mg/kg per d) or PD 123319 alone, and were compared with control animals. In normotensive animals, chronic blockade of AT2 receptors did not affect the plasma level of angiotensin II and the vascular reactivity to angiotensin II mediated by the AT1 receptor. Chronic blockade of AT1I in rats receiving Ang II resulted in normal arterial pressure, but it induced significant aortic hypertrophy and fibrosis. Chronic blockade of AT2 receptors in Ang II-induced hypertensive rats had no effect on arterial pressure, but antagonized the effect of Ang II on arterial hypertrophy and fibrosis, suggesting that in vivo vasotrophic effects of Ang II are at least partially mediated via AT2 subtype receptors.
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PMID:Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure. 875 52

We investigated the ability of angiotensin II (Ang II) or the stable analogue [Sar1]-Ang II to increase intracellular and extracellular free arachidonic acid in primary cultures of rabbit proximal tubular epithelial cells to better characterize the receptor subtype and orientation of phospholipase A2 (PLA2)-mediated signaling. Proximal tubular cells were labeled with [3H]arachidonic acid for 4 hours and then treated with Ang II or [Sar1]-Ang II. Lipids were extracted from labeled cells, separated by thin-layer chromatography, and quantified by liquid scintillation counting. Ang II (10 mumol/L, 1 minute) stimulated an increase in intracellular free [3H]arachidonic acid from 21.0 +/- 2.0 to 32.2 +/- 2.8 disintegrations per minute/microgram protein, an effect that was potentiated by EGTA. [Sar1]-Ang II stimulated a time- and concentration-dependent increase in [3H]arachidonic acid release from labeled cells. Release of [3H]arachidonic acid was maximal at 10 mumol/L [Sar1]-Ang II, with an EC50 of approximately 3 mumol/L. Ang II receptor antagonists caused concentration-dependent inhibition of [Sar1]-Ang II-stimulated [3H]arachidonic acid release with the following order of potency: CGP 42112 = PD 123319 > losartan. Furthermore, in proximal tubular epithelial cells grown on polyester membrane filters, the Ang II receptor that mediated arachidonic acid release was predominantly apical rather than basolateral. These observations are consistent with activation of a Ca(2+)-independent, apical PLA2 isoform in epithelial cells through an Ang II type 2 receptor subtype.
Hypertension 1996 Oct
PMID:Angiotensin II type 2 receptor subtype mediates phospholipase A2-dependent signaling in rabbit proximal tubular epithelial cells. 884 95

The vasoactive peptides angiotensin II (Ang II) and endothelin-1 (ET-1) have been implicated in cardiac hypertrophy. This study investigates Ang II and ET-1 effects on intracellular free calcium concentration and the receptor subtype through which agonist-induced calcium responses are mediated in isolated cardiomyocytes and fibroblasts from hypertrophied hearts of spontaneously hypertensive rats (SHR). We measured intracellular free calcium concentration by fura 2 methodology and determined receptor status by radioligand binding assays. Ang II (10(-12) to 10(-7) mol/L) had no effect on cardiomyocyte calcium levels in control Wistar-Kyoto rats but significantly increased (P < .01) intracellular free calcium concentration in a dose-dependent manner in cardiomyocytes from SHR. Ang II total and specific binding were increased (P < .05) in SHR cardiomyocytes. Calcium responses elicited by 10(-7) to 10(-5) mol/L Ang II were significantly reduced (P < .01) in SHR fibroblasts despite no significant change in Ang II receptor density. The angiotensin type 1 receptor blocker losartan (1 mumol/L) blocked Ang II-stimulated calcium transients, whereas the angiotensin type 2 receptor blocker PD 123319 had no effect. ET-1- and sarafotoxin S6c-induced calcium responses in cardiomyocytes and fibroblasts were not different between hypertensive and control groups. In conclusion, Ang II and ET-1 elicit distinct and differential responses in a cell-specific manner in cardiomyocytes and fibroblasts from hypertrophied hearts of SHR. Whereas Ang II-mediated effects, which are elicited via angiotensin type 1 receptors, are detectable in cardiomyocytes from SHR, responses to Ang II are blunted in fibroblasts from SHR, and ET-1-related actions are similar in cells from both rat groups. Stimulation of cardiomyocytes by Ang II in hypertrophied hearts associated with pressure overload in genetic hypertension suggests that Ang II could modulate the function of cardiomyocytes of SHR but not those of Wistar-Kyoto rats, whereas cardiac actions of ET-1 do not change with the development of hypertension.
Hypertension 1996 Nov
PMID:Intracellular Ca2+ modulation by angiotensin II and endothelin-1 in cardiomyocytes and fibroblasts from hypertrophied hearts of spontaneously hypertensive rats. 890 26

