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Invited Symposium: Hypertension I: Structure of Small Arteries in Hypertension






Abstract

Introduction

Materials & Methods

Results

Discussion & Conclusion

References




Discussion
Board

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Early Vascular Structural Changes After Short Term RAS Inhibition: Evidence for a Reversible Component of Regression


Contact Person: Taben M. Hale (4tmh@qlink.queensu.ca)

Introduction

It has been well established that drugs that antagonize the renin-angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 (AT1) receptor antagonists can induce a persistent lowering of blood pressure even after the withdrawal of treatment. These drugs have also been shown to cause a regression of vascular structure after long-term treatment. It has been suggested that there is a causal link between this structural sownregulation and the persistent lowering of blood pressure.

Six weeks of ACE inhibitor treatment induces a 20-30% reduction in structurally-based vascular resistance properties (Adams et al, 1990). The present study investigated whether the regression induced after only two weeks of RAS inhibition is proportional to the duration of treatment, i.e. one third of the regression observed after six weeks of therapy. To assess this we used an established hemodynamic technique based on the Poiseuille relationship to determine the regression of structurally-based vascular resistance at both maximum constriction and maximum dilation.

Enalapril, an ACE inhibitor, or losartan, an AT1 receptor antagonist was given to SHR in the drinking water for two weeks prior to assessment.

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Materials and Methods

Treatment Groups (2 weeks)

  1. SHR (275-350 g), untreated
  2. SHR (275-350 g), losartan (30 mg/kg per day, p.o.)
  3. SHR (275-350 g), enalapril (30 mg/kg per day, p.o.)

Vascular Assessment

  1. Rats anaesthetized with Inactin (100 mg/kg, i.p.)
  2. Catheterization of right common iliac artery
  3. Perfusion of right hindlimb (Folkow et al. 1970)
  4. Perfusion using dextran-tyrodes solution
  5. Maximum dilation (sodium nitroprusside, 20µg/ml
  6. Assessment of flow-pressure relationship (0.5 - 4 ml/min per 100 g BW)
  7. alpha1 adrenoceptor-response relationship to methoxamine (MXA 0.5 - 64 µg/ml)
  8. Maximum constriction (ANG II 200ng/ml, ADH 21 µg/ml, MXA 64 µg/ml)

Cardiac Assessment

Hearts excised, blotted dry, right ventricle and left ventricle plus septum separated and weighed

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Results

Fig. 1: Enalapril and losartan both induce a similar reduction of structurally-based vascular resistance properties (at maximum vasoconstriction) below control after 2 weeks of treatment (15%, 16% *p < .05).

Fig. 2: Enalapril and losartan both induce reduction in left ventricle to body weight ratio (18%, 12% *p < .05) below control values.

Fig. 3: Comparison of log EC50, slope of alpha1 adrenoceptor concentration-response curve, and the slope of the flow-pressure curves with the different treatments.

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Discussion and Conclusion

  1. The two week treatment produced an unexpectedly large degree of regression of structurally-based vascular resistance properties (see Fig. 1).
  2. The amount of regression observed was well in excess of the expected 6-8% and therefore was not in proportion to the duration of treatment.
  3. Based on previous published findings (Lundie, 1997), it appears that more than 4 weeks of treatment is required to produce a persistent lowering of blood pressure during the off treatment interval.
  4. Taken together, the present data combined with previous findings suggest that a short-term treatment produces qualitatively different changes than does a more prolonged (6-10 week) treatment. This difference likely indicates that an early decrease in structure represents a more transient or reversible component of regression.

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    References

    1. Adams MA, Bobik A, Korner PI (1990) Enalapril can prevent vascular amplifier development in spontaneously hypertensive rats. Hypertension (16:252-260)
    2. Folkow B, Hallback M, Lundgren Y, Weiss L (1970) Background of increased flow resistance and vascular reactivity in spontaneously hypertensive rats. Acta Physiol Scand (80:93-106)
    3. Lundie MJ, Friberg P, Kline RL, Adams MA (1997) Long-term inhibition of the renin-angiotensin system in genetic hypertension: analysis of the impact on blood pressure and cardiovascular structural changes. Journal of Hypertension (15:339-348)

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Hale, T.M.; Bushfield, T.L.; Adams, M.A.; (1998). Early Vascular Structural Changes After Short Term RAS Inhibition: Evidence for a Reversible Component of Regression. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/mulvany/hale0778/index.html
© 1998 Author(s) Hold Copyright