Endothelin-1 is the most potent endogenous

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1 AJH 2000;13: Microvascular Responses to Endothelin in Deoxycorticosterone Acetate-Salt Hypertensive Rats Hongli Zhao, Irving G. Joshua, and James P. Porter The objective of the present study was to determine if endothelin-1 played a role in the elevated peripheral resistance in deoxycorticosterone-acetate (DOCA)-salt hypertension. Radioimmunoassay showed that the concentration of endothelin-1 was higher in thoracic aorta of the DOCA-salt group than that of the control normotensive (CN) group. Responses of arterioles in the rat cremaster to endothelin-1 were also observed using in vivo closed circuit television microscopy. Microvascular sensitivity to endothelin-1 was decreased in the DOCA-salt group. In the presence of an endothelin type A (ET-A) receptor antagonist, low concentrations of endothelin-1 induced a significant vasoconstriction in the DOCA-salt group. In the presence of endothelin type B (ET-B) receptor antagonist, microvascular responses to endothelin-1 were attenuated in the DOCA-salt group. These results indicated that the increased tissue level of endothelin-1 may decrease the ET-A receptormediated vascular response to endothelin-1. However, the ET-B receptor-mediated vasoconstriction is potentiated during DOCA-salt hypertension. Am J Hypertens 2000;13: American Journal of Hypertension, Ltd. KEY WORDS: Endothelin-1, DOCA-salt hypertension, endothelin antagonist, microcirculation, rat. Endothelin-1 is the most potent endogenous vasoconstrictor produced by the vascular endothelial cells. Two kinds of endothelin receptor subtypes exist on the vasculature: endothelin type A (ET-A) and endothelin type B (ET-B) receptors. 1 The long-lasting potent vasoconstrictor effect of endothelin-1 is mediated by both ET-A 1,2 and ET-B 3 6 receptors on vascular smooth muscle cells, whereas its transient vasodilator effect is mediated by Received July 20, Accepted January 5, From the Department of Physiology and Biophysics, University of Louisville, School of Medicine, Louisville, Kentucky. This study was sponsored by the American Heart Association and its Kentucky affiliate. Address correspondence and reprint requests to Irving G. Joshua, PhD, 1115 HSC, Department of Physiology and Biophysics, University of Louisville, Louisville, KY ET-B receptors on vascular endothelial cells. 7 This ET-B receptor-mediated vasodilation is believed to be caused by the stimulation of endogenous nitric oxide production. Previous studies have shown that microvascular responses to norepinephrine and vasopressin may play a role in maintenance of elevated peripheral resistance in DOCA-salt hypertension. 8,9 Recent studies have focused on the role of endothelin-1 in this model of hypertension. Day et al 10 showed that endothelin-1 content is increased in isolated thoracic aorta of DOCA-salt hypertensive rats. Using isolated mesenteric resistance arterioles, Deng and Schiffrin 11 noted that vascular contractile sensitivity to endothelin-1 is reduced in DOCA-salt hypertension in comparison to controls. On the other hand, Kirchner et al 12 showed that endothelium-dependent nitric oxide production is attenuated in DOCA-salt hypertension. Hirata et 2000 by the American Journal of Hypertension, Ltd /00/$20.00 Published by Elsevier Science, Inc. PII S (00)

2 820 ZHAO ET AL AJH JULY 2000 VOL. 13, NO. 7 al 13 further indicated that the ET-B receptor-induced nitric oxide production is also reduced in this type of hypertension. In addition, intravenous administration of the ET-A antagonist, FR , to DOCA-salt hypertensive rats produces a pronounced hypotensive effect. 14 Similarly, oral administration of a nonselective endothelin receptor antagonist, bosentan, to hypertensive rats also decreases blood pressure and reduces endothelin-induced vascular hypertrophy. 