AT₁ receptor inhibition does not reduce arterial wall hypertrophy or PDGF-A expression in renal hypertension

Abstract

. AT 1 receptor inhibition does not reduce arterial wall hypertrophy or PDGF-A expression in renal hypertension. Am. J. Physiol. Heart Circ. Physiol. 278: H613-H622, 2000.-To separate the role of ANG II from pressure in hypertrophy of the vascular wall in one-kidney, one-clip (1K1C) hypertension, experimental and shamoperated rats were given the AT 1 -receptor antagonist losartan (20 mg · kg Ϫ1 · day Ϫ1 ) or tap water for 14 days. Mean arterial pressure was elevated in both experimental groups compared with controls. Rats were anesthetized with pentobarbital sodium, and the thoracic aorta and carotid, small mesenteric, and external spermatic arteries were harvested and embedded in paraffin. Tissue sections were used for morphological analysis, immunohistochemistry for 5-bromo-2Ј-deoxyuridine (BrdU) and platelet-derived growth factor (PDGF)-AA, stereological measurements, and in situ hybridization with a 35 S-labeled riboprobe for PDGF-A mRNA. Elevated cross-sectional areas of thoracic, carotid, and small mesenteric artery in 1K1C rats were not reduced by losartan. The internal diameter of the external spermatic artery and microvascular density of the cremaster muscle were reduced in 1K1C rats. The number of BrdU-positive nuclei per cross section did not differ between 1K1C and control arteries. PDGF-A mRNA was elevated in the arterial walls of 1K1C rats compared with controls and was hardly changed by losartan. PDGF-A protein stained strongly in the media of 1K1C arteries and was not inhibited by losartan; it appeared in the adventitia of all aortas and carotid arteries. These observations demonstrate that effects of ANG II mediated through the AT 1 receptor are not necessary for hypertrophy of the vascular wall during 1K1C hypertension or expression of PDGF-A.one-kidney, one-clip hypertension; losartan; arterial pressure; angiotensin; platelet-derived growth factor DURING THE COURSE of hypertension, individual arteries adapt to mechanical and hormonal stresses through alterations in medial thickness and/or internal and external diameters, depending on the size and function of the particular blood vessel. The larger arteries increase wall cross-sectional area with the development of outward hypertrophy (30, 45). The smaller arterioles undergo a decrease in lumen size without an increase in wall area and/or rarefaction, the reduction in number of functional vessels (16,31,38). Lumen reduction in the absence of hypertrophy is termed ''inward, eutrophic remodeling.'' Both ANG II and pressure have been implicated as stimuli for the vascular changes associated with hypertension (4,9,18,30,45). ANG II is a hypertrophic (18) as well as hyperplastic stimulus (47) of vascular smooth muscle cells (VSMCs) and has been shown to induce platelet-derived growth factor (PDGF)-A chain expression (28). Recently, we have shown that vascular hypertrophy following chronic infusion of ANG II was entirely prevented when the blood pressure was kept from rising by the simultaneous administration of minoxidil (34). Pressure, like ANG II,...

Differential effects of diet-induced obesity on BKCa β1-subunit expression and function in rat skeletal muscle arterioles and small cerebral arteries

“…In a separate study, cerebral arteries from OZR had increased myogenic tone and inward remodeling (53). Inward, eutrophic remodeling has been observed in cremaster muscle arterioles in one-kidney one-clip hypertension (55). In cerebral arteries from HFD-fed rats reduced lumen diameter, increased wall thickness and wall-to-lumen ratio were observed (10).…”

Role of Angiotensin II and Free Radicals in Blood Pressure Regulation in a Rat Model of Renal Hypertension

“…27 Therefore, blocking the angiotensin type 1 (AT 1 ) receptor with losartan will leave BP virtually unchanged. 28 Rats were treated with losartan for 2 weeks to …”

“…27 Therefore, blocking the angiotensin type 1 (AT 1 ) receptor with losartan will leave BP virtually unchanged. 28 Rats were treated with losartan for 2 weeks to delineate involvement of Ang II through the AT 1 receptor in oxidative stress and with tempol to assess involvement of superoxide anion. Tempol, a SOD mimetic permeable for cell membrane, 29 was shown to lower BP efficiently in spontaneously hypertensive but not Wistar-Kyoto rats.…”

Imatinib ameliorates renal morphological changes in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

“…Such elevated PDGF levels directly stimulated by the elevated arterial pressure may synergize with the elevated intrarenal ANG II levels to elicit renal functional and morphological derangements. In this regard, elevated arterial blood pressure increases PDGF expression as well as the expression of PDGF receptors in various tissues (8,9,19,26,28,36,42,43,50,68). PDGF is a 28-to 35-kDa peptide present in platelets and is secreted from vascular smooth muscle cells (VSMCs), endothelial cells, macrophages, and fibroblasts (17, 47).…”

“…MAPKs phosphorylate JNKs, which in turn results in the phosphorylation of many transcription factors, including the c-Jun component of the activator protein-1 transcription family (5). C-Jun is known to be required for PDGF-induced VSMC migration and proliferation, and JNK knockdown can attenuate cell migration and proliferation in PDGF-stimulated VSMCs (5).Although ANG II can directly activate PGDF receptors and induce PDGF expression (14,26,29,34,57), increases in arterial blood pressure directly induce PDGF expression and activate the PGDF receptor (8,19,36,37,42,43,50,54,68). Increased aortic steady-state mRNA levels of PDGF receptors were shown to be induced in DOCA salt-hypertensive rats (50).…”