In the present study, we investigated renal microvascular responses to ANG-(1-7) and ANG IV. Diameter changes of small interlobular arteries, afferent arterioles, and efferent arterioles were assessed by using isolated perfused hydronephrotic rat kidneys. ANG-(1-7) and ANG IV concentration dependently decreased the diameters of all investigated renal microvessel, however, with a much lower potency than ANG II. The ANG II type 1 receptor blocker irbesartan completely reversed the responses to ANG-(1-7) and ANG IV, whereas the ANG II type 2 receptor blocker PD-123319 had no effect. Both ANG-(1-7) and ANG IV failed to alter renal microvascular constriction induced by ANG II. In addition, subnanomolar concentrations of ANG-(1-7) had no effect on the myogenic-induced tone of interlobular arteries and afferent arterioles. Thus our data indicate that at high concentrations, ANG-(1-7) and ANG IV are able to activate the ANG II type 1 receptor, thereby inducing renal microvascular constriction. The failure of ANG-(1-7) and ANG IV to reduce ANG II- and pressure-induced constrictions suggests that these fragments do not exert a vasodilator and/or ANG II antagonistic action in the kidney.

van Rodijnen WF, Korstjens IJ, Legerstee N, ter Wee PM, Tangelder GJ. Direct vasoconstrictor effect of prostaglandin E 2 on renal interlobular arteries: role of the EP3 receptor. Am J Physiol Renal Physiol 292: F1094 -F1101, 2007. First published December 5, 2006; doi:10.1152/ajprenal.00351.2005.-Evidence indicates that prostaglandin E2 (PGE2) preferentially affects preglomerular renal vessels. However, whether this is limited to small-caliber arterioles or whether larger vessels farther upstream also respond to PGE2 is currently unclear. In the present study, we first investigated the effects of PGE 2 along the preglomerular vascular tree and subsequently focused on proximal interlobular arteries (ILAs). Proximal ILAs in hydronephrotic rat kidneys as well as isolated vessels from normal kidneys constricted in response to PGE2, both under basal conditions and after the induction of vascular tone. By contrast, smaller vessels, i.e., distal ILAs and afferent arterioles, exhibited PGE2-induced vasodilation. Endothelium removal and pretreatment of single, isolated proximal ILAs with an EP1 receptor blocker (SC51322, 1 mol/l) or a thromboxane A2 receptor blocker (SQ29548, 1 mol/l) did not prevent vasoconstriction to PGE2. Furthermore, in the presence of SC51322, responses of these vessels to PGE2 and the EP1/EP3 agonist sulprostone were superimposable, indicating that PGE2-induced vasoconstriction is mediated by EP3 receptors on smooth muscle cells. Immunohistochemical staining of proximal ILAs confirmed the presence of EP3 receptor protein on these cells and the endothelium. Adding PGE2 to normal isolated kidneys induced a biphasic flow response, i.e., an initial flow increase at PGE2 concentrations Յ0.1 mol/l followed by a flow decrease at 1 mol/l PGE2. Thus our results demonstrate that PGE2 affects multiple segments of the preglomerular vascular tree in a different way. At the level of the proximal ILAs, PGE2 had a direct vasoconstrictor action mediated by EP3 receptors. interlobular arteries; vasoconstriction PGE 2 IS ONE OF the major cyclooxygenase-derived products produced by the kidney (17). The actions of PGE 2 intrarenally include both tubular and vascular effects (2). The latter are important for regulating renal function under various circumstances. So far, the effects of PGE 2 on smaller pre-and postglomerular arterioles have mainly received attention. The postglomerular efferent arterioles were found to be insensitive to PGE 2 (4, 23), while for the preglomerular afferent arterioles (AAs) and distal interlobular arteries (ILAs) most studies indicated vasodilation (4,8,23), although vasoconstriction in certain instances has been reported as well (9, 23). Whether larger vessels further upstream of the glomerulus are also sensitive to PGE 2 is currently unknown. Previous studies have demonstrated that larger preglomerular vessels constrict in response to inflammatory mediators, such as serotonin and leukotrienes (5, 19), suggesting a similar mode of action for PGE 2 .In general, the actions of PGE 2 are m...

