Angiotensin-converting enzyme inhibition and AT1 receptor blockade modify the pressure-natriuresis relationship by additive mechanisms in rats with human renin and angiotensinogen genes.

The intrarenal factors responsible for hypertension in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes are unclear. The pressure-natriuresis and -diuresis relationships in response to chronic angiotensin-converting enzyme (ACE) inhibition and AT1 receptor blockade were evaluated. Renal renin-angiotensin and nitric oxide (NO) system gene expression was also investigated. Six-week-old dTGR were treated for 3 wk with submaximal doses of cilazapril (10 mg/kg, orally) or losartan (10 mg/kg, orally) or with the drug combination. In untreated dTGR, pressure-natriuresis relationships were maximally shifted rightward by approximately 70 to 80 mmHg, and both renal blood flow (RBF) and GFR were markedly decreased. Submaximal cilazapril and losartan dosages both decreased systolic BP by 30 mmHg and shifted the pressure-natriuresis curves leftward by 25 to 30 mmHg. Cilazapril increased RBF and GFR to values observed in normotensive control animals but did not significantly affect fractional sodium excretion (FENa) or fractional water excretion (FEH2O) curves. In contrast, losartan had no significant effect on RBF or GFR but shifted the FENa and FEH2O curves leftward. The cilazapril and losartan combination completely normalized BP and shifted the pressure-natriuresis curves leftward more than did either drug alone. When cilazapril and losartan were administered at higher doses (30 mg/kg, orally), the two drugs equally shifted the pressure-natriuresis curves leftward, by 50 mmHg. Both drugs increased RBF and GFR; however, only losartan shifted FENa and FEH2O curves leftward. Human and rat renin and angiotensinogen genes were downregulated in dTGR and were increased by losartan and cilazapril treatments, whereas no changes in the expression of rat ACE and AT1A receptor genes were observed. Endothelial NO synthase expression was increased by cilazapril but not by losartan. Neither inducible NO synthase nor neural NO synthase gene expression was affected by drug treatments. Therefore, submaximal ACE inhibition enhanced sodium excretion mainly by increasing RBF and GFR, whereas submaximal AT1 receptor blockade decreased tubular sodium and water reabsorption. The combination of the two drugs produced an additive effect. The ACE inhibitor effects may involve increased endothelial NO synthase expression, perhaps related to the inhibition of bradykinin degradation.

[1]  D. Ganten,et al.  Hypertension-induced end-organ damage : A new transgenic approach to an old problem. , 1999, Hypertension.

[2]  D. Ganten,et al.  Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension. , 1999, Hypertension.

[3]  D. Ganten,et al.  Pressure-natriuresis and -diuresis in transgenic rats harboring both human renin and human angiotensinogen genes. , 1998, Journal of the American Society of Nephrology : JASN.

[4]  R. Paniagua,et al.  Renal effects of renin-angiotensin system blockade. , 1998, Current opinion in nephrology and hypertension.

[5]  A. Hansson,et al.  Cortical and medullary hemodynamics in deoxycorticosterone acetate-salt hypertensive mice. , 1998, Journal of the American Society of Nephrology : JASN.

[6]  A. Hansson,et al.  Nitric oxide synthase and renin-angiotensin system gene expression in salt-sensitive and salt-resistant Sabra rats. , 1997, Hypertension.

[7]  A. Cowley,et al.  Role of the renal medulla in volume and arterial pressure regulation. , 1997, The American journal of physiology.

[8]  M. Adams,et al.  The persistent effect of long-term enalapril on pressure natriuresis in spontaneously hypertensive rats. , 1997, The American journal of physiology.

[9]  F. Luft,et al.  Pressure natriuresis in salt-sensitive and salt-resistant Sabra rats. , 1997, Hypertension.

[10]  R. Largo,et al.  Endothelin-1 upregulation in the kidney of uninephrectomized spontaneously hypertensive rats and its modification by the angiotensin-converting enzyme inhibitor quinapril. , 1997, Hypertension.

[11]  N. Samani,et al.  Tissue expression of components of the renin-angiotensin system in experimental post-infarction heart failure in rats: effects of heart failure and angiotensin-converting enzyme inhibitor treatment. , 1997, Clinical science.

[12]  L. Navar,et al.  Renal responses to AT1 blockade in angiotensin II-induced hypertensive rats. , 1997, Journal of the American Society of Nephrology : JASN.

[13]  J. Ménard,et al.  High human renin hypertension in transgenic rats. , 1997, Hypertension.

[14]  F. Luft,et al.  Lifelong angiotensin-converting enzyme inhibition, pressure natriuresis, and renin-angiotensin system gene expression in transgenic (mRen-2)27 rats. , 1996, Journal of the American Society of Nephrology : JASN.

[15]  M. Schambelan,et al.  Tissue-specific regulation of type 1 angiotensin II receptor mRNA levels in the rat. , 1996, Hypertension.

[16]  S. Majid,et al.  Paracrine regulation of the renal microcirculation. , 1996, Physiological reviews.

[17]  F. Luft,et al.  Effect of captopril and angiotensin II receptor blockade on pressure natriuresis in transgenic TGR(mRen-2)27 rats. , 1995, Hypertension.

[18]  D. Ganten,et al.  Angiotensin II receptor blockade in TGR(mREN2)27: effects of renin–angiotensin-system gene expression and cardiovascular functions , 1995, Journal of hypertension.

[19]  T. Unger,et al.  Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. , 1995, Pharmacological reviews.

[20]  R. Kline,et al.  Modification of pressure natriuresis by long-term losartan in spontaneously hypertensive rats. , 1994, Hypertension.

[21]  V. Gross,et al.  Abnormal pressure‐natriuresis in transgenic renin gene rats , 1994, Journal of hypertension.

[22]  J. van der Mark,et al.  Altered pressure natriuresis in chronic angiotensin II hypertension in rats. , 1994, The American journal of physiology.

[23]  O. Carretero,et al.  Local Hormonal Factors (Intracrine, Autocrine, and Paracrine) in Hypertension , 1991, Hypertension.

[24]  P. Timmermans,et al.  Effects of DuP 753 on renal function of normotensive and spontaneously hypertensive rats. , 1991, American journal of hypertension.

[25]  S. Harrap,et al.  PERSISTENT EFFECTS ON BLOOD PRESSURE AND RENAL HAEMODYNAMICS FOLLOWING CHRONIC ANGIOTENSIN CONVERTING ENZYME INHIBITION WITH PERINDOPRIL , 1986, Clinical and experimental pharmacology & physiology.

[26]  M. Sjöquist,et al.  Superficial and juxtamedullary nephron function during converting enzyme inhibition. , 1986, The American journal of physiology.

[27]  Hall Je Regulation of glomerular filtration rate and sodium excretion by angiotensin II. , 1986 .

[28]  J. Hall Regulation of glomerular filtration rate and sodium excretion by angiotensin II. , 1986, Federation proceedings.

[29]  P. Harris,et al.  Tubular transport responses to angiotensin. , 1985, The American journal of physiology.

[30]  J. Granger,et al.  Acute and chronic actions of bradykinin on renal function and arterial pressure. , 1985, The American journal of physiology.

[31]  R. Zusman,et al.  Renin- and non-renin-mediated antihypertensive actions of converting enzyme inhibitors. , 1984, Kidney international.

[32]  L. Navar,et al.  Influence of Converting Enzyme Inhibition on Renal Hemodynamics and Glomerular Dynamics in Sodiumhyphenrestricted Dogs , 1982, Hypertension.

[33]  H. E. Williamson,et al.  Mechanism of natriuretic action of bradykinin. , 1969, The American journal of physiology.