Angiotensin II type 2 receptor gene transfer downregulates angiotensin II type 1a receptor in vascular smooth muscle cells

Two distinct subtypes of angiotensin (Ang) II receptors, type 1 (AT(1)) and type 2 (AT(2)), have been identified. Vascular smooth muscle cells (VSMCs) usually express AT(1) receptor. To elucidate the direct effects of the AT(2) receptor on the AT(1) receptor in VSMCs, we transfected AT(2) receptor gene into cultured rat VSMCs. Overexpression of AT(2) receptor significantly decreased expression of AT(1a) receptor at both the mRNA and protein levels in the presence and absence of Ang II in VSMCs. Overexpression of AT(2) receptor increased expression of bradykinin and inducible NO in the presence and absence of Ang II in VSMCs. Bradykinin B(2) receptor antagonist HOE-140 and NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) inhibited the decreases in AT(1a) receptor expression by the overexpression of AT(2) receptor in VSMCs. L-Arginine augmented the decrease in AT(1a) receptor expression. Overexpression of AT(2) receptor suppressed basal DNA synthesis and proliferation of VSMCs and abolished response of DNA synthesis to Ang II in VSMCs. Our results demonstrate that overexpression of the AT(2) receptor downregulates AT(1a) receptor expression in rat VSMCs in a ligand-independent manner that is mediated by the bradykinin/NO pathway. Downregulation of AT(1a) receptor is a novel mechanism by which the AT(2) receptor regulates growth and metabolism of VSMCs.     

Differential effects of angiotensin II type-1 receptor antisense oligonucleotides on renal function in spontaneously hypertensive rats

The effect of selectively decreasing renal angiotensin II type 1 (AT1) receptor expression on renal function and blood pressure has not been determined. Therefore, we studied the consequences of selective renal inhibition of AT1 receptor expression in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in vivo. Vehicle, AT1 receptor antisense oligodeoxynucleotides (AS-ODN), or scrambled oligodeoxynucleotides were infused chronically into the cortex of the remaining kidney of conscious, uninephrectomized WKY and SHR on a 4% NaCl intake. Basal renal cortical membrane AT1 receptor protein was greater in SHR than in WKY. In WKY and SHR, AS-ODN decreased renal but not cardiac AT1 receptors. AT1 receptor AS-ODN treatment increased plasma renin activity to a greater extent in WKY than in SHR. However, plasma angiotensin II and aldosterone were increased by AS-ODN to a similar degree in both rat strains. In SHR, sodium excretion was increased and sodium balance was decreased by AS-ODN but had only a transient ameliorating effect on blood pressure. Urinary protein and glomerular sclerosis were markedly reduced by AS-ODN-treated SHR. In WKY, AS-ODN had no effect on sodium excretion, blood pressure, or renal histology but also modestly decreased proteinuria. The major consequence of decreasing renal AT1 receptor protein in the SHR is a decrease in proteinuria, probably as a result of the amelioration in glomerular pathology but independent of systemic blood pressure and circulating angiotensin II levels.     

Altered AT1 receptor regulation of ETB receptors in renal proximal tubule cells of spontaneously hypertensive rats

The renin-angiotensin and endothelin systems regulate blood pressure, in part, by affecting renal tubular sodium transport. In rodents, ETB receptors decrease proximal tubular reabsorption, whereas AT1 receptors produce the opposite effect. We hypothesize that ETB and AT1 receptors interact at the receptor level, and that the interaction is altered in spontaneously hypertensive rats (SHRs). In immortalized renal proximal tubule (RPT) cells from Wistar-Kyoto (WKY) rats, angiotensin II, via AT1 receptors, increased ETB receptor protein in a time- and concentration-dependent manner. In contrast, in SHR RPT cells, angiotensin II (10(-8) M/24 hours) had no effect on ETB receptor protein. AT1/ETB receptors colocalized and co-immunoprecipitated in both rat strains but long-term angiotensin II (10(-8) M/24 hours) treatment increased AT1/ETB co-immunoprecipitation in WKY but not in SHR cells. Short-term angiotensin II (10(-8) M/15 minutes) treatment decreased ETB receptor phosphorylation in both WKY and SHR cells, and increased ETB receptors in RPT cell surface membranes of RPT cells in WKY but not SHRs. Basal cell surface membrane ETB receptor expression was also higher in WKY than in SHRs. We conclude that AT1 receptors regulate ETB receptors by receptor interaction and modulation of receptor expression. The altered AT1 receptor regulation of ETB receptors in SHRs may play a role in the pathogenesis of hypertension.     