Abstract-Fawn-Hooded rats possess an increased risk to develop glomerular damage. Both an impaired control of preglomerular resistance and an elevated postglomerular resistance have been implicated. In the present study, we directly assessed the myogenic reactivity of distal interlobular arteries and afferent arterioles from hypertensive and normotensive Fawn-Hooded rats compared with Sprague-Dawley and Wistar rats, which are known to be resistant for developing renal disease. Pressure-response curves were made in isolated perfused hydronephrotic kidneys from these rats. In addition, increasing concentrations of angiotensin II were added to the perfusate to determine the reactivity of interlobular arteries, afferent arterioles, and efferent arterioles to this peptide. Preglomerular vessels from hypertensive and normotensive Fawn-Hooded rats exhibited an impaired reactivity to both pressure and angiotensin II compared with that of Sprague-Dawley and Wistar rats. Basal efferent arteriolar diameters were similar among the 4 strains of rat. In addition, efferent arterioles from hypertensive and normotensive Fawn-Hooded rats displayed a reduced sensitivity to angiotensin II. Our observations demonstrate that in Fawn-Hooded rats, 2 components of preglomerular resistance control are impaired: the myogenic and the angiotensin II response. In addition, efferent arteriolar reactivity to angiotensin II is not elevated but lowered in these rats. Therefore, a deficit in preglomerular resistance control is the most important intrinsic factor involved in the increased susceptibility of Fawn-hooded rats to develop renal disease. Key Words: rats, Fawn-hooded Ⅲ hydronephrosis Ⅲ renal circulation Ⅲ pressure Ⅲ angiotensin II Ⅲ vasoconstriction G lomerular hypertension is generally thought to play an important role in the pathophysiology of chronic renal failure. 1 In a genetic rat model of this disease, ie, the Fawn-Hooded hypertensive (FHH) rat, an elevated glomerular capillary pressure precedes the development of proteinuria and focal glomerulosclerosis. 2,3 In these animals, systemic arterial pressure is already moderately elevated at a relatively young age. 4,5 Simons et al 3 reported that glomerular capillary pressure correlated closely to the level of systemic arterial pressure in FHH rats treated with antihypertensive agents. Moreover, autoregulation of glomerular capillary pressure was found to be impaired, 6 suggesting that a disturbed control of the preglomerular resistance contributes to glomerular hypertension in this strain of rat.In a genetically closely related normotensive strain of the FHH rat, ie, the Fawn-Hooded low blood pressure (FHL) rat, renal damage develops at a slower rate. 7 However, when in these rats systemic arterial blood pressure is elevated by nitro-L-arginine methyl ester treatment, the incidence of focal glomerulosclerosis increases markedly. 8 These data indicate that also FHL rats possess an increased susceptibility to develop glomerular hypertension, leading to chronic renal failure eventually....

Contraction of vascular smooth muscle is determined not only by levels of intracellular free calcium but also by the sensitivity of its contractile apparatus. A potential modulator of the latter is rho-kinase. We addressed the question of a possible central role for rhokinase in the regulation of periglomerular microvascular tone. In the rat hydronephrotic kidney model, diameter changes of distal interlobular arteries, afferent and efferent arterioles were measured using three distinctly different stimuli: intravascular pressure changes, angiotensin II (AngII) and membrane depolarization, which is a physiological component of many signaling pathways, as evoked in two ways. Two selective, structurally different rho-kinase inhibitors, Y-27632 and HA-1077, were employed, as well as a selective protein kinase C alpha inhibitor. Preglomerular vasoconstriction induced by direct membrane depolarization, increases in pressure or AngII all depended for their effect on rho-kinase. A differing role for rho-kinase in efferent arteriolar constriction to AngII as compared to preglomerular microvessels was not found. In conclusion, our data indicate that in the kidney, rho-kinase is involved in a variety of signaling pathways leading to microvascular constriction. It plays a pivotal role not only in preglomerular but also in postglomerular tone.

Angiotensin II (Ang II) type 1 (AT 1 ) receptor blockers differ in their affinity for the AT 1 -receptor, suggesting a dissimilar potency for inhibiting Ang II-induced vascular constriction. In the present study, we compared the effects of candesartan, irbesartan and losartan on the renal microvascular constriction to locally-formed Ang II, using isolated, perfused hydronephrotic rat kidneys. Addition of 1 nmol/L angiotensin I (Ang I, the precursor of Ang II) significantly reduced the diameters of interlobular arteries (ILAs; -47.6±2.6%), afferent arterioles (AAs; -43.6±2.3%) and efferent arterioles (EAs; -31.6±2.4%). Candesartan and irbesartan were more potent in antagonising the constriction to Ang I than losartan. By contrast, candesartan and irbesartan differed only slightly in potency. After a washing period of 60 minutes with drug-free medium, a second application of Ang I failed to induce vasoconstriction only in candesartan-treated kidneys. Pretreatment of hydronephrotic kidneys with candesartan, to further explore its antagonistic properties, shifted the dose-response curves of Ang II approximately 2 log units to the right without reducing the maximal Ang IIinduced constriction of ILAs, AAs or EAs. Additionally, dose-response curves of Ang II were similar after short (10 minutes) and prolonged (60 minutes) preincubation with candesartan. Our findings indicate that candesartan and irbesartan are more potent inhibitors of renal microvascular constriction to locallyformed Ang II than losartan. The inhibitory effect of candesartan is more prolonged, suggesting a slow dissociation from the AT 1 -receptor. Additionally, candesartan was found to block the Ang II-induced constriction of renal microvessels in a surmountable manner. IntroductionThe renin angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of systemic blood pressure and local renal haemodynamics. One of its effector peptides, angiotensin II (Ang II), acts as a strong vasoconstrictor and stimulates sodium and fluid retention. Increased levels of Ang II are thought to be critically involved in the development and maintenance of hypertension and congestive heart failure. In these clinical settings, pathophysiological actions of Ang II are predominantly mediated via the Ang II type 1 (AT 1 )