Preferential inhibitory effect of nifedipine on angiotensin II-induced renal vasoconstriction

The inhibitory effects of nifedipine on renal vasoconstrictor response to angiotensin II, norepinephrine, or renal nerve stimulation were tested in anesthetized dogs. Intrarenal infusions of nifedipine (0.3, 1, and 3 micrograms/min) dose-dependently suppressed the renal vasoconstriction induced by intrarenal injections of angiotension II (0.03, 0.05, and 0.1 microgram) or norepinephrine (0.3-1 micrograms) but not that by renal nerve stimulation (4-7 Hz). However, the inhibitory effect of nifedipine on angiotensin II-induced vasoconstriction was greater than its effect on norepinephrine-induced or renal nerve stimulation-induced vasoconstriction (i.e., 50% reduction in renal blood flow). Furthermore, a greater renal vasodilation induced by intrarenal bolus injections of nifedipine (1,3, and 10 micrograms) but not by acetylcholine (0.1 and 0.3 microgram) was observed during the reduction in the perfusion pressure of the contralateral kidney to approximately 50 mm Hg, which resulted in an increase in plasma renin activity and plasma angiotensin II concentration but no change in plasma norepinephrine concentration. There was a significant positive correlation between plasma renin activity and plasma angiotensin II concentration before nifedipine injections and the subsequent increase in renal blood flow produced by each dose of nifedipine. These results indicate that nifedipine has a relatively preferential inhibitory effect on the renal vasoconstriction produced by both exogenous and endogenous angiotensin II in canine renal vasculature.     

Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats.

Torasemide is a loop diuretic that is effective at low once-daily doses in the treatment of arterial hypertension. Because its antihypertensive mechanism of action may not be based entirely on the elimination of salt and water from the body, a vasodilator effect of this drug can be considered. In the present study, the ability of different concentrations of torasemide to modify angiotensin II (Ang II)-induced vascular responses was examined, with the use of an organ bath system, in endothelium-denuded aortic rings from spontaneously hypertensive rats. Ang II-induced increases of intracellular free calcium concentration ([Ca(2+)](i)) were also examined by image analysis in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. A dose-response curve to Ang II was plotted for cumulative concentrations (from 10(-9) to 10(-6) mol/L) in endothelium-denuded aortic rings (pD(2)=7.5+/-0.3). Isometric contraction induced by a submaximal concentration of Ang II (10(-7) mol/L) was reduced in a dose-dependent way by torasemide (IC(50)=0.5+/-0.04 micromol/L). Incubation of VSMCs with different concentrations of Ang II (from 10(-10) to 10(-6) mol/L) resulted in a dose-dependent rise of [Ca(2+)](i) (pD(2)=7.5+/-0.3). The stimulatory effect of [Ca(2+)](i) induced by a submaximal concentration of Ang II (10(-7) mol/L) was blocked by torasemide (IC(50)=0.5+/-0.3 nmol/L). Our findings suggest that torasemide blocks the vasoconstrictor action of Ang II in vitro. This action can be related to the ability of torasemide to block the increase of [Ca(2+)](i) induced by Ang II in VSMCs. It is proposed that these actions might be involved in the antihypertensive effect of torasemide observed in vivo.     

Antifibrotic effect of adrenomedullin on coronary adventitia in angiotensin II-induced hypertensive rats