Rat strain effects of AT1 receptor activation on D1 dopamine receptors in immortalized renal proximal tubule cells

The dopaminergic and renin-angiotensin systems regulate blood pressure, in part, by affecting sodium transport in renal proximal tubules (RPTs). We have reported that activation of a D1-like receptor decreases AT1 receptor expression in the mouse kidney and in immortalized RPT cells from Wistar-Kyoto (WKY) rats. The current studies were designed to test the hypothesis that activation of the AT1 receptor can also regulate the D1 receptor in RPT cells, and this regulation is aberrant in spontaneously hypertensive rats (SHRs). Long-term (24 hours) stimulation of RPT cells with angiotensin II, via AT1 receptors increased total cellular D1 receptor protein in a time- and concentration-dependent manner in WKY but not in SHR cells. Short-term stimulation (15 minutes) with angiotensin II did not affect total cellular D1 receptor protein in either rat strain. However, in the short-term experiments, angiotensin II decreased cell surface membrane D1 receptor protein in WKY but not in SHR cells. D1 and AT1 receptors colocalized (confocal microscopy) and their coimmunoprecipitation was greater in WKY than in SHRs. However, AT1/D1 receptor coimmunoprecipitation was decreased by angiotensin II (10(-8) M/24 hours) to a similar extent in WKY (-22+/-8%) and SHRs (-22+/-12%). In summary, these studies show that AT1 and D1 receptors interact differently in RPT cells from WKY and SHRs. It is possible that an angiotensin II-mediated increase in D1 receptors and dissociation of AT1 from D1 receptors serve to counter regulate the long-term action of angiotensin II in WKY rats; different effects are seen in SHRs.     

Existence of a mutation of angiotensin AT1 receptor gene promoter region involved in inhibition of AT1 receptor gene transcription in spontaneously hypertensive rats.

The angiotensin type 1a (AT1a) receptor gene is overexpressed in the brain and peripheral tissues of spontaneously hypertensive rats (SHR). We examined whether there are mutations responsible for overexpression of the AT1a receptor gene in the SHR AT1a receptor promoter region. Genomic DNA was extracted from the livers of SHR and Wistar Kyoto rats (WKY) of Izumo strain (SHR/Izm and WKY/Izm, respectively). Fragments of the AT1a receptor gene promoter region were amplified by polymerase chain reaction (PCR). Amplified fragments were purified by agarose gel electrophoresis, and the purified fragments were cloned using pTBlue T-Vector. Sequence analysis identified one single base mutation unique to the SHR AT1a receptor gene promoter region when compared to that of WKY. The sequence of the mutation site in SHR was the same as that of Sprague Dawley rats. Using an electrophoretic mobility shift assay, we compared gel patterns formed by DNA-protein complexes using ds-oligonucleotides representing region-1624 to-1595 of the SHR and WKY AT1a receptor promoters. There were 3 major similar DNA-protein complexes against WKY and SHR oligonucleotides. In addition, the oligonucleotide bearing the SHR sequence produced an extra band. Promoter/luciferase reporter assay demonstrated that the promoter activity of SHR AT1a receptor promoters (-2050 to +57) was lower than that of WKY. These results suggest that there is one single mutation unique to the SHR AT1a receptor gene promoter region, but that the mutation is not responsible for overexpression of the AT1 a receptor gene in SHR.     

Alterations in sarcoplasmic reticulum and angiotensin II receptor type 1 gene expression in spontaneously hypertensive rat hearts

Left ventricular hypertrophy (LVH) is an adaptive change in response to hypertensive pressure overload. Some evidence indicates that the decrease in sarcoplasmic reticulum (SR) Ca2+-ATPase mRNA expression, which may contribute to a diastolic dysfunction of the heart, occurs in the experimental pressure overload model. Also, recent studies have demonstrated that angiotensin II (Ang II) and angiotensin II receptor type 1 (AT1) play important roles in LVH. The purpose of this study was to investigate the function of the SR and the role of AT1 in genetic hypertension in spontaneously hypertensive rats (SHR) at ages 10 and 18 weeks. In SHR, cardiac hypertrophy has already developed at 10 weeks of age. SR Ca2+-ATPase activity and mRNA expression were significantly lower in SHR than in Wistar-Kyoto rats (WKY). Plasma renin activity in SHR was unchanged compared with WKY, whereas the Ang II concentration in SHR was significantly higher than that in WKY. AT1 mRNA expression in SHR was similar to that in WKY. These results suggest that in the early stage of hypertension in SHR Ang II may stimulate hypertrophy in the cardiomyocytes through the AT1, which is not downregulated by a high concentration of Ang II.     

