Orthostatic Hypotension Induced by Postural Change in the Rat (Tilt Test)

Philippe Guillaume1, Stéphane Hervé1, Sandra Picard1, Pierre Lacroix1

1 Porsolt and Partners Pharmacology, Boulogne‐Billancourt, France
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.45
DOI:  10.1002/0471141755.ph0545s40
Online Posting Date:  March, 2008
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Postural‐change‐induced (orthostatic) hypotension is defined as an excessive drop in arterial blood pressure occurring when moving toward an upright position. This side effect, which may limit the therapeutic use of some agents, can occur with drugs, such as adrenoceptor blockers and vasodilators, that dampen sympathetic reflex activity. Described in this unit is a procedure for evaluating the effects of test substances on the changes in blood pressure and heart rate that occur in an anesthetized, normotensive rat during a tilting challenge (head‐up position). In addition to being a relatively simple technique, this assay yields reproducible orthostatic hypotensive responses and allows for the investigation, in the same preparation, of several ascending doses of a test substance. Examples of results obtained with prazosin, an α1‐adrenoceptor antagonist that is notorious for causing orthostatic hypotension, are provided for illustrative purposes. Curr. Protoc. Pharmacol. 40:5.45.1‐5.45.8. © 2008 by John Wiley & Sons, Inc.

Keywords: animal models; safety pharmacology; cardiovascular effects; orthostatic hypotension; arterial blood pressure

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Table of Contents

  • Commentary
  • Literature Cited
  • Figures
  • Tables
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Basic Protocol 1:

  • Male Wistar (Han) rats weighing 180 to 220 g at the beginning of the experiment (Elevage Janvier, France)
  • 5 mg/ml sodium pentobarbital (e.g., Ceva Santé Animale; http://www.ceva.com) in sterile physiological saline (0.9% NaCl)
  • 150 IU/ml heparin in physiological saline (add from 5000 IU/ml heparin solution purchased, e.g., from Sanofi Pharma Choay)
  • Physiological (isotonic) saline (0.9% NaCl), sterile
  • Test substance
  • Animal balance accurate to 1 g (e.g., Sartorius type 1401.001.2)
  • Macrolon cages (41 × 25 × 18 cm or 44 × 28 × 19 cm)
  • Wood litter
  • Rat chow
  • 5‐ml Terumo syringes, type B5‐05S or BS‐01T, and 25‐G or 23‐G needles
  • Surgical tools (scalpel, chisel, clips, etc.)
  • 0.58 mm i.d. × 0.96 mm o.d. polyethylene catheters for i.v. injection
  • 0.86 mm i.d. × 0.96 mm o.d. polyethylene catheters for ABP measurements
  • Blood pressure recorder (TA 240, Gould Instrument Systems) equipped with a pressure processor (11‐G4113‐01, Gould Instrument Systems) and a pressure transducer (P23XL, Spectramed)
  • Tilting board (home‐made; Fig. ; further described under step 4, below)
  • Additional reagents and equipment for injection of rat (Donovan and Brown, )
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Literature Cited

Literature Cited
   Akiyama, K., Hora, M., Yamagishi, R., and Kitazawa, M. 2002. Effects of KMD‐3213, a uroselective α1A‐adrenoceptor antagonist, on the tilt‐induced blood pressure response in normotensive rats. Jpn. J. Pharmacol. 90: 131‐137.
   Carruthers, S.G. 1994. Adverse effects of alpha 1‐adrenergic blocking drugs. Drug Safety 11: 12‐20.
   Dampney, R.A.L., Coleman, M.J., Fontes, M.A.P., Hirooka, Y., Horiuchi, J., Li, Y‐W., Polson, J.W., Potts, P.D., and Tagawa, T. 2002. Central mechanisms underlying short‐ and long‐term regulation of the cardiovascular system. Clin. Exp. Pharmacol. Physiol. 29: 261‐268.
   Donovan, J.D. and Brown, P. 2006. Parenteral injections. Curr Protoc. Immunol. 73: 1.6.1‐1.6.10.
   Golin, R.M., Gotoh, E., Said, S.I., and Ganong, W.F. 1988. Pharmacological evidence that the sympathetic nervous system mediates the increase in renin secretion produced by immobilization and head‐up tilt in rats. Neuropharmacology 27: 1209‐1213.
   Hashimoto, Y., Ohashi, R., Minami, K., and Narita, H. 1999. Comparative study of TA‐606, a novel angiotensin II receptor antagonist, with losartan in terms of species difference and orthostatic hypotension. Jpn. J. Pharmacol. 81: 63‐72.
   Matos de Moura, M., Sousa dos Santos, R.A., and Peliky Fontes, M.A. 2005. Evidence for a functional cardiac interaction between losartan and angiotensin‐(1‐7) receptors revealed by orthostatic tilting test in rats. Br. J. Pharmacol. 144: 755‐760.
   McCall, R.B. and Humphrey, S.J. 1981. Evidence of a central depressor action of postsynaptic alpha 1‐adrenergic receptor antagonists. J. Auton. Nerv. Syst. 3: 9‐23.
   Ohlstein, E.H., Gellai, M., Brooks, D.P., Vickery, L., Jugus, J., Sulpizio, A., Ruffolo, R.R., Weinstock, J., and Edwards, R.M. 1992. The antihypertensive effect of the angiotensin II receptor antagonist DuP 753 may not be due solely to angiotensin II receptor antagonism. J. Pharmacol. Exp. Ther. 262: 595‐601.
   Persson, B., Yao, T., and Thorén, P. 1981. Correlation between decreased heart rate and central inhibition of sympathetic discharge after prazosin administration in the spontaneous hypertensive rat. Clin. Exp. Hypertens. 3: 245‐255.
   Schwartz, K.M., Urthaler, F., and James, T.N. 1982. The direct negative chronotropic action of prazosin on the canine sinus node. J. Pharmacol. Exp. Ther. 221: 801‐805.
   Stella, A., Dampney, R.A., Golin, R., and Zanchetti, A. 1978. Differences in reflex control of arterial blood pressure and renin release during head‐up tilting in the cat. Clin. Sci. Mol. Med. Suppl. 4: 179S‐181S.
   Take, H., Shibata, K., Awaji, T., Hirasawa, A., Ikegaki, I., Asano, T., Takada, T., and Tsujimoto, G. 1998. Vascular α1‐adrenoceptor subtype selectivity and α1‐blocker‐induced orthostatic hypotension. Jpn. J. Pharmacol. 77: 61‐70.
   Tsunoo, M., Shishito, A., Yoshii, Y., Komori, M., and Shimoyama, M. 1990. Phase I clinical trial of YM617, a new α1 adrenoceptor antagonist—First report: A single oral dose of conventional formulation in healthy male subjects. Rinshoiyaku 12: 2503‐2528 (text in Japanese with English abstract).
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