Models of Cardiovascular Disease: Measurement of Antihypertensive Activity in the Conscious Rat (SHR, DOCA‐Salt, and Goldblatt Hypertension Models)

Philippe Guillaume1, Daniel Provost1, Pamela Legrand1, Michael Godes2, Pierre Lacroix1

1 Porsolt and Partners Pharmacology, Boulogne‐Billancourt, France, 2 Center for Cardiovascular Research/Institute of Pharmacology, Berlin, Germany
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.53
DOI:  10.1002/0471141755.ph0553s44
Online Posting Date:  March, 2009
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Abstract

The protocols described in this unit are used to assess the effects of new chemical entities on hypertension in conscious rats. In the spontaneously hypertensive rat (SHR) model, the results obtained with the reference compounds clonidine, prazosin, propranolol, and captopril are provided for illustration. All compounds demonstrate antihypertensive activity, with captopril and prazosin being the least and the most active, respectively. In the deoxycorticosterone acetate (DOCA)‐salt model in the rat, the test substance shown as an example (a potential endothelin ETA‐receptor antagonist) prevents the development of hypertension in the first phase. However, the effects of treatment disappear in the very last phase of the study, suggesting the development of a malignant hypertension resistant to treatment in this model. In the Goldblatt hypertension rat model (renal artery stenosis), losartan prevents the development of hypertension. It does not modify the weight of the right and left kidneys but slightly reduces the degree of cardiac hypertrophy. Curr. Protoc. Pharmacol. 44:5.53.1‐5.53.15. © 2009 by John Wiley & Sons, Inc.

Keywords: cardiovascular disease; hypertension; SHR; DOCA‐salt; Goldblatt hypertension

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Measuring Antihypertensive Activity in the Spontaneously Hypertensive Rat (SHR)
  • Basic Protocol 2: Measuring Antihypertensive Activity in the Pharmacologically Induced Hypertensive Rat (DOCA‐Salt)
  • Basic Protocol 3: Measuring Antihypertensive Activity in the Goldblatt Hypertension (Renal Artery Stenosis) Rat Model
  • Commentary
  • Literature Cited
  • Figures
     
 
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Materials

Basic Protocol 1: Measuring Antihypertensive Activity in the Spontaneously Hypertensive Rat (SHR)

  Materials
  • Male spontaneous hypertensive rats (SHR/Kyo; Elevage Janvier) 16 weeks old and 340 to 360 g
  • 30 mg/ml chloral hydrate (Cooper, Rhone‐Poulenc Rorer)
  • 5000 IU/ml sodium heparin (Sanofi‐Winthrop) in isotonic saline (Laboratoire Aguettant)
  • Penicillin G Diamant (Rhone‐Poulenc Rorer)
  • Isotonic saline (Laboratoire Aguettant)
  • Test compound(s)
  • 0.5% (w/v) carboxymethylcellulose (Cooper, Rhone‐Poulenc Rorer)
  • 6% (w/v) sodium pentobarbital in 0.9% (w/v) NaCl (physiological saline)
  • Polypropylene cages with 191‐in.2 (1232‐cm2, 28 × 44–cm) floor area
  • Animal balance accurate to 1 g (e.g., Sartorius)
  • Scalpel
  • 0.86‐mm i.d., 1.27‐mm o.d. catheter
  • Surgical thread (4.0 silk ligature)
  • Autoclavable stainless steel button (15‐mm diameter; Instech Solomon)
  • Tether assembly (Instech Solomon)
  • Single‐channel cannula swivel (Instech Solomon)
  • Harvard‐lock sutures with needles (Harvard Apparatus)
  • Blood pressure recorder (TA 240 graphic recorder; Gould Instrument Systems) equipped with:
    • Pressure processor
    • Isolated physiologic pressure transducer
  • 5‐ml syringes
  • 25‐G, 5/8‐in. Luer‐lock needles
  • 25 × 12/10–mm Luer gastric probes with olive extremity

Basic Protocol 2: Measuring Antihypertensive Activity in the Pharmacologically Induced Hypertensive Rat (DOCA‐Salt)