H2O2 stimulation of the Cl-/HCO3- exchanger by angiotensin II and angiotensin II type 1 receptor distribution in membrane microdomains

The present study tested the hypothesis that angiotensin II (Ang II)-induced oxidative stress and Ang II-stimulated Cl(-)/HCO(3)(-) exchanger are increased and related to the differential membrane Ang II type 1 (AT(1)) receptor and reduced nicotinamide-adenine dinucleotide phosphate oxidase expression in immortalized renal proximal tubular epithelial (PTE) cells from the spontaneously hypertensive rat (SHR) relative to its normotensive control (Wistar Kyoto rat [WKY]). The exposure of cells to Ang II increased Cl(-)/HCO(3)(-) exchanger activity with EC(50)s of 0.10 and 12.2 nmol/L in SHR and WKY PTE cells, respectively. SHR PTE cells were found to overexpress nicotinamide-adenine dinucleotide phosphate oxidase 2 and 4 and were endowed with an enhanced ability to generate H(2)O(2). The reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor apocynin reduced the production of H(2)O(2) in SHR PTE cells and abolished their hypersensitivity to Ang II. The expression of the glycosylated form of the AT(1) receptor in both lipid and nonlipid rafts were higher in SHR cells than in WKY PTE cells. Pretreatment with apocynin reduced the abundance of AT(1) receptors in both microdomains, mainly the glycosylated form of the AT(1) receptor in lipid rafts, in SHR cells but not in WKY PTE cells. In conclusion, differences between WKY and SHR PTE cells in their sensitivity to Ang II correlate with the higher H(2)O(2) generation that provokes an enhanced expression of glycosylated and nonglycosylated AT(1) receptor forms in lipid rafts.     

Activation of D3 dopamine receptor decreases angiotensin II type 1 receptor expression in rat renal proximal tubule cells

The dopaminergic and renin angiotensin systems interact to regulate blood pressure. Disruption of the D(3) dopamine receptor gene in mice produces renin-dependent hypertension. In rats, D(2)-like receptors reduce angiotensin II binding sites in renal proximal tubules (RPTs). Because the major D(2)-like receptor in RPTs is the D(3) receptor, we examined whether D(3) receptors regulate angiotensin II type 1 (AT(1)) receptors in rat RPT cells. The effect of D(3) receptors on AT(1) receptors was studied in vitro and in vivo. The D(3) receptor agonist PD128907 decreased AT(1) receptor protein and mRNA in WKY RPT cells and increased it in SHR cells. PD128907 increased D(3) receptors in WKY cells but had no effect in SHR cells. D(3)/AT(1) receptors colocalized in RPT cells; D(3) receptor stimulation decreased the percent amount of D(3) receptors that coimmunoprecipitated with AT(1) receptors to a greater extent in WKY than in SHR cells. However, D(3) receptor stimulation did not change the percent amount of AT(1) receptors that coimmunoprecipitated with D(3) receptors in WKY cells and markedly decreased the coimmunoprecipitation in SHR cells. The D(3) receptor also regulated the AT(1) receptor in vivo because AT(1) receptor expression was increased in kidneys of D(3) receptor-null mice compared with wild type littermates. D(3) receptors may regulate AT(1) receptor function by direct interaction with and regulation of AT(1) receptor expression. One mechanism of hypertension may be related to increased renal expression of AT(1) receptors due decreased D(3) receptor regulation.     