OBJECTIVE: The extracellular matrix (ECM) determines the structural integrity of the heart and vasculature, participating in cardiovascular remodeling. We previously reported that adrenomedullin (AM) inhibited cellular proliferation and protein synthesis of cardiac fibroblasts; however, the precise mechanisms of AM actions as an antifibrotic factor remain unknown. The purpose of this study was to examine the biological actions of AM against the profibrotic factor angiotensin II (Ang II) in coronary adventitia. METHODS AND RESULTS: Rats with hypertension induced by Ang II infusion were administered 0.06 mug/kg/min recombinant human AM subcutaneously for 14 days. The AM infusion significantly (p<0.05) reduced the Ang II-induced increase of coronary adventitial fibroblasts expressing Ki-67 and alpha-smooth muscle actin (alpha-SMA) in the left ventricle, by 65%, and 62%, respectively, without affecting systolic blood pressure, left ventricle/body weight, or cross-sectional area of myocardial fibers. Collagen deposition of coronary arteries was reduced by the AM infusion (-24%, p<0.01), and these effects of AM were accompanied by significant reductions in gene expression of type 1 collagen (-49%, p<0.05) and transforming growth factor-beta1 (TGF-beta1) (-55%, p<0.01). In cultured cardiac fibroblasts, 10(-7) mol/L AM exerted an inhibitory effect on TGF-beta1-induced alpha-SMA expression (p<0.01) that was mimicked by 8-bromo-cAMP and attenuated by the protein kinase A inhibitor H-89. CONCLUSION: AM decreased Ang II-induced collagen deposition surrounding the coronary arteries, inhibiting myofibroblast differentiation and expressions of ECM-related genes in rats. The present findings further support the biological action of AM as an antifibrotic factor in vascular remodeling.     

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.     

Altered angiotensin II-induced small artery contraction during the development of hypertension in spontaneously hypertensive rats.

This study assessed whether the angiotensin-II (Ang II)-induced contractile responsiveness of resistance arteries is altered during the development of hypertension in spontaneously hypertensive rats (SHR). Structural parameters and Ang II-stimulated contraction were determined in small mesenteric arteries from 6-week-old (phase of developing hypertension) and 21-week-old SHR (phase of established hypertension), compared with age-matched Wistar-Kyoto rats (WKY). To ascertain whether effects were specific for Ang II, contractile responses to another vasoactive agonist, vasopressin (AVP), were also determined. Systolic blood pressure was measured in conscious rats by the tail-cuff method. Segments of third-order mesenteric arteries (approximately 200 microm in diameter and 2 mm in length) were mounted in a pressurized system with the intraluminal pressure maintained at 45 mm Hg. Blood pressure was significantly increased in SHR (P < .001) and was higher in adult than in young SHR (P < .001). Ang II dose-dependently increased contraction, with responses significantly greater (P < .05) in SHR than in age-matched WKY. SHR, in the early phase of hypertension, exhibited significantly augmented contractile responses (Emax = 70 +/- 5%), compared with SHR with established hypertension (Emax = 33 +/- 5%). These effects were not generalized, as responses to AVP were not significantly different between young and adult SHR. Functional Ang II-elicited alterations were associated with structural modifications: 6-week-old SHR had smaller media to lumen ratio compared with 21-week-old SHR (8.1% +/- 0.17% v 10.6% +/- 0.20%, P < .01). In young SHR vessels the media cross-sectional area was unchanged relative to age-matched WKY rats, suggesting eutrophic remodeling (remodeling index 101.4% v 93.3% young v adult), whereas the cross-sectional area of adult vessels was increased in comparison to WKY rats, suggesting mild hypertrophic remodeling (growth index -1.0% v 15.2%, young v adult). In conclusion, the present study demonstrates that in SHR with early hypertension and slight medial thickening, Ang II-mediated vascular contractile responsiveness is significantly augmented compared with SHR with established hypertension and more severe vascular structural changes. These findings indicate attenuation, as hypertension progresses, of the initially enhanced vascular reactivity to Ang II that is present during the development of hypertension in SHR.     