Nitric oxide seems to be involved in the mechanisms underlying the antihypertensive and renal responses of losartan in spontaneously hypertensive rats (SHR). We investigated the contribution of nitric oxide to the effect of this angiotensin II (Ang II) type 1 (AT1) receptor antagonist on the constrictor response of phenylephrine in aortic rings from SHR. Furthermore, since it has been suggested that Ang II could bind to unblocked AT2 receptors, during administration of an AT1 receptor antagonist, we also studied the effect of the AT2 receptor antagonist PD 123319 on the contractile response to phenylephrine in aortic rings from SHR. To this end, we studied dose-response curves of phenylephrine (10(-9) to 10(-5) mol/L) in the presence and absence of losartan (10(-9), 10(-7), and 10(-5) mol/L) in SHR aortic rings. Preincubation with losartan reduced the constrictor response to phenylephrine but not to KCl (10 to 120 mmol/L) in a dose-dependent manner. On the other hand, the presence of captopril (10(-5) mol/L) in the incubation medium did not alter the response to phenylephrine, even at the dose of 10(-3) mol/L. The reduced response to phenylephrine in the presence of losartan was abolished in both endothelium-denuded rings and rings treated with a nitric oxide synthesis inhibitor. A similar situation was observed in PD 123319-pretreated rings, in which the effect of losartan on the contractile response to phenylephrine was reversed. Losartan was not able to stimulate the production of aortic cGMP compared with the control group. Likewise, losartan did not modify the relaxing responses to either acetylcholine or sodium nitroprusside in phenylephrine-preconstricted aortic rings. Furthermore, losartan did not alter isometric tension in aortic rings in either basal or phenylephrine-preconstricted conditions. These data demonstrate that Ang II potentiates the vasoconstriction induced by phenylephrine through the stimulation of AT1 receptors. Moreover, AT2 receptors and nitric oxide appear to be involved in this effect.
Hypertension 1996 Dec
PMID:Losartan reduces phenylephrine constrictor response in aortic rings from spontaneously hypertensive rats. Role of nitric oxide and angiotensin II type 2 receptors. 895 84

Angiotensin-(1-7) is a novel peptide of the renin-angiotensin system that counteracts the pressor and proliferative responses to angiotensin II. We now report that cultured bovine aortic endothelial cells contain a saturable, high-affinity [125I]angiotensin-(1-7) binding site with an affinity of 19.3 +/- 10.7 nmol/L and a density of 1351 +/- 710 fmol/mg protein. Angiotensin-(1-7) competed at a second lower-affinity site, with an IC50 of 2.9 mumol/L. The high-affinity angiotensin II receptor antagonist sarcosine1-isoleucine8-angiotensin II blocked [125I]angiotensin-(1-7) binding to bovine aortic endothelial cells at both a high- (IC50 = 1.3 nmol/L) and a low-affinity (IC50 = 6.2 mumol/L) binding site. In contrast, D-alanine7-angiotensin-(1-7) completely blocked [125I]angiotensin-(1-7) binding, with an IC50 of 19.8 nmol/L, suggesting that D-alanine7-angiotensin-(1-7) may selectively block responses to angiotensin-(1-7) in endothelial cells. Neither the AT1 antagonist losartan nor the AT2 antagonist PD 123319 exhibited significant competition for [125I]angiotensin-(1-7) binding to endothelial cells isolated from bovine aorta, in agreement with the absence of detectable mRNAs encoding typical angiotensin receptor subtypes 1 or 2 (AT1 or AT2). Angiotensin II also competed for [125I]angiotensin-(1-7) binding to bovine aortic endothelial cells; however, the relative affinity was 13-fold lower than angiotensin-(1-7), suggesting a preference for angiotensin-(1-7) over angiotensin II. These results demonstrate that bovine aortic endothelial cells contain a unique non-AT1, non-AT2 angiotensin receptor that preferentially binds angiotensin-(1-7).
Hypertension 1997 Jan
PMID:Bovine aortic endothelial cells contain an angiotensin-(1-7) receptor. 903 32


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