Blockade of angiotensin II type 1 receptor and not of endothelin receptor prevents hypertension and cardiovascular disease in transgenic (mREN2)27 rats via adrenocortical steroid-independent mechanisms.

We investigated the role of angiotensin II (Ang II) and endothelin-1 (ET-1) in transgenic (mREN2)27 rats, a model of the monogenic renin-dependent form of severe hypertension and cardiovascular disease. Four-week-old heterozygous male transgenic (mREN2)27 rats (n=24) were matched according to body weight (BW) and blood pressure (BP) and randomly allocated to receive a placebo (group P), the mixed endothelin type A and B receptor antagonist bosentan (100 mg/kg BW PO, group B), the Ang II type 1-specific receptor antagonist irbesartan (50 mg/kg BW PO, group I), or the endothelin type A-selective antagonist BMS-182874 (52 mg/kg BW PO, group BMS). After 4 weeks of treatment, during which BW and BP were measured weekly, animals were euthanized, and the heart, left ventricle, right ventricle, adrenal gland, brain, and kidney were weighed. The plasma levels of adrenocortical steroids were measured by high-performance liquid chromatography. The tension responses of ET-free segments of the thoracic aorta to 5 x 10(-6) mmol/L phenylephrine, 60 mmol/L KCl, and cumulative doses of ET-1 were assessed. The density of ET-1 receptor subtypes in the aorta and vascular structural changes in the mesenteric arterioles (100 to 200 microm ID) were also measured with autoradiography and myography, respectively. Compared with all other groups, group I rats showed significantly (P<0.001) lower systolic BP (group I, 161+/-8 mm Hg; group P, 269+/-23 mm Hg; group B, 275+/-17 mm Hg; and group BMS, 254+/-21 mm Hg), left ventricular weight (2.28+/-0.15 versus 3. 71+/-0.26, 3.38+/-0.27, and 3.96+/-0.51 mg/g BW, respectively), tension responses to vasoconstrictors, and normalized media thickness of the mesenteric arterioles (22.3+/-0.6 versus 25.3+/-0.5, 25.5+/-0.7, and 24.1+/-1.5 microm, respectively). Compared with levels in group P (78+/-25 pmol/mL), plasma aldosterone levels were significantly decreased in group B (51+/-11 pmol/mL) and group I (40+/-16 pmol/mL). Thus, endogenous ET-1 and Ang II contribute to the regulation of aldosterone, but only Ang II is crucial for the development of hypertension and related target organ damage via the Ang II type 1 receptor. Endogenous Ang II does not appear to enhance cardiovascular production of ET-1 in this model of hypertension within the time span of our experiment.

[1]  A. Pessina,et al.  Interactions between endothelin-1 and the renin–angiotensin–aldosterone system , 1999 .

[2]  A. Bauch,et al.  Endothelin system-dependent cardiac remodeling in renovascular hypertension. , 1999, Hypertension.

[3]  Y. Pinto,et al.  Dissociation of blood pressure reduction from end‐organ damage in TGR(mREN2)27 transgenic hypertensive rats , 1998, Journal of hypertension.

[4]  E. Schiffrin.  Endothelin and endothelin antagonists in hypertension , 1998, Journal of hypertension.

[5]  G. Albertin,et al.  11β‐Hydroxysteroid dehydrogenase expression and activity in the human adrenal cortex , 1998 .

[6]  G. Heyndrickx,et al.  Angiotensin II and endothelin‐1 receptor antagonists have cumulative hypotensive effects in canine Page hypertension , 1998, Journal of hypertension.

[7]  M. Raschack,et al.  Nephroprotection of an ETA-Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats , 1998 .

[8]  D. Ganten,et al.  Changes of blood pressure and aortic strip contractile responses to ET-1 of heterozygous female transgenic rats, TGR(mRen2)27. , 1998, Pharmacological research.

[9]  T. Lüscher,et al.  Angiotensin II Increases Vascular and Renal Endothelin-1 and Functional Endothelin Converting Enzyme Activityin Vivo:Role of ETAReceptors for Endothelin Regulation , 1997 .

[10]  T. Lüscher,et al.  Angiotensin II increases tissue endothelin and induces vascular hypertrophy: reversal by ET(A)-receptor antagonist. , 1997, Circulation.

[11]  S. Rajagopalan,et al.  Role for endothelin-1 in angiotensin II-mediated hypertension. , 1997, Hypertension.

[12]  T. Lüscher,et al.  Blood pressure and vascular effects of endothelin blockade in chronic nitric oxide-deficient hypertension. , 1997, Hypertension.

[13]  J. R. Mcneill,et al.  Effect of an endothelin antagonist on hemodynamic responses to angiotensin II. , 1996, Hypertension.

[14]  H. van Essen,et al.  Disproportional arterial hypertrophy in hypertensive mRen-2 transgenic rats. , 1996, Hypertension.

[15]  E. Schiffrin,et al.  Effect of endothelin antagonism on blood pressure and vascular structure in renovascular hypertensive rats. , 1996, The American journal of physiology.

[16]  G. Albertin,et al.  Endothelin adrenocortical secretagogue effect is mediated by the B receptor in rats. , 1996, Hypertension.

[17]  E. Schiffrin,et al.  Vascular and cardiac overexpression of endothelin‐1 gene in one‐kidney, one clip Goldblatt hypertensive rats but only in the late phase of two‐kidney one clip Goldblatt hypertension , 1996, Journal of hypertension.