Proximal tubular fluid angiotensin II levels in angiotensin II-induced hypertensive rats

BACKGROUND: It has been shown that infusions of low-dose angiotensin II (Ang II) for 2 weeks lead to impaired pressure natriuresis and autoregulatory capability. Although intrarenal renin content and renin mRNA levels are markedly reduced, whole-kidney Ang II content has been shown to be increased. However, the intrarenal distribution of the increased intrarenal Ang II has not been established. OBJECTIVE: To determine the concentrations of Ang II in the proximal tubule fluid achieved in hypertensive rats (n = 16) infused with Ang II, previously prepared by infusion with Ang II at 60 ng/min via osmotic minipump for 13 days. METHODS: Rats were anesthetized with pentobarbital sodium and prepared for micropuncture, and then several free-flow proximal tubular fluid collections were obtained and pooled for each rat. At the end of each experiment, a blood sample was collected and the micropunctured kidney was excised and homogenized in chilled methanol. All samples were extracted immediately after collection and stored at 20 degrees C until the day of Ang II radioimmunoassay. RESULTS: Mean arterial blood pressure averaged 179 +/- 3 mmHg, renal plasma flow was 1.89 +/- 0.15 ml/min per g, and glomerular filtration rate averaged 0.58 +/- 0.04 ml/min per g. The Ang II concentration in proximal tubular fluid averaged 4.5 +/- 1.1 pmol/ml, a value substantially greater than the Ang II concentrations in plasma (0.17 +/- 0.03 pmol/ml), urine (0.06 +/- 0.01 pmol/ml), or total kidney tissue (0.40 +/- 0.10 pmol/g). Plasma renin activity (1.0 +/- 0.21 ng Ang I/ml per h) was markedly suppressed, as observed previously.CONCLUSIONS These findings indicate that Ang II concentrations in proximal tubular fluid collected from kidneys of anesthetized hypertensive rats infused with Ang II are in the nanomolar range, similar to those observed in normotensive rats. The inappropriate maintenance of nanomolar concentrations of Ang II in proximal tubular fluid of Ang II-infused hypertensive rats, even at markedly increased arterial pressures, may contribute to the impaired pressure natriuresis capability previously reported and, thereby, to the development and maintenance of hypertension in this model.     

Angiotensin II-induced proliferation of aortic myocytes in spontaneously hypertensive rats

In order to determine whether the morphological modifications observed in arterial media of spontaneously hypertensive rats (SHR) could be induced by an abnormal response of the smooth muscle cells to vasoactive agents, we studied the action of angiotensin (Ang) II on cultured aortic smooth muscle cells from both SHR and Wistar-Kyoto rats (WKY). Under our experimental conditions, Ang II exerts a mitogenic action on SHR cells, whereas its effect is very weak on WKY cells. Phospholipase C activation and c-fos and c-myc proto-oncogene expressions induced by Ang II are considerably enhanced in SHR cells, and these abnormalities may be linked to an increased number of Ang II receptors.     

CoenzymeA glutathione disulfide is a potent modulator of angiotensin II-induced vasoconstriction

CoenzymeA glutathione disulfide (CoASSG) has recently been isolated from bovine adrenal glands and is assumed to play an important role in blood pressure (BP) control. We used the isolated perfused rat kidney to investigate the modulating effects of CoASSG on angiotensin II (AngII)-induced vasoconstriction. Permanent perfusion with CoASSG (1 micromol/L) for 60 min induced a significant (P < .05) shift to the left in the dose-response curve for AngII (about 3.1-fold), whereas the dose-response curve for norepinephrine (NE) was unaffected. During continuous perfusion with 1 micromol/L CoASSG, the repetitive application of 10 pmol AngII significantly increased its vasoconstriction by 170% +/- 14% (P < .05) and 235% +/- 50% (P < .05) for 60 and 120 min, respectively. The potentiation of AngII by permanent perfusion with CoASSG is dose- and time-dependent and shows a plateau at 120 min. Glutathione, oxidized coenzymeA, and coenzymeA (each 1 micromol/L) are not able to enhance the vasoconstriction induced by AngII. We conclude that CoASSG is able to potentiate the vasoactive properties of AngII, and that CoASSG might play an important role in BP regulation via modulating effects of AngII.     

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.     