  Materials
  • Male Crl:CD (SD) Sprague Dawley rats (6 weeks old, 150 to 200 g; Charles River)
  • Powdered food (SAFE 113)
  • Isoflurane (Minerve)
  • Carprofen (Rimadyl; Pfizer)
  • Amoxicillin (Clamoxyl LA; Pfizer)
  • Test compound(s)
  • NaCl (Sigma), dissolved in drinking water
  • KCl (Sigma), dissolved in drinking water
  • 25‐mg deoxycorticosterone acetate (DOCA) pellet (21‐day slow release, Innovative Research of America cat. no. M‐121)
  • Isotonic saline (Laboratoire Aguettant)
  • Macrolon cages with 250‐in.2 (1610‐cm2, 35 × 46–cm) floor area
  • Animal balance accurate to 1 g (e.g., Sartorius)
  • Surgical thread (4.0 silk ligature)
  • Tail cuff apparatus (e.g., BP‐2000, Visitech Systems)

Basic Protocol 3: Measuring Antihypertensive Activity in the Goldblatt Hypertension (Renal Artery Stenosis) Rat Model

  Materials
  • Male Rj: Sprague Dawley rats (6 to 7 weeks old, 200 to 250 g; Janvier)
  • Powdered food (SAFE 113)
  • Ketamine 1000 (Virbac Santé Animale)
  • Xylazine (Rompum, Bayer)
  • Carprofen (Rimadyl, Pfizer)
  • Isotonic saline (Laboratoire Aguettant)
  • Losartan (Cozaar‐50 mg, GlaxoSmithKline)
  • Amoxicillin (Clamoxyl LA, Pfizer)
  • Test compound(s)
  • Isoflurane (Minerve)
  • 3‐ml EDTA glass tubes (Venoject)
  • Macrolon cages with 250‐in.2 (1610‐cm2, 35 × 46–cm) floor area
  • Animal balance accurate to 1 g (e.g., Sartorius)
  • U‐shaped silver clip (0.20‐mm i.d., Fine Science Tools)
  • Surgical thread (4.0 silk ligature)
  • Tail cuff apparatus (BP‐2000, Visitech Systems)
  • Microcapillary tubes
  • Laboratory ultracentrifuge (3 to 16K, Sigma)
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Figures

Videos

Literature Cited

Literature Cited
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   Clapham, J.C., Hamilton, T.C., and Longman, S.D., 1991. Antihypertensive and hemodynamic properties of the potassium channel‐activating (–) enantiomer of cromakalim in animal models. Arzneim.‐Forsch./Drug Res. 41:385‐391.
   Crofton, J.T., Share, L., and Shade, R.E. 1978. The importance of vasopressin in the development and maintenance of DOCA‐salt hypertension in the rat. Hypertension 1:31‐38.
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   Leenen, F.H.H. and De Jong, W. 1975. Plasma renin and sodium balance during development of moderate and severe renal hypertension in rats. Circ. Res. 36‐37:179‐184.
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   Pfeffer, M.A. and Frohlich, E.D. 1973. Hemodynamic and myocardial function in young and old normotensive and spontaneously hypertensive rats. Circ. Res. 32:28‐36.
   Pu, Q., Amiri, F., Gannon, P., and Schiffrin, E.L. 2005. Dual angiotensin‐converting enzyme/neutral endopeptidase inhibition on cardiac and renal fibrosis and inflammation in DOCA‐salt hypertensive rats. J. Hypertens. 23:401‐409.
   Roba, J.L. 1976. The use of spontaneously hypertensive rats for the study of anti‐hypertensive agents. Lab. Anim. Sci. 26:305‐319.
   Seymour, A.A., Norman, J.A., Asaad, M.M., Fennel, S.A., Little, D.K., Kratunis, V.J., and Roger, W.L. 1991. Antihypertensive and renal activity of SQ28,603, an inhibitor of neutral endopeptidase. J. Cardiovasc. Pharmacol. 17:296‐304.
   Stoepel, K., Heise, A., and Kazda, S. 1981. Pharmacological studies of the antihypertensive effect of nitrendipine. Arzneim.‐Forsch./Drug Res. 31:2056‐2061.
   Wenzel, U., Wuolf, G., Jacob, I., Schwegler, C., Qasqas, A., Amann, K., Helmchen, U., and Stahl, R. 2003. Beneficial and adverse renal vascular effects of the vasopeptidase inhibitor omapatrilat in renovascular hypertensive rats. Nephrol. Dial. Transplant. 18:2005‐2013.
   Yamori, Y., Matsumoto, M., and Yamabe, H. 1969. Augmentation of spontaneous hypertension by chronic stress in rats. Jpn. Circ. J. 33:399‐409.
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