Altered myogenic constriction and endothelium-derived hyperpolarizing factor-mediated relaxation in small mesenteric arteries of hypertensive subtotally nephrectomized rats

et al. 2013

J Pharmacol Exp Ther

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Transactivation of epidermal growth factor receptor (EGFR) signaling by G protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, and cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. The main objective of the present study was to investigate cardiac, vascular, and renal effects of EGFR inhibition by 4- in the hypertensive chronic kidney disease model. Rats underwent 5/6 nephrectomy (5/ 6Nx) and were treated with PKI-166, lisinopril or vehicle from week 6 after disease induction until week 12. Sham animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx, including proteinuria, diminished creatinine clearance, and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (left ventricle end-diastolic pressure) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in the heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.

Section: Methodsmentioning

confidence: 99%

“…During the treatment period, proteinuria and tail-cuff blood pressure were assessed every 3 weeks. As blood pressure levels stabilize around 6 weeks after 5/6Nx (Gschwend et al, 2002;Vettoretti et al, 2006;Windt et al, 2008b), we initiated drug treatments at this time point to alleviate effects of PKI-166 on development of the disease model.…”

mentioning

confidence: 99%

Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

Ulu

Mulder

et al. 2013

J Pharmacol Exp Ther

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“…15 It is known that the myogenic response, the exact mechanism of which has, to date, not been fully explored, shares similar pathways (GPCR, PLC, PKC, RhoA/Rho kinase) [33][34][35] with vasoconstrictive agents such as noradrenaline, endothelin and AII. These pathways, which are activated during hypertension, have been implicated as strongly potentiating myogenic responses.…”

Section: Myogenic Constrictionmentioning

confidence: 99%

“…In both cases, treatment with ACE inhibitors (ACE-i) reverses altered MC, implicating a role of the renin-angiotensin-aldosterone system (RAAS). [14][15][16] The metabolism of oxygen by vascular smooth muscle cells (VSMCs) generates potentially harmful reactive oxygen species (ROS), including superoxide anion and hydroxyl radicals, as well as hydrogen peroxide. Under normal physiological conditions, the extent and rate of oxidant formation is balanced by the rate of oxidant elimination by the antioxidant enzymatic system, involving such as superoxide dismutase (SOD) and catalase.…”

Section: Introductionmentioning

confidence: 99%

Losartan protects mesenteric arteries from ROS-associated decrease in myogenic constriction following 5/6 nephrectomy

J Renin Angiotensin Aldosterone Syst

Dokkum

Goris

et al. 2011

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Background: Chronic renal failure (CRF) is associated with hypertension, proteinuria, loss of myogenic constriction (MC) of mesenteric arteries and increased production of reactive oxygen species (ROS) under experimental conditions. Previous results showed that ACE (angiotensin-converting enzyme activity) inhibitor therapy is effective in slowing down the progression of disease. Therefore, we wanted to study whether the inverse AT 1 (angiotensin II type 1) receptor agonist, losartan (LOS) was effective in preventing loss of MC in a rat model of CRF and whether acute ROS scavengers could improve MC. Methods: Rats underwent 5/6 nephrectomy (5/6 Nx) and were treated with vehicle or LOS (20 mg/kg/day; 5/6 Nx + LOS) for 12 weeks. Thereafter, the MC of the mesenteric arteries were measured in the presence and/or absence of tempol and catalase. Systolic blood pressure and proteinuria were measured weekly. Results: Systolic blood pressure and proteinuria in the 5/6 Nx + LOS group were significantly lower than in the 5/6 Nx group. Moreover, the MC of 5/6 Nx + LOS arteries was significantly increased compared with the untreated 5/6 Nx group (maximum MC, 32.3 ± 6.9 vs 8.9 ± 3.8% (p < 0.01)). Tempol + catalase significantly increased the MC in the 5/6 Nx group, but not in the 5/6 Nx + LOS group (increase in MC, 59.7 ± 13.0 (p < 0.05) vs. 17.0 ± 15.1%). Conclusion: These results support the roles of the RAAS (renin-angiotensin-aldosterone system) and ROS in the vascular dysfunction of systemic vessels in CRF.