Immunisation of spontaneously hypertensive rats against angiotensin I

Immunization against angiotensin I has been considered in comparison with the immunization against renin, in the spontaneously hypertensive rat (SHR). Among 6 different methods of immunization, two (AI-gluta-LPH and AI-Carbo-LPH coupling) permitted to obtain high levels of antibodies against angiotensin I (higher than 1/10,000), after four injections of 50 micrograms AI at three weeks interval. The titration of the antibodies was realized in radio-immuno-assay (RIA), with the determination of the cross-reactivity with AII by the same method. Characterization of the isotypes and the affinity calculation were realized with the ELISA method. The average level of antibodies is about 1/10,000 to 1/100,000, and the cross reactivity of the antibodies for AII is about 0.1 p. 100 in RIA. In ELISA, the study of the different isotypes shows a good maturation of the immune system with a sharp elevation of the IgG1 and IgG2 alpha isotypes, after 2 or 3 injections. The affinity of the antibodies purified by affinity chromatography is about 10.3 10(-9) M. The weekly measure of the arterial pressure during 6 months does not reveal at any moment a fall of pressure during the immunizations. The average pressure of the immunized group (209.4 +/- 23.8 mmHg, n = 40) is non significantly different from the average pressure of the mock group (208.5 +/- 22.6 mmHg, n = 10).     

Soluble guanylate cyclase stimulation on cardiovascular remodeling in angiotensin II-induced hypertensive rats

It is unknown whether long-term pharmacological stimulation of soluble guanylate cyclase (sGC), elevating intracellular cGMP levels, has a beneficial effect on hypertension. The purpose of this study is to investigate the effects of BAY41-2272, an orally available sGC stimulator, on cardiovascular remodeling in hypertensive rats. Eight-week-old male Wistar rats with hypertension induced by angiotensin II infused subcutaneously at 250 ng/kg per minute were treated orally with a low ([L] 2 mg/kg per day) or high ([H] 10 mg/kg per day) dose of BAY41-2272 for 14 days. BAY41-2272-H partially suppressed the rise in blood pressure and reduced the heart weight (4.20+/-0.34 versus 3.68+/-0.20 mg/g; P<0.01), whereas BAY41-2272-L had no effect. However, both doses decreased the angiotensin II-induced left ventricular accumulation of collagen in the perivascular area (L, -20%, P<0.05; H, -30%, P<0.01) and myocardial interstitium (L, -21%, P<0.05; H, -38%, P<0.01), reducing the number of activated fibroblasts surrounding coronary arteries (L, -74%; H, -79%; P<0.05). BAY41-2272 downregulated the angiotensin II-induced left ventricular gene expression of type 1 collagen (L, -41%, P<0.05; H, -49%, P<0.01) and transforming growth factor-beta1 (L, -49%, P<0.05; H, -65%, P<0.01). cGMP levels were elevated by BAY41-2272 not only in the left ventricle, but also in cultured cardiac fibroblasts, resulting in reduced thymidine incorporation into the cells. Thus, stimulation of sGC by BAY41-2272 attenuates fibrosis of the left ventricle in rats with angiotensin II-induced hypertension partly in a pressure-independent manner, suggesting an important role for sGC generating cGMP in inhibiting cardiovascular remodeling.     

Inhibitory effect of melatonin on alpha1-adrenergic-induced vasoconstriction in mesenteric beds of spontaneously hypertensive rats

BACKGROUND: The aim of this study was to assess the effects of melatonin on alpha1-adrenergic pathway in mesenteric arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. METHODS AND RESULTS: The SHR are characterized by a higher vasoconstriction (P < .001) and inositol phosphate formation (P < .001) in response to phenylephrine (PHE) and an increased superoxide anion production (P < .001) in mesenteric arteries. Melatonin and 2-iodomelatonin produced a significant inhibition of the PHE-induced vasoconstriction in isolated and perfused mesenteric beds (P < .001) with the same magnitude in SHR and WKY rats. Melatonin significantly decreased the inositol phosphate (IPs) formation in isolated mesenteric arteries from SHR compared to WKY rats (P < .001). The inhibitory effect of melatonin was increased by the removal of endothelium (P < .001). No effects of superoxide dismutase (SOD), tempol, or catalase were observed on the PHE-induced vasoconstriction. Moreover, no superoxide anion scavenging effect of 2-iodomelatonin was observed in isolated mesenteric vascular muscle cells using lucigenin. CONCLUSIONS: The present study showed that high melatonin concentrations inhibit the alpha1-adrenergic-induced vasoconstriction and inositol phosphate formation in mesenteric arteries from SHR and WKY rats. The vasorelaxant effect of the melatonin receptors agonist, 2-iodomelatonin, and the absence of any vasoactive effect of antioxidants such as SOD, tempol, and catalase suggest that melatonin exerts its inhibition on alpha1-adrenergic-induced vasoconstriction of mesenteric arteries through a low-affinity membrane receptor negatively coupled to the IPs formation and that this effect is independent of its antioxidant properties.     