15 These studies suggested the involvement of endothelin-1 in the development and maintenance of DOCA-salt hypertension. To further test whether or not the in vivo vascular response to endothelin-1 is altered in DOCA-salt hypertension, we compared the effects of endothelin-1 mediated vasoconstriction and vasodilation in the striated muscle microcirculation of DOCA-salt hypertensive and normotensive rats. In addition, we measured endothelin-1 content in blood samples and thoracic aorta in both groups of rats. MATERIALS AND METHODS Animal Preparation Two groups of male Sprague- Dawley rats were used in the experiments: DOCA-salt hypertensive and control normotensive (CN). All Sprague-Dawley rats (110 to 130 g) were unilaterally nephrectomized under sodium pentobarbital anesthesia (50 mg/kg). After a 1-week postsurgical period, the experimental rats received a subcutaneous injection of DOCA suspended in corn oil at a concentration of 30 mg/kg, twice per week. These rats were also fed a high sodium-chloride (2.50%) and high-potassium (1.65%) diet. The CN rats were fed a normal diet. Blood pressure was measured indirectly on a weekly basis using a tail-cuff and a pneumatic pulse transducer (Narco Bio-systems, Inc., Houston, TX). DOCAsalt hypertensive rats were studied after their tail-cuff blood pressure rose higher than 140 mm Hg. The process for the induction of hypertension usually took 4 to 5 weeks after the uninephrectomy. Cremaster Preparation The rat was anesthetized with an intraperitoneal injection of sodium pentobarbital (50 mg/kg). A heating pad was placed under the animal to maintain rectal temperature at 37 C. The trachea was intubated to insure a patent airway, which allowed the animal to breathe room air spontaneously. The rat s left carotid artery was cannulated for continuous monitoring of the mean arterial pressure. The cremaster muscle was prepared using the technique described by Miller and Wiegman. 16 The left scrotum was incised to expose the cremaster muscle surrounding the left testicle. Then the cremaster was gently dissected free from the testicle by removing all connective tissue and severing all the collateral vessels to the testicle. Throughout the process, a physiologic solution was used to keep the cremaster moist. The rat was then transferred to a board designed so that the rat s hind limbs straddled a 50-mL tissue bath. The cremaster was suspended by silk sutures in a flat position over an optical port in the bath filled with a physiologic salt solution (in mmol/l): 25.5 NaHCO 3, NaCl, 4.7 KCl, 1.19 KH 2 PO 4, 1.19 MgSO 4 7H 2 O, 11.6 dextrose, and 2.55 CaCl 2 2H 2 O. The bath temperature was maintained at 34.5 C (the in situ scrotal sac temperature of conscious rats) with an immersed insulated heating coil. Bath ph ( ) was controlled by varying the amounts of carbon dioxide and nitrogen bubbled through the bath. The bubbling of these gases also insured complete mixing of drugs. The bath ph was continuously monitored using a ph electrode. The preparation was positioned on the stage of a trinocular microscope for observation of the cremaster microcirculation via closed-circuit television microscopy. The single largest arteriole that supplies blood to the cremaster muscle was termed the first-order arteriole (1A). Branches of 1A were termed second-order arterioles (2A), and their branches were termed thirdorder arterioles (3A). A single 3A vessel was chosen for observation in each rat. The image of the cremaster was recorded on videotape and displayed on a calibrated monitor at approximately 1000 to 1600 magnification. Luminal diameters were measured from the television monitor screen at 1-min intervals during control and experimental periods. Experimental Protocol 1 In the first series of studies, we observed the responses of cremaster arterioles to endothelin-1 (bath concentration: to 10 8 mol/l). The experiments began with a 5-min control period, followed by the topical application of endothelin-1. Drug concentrations were increased tenfold at 10-min intervals. Experimental Protocol 2 In the second series of experiments, the responses of cremaster arterioles to low concentrations of endothelin-1 (10 14 to mol/l) were observed after a 10-min pretreatment with the ET-A receptor antagonist, BQ 123 (10 6 mol/l). Concentrations of endothelin-1 were increased tenfold at 10-min intervals. Experimental Protocol 3 In the third series of experiments, the dose-response effects of endothelin-1 (10 13 to 10 8 mol/l) on cremaster arterioles were determined in the presence of the ET-B receptor antagonist, BQ 788. After a 5-min control period, BQ 788 (10 6 mol/l) was administrated to the bath for 10 min before the topical application of endothelin-1 (10 13 to 10 8 mol/l). BQ 788 was maintained in the bath throughout the dose-response study.