AT(2) receptor stimulation enhances antihypertensive effect of AT(1) receptor antagonist in hypertensive rats

In the present study, we investigated the role of the angiotensin type 2 (AT(2)) receptor in the regulation of blood pressure in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). We tested the hypothesis that AT(2) receptor activation may contribute to the antihypertensive effects of angiotensin type 1 (AT(1)) receptor antagonists. Mean arterial pressure (MAP) and heart rate were measured over a 4-day protocol in various groups of rats that received the following drug combinations: the AT(1) receptor antagonist candesartan (0.01 or 0.1 mg/kg IV) alone, the AT(2) receptor agonist CGP42112 (1 microg/kg per minute) alone, and candesartan plus CGP42112. In both SHR and WKY, 4-hour infusions of saline and CGP42112 alone did not alter MAP. In WKY, both doses of candesartan alone caused small decreases in MAP, which were similar when combined with CGP42112. In SHR, candesartan (0.1 mg/kg) caused an immediate, marked decrease in MAP, which was unaffected when combined with CGP42112. By contrast, in separate SHR, a 10-fold lower dose of candesartan (0.01 mg/kg) caused a slower-onset depressor response, which was enhanced when combined with CGP42112. The involvement of AT(2) receptors was confirmed in another group of SHR, since this facilitation of the antihypertensive effect of candesartan by CGP42112 was abolished by the coinfusion of the AT(2) receptor antagonist PD123319 (50 microg/kg per minute) with the candesartan/CGP42112 combination. Collectively, these data suggest that in SHR, AT(2) receptor activation can facilitate the initial depressor response caused by an AT(1) receptor antagonist.     

Transforming growth factor-beta1 modulates angiotensin II-induced calcium release in vascular smooth muscle cells from spontaneously hypertensive rats

OBJECTIVES: To investigate the role of transforming growth factor-beta1 (TGF-beta1) on Ca2+-dependent mechanisms elicited by angiotensin II in aortic vascular smooth muscle cells (VSMC) of Wistar- Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). METHODS: Cai2+ release induced by angiotensin II (1 micromol/ l) was studied in cultured VSMC isolated from the aortas of 6-week-old WKY rats and SHR. Intracellular Ca2+ (Cai2+) was assessed in Fura-2 loaded cells using fluorescent imaging microscopy. Angiotensin II receptors were analysed by binding studies. RESULTS: Pretreatment of VSMC for 24 h with TGF-beta1 significantly increased angiotensin II-induced Cai2+ mobilization from internal stores in SHR, while Ca2+ influx was not altered. This effect involves tyrosine kinase and is not due to an increase in angiotensin II binding sites, or a change in the affinity of the receptors. By contrast, TGF-beta1 did not modify the response of VSMC from WKY rats to angiotensin II. CONCLUSIONS: These results help our understanding of the interactions between the pathways activated by TGF-beta1 and the G protein-coupled receptor signalling pathway, and their role in genetic hypertension.     

The Mechanism of Distinct Diurnal Variations of Renin-Angiotensin System in Aorta and Heart of Spontaneously Hypertensive Rats

Diurnal variations in plasminogen activator inhibitor-1 mRNA expression are different between the spontaneously hypertensive rats (SHRs) and the Wistar-Kyoto (WKY) rats, and between the aorta and the heart. To elucidate the mechanisms, we examined diurnal changes in the circulating renin-angiotensin system in the SHR and WKY rats. Diurnal variations in plasma renin activity (PRA), plasma angiotensin I, and aldosterone concentrations were similar between the SHR and WKY rats. On the other hand, plasma angiotensin II (Ang II) concentration in the SHR was lower than that in the WKY rats at most time points, but increased to the level of the WKY rats in the late light phase. Treatment with AT1 receptor antagonist candesartan increased plasma Ang II concentration except at ZT 8 and lessened its diurnal variation in the SHR. At the peak in plasma Ang II in the SHR, Ang II regulated genes such as transforming growth factor-β1 and p22phox were upregulated in the aorta. On the other hand, these genes were upregulated throughout the day in the heart of SHR. Candesartan treatment increased AT1a receptor mRNA expression in the heart but not in the aorta of SHR. These findings suggest that an AT1 receptor-mediated mechanism might cause a surge in plasma Ang II concentration at the late light phase in the SHR. Homologous down-regulation of AT1a receptor by Ang II may dampen the effect of a surge in plasma Ang II concentration in the heart of SHR.     

Angiotensin II stimulates collagen synthesis in human vascular smooth muscle cells. Involvement of the AT(1) receptor, transforming growth factor-beta, and tyrosine phosphorylation.