厄贝沙坦对自发性高血压大鼠瘦素、脂联素的影响

目的 探讨血管紧张素Ⅱ受体拮抗剂（ARB）厄贝沙坦对自发性高血压大鼠（SHR）瘦素、脂联素的影响及可能机制.方法 24只雄性SHR大鼠随机分为SHR模型组（SHR-C）、SHR氢氯噻嗪组（SHR-H）和SHR厄贝沙坦组（SHR-I）,每组8只;另设同源雄性Wistar Kyoto（WKY）大鼠8只为对照组.SHR-I组应用厄贝沙坦30 mg·kg-1·d-1灌胃,SHR-H组应用氢氯噻嚷10 mg·kg-1·d-1灌胃,SHR-C和WKY组均配以等量蒸馏水灌胃,连续8周后,测尾动脉收缩压（SBP）;颈动脉取血,检测血清血糖、胰岛素、瘦素和脂联素浓度;取大鼠附睾脂肪组织,通过反转录和聚合酶链反应（RT-PCR）,分析附睾脂肪瘦素mRNA和脂联素mRNA表达水平.结果 与WKY组比较,SHR-C组大鼠收缩压显著升高（P＜0.01）;与SHR-C组比较,SHR-I组和SHR-H组大鼠收缩压显著降低（P＜0.01）.与WKY组比较,SHR-C组大鼠胰岛素抵抗指数（HOMA-IR）显著升高（P＜0.01）;与SHR-H组和SHR-C组比较,SHR-I组大鼠HOMA-IR明显降低（P＜0.05）.与WKY组比较,SHR-C组大鼠血清瘦素浓度和脂肪瘦素mRNA表达水平显著增高（P＜0.01）;与SHR-C组比较,SHR-I组大鼠血清瘦素浓度显著降低（P＜0.01）,脂肪瘦素mRNA表达水平明显降低（P＜0.05）.与WKY组比较,SHR-C组大鼠血清脂联素浓度和脂肪脂联素mRNA表达水平显著降低（P＜0.01）;与SHR-C组比较,SHR-I组大鼠血清脂联索浓度和脂肪脂联索mRNA表达水平显著升高（P＜0.01）.结论 厄贝沙坦能改善自发性高血压大鼠胰岛索的敏感性,减少其脂肪组织瘦素的合成和分泌,增加脂联素的合成和分泌.     

Effects of angiotensin II receptor antagonists on insulin resistance syndrome and leptin in sucrose-fed spontaneously hypertensive rats.