3 AJH JULY 2000 VOL. 13, NO. 7 ENDOTHELIN AND DOCA-SALT HYPERTENSION 821 TABLE 1. CHARACTERISTICS OF THE STUDY GROUPS FOR CREMASTER PREPARATION Number BW (g) BD ( m) MABP (mm Hg) DOCA-salt * * CN DOCA-salt deoxycorticosterone acetate-salt hypertensive group; CN control normotensive group; BW body weight; BD basal diameters of the third-order cremaster arterioles; MABP mean arterial blood pressure. P.05 v controls. Experimental Protocol 4 In the fourth series of experiments, tissue and blood concentrations of endothelin were measured using radioimmunoassay (RIA). Experimental rats were anesthetized with an intraperitoneal injection of sodium pentobarbital (50 mg/kg). A 0.9-mL sample of carotid arterial blood was collected into a tube containing 0.1 ml EDTA (10 mg/ml) at 4 C. The sample was centrifuged at 6000 g for 20 min. The supernatant was stored in a freezer at 80 C for future measurement. After thawing, an equal amount of Buffer A (1% trifluoroacetic acid [TFA] in distilled water) was added to the plasma. The mixture was centrifuged at 6000 g for 20 min at 4 C. The supernatant was passed through a C-18 Sep-column pretreated with Buffer A and Buffer B (60% acetonitrile in 1% TFA in distilled water). The column was washed with Buffer A twice and the peptide was eluted with Buffer B. The eluant was collected in a polypropylene tube and evaporated by a lyophilizer to dryness. Radioimmunoassay was performed using a radioimmunoassay kit for endothelin-1 (Peninsula Laboratories, Belmont, CA). The sensitivity of this kit is reported to be 1 pg. Segments of thoracic aorta were cleaned of connective tissue and were stored in a freezer at 80 C until they were processed. Frozen tissues were weighed and added to 2 ml cold Buffer A. Tissues were then homogenized with a polytron. The homogenate was centrifuged at 6000 g for 20 min at 4 C. The supernatant was loaded on the pretreated C-18 Sep-column and the subsequent procedures were the same as for plasma samples. Preparation of Drugs Endothelin-1 and BQ 788 were obtained from Peptides International (Louisville, KY). BQ 123 was obtained from Alexis Corporation (San Di- FIG. 1. Dose-response effect of endothelin-1 (ET) on the 3A vessels of the DOCA-salt and control groups of rats. n number of rats used in the experiment. Arteriolar responses (means SEM) are expressed as percentage of resting diameters during the 5-min control period. The pd2 values were significantly different between the DOCA-salt group and the control group of rats.

4 822 ZHAO ET AL AJH JULY 2000 VOL. 13, NO. 7 FIG. 2. Effects of an ET-A receptor antagonist, BQ 123, or an ET-B receptor antagonist, BQ 788, on resting vascular diameters in the DOCA-salt and the control groups of rats. Arteriolar responses (means SEM) are expressed as percentage of resting diameters during the 5-min control period. ego, CA). Endothelin-1 and BQ 788 were prepared in distilled water. BQ 123 was prepared in a 0.1 mol/l sodium bicarbonate solution and refrigerated in the dark until it was used. The C-18 Sep-column and the radioimmunoassay kit were purchased from Peninsula Laboratories (Belmont, CA). Statistical Analysis Data were reported as means standard error of the mean (SEM). Microvascular diameters were expressed as percent change from baseline values. The ED 50 dose was graphically determined and the value was converted to a pd 2 value (pd 2 log ED 50 ) as an indication of microvascular reactivity. Statistical analyses were performed using either Student s t tests or analysis of variance followed by Duncan s Multiple Range test for multiple comparisons. A P value of.05 was considered statistically significant. RESULTS Table 1 shows body weight, mean arterial blood pressure, and basal diameters of third-order arterioles of DOCA-salt and CN rats for cremaster preparation. Blood pressures and body weights of DOCA-salt rats were significantly higher than those of CN rats. Vascular diameters during the control periods did not show statistical difference between the two groups of rats. Fig. 1 shows the dose-response effects of endothelin-1 (10 13 to 10 8 mol/l) on the cremaster arteriolar diameters in the two groups of rats. The dose-response curve for the DOCA-salt hypertensive group shifted significantly to the right. Arteriolar reactivity to endothelin-1 expressed as a pd 2 value ( log ED 50 ) was significantly lower in the DOCA-salt group ( ) than in the CN group ( ). Fig. 2 shows the effects of both the ET-A receptor antagonist, BQ 123 (10 6 mol/l), and the ET-B receptor antagonist, BQ 788 (10 6 mol/l), on the resting diameters of both the DOCA-salt and control groups of rats. Neither BQ 123 nor BQ 788 had any effect on resting diameters in the two groups of rats. Fig. 3 shows the presence of the ET-A receptor antagonist, BQ 123 (10 6 mol/l), arteriolar responses to low concentrations of endothelin-1 (10 14 to mol/l) were present in the two groups of rats. Topical

