Gender differences in development of hypertension in spontaneously hypertensive rats: role of the renin-angiotensin system.

Previous data strongly support a role for androgens in promoting the gender difference in hypertension in the spontaneously hypertensive rat(s) (SHR), but the mechanism is not clear. Because males develop higher blood pressures than do females, we hypothesize that androgens may affect the renin-angiotensin system to promote the development of hypertension in male SHR. The present study was performed to determine the effect of converting enzyme inhibition (CEI) on the development of hypertension in SHR. Male, female, castrated male, and ovariectomized (ovx) female SHR (n=10 per gender per treatment group) received enalapril (250 mg/L) in drinking water for 8 to 10 weeks. Some ovx females were also given testosterone chronically. At 17 to 19 weeks of age, 24-hour protein excretion and mean arterial pressure were measured. By 13 weeks of age, male rats had higher systolic blood pressures by tail plethysmography than did the other rats, and CEI reduced blood pressures to similar levels in all groups. At 17 to 19 weeks, the same trend was found by direct measurement of mean arterial pressure. The ovx females treated with testosterone had serum testosterone and blood pressure levels similar to those found in males. CEI reduced mean arterial pressure to similar levels in all gender groups. Untreated males and ovx females given testosterone had significantly higher levels of urinary protein excretion than did the other groups, and CEI had no effect on proteinuria in any of the rats. These data suggest that the development of hypertension in SHR regardless of sex steroids is mediated by the renin-angiotensin system. However, the data further suggest that androgens promote the exacerbation of hypertension in male SHR via a mechanism involving the renin-angiotensin system.

[1]  Gerhard Giebisch,et al.  The Kidney: Physiology and Pathophysiology , 1992 .

[2]  G. Somes,et al.  Ambulatory blood pressure recordings in children and adolescents. , 1994, Pediatrics.

[3]  L. Juncos,et al.  Pressure-induced constriction of the afferent arteriole of spontaneously hypertensive rats. , 1992, Hypertension.

[4]  M. Chappell,et al.  Estrogen regulation of angiotensin-converting enzyme mRNA. , 1999, Hypertension.

[5]  E. Frohlich,et al.  Effects of ANG-converting enzyme and alpha 1-adrenoceptor inhibition on intrarenal hemodynamics in SHR. , 1994, The American journal of physiology.

[6]  J. Hall,et al.  Abnormal pressure natriuresis. A cause or a consequence of hypertension? , 1990, Hypertension.

[7]  S. Glasson,et al.  Captopril and hypertension development in the SHR. , 1980, Clinical and experimental hypertension.

[8]  T. Berg,et al.  The role of endogenous bradykinin in blood pressure homeostasis in spontaneously hypertensive rats , 1996, British journal of pharmacology.

[9]  C. Dunnett.  A Multiple Comparison Procedure for Comparing Several Treatments with a Control , 1955 .

[10]  W. Arendshorst,et al.  Role of angiotensin in the renal vasoconstriction observed during the development of genetic hypertension. , 1990, Kidney international. Supplement.

[11]  J. Morton,et al.  Angiotensin II receptor antagonist losartan has persistent effects on blood pressure in the young spontaneously hypertensive rat: lack of relation to vascular structure. , 1992, Journal of vascular research.

[12]  E. Jackson,et al.  Angiotensin II: enhanced renal responsiveness in young genetically hypertensive rats. , 1995, The Journal of pharmacology and experimental therapeutics.

[13]  B. Iversen,et al.  Effects of antihypertensive drugs on autoregulation of RBF and glomerular capillary pressure in SHR. , 1998, The American journal of physiology.

[14]  R. A. Norman,et al.  Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension. , 1972, The American journal of medicine.

[15]  W. Arendshorst,et al.  Abnormalities in glomerular function in rats developing spontaneous hypertension. , 1984, The American journal of physiology.

[16]  G. Vinson,et al.  Young SHR express increased type 1 angiotensin II receptors in renal proximal tubule , 1998 .

[17]  S. Oparil,et al.  Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats. , 1992, Hypertension.

[18]  S. Rosenkranz,et al.  Estrogen modulates AT1 receptor gene expression in vitro and in vivo. , 1998, Circulation.

[19]  J. Granger,et al.  Gender differences in hypertension in spontaneously hypertensive rats: role of androgens and androgen receptor. , 1999, Hypertension.

[20]  S. Rosenkranz,et al.  Estrogen Modulates AT 1 Receptor Gene Expression In Vitro and In Vivo Brief Rapid Communication , 1998 .

[21]  C. Gomez-Sanchez,et al.  The intravenous furosemide test: a simple way to evaluate renin responsiveness. , 1976, Annals of internal medicine.

[22]  E. Schiffrin,et al.  Vascular angiotensin II receptors in SHR. , 1984, Hypertension.

[23]  J. Ingelfinger,et al.  Androgen regulation of rat renal angiotensinogen messenger RNA expression. , 1989, The Journal of clinical investigation.

[24]  H. Hirche,et al.  [Blood pressure in children and adolescents aged 4 to 18. Correlation of blood pressure values with age, sex, body height, body weight and skinfold thickness (Essen Blood Pressure Study)]. , 1987, Monatsschrift Kinderheilkunde : Organ der Deutschen Gesellschaft fur Kinderheilkunde.

[25]  M. Fregly,et al.  Role of gonadal hormones in hypertension in the Dahl salt-sensitive rat. , 1992, Clinical and experimental hypertension. Part A, Theory and practice.

[26]  J. Sowers,et al.  Ambulatory blood pressure monitoring in a nonacademic setting. Effects of age and sex. , 1992, American journal of hypertension.

[27]  H. Schunkert,et al.  Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. , 1997, Circulation.

[28]  J. Chao,et al.  Regulation of bradykinin B2‐receptor expression by oestrogen , 1997, British journal of pharmacology.

[29]  N. Ashton,et al.  Sexual dimorphism in renal function and hormonal status of New Zealand genetically hypertensive rats. , 1991, Acta endocrinologica.

[30]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[31]  G. Haddad,et al.  Characterization and hemodynamic implications of renal vascular angiotensin II receptors in SHR. , 1996, Journal of molecular and cellular cardiology.

[32]  J. Laragh,et al.  Renin relationship to sex, race and age in a normotensive population. , 1986, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[33]  L. Bang,et al.  24-h ambulatory blood pressure in 352 normal Danish subjects, related to age and gender. , 1995, American journal of hypertension.

[34]  M. Katori,et al.  Lack of contribution of circulatory kinin elevated by captopril to induce hypotension in normotensive and hypertensive rats. , 1996, Immunopharmacology.

[35]  J. Staessen,et al.  Reference values for ambulatory blood pressure: a meta-analysis. , 1990, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[36]  H. Hirche,et al.  Blutdruck bei Kindern und Adoleszenten im Alter von 4 bis 18 Jahren. Korrelation der Blutdruckwerte mit Alter, Geschlecht, Körperlänge, Körpergewicht und Hautfaltendicke (Essener Blutdruckstudie) , 1987 .

[37]  D. Ely,et al.  Castration lowers and testosterone restores blood pressure in several rat strains on high sodium diets. , 1994, Clinical and experimental hypertension.

[38]  J. Granger,et al.  Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats. , 1998, Hypertension.