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Vasopeptidase Inhibition Restores Renovascular Endothelial Dysfunction in Salt-Induced Hypertension

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Vasopeptidase Inhibition Restores Renovascular Endothelial Dysfunction in Salt-Induced Hypertension J Am Soc Nephrol 12: 2280–2287, 2001 Vasopeptidase Inhibition Restores Renovascular Endothelial Dysfunction in Salt-Induced Hypertension THOMAS QUASCHNING,* LIVIUS V. D’USCIO,* SIDNEY SHAW,† HERMANN-JOSEF GRO¨ NE,‡ FRANK RUSCHITZKA,§ and THOMAS F. LU¨ SCHER§ *Cardiovascular Research, Institute of Physiology, University of Zu¨rich, Zu¨rich, Switzerland; †Clinical Research, Inselspital, University of Bern, Bern, Switzerland; ‡Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; and §Cardiovascular Center and Cardiology, University of Zu¨rich, Zu¨rich, Switzerland. Abstract. Renovascular hemodynamics plays a pivotal role in 6%; P Ͻ 0.05) as well as contractions to endothelin-1 (ET-1) the regulation of BP. The effect of the vasopeptidase inhibitor (98 Ϯ 5% versus 128 Ϯ 5%; P Ͻ 0.05) and big ET-1 (47 Ϯ 6% omapatrilat (O) and the ACE-inhibitor captopril (C) on endo- versus 116 Ϯ 7%; P Ͻ 0.05) were markedly reduced as thelial function in the renal circulation in salt-induced hyper- compared with control animals, whereas standardized aortic tension were investigated. Dahl salt-sensitive rats (n ϭ 6 per weight and heart weight (4.9 Ϯ 0.4 versus 3.2 Ϯ 0.3 g/kg; group) on standard or salt-enriched chow were treated for 8 wk P Ͻ 0.05) increased. Treatment with O restored endotheli- with O (36 Ϯ 4 mg/kg per d), C (94 Ϯ 2 mg/kg per d), or um-dependent relaxations (88 Ϯ 6%; P Ͻ 0.05 versus C) placebo. Renal arteries were suspended in organ chambers for and contractions to ET-1 (120 Ϯ 6%) and big ET-1 (98 Ϯ isometric tension recording. Vascular hypertrophy was as- 9%). O prevented vascular hypertrophy (0.23 Ϯ 0.019 mg/ sessed by determination of standardized heart weight and aortic mm2 versus 0.31 Ϯ 0.018 mg/mm2 in high-salt diet; P Ͻ weight, and morphologic analysis of glomerular injury was 0.05), but, in contrast to C, it only had a modest effect on performed. Systolic BP of salt-fed, placebo-treated animals glomerular injury. In conclusion, O restored renovascular increased to 196 Ϯ 6 mmHg, which was reduced by O (162 Ϯ endothelial function and prevented vascular hypertrophy in 5 mmHg; P Ͻ 0.05) and C (164 Ϯ 7 mmHg; P Ͻ 0.05) to a salt-induced hypertension and therefore may advance as a comparable degree. In salt-induced hypertension, endothelium- beneficial approach in the therapy of various forms of dependent relaxations in renal arteries (56 Ϯ 6 versus 100 Ϯ hypertension. Inhibition of the angiotensin-converting enzyme (ACE) is a (10). Hence the overall effect of NEP inhibition on vascular well-established treatment option for patients with hyperten- tone will depend on the effects of a compound on the proces- sion and improves morbidity and mortality in large clinical sion of these different vasoactive substances and is—espe- studies (1, 2). The mechanisms involved in the vasculoprotec- cially in molecules, which inhibit other systems as well— tive effects of ACE inhibitors appear—in large part—to be difficult to predict. Nevertheless, omapatrilat (O), a new related to their effects on endothelial function. Indeed, in vasopeptidase inhibitor, effectively lowers BP in salt-depen- human coronary arteries and saphenous veins, endothelium- dent and volume-dependent as well as in renin-dependent dependent relaxations to bradykinin are enhanced after prein- forms of hypertension (11). The combination of ACE and NEP cubation with an ACE inhibitor (3, 4). inhibition may be particularly useful in the treatment of hy- Vasopeptidase inhibition represents a new therapeutic prin- pertension (5, 12–14) and heart failure (15–19). ciple in hypertension (5–7) and heart failure (8), which in- Vasopeptidase inhibitors lower BP in a broader range of cludes inhibition of neutral endopeptidase (NEP) in addition to conditions than inhibition of ACE or NEP alone, and their ACE inhibition. NEP catalyzes the degradation of a number of effectiveness seems to be independent of the activity of the endogenous vasodilator peptides, including atrial natriuretic renin-angiotensin system or the degree of salt retention (20). O peptide, brain natriuretic peptide, C-type natriuretic peptide, is a new vasopeptidase inhibitor that induces long-lasting an- substance P, and bradykinin, as well as vasoconstrictor pep- tihypertensive effects in experimental hypertension (12), tides, including endothelin-1 (ET-1) (9) and angiotensin II greater than those elicited by selective inhibition of either enzyme alone (11). Furthermore, O lowers BP and attenuates cardiac hypertrophy in diabetic hypertensive rats (21). Mean- Received May 9, 2000. Accepted February 27, 2001. while, first clinical data are available, demonstrating hemody- Correspondence to Dr. Thomas F. Lu¨scher, Professor and Head of Cardiology, namic benefits of treatment with O in patients with hyperten- University Hospital, CH-8091 