5 AJH JULY 2000 VOL. 13, NO. 7 ENDOTHELIN AND DOCA-SALT HYPERTENSION 823 FIG. 3. Effects of pretreatment with BQ 123 on cremaster arteriolar responses to low concentrations of endothelin-1 (ET, mol/l) in the DOCA-salt and the control rats. n number of rats used in the experiment. Arteriolar responses (means SEM) are expressed as percent of resting diameters during the 5-min control period. *P.05 in comparison between the two groups. administration of endothelin-1 (10 14 to mol/l) in the presence of BQ 123 caused significant vasodilation in the CN group (117 9% of control diameter) and a significant vasoconstriction in the DOCA-salt group (70 9%). Fig. 4 illustrates the dose-response effects of endothelin-1 (10 13 to 10 8 mol/l) to cremaster arterioles in the presence of the ET-B antagonist, BQ 788. When compared to the control group, the dose-response curve for the DOCA-salt hypertensive group shifted significantly to the right. However, the pd 2 values did not show significant difference between the DOCAsalt group ( ) and the CN group ( ). Fig. 5 shows the concentrations of endothelin in thoracic aorta and plasma in both groups of animals. The concentration of endothelin in thoracic aorta of DOCA-salt rats ( pg/g) was significantly higher than that of control rats ( pg/g). In contrast, there were no significant differences in the plasma concentrations of endothelin in both groups of rats (58 10 fmol/ml for DOCA-salt v fmol/ml for CN). DISCUSSION In the present study, we topically applied exogenous endothelin-1 (10 13 to 10 8 mol/l) to the rat cremaster to compare its vasoactive effect in DOCA-salt hypertensive versus control rats (Fig. 1). Endothelin-1 caused a dose-dependent vasoconstriction of thirdorder cremaster arterioles in both groups of rats. Arteriolar sensitivity to endothelin-1 was decreased in DOCA-salt rats, especially when concentrations of endothelin-1 were low (10 13 to 10 9 mol/l). This result was consistent with the study of Nguyen et al, 17 who showed that responses of isolated aorta and mesenteric arteries to endothelin-1 were less in the DOCAsalt hypertensive group than in the normotensive control group. They explained this by demonstrating that the vascular endothelin receptor was downregulated in DOCA-salt hypertensive rats. Further studies indicated that during DOCA-salt hypertension, the exaggerated production of endothelin 18 might be the reason for the downregulation of ET-A receptors. To test whether the exaggerated production of endothelin-1 correlates with the decreased microvascular sensitivity to endothelin-1 during DOCA-salt

6 824 ZHAO ET AL AJH JULY 2000 VOL. 13, NO. 7 FIG. 4. Effects of pretreatment with BQ 788 on cremaster arteriolar responses to endothelin-1 (ET, to 10 8 mol/l) in the DOCA-salt and the control rats. n number of rats used in the experiment. Arteriolar responses (means sem) are expressed as percentage of resting diameters during the 5-min control period. *P.05 in comparison between the two groups. The pd2 values were similar between the two groups of rats. hypertension, we measured the concentration of endothelin in thoracic aorta and in plasma samples from DOCA-salt and control rats. We found that the concentration of endothelin in thoracic aorta was significantly higher in DOCA-salt rats than in normotensive rats (Fig. 5). In contrast, plasma concentrations of endothelin were similar in both groups of rats. It has been demonstrated that the majority of endothelin-1 is abluminally secreted from vascular endothelial cells. 19 In addition, the elimination of endothelin-1 from the bloodstream occurs rapidly. 