In order to investigate the usefulness of angiotensin II type 1 receptor (AT1) antagonists (ARA) in the treatment of hypertension with insulin resistance syndrome, we studied the effects of a high dose sucrose diet and ARA on insulin sensitivity, plasma lipids, and leptin in spontaneous hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). SHR and WKY were divided into three groups and treated for 12 weeks: those fed a standard chow, those given a sucrose-rich chow or those given a sucrose-rich chow and ARA. While in SHR the weight of both subcutaneous and mesenteric adipose tissue was greater in the sucrose-rich chow fed animals than in the standard chow fed animals, ARA treatment significantly decreased the weights of both subcutaneous and mesenteric adipose tissue. ARA treatment decreased free fatty acid and triglyceride in SHR, and increased high density lipoprotein cholesterol in SHR and WKY. Homeostasis model assessment-insulin resistance (HOMA-IR) index, plasma levels of leptin, and leptin mRNA in mesenteric adipose tissue were significantly greater in the sucrose-rich chow fed animals than in the standard chow fed animals, and significantly lower in the ARA-treated sucrose-rich chow fed animals than in the sucrose-rich chow fed animals in both SHR and WKY. ARA improved insulin resistance, and reduced plasma leptin and leptin mRNA in adipose tissue. These results suggest that the improvement of insulin resistance by ARA may be attributed, at least in part, to the reduction of adipose tissue weight. It is concluded that ARA is useful in the treatment of patients with hypertension and concomitant insulin resistance syndrome.     

Heme oxygenase-1 is upregulated in the kidney of angiotensin II-induced hypertensive rats : possible role in renoprotection

In this study, we investigated the regulation and physiological role of heme oxygenase-1 (HO-1) in the kidney of rats with hypertension. Rats were continuously administered either angiotensin II (Ang II) or norepinephrine with an osmotic minipump for up to 7 days. Ang II infusion decreased the glomerular filtration rate (GFR) as determined through creatinine clearance (3.2+/-0.2 versus 1.2+/-0.2 mL/min with Ang II infusion, P<0.01) and increased proteinuria (9. 7+/-1.3 versus 28.1+/-7.2 mg/d with Ang II infusion, P<0.01). In contrast, norepinephrine did not alter these laboratory values. Ang II infusion significantly increased HO-1 expression in mRNA (442+/-98% of control at day 5, P<0.01) and protein levels (314+/-49% of control at day 5, P<0.01). Immunohistochemistry showed that in the kidney of normotensive rats, HO-1 was expressed mainly in the basal side in the renal tubules. After Ang II infusion, HO-1 staining was more extensively dispersed in the tubular epithelial cells. The intraperitoneal administration of zinc protoporphyrin, an HO inhibitor, to Ang II-infused rats further decreased GFR (0.8+/-0. 1 mL/min) and increased proteinuria (52.5+/-13.0 mg/d). In contrast, the administration of hemin, an HO inducer, ameliorated the Ang II-induced decrease in GFR (2.4+/-0.2 mL/min) and increase in proteinuria (9.3+/-4.5 mg/d). These data suggest that HO-1 upregulation in the kidney of Ang II-induced hypertensive rats may exert a renoprotective effect against Ang II-induced renal injury.     

Renal vasoconstriction by the endothelial cell-derived peptide endothelin in spontaneously hypertensive rats

The effects of endothelin on systemic and renal hemodynamics in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats were examined. Endothelin (500 ng i.v. +1,000 ng/hr per 300-g rat) elevated mean blood pressure by 13% (p less than 0.02) and decreased renal blood flow by 71% and glomerular filtration rate by 66% (both p less than 0.01), resulting in a 430% (p less than 0.05) increase in renal vascular resistance (RVR) in SHR. This rise in blood pressure was associated with a significant increase in hematocrit (+8%), but a decrease in urinary sodium excretion (-51%). This dose of endothelin reduced cardiac output by 40% (p less than 0.001) and brought about a 96% (p less than 0.01) rise in systemic vascular resistance (SVR). However, the SVR increase was significantly smaller than the RVR increase. These changes in systemic and renal hemodynamics were observed in a dose-dependent manner, and the degrees of change did not differ between the two strains. Additional infusion of atrial natriuretic peptide (0.33 microgram/kg/min) into SHR completely reversed the changes in blood pressure and renal hemodynamics caused by endothelin, resulting in pronounced natriuresis (+760%). The renal vascular casting study revealed that endothelin mainly constricted the arcuate and interlobular arteries, as well as afferent arterioles. These results suggest that endothelin may be involved in blood pressure and body fluid volume regulation through systemic and renal vasoconstriction.