Zu¨rich, Switzerland. Phone: 0041 1 255 21 21; Fax: 0041 1 255 42 51; E-mail: [email protected] sion (14, 22–24) and heart failure (8, 25–27). The first large- 1046-6673/1211-2280 scale clinical study on heart failure indicates reduced morbidity Journal of the American Society of Nephrology and mortality on treatment with O as compared with ACE Copyright © 2001 by the American Society of Nephrology inhibitor treatment (28). J Am Soc Nephrol 12: 2280–2287, 2001 Omapatrilat and Endothelial Function 2281 Despite obvious clinical benefit of vasopeptidase inhibitors mol/L) were obtained in quiescent preparations. To avoid the devel- in heart failure and hypertension, their mechanism of action is opment of tachyphylaxis, only single concentrations of angiotensin I Ϫ7 still poorly understood. A positive influence of O on vessel and angiotensin II were used (10 mol/L). All drugs used in the stiffness (19) and vascular remodeling (29, 30) has been shown organ bath were obtained from Sigma Chemical Co (Buchs, Switzer- before. Also, long-term vasopeptidase inhibition exerts bene- land) apart from ET-1 and big ET-1, which were purchased from Novabiochem/Calbiochem AG (La Jolla, CA). ficial effects in the renal circulation (26). Influences of va- sopeptidase inhibitors on endothelial function in the renal artery may substantially improve renal hemodynamics and Vascular and Cardiac Hypertrophy therefore contribute to their beneficial systemic effects. For assessment of vascular hypertrophy, aortic rings were blotted Therefore, this study was designed to investigate the effects dry and weighed, and the arterial surface area of opened rings was measured as described (33). Aortic surface area was calculated using of long-term treatment with the vasopeptidase inhibitor O on formulas for diameter and radius of a cylinder for each individual ring, renovascular endothelial function as well as its effects on and values were averaged. After exsanguination of the animals, hearts vascular hypertrophy in a model of salt-induced hypertension. were removed, isolated, and snap-frozen in liquid nitrogen. Wet weight of hearts was measured, standardized for body weight, and Materials and Methods reported as mg heart weight/kg body weight. Animals Male Dahl salt-sensitive rats 12 wk of age were obtained from Morphologic Analysis of Glomerular Injury Charles River WIGA GmbH (Sulzfeld, Germany) and randomly as- Renal injury was assessed as described previously (34). Briefly, signed to one of four treatment regimens: (1) standard chow (control); paraffin-embedded sections of whole kidneys (5 to 7 ␮m) stained with (2) salt-enriched (4% NaCl) chow (Harlan Teklad, Madison, WI), periodic acid-Schiff reagent were viewed by light microscopy at a ϩ which was given alone (salt diet); (3) together with O (salt O); or magnification of ϫ40 using a Zeiss microscope (Carl Zeiss GmbH, ϩ (4) with captopril (C) (salt C). O and C were provided by Bristol- Jena, Germany). One hundred glomeruli per slide were evaluated. Myers Squibb Pharmaceutical Research Institute (Princeton, NJ). The Morphologic evaluation of glomerular injury was performed using rats were treated for 8 wk, and chow and drug intakes were monitored semi-quantitative scoring methods. Lesions were graded by glomer- during the entire study. Systolic arterial BP and heart rate (HR) were ulosclerosis (grade 1 to 4: 1 to 25%, 26 to 50%, 51 to 76%, and 76 to measured by the tail-cuff method with a pulse transducer (model LE 100% sclerosis, respectively). The glomerular injury score was cal- 5000; Letica, Barcelona, Spain) (31). The study design and the ex- culated by summarizing the products of severity grade times the perimental protocols were approved by the institutional animal care percentage of glomeruli displaying the same degree of severity. committee (Kommission fu¨r Tierversuche des Kantons Zu¨rich, Switzerland). Calculations and Statistical Analyses Tissue Harvesting Relaxations to agonists in isolated arteries are reported as percent precontraction in rings precontracted with norepinephrine to about Animals were anesthetized with pentobarbital (50 mg/kg intraperi- 70% of contraction induced by KCl (100 mmol/L). The contractions toneally) after 8 wk treatment, and blood samples were collected were expressed as a percentage of 100 mmol/L KCl–induced contrac- through puncture of the right ventricle. The renal arteries were re- tions, which were obtained at the beginning of each experiment. moved, dissected free from adherent connective tissue, and placed Results are presented as mean Ϯ SEM. Functional endothelin-con- immediately into cold (4°C) modified Krebs-Ringer bicarbonate so- verting-enzyme (ECE) activity was calculated as the ratio of the lution: 118.6 mmol/L NaCl, 4.7 mmol/L KCl, 2.5 mmol/L CaCl , 1.2 Ϫ 2 contraction to big ET-1 (10 7 mol/L) divided by the contraction to mmol/L MgSO , 1.2 mmol/L KH PO , 25.1 mmol/L NaHCO , 0.026 Ϫ 4 2 4 3 ET-1 (10 7 mol/L). In all experiments, n equals the number of rats per mmol/L ethylenediaminetetraacetic acid, and 10.1 mmol/L glucose.
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