Angiotensin II is an established regulator of vascular tone and smooth muscle cell (SMC) growth. However, there are little data about its effect on collagen synthesis by SMCs and none regarding the mechanism of such an effect. We studied the effect of angiotensin II on collagen production by human arterial SMCs, using uptake of [(3)H]proline into collagenase-digestible proteins, and by ribonuclease protection assay for mRNA encoding the proalpha1 chain of type I collagen, the major collagen in arteries. This revealed a dose-dependent increase in relative collagen synthesis rate and a dose-dependent increase in proalpha1(I) collagen mRNA abundance, with the half-maximal effect at 1.7 nmol/L. Angiotensin II-stimulated collagen expression was associated with a 6-fold increase in transforming growth factor-beta (TGF-beta) production and was inhibited by a neutralizing antibody to TGF-beta. Both collagen production and TGF-beta release were inhibited by the AT(1)-specific antagonist, losartan, but not by the AT(2) receptor antagonist, PD123319. To determined if tyrosine phosphorylation was functionally linked to collagen synthesis, we studied the effect of 2 mechanistically distinct inhibitors of tyrosine kinase, genistein, and tyrphostin A25. These inhibitors abrogated angiotensin II-mediated procollagen mRNA expression and angiotensin II-mediated TGF-beta production, whereas the inactive homolog tyrphostin A1 had no effect. We conclude that angiotensin II stimulates collagen production in human arterial SMCs via the AT(1) receptor and an autocrine loop of TGF-beta, induction of which requires tyrosine phosphorylation.     

Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity

The functional balance between angiotensin II (Ang II) and nitric oxide (NO) plays a key role in modulating salt sensitivity. Estrogen has been shown to downregulate angiotensin type 1 (AT1) receptor expression and to increase the bioavailability of endothelium-derived NO, which decreases AT1 receptor expression. The present study tests the hypothesis that in the presence of genetic salt sensitivity, deficiency of endogenous estrogens after ovariectomy (OVX) fosters an upregulation of Ang II. Female Dahl salt-resistant (DR), Dahl salt-sensitive (DS), Wistar-Kyoto (WKY), and spontaneously hypertensive (SHR) rats underwent bilateral OVX or sham surgery (SHX) and were fed a normal salt diet (0.5% NaCl) for 14 weeks. Systolic blood pressures were measured every 2 weeks and were not significantly different between OVX and SHX for DR, WKY, and SHR groups. However, at the end of 14 weeks of normal salt diet, hypertension developed in DS OVX but not SHX rats (160+/-3 versus 136+/-3 mm Hg; P<0.05). Hypertension also developed in DS OVX rats pair-fed a normal salt diet (166+/-7 mm Hg). Development of hypertension in DS OVX rats was prevented by estrogen replacement (132+/-3 mm Hg), AT1 receptor blockade (119+/-3 mm Hg), or feeding a very low salt diet (0.1% NaCl; 129+/-4 mm Hg). Renal AT1 receptor protein expression was significantly elevated 2-fold in DS OVX relative to SHX rats and was prevented by estrogen replacement. These data strongly suggest that after OVX in salt-sensitive rats there is a lower threshold for the hypertensinogenic effect of salt that is linked to an activation of Ang II.     

Glomerular dimensions in spontaneously hypertensive rats: effects of AT1 antagonism

OBJECTIVE: A reduction in glomerular number and/or size has been implicated in the development of hypertension. This study investigated whether differences in glomerular number and/or size occur during the development of hypertension in the spontaneously hypertensive rat (SHR) and whether angiotensin II is responsible for any glomerular differences. METHODS: SHR (n=6) and Wistar-Kyoto (WKY) rats (n=6) were administered the angiotensin II type I receptor antagonist TCV-116 from 4 to 10 weeks of age. At 10 weeks of age, the kidneys from these rats and those from untreated SHR (n=6) and WKY rats (n=6) controls were perfusion fixed at physiological pressures and analysed using unbiased stereological techniques. RESULTS: There were no significant differences in glomerular number, glomerular volume or total glomerular volume between SHR and WKY rats. Treatment of SHR with TCV-116 significantly lowered systolic blood pressure but had no significant effect on glomerular number or volume or total glomerular volume. Treatment of WKY rats with TCV-116 reduced systolic blood pressure, body weight, glomerular volume and total glomerular volume; however, total glomerular volume per body weight of treated WKY rats was not significantly different from that of untreated WKY rats. CONCLUSION: There were no differences in glomerular number or volume in SHR compared with WKY rats at 10 weeks of age. We therefore conclude that glomerular changes are not responsible for the development of hypertension in SHR. Angiotensin II, via the type 1 receptor, does not contribute to glomerular growth during the development of hypertension in the SHR.     