[18]  J. Firth,et al.  Endothelin in the kidney in malignant phase hypertension. , 1995, Hypertension.

[19]  J. Mullins,et al.  Haemodynamic effects of losartan and the endothelin antagonist, SB 209670, in conscious, transgenic ((mRen‐2)27), hypertensive rats , 1995, British journal of pharmacology.

[20]  G. Mazzocchi,et al.  Morphology and function of the adrenal zona glomerulosa of transgenic rats TGR [mREN2] 27: Effects of prolonged sodium restriction , 1995, The Journal of Steroid Biochemistry and Molecular Biology.

[21]  E. Porteri,et al.  Effects of low and high doses of fosinopril on the structure and function of resistance arteries. , 1995, Hypertension.

[22]  M. Nakashima,et al.  Angiotensin AT1 receptor-mediated attenuation of cardiac hypertrophy due to volume overload: involvement of endothelin. , 1995, European journal of pharmacology.

[23]  T. Waldron,et al.  Antihypertensive effects of a novel endothelin-A receptor antagonist in rats. , 1995, Hypertension.

[24]  H. Scholz,et al.  Role of endogenous endothelins in the renin system of normal and two-kidney, one clip rats. , 1995, Hypertension.

[25]  E. Ohlstein,et al.  Angiotensin type 1 receptors mediate smooth muscle proliferation and endothelin biosynthesis in rat vascular smooth muscle. , 1994, The Journal of pharmacology and experimental therapeutics.

[26]  G. Albertin,et al.  Gene expression, localization, and characterization of endothelin A and B receptors in the human adrenal cortex. , 1994, The Journal of clinical investigation.

[27]  E. Porteri,et al.  Delayed development of hypertension after short-term nitrendipine treatment. , 1994, Hypertension.

[28]  W. Neidhart,et al.  Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. , 1994, The Journal of pharmacology and experimental therapeutics.

[29]  S. Anderson,et al.  Altered renal vascular responses in the aging rat kidney. , 1994, The American journal of physiology.

[30]  M. Webb,et al.  Endothelin-1 and angiotensin-II stimulate delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for common signaling mechanisms. , 1994, Molecular endocrinology.

[31]  B. Chua,et al.  Regulation of endothelin-1 mRNA by angiotensin II in rat heart endothelial cells. , 1993, Biochimica et biophysica acta.

[32]  A. Nogami,et al.  Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. , 1993, The Journal of clinical investigation.

[33]  D. Ganten,et al.  The role of the adrenal gland in hypertensive transgenic rat TGR(mREN2)27. , 1992, Endocrinology.

[34]  D. Ganten,et al.  Increased Vascular Angiotensin Formation in Female Rats Harboring the Mouse Ren‐2 Gene , 1992, Hypertension.

[35]  Y. Hirata,et al.  Induction of Endothelin‐1 Gene by Angiotensin and Vasopressin in Endothelial Cells , 1992, Hypertension.

[36]  D. Ganten,et al.  Sexual dimorphism of blood pressure: Possible role of the renin-angiotensin system , 1991, The Journal of Steroid Biochemistry and Molecular Biology.

[37]  A. Pessina,et al.  Decreased density of endothelin-1 binding sites in aortic smooth muscle cells of spontaneously hypertensive rats. , 1991, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[38]  M. Mulvany,et al.  Structure and function of small arteries. , 1990, Physiological reviews.

[39]  T. Resink,et al.  Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. , 1990, Cell regulation.

[40]  T. Quertermous,et al.  Functional analysis of the endothelin-1 gene promoter. Evidence for an endothelial cell-specific cis-acting sequence. , 1990, The Journal of biological chemistry.

[41]  T. Resink,et al.  Endothelin stimulates phospholipase C in cultured vascular smooth muscle cells. , 1988, Biochemical and biophysical research communications.

[42]  M. Kuhar,et al.  Neurotransmitter Receptor Binding , 1984 .

[43]  M. Mulvany,et al.  Direct Evidence that the Greater Contractility of Resistance Vessels in Spontaneously Hypertensive Rats is Associated with a Narrowed Lumen, a Thickened Media, and an Increased Number of Smooth Muscle Cell Layers , 1978, Circulation research.

[44]  M. Mulvany,et al.  Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. , 1977, Circulation research.

[45]  G. Jansen,et al.  Early-onset but not late-onset endothelin-A-receptor blockade can modulate hypertension, cerebral edema, and proteinuria in stroke-prone hypertensive rats. , 1999, Hypertension.

[46]  G. Jansen,et al.  Cerebral Edema , and Proteinuria in Stroke-Prone Hypertensive Rats Receptor Blockade Can Modulate − Early-Onset , 1999 .

[47]  A. Mimran,et al.  Prevention of the cardiovascular and renal effects of angiotensin II by endothelin blockade. , 1998, Hypertension.

[48]  T. Lüscher,et al.  Effects of chronic ETA-receptor blockade in angiotensin II-induced hypertension. , 1997, Hypertension.

[49]  T. Lüscher,et al.  Angiotensin II increases vascular and renal endothelin-1 and functional endothelin converting enzyme activity in vivo: role of ETA receptors for endothelin regulation. , 1997, Biochemical and biophysical research communications.

[50]  A. Pessina,et al.  In vitro vascular reactivity to endothelin: a comparison between young and old normotensive and hypertensive rats. , 1990, Clinical and experimental hypertension. Part A, Theory and practice.