20 Therefore, it is not surprising that the plasma level of endothelin was similar in both groups of rats, even though the tissue level of endothelin was greatly elevated in the DOCA-salt group. Based on our results, it appears that the increased production of endothelin may be the reason for the decreased vascular sensitivity to endothelin-1. The mechanism for the increased concentration of endothelin during DOCA-salt hypertension has yet to be clarified. Lariviere et al 18 indicated that the elevated endothelin-1 level in endothelial cells may be related to the increased shear stress, which is considered to be a potent stimulator of endothelin production. Our previous study showed that at low levels of endothelin-1, the effect of the ET-B receptor is to mediate vasodilation by stimulation of nitric oxide production. 21 In the present study, we tested whether the ET-B receptor-mediated vasodilation is altered during DOCA-salt hypertension. We used the ET-A receptor antagonist BQ 123 to compare the effects of endothelin stimulation of the ET-B receptor on vascular diameters in two groups of rats. Our results showed that pretreatment of BQ 123 had no effect on resting diameters of cremaster arterioles in both groups of rats (Fig. 2). This suggests that endothelin-1 may not play a significant role in regulating vascular basal tone in the cremaster circulation. However, after addition of exogenous endothelin-1, our results showed that stimulation of the ET-B receptor caused a significant vasoconstrictor in DOCA-salt hypertensive rats in comparison to its vasodilator effect in normotensive rats (Fig. 3). Based on this study,

7 AJH JULY 2000 VOL. 13, NO. 7 ENDOTHELIN AND DOCA-SALT HYPERTENSION 825 FIG. 5. Endothelin content in plasma and aorta of the DOCA-salt and the control rats. Values given are means SEM. n number of rats. Endothelin content is expressed as pg/g of the aorta, and as fmol/ml of the plasma. *P.05 in comparison between the two groups. it appears that the ET-B receptor-mediated vasodilation is abolished, and instead a vasoconstriction is produced in DOCA-salt hypertension. Similarly, Hirata et al 13 also suggested that the ET-B receptormediated vasodilation was greatly attenuated in DOCA-salt hypertension, based on the direct measurements of nitric oxide levels in isolated renal arterioles stimulated with ET-B receptor agonists. In contrast, we observed directly the vascular diameter changes in response to endothelin-1 in the presence of BQ 123. It has long been believed that the ET-B receptor on vascular endothelial cells, which mediates vasodilation via the stimulation of nitric oxide production, plays a predominant role, whereas the ET-B receptor on vascular smooth muscle cells, which causes vasoconstriction, is negligible in most vascular beds under normal physiologic conditions. Our results indicated that the ET-B receptor on vascular smooth muscle cells might dominate the ET-B receptor-induced vascular response in DOCA-salt hypertension. These results suggest that the alteration of the ET-B receptor-mediated vascular response in DOCA-salt hypertension may involve two mechanisms: an attenuated ET-B receptor-mediated vasodilation and an increased ET-B receptor-mediated vasoconstriction. To assess the role of the ET-B receptor in mediating microvascular constriction, we used the ET-B receptor antagonist BQ 788. It appears that the application of BQ 788 alone had no effect on the cremaster vascular basal tone (Fig. 2). In the presence of BQ 788, endothelin-1 induced vasoconstriction was blunted in DOCAsalt hypertension (Fig. 4). This further demonstrated the involvement of the ET-B receptor-induced vasoconstriction in this type of hypertension. Recent studies have shown that elevated endothelin-1 production could attenuate endogenous nitric oxide production. Hirahashi et al 22 and Markewitz et al 23 found that endothelin-1 inhibits the expression of inducible nitric oxide synthase and eventually attenuates nitric oxide production. Thus the possibility exists that during DOCA-salt hypertension, the increased tissue concentration of endothelin-1 could severely impair nitric oxide production via the inhibition of the expression of inducible nitric oxide synthase. In summary, the ET-A receptor-mediated vasoconstriction was reduced, whereas the ET-B receptor induced-vasoconstriction was enhanced with DOCAsalt hypertension. The increased tissue concentration of endothelin may cause the selective downregulation of ET-A receptors, which may be responsible for a portion of the altered vascular response to endothelin-1 in DOCA-salt hypertension.