Angiotensin II regulates the cell cycle of vascular smooth muscle cells from SHR

We have demonstrated that spontaneously hypertensive rats (SHR)-derived vascular smooth muscle cells (VSMC) show the exaggerated growth and produce angiotensin II (Ang II). In the current study, we investigated the role of endogenous Ang II in the regulation of the cell cycle in VSMC from SHR. Levels of Ang II in conditioned medium from SHR-derived VSMC cultured without serum were significantly higher than levels in conditioned medium from Wistar-Kyoto (WKY) rat-derived VSMC. Basal DNA synthesis was higher in quiescent VSMC from SHR than that in cells from WKY rats. An Ang II type 1 receptor antagonist, CV11974, significantly inhibited the elevation in DNA synthesis in quiescent VSMC from SHR but did not affect it in cells from WKY rats. Cellular DNA content analysis by flow cytometry revealed that the proportion of cells in S phase was higher, whereas the proportion of cells in G1+G0 phase was lower in VSMC from SHR than those in cells from WKY rats. CV11974 significantly decreased the proportion of cells in S phase and correspondingly increased the proportion of cells in G1+G0 phase in VSMC from SHR, but it did not affect the proportion in cells from WKY rats. Cyclin-dependent kinase 2 (CDK2) activity, which is known to induce the progression from G1 to S phase, was higher in VSMC from SHR than in cells from WKY rats. Expression of CDK2 inhibitor p27(kip1) mRNA was markedly higher in VSMC from SHR than in cells from WKY rats. CV11974 decreased expression of p27(kip1) mRNA in VSMC from SHR, whereas CV11974 increased it in cells from WKY rats. These findings indicate that enhanced production of endogenous Ang II regulates the cell cycle especially in the progression from G1 to S phase, and increases CDK2 activity, which is independent of p27(kip1) in VSMC from SHR.     

Cysteinyl leukotrienes are involved in angiotensin II-induced contraction of aorta from spontaneously hypertensive rats

OBJECTIVE: Non specific lipoxygenase inhibitors have been reported to reduce the in vitro constrictor response and the in vivo pressor effect of angiotensin II in rats. The aim of this study was to assess the role of cysteinyl leukotrienes, in the vascular response to angiotensin II in spontaneously hypertensive rats (SHR). METHODS: Rings of thoracic aorta from SHR and normotensive Wistar-Kyoto rats (WKY) were compared in terms of contractile responses and release of cysteinyl leukotrienes in response to angiotensin II. RESULTS: Pretreatment with the specific 5-lipoxygenase inhibitor AA861 10 microM reduced the efficacy of angiotensin II in intact and endothelium-denuded aorta from SHR (% inhibition vs. control: 65+/-12.6% with endothelium (n=6), P<0.05; 43+/-7.2% without endothelium (n=6), P<0.05) but not in aorta from WKY. In addition, in aorta from SHR, the CysLT(1) receptor antagonist MK571 1 microM reduced by 55+/-6.1% (n=6, P<0.05) the contractile effects of angiotensin II in rings with endothelium but not in endothelium-denuded rings. Angiotensin II induced a 8.6+/-2.1-fold increase in cysteinyl leukotriene production in aorta rings from SHR with endothelium which was prevented by the AT(1) receptor antagonist losartan 1 microM but not by the AT(2) receptor antagonist PD123319 0.1 microM. In aorta rings from WKY, cysteinyl leukotriene production remained unchanged after exposition to angiotensin II. The cysteinyl leukotrienes (up to 0.1 microM) induced contractions in aorta rings from SHR but not from WKY. CONCLUSIONS: These data suggest that cysteinyl leukotrienes, acting at least in part on endothelial CysLT(1) receptors, are involved in the contractile response to angiotensin II in isolated aorta from SHR but not from WKY.