“…Taken together, these phenomena lead to elevated renin and consequently ANG II levels as well as subsequent development of renal damage after 5/6Nx. Intervention in the RAAS by both angiotensin-converting enzyme inhibition or by blocking AT1R is effective in slowing down the progression of renal damage in this model, which collectively point to the pathogenic role of ANG II in this model (15,16). The importance of RAAS is further substantiated by experiments showing that sustained ANG II administration dose dependently induces proteinuria accompanied by progressive glomerular damage in otherwise healthy individuals (8), while short-term ANG II infusion, sufficient to affect renal hemodynamics, does not elicit proteinuria (13).…”

mentioning

confidence: 99%

Vascular smooth muscle function of renal glomerular and interlobar arteries predicts renal damage in rats

American Journal of Physiology-Renal Physiology

Henning

Goris

et al. 2012

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Vavrinec P, Henning RH, Goris M, Vavrincova-Yaghi D, Buikema H, van Dokkum RP. Vascular smooth muscle function of renal glomerular and interlobar arteries predicts renal damage in rats. Am J Physiol Renal Physiol 303: F1187-F1195, 2012. First published July 11, 2012 doi:10.1152 doi:10. /ajprenal.00653.2011 was shown that individuals with good baseline (a priori) endothelial function in isolated (in vitro) renal arteries developed less renal damage after 5 ⁄6 nephrectomy (5/6Nx; Gschwend S, Buikema H, Navis G, Henning RH, de Zeeuw D, van Dokkum RP. J Am Soc Nephrol 13: 2909 -2915, 2002). In this study, we investigated whether preexisting glomerular vascular integrity predicts subsequent renal damage after 5/6Nx, using in vivo intravital microscopy and in vitro myogenic constriction of small renal arteries. Moreover, we aimed to elucidate the role of renal ANG II type 1 receptor (AT1R) expression in this model. Anesthetized rats underwent intravital microscopy to visualize constriction to ANG II of glomerular afferent and efferent arterioles, with continuous measurement of blood pressure, heart rate, and renal blood flow. Thereafter, 5/6Nx was performed, interlobar arteries were isolated from the extirpated kidney, and myogenic constriction was assessed in a perfused vessel setup. Blood pressure and proteinuria were assessed weekly for 12 wk, and focal glomerulosclerosis (FGS) was determined at the end of study. Relative expression AT1R in the kidney cortex obtained at 5/6Nx was determined by PCR. Infusion of ANG II induced significant constriction of both afferent and efferent glomerular arterioles, which strongly positively correlated with proteinuria and FGS at 12 wk after 5/6Nx. Furthermore, in vitro measured myogenic constriction of small renal arteries negatively correlated with proteinuria 12 wk after 5/6Nx. Moreover, in vivo vascular reactivity negatively correlated with in vitro reactivity. Additionally, relative expression of AT1R positively correlated with responses of glomerular arterioles and with markers of renal damage. Both in vivo afferent and efferent responses to ANG II and in vitro myogenic constriction of small renal arteries in the healthy rat predict the severity of renal damage induced by 5/6Nx. This vascular responsiveness is highly dependent on AT1R expression. Intraorgan vascular integrity may provide a useful tool to guide the prevention and treatment of renal end-organ damage.predictive value of vascular function; in vivo microscopy; 5 ⁄6 nephrectomy; renal damage; renal vascular smooth muscle; myogenic constriction; ANG II type 1 receptor WHILE THE SUSCEPTIBILITY TO develop renal damage varies considerably among individuals, its determinants are still incompletely understood. The extent of existing systemic factors, such as diabetes or hypertension, cannot fully explain the predisposition to renal failure, suggesting additional factors to be involved (9). In general, the factors governing this individual vulnerability to renal damage are thought to be intrinsic to the kidney and prob...