8 826 ZHAO ET AL AJH JULY 2000 VOL. 13, NO. 7 REFERENCES 1. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S: Cloning and expression of a cdna encoding an endothelin receptor. Nature 1990;348(6303): Lin HY, Kaji EH, Winkel GK, Ives HE, Lodish HF: Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor. Proc Natl Acad Sci USA 1991;88(8): Ihara M, Saeki T, Funabashi K, Nakamichi K, Yano M, Fukuroda T, Miyaji M, Nishikibe M, Ikemoto F: Two endothelin receptor subtypes in porcine arteries. J Cardiovasc Pharmacol 1991;17(suppl 7):S119 S Fukuroda T, Nishikibe M, Ohta Y, Ihara M, Yano M, Ishikawa K, Fukami T, Ikemoto F: Analysis of responses to endothelins in isolated porcine blood vessels by using a novel endothelin antagonist, BQ-153. Life Sci 1992;50(15):PL107 PL Panek RL, Major TC, Hingorani GP, Doherty AM, Taylor DG, Rapundalo ST: Endothelin and structurally related analogs distinguish between endothelin receptor subtypes. Biochem Biophys Res Commun 1992;183(2): Moreland S, McMullen DM, Delaney CL, Lee VG, Hunt JT: Venous smooth muscle contains vasoconstrictor ET- B-like receptors. Biochem Biophys Res Commun 1992; 184(1): Takayanagi R, Kitazumi K, Takasaki C, Ohnaka K, Aimoto S, Tasaka K, Ohashi M, Nawata H: Presence of non-selective type of endothelin receptor on vascular endothelium and its linkage to vasodilation. FEBS Lett 1991;282(1): Schlegel PA, Monney M, Brunner HR: Isolated perfused mesenteric arteries of hypertensive and normotensive rats: response to norepinephrine, lysine vasopressin and angiotensin II. Clin Exp Hypertens [A] 1985;7(11): Lariviere R, St-Louis J, Schiffrin EL. Vascular binding sites and biological activity of vasopressin in DOCAsalt hypertensive rats. J Hypertens 1988;6(3): Day R, Lariviere R, Schiffrin EL: In situ hybridization shows increased endothelin-1 mrna levels in endothelial cells of blood vessels of deoxycorticosterone acetate-salt hypertensive rats. Am J Hypertens 1995;8(3): Deng LY, Schiffrin EL: Effects of endothelin on resistance arteries of DOCA-salt hypertensive rats. Am J Physiol 1992;262(6 Pt 2):H1782 H Kirchner KA, Scanlon PH Jr, Dzielak DJ, Hester RL: Endothelium-derived relaxing factor responses in DOCA-salt hypertensive rats. Am J Physiol 1993;265(3 Pt 2):R568 R Hirata Y, Hayakawa H, Suzuki E, Kimura K, Kikuchi K, Nagano T, Hirobe M, Omata M: Direct measurements of endothelium-derived nitric oxide release by stimulation of endothelin receptors in rat kidney and its alteration in salt-induced hypertension. Circulation 1995;91(4): Fujita K, Matsumura Y, Kita S, Miyazaki Y, Hisaki K, Takaoka M, Morimoto S: Role of endothelin-1 and the ET-A receptor in the maintenance of deoxycorticosterone acetate-salt-induced hypertension. Br J Pharmacol 1995;114(5): Li JS, Lariviere R, Schiffrin EL: Effect of a nonselective endothelin antagonist on vascular remodeling in deoxycorticosterone acetate-salt hypertensive rats. Evidence for a role of endothelin in vascular hypertrophy. Hypertension 1994;24(2): Miller FN, Wiegman DL: Anesthesia-induced alteration of small vessel response to norepinephrine. Eur J Pharmacol 1977;44(4): Nguyen PV, Parent A, Deng LY, Fluckiger JP, Thibault G, Schiffrin EL: Endothelin vascular receptors and responses in deoxycorticosterone acetate-salt hypertensive rats. Hypertension 1992;19(2 suppl):ii98 II Lariviere R, Thibault G, Schiffrin EL: Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not in spontaneously hypertensive rats. Hypertension 1993;21(3): Wagner OF, Christ G, Wojta J, Vierhapper H, Parzer S, Nowotny PJ, Schneider B, Waldhausl W, Binder BR: Polar secretion of endothelin-1 by cultured endothelial cells. J Bio Chem 1992;267(23): Levin ER. Endothelins as cardiovascular peptides. Am J Nephrol 1996;16(3): Zhao H, Joshua IG: Release of endogenous nitric oxide mediates arteriolar dilation to endothelin in rat striated muscle. J Cardiovasc Pharmacol 1998;31: Hirahashi J, Nakaki T, Hishikawa K, Marumo T, Yasumori T, Hayashi M, Suzuki H, Saruta T: Endothelin-1 inhibits induction of nitric oxide synthase and GTP cyclohydrolase I in rat mesangial cells. Pharmacology 1996;53(4): Markewitz BA, Michael JR, Kohan DE: Endothelin-1 inhibits the expression of inducible nitric oxide synthase. Am J Physiol 1997;272(6 Pt 1):L1078 L1083.

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