Renal microvascular actions of angiotensin II fragments.

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.

Reduced reactivity of renal microvessels to pressure and angiotensin II in fawn-hooded rats.

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.

Comparison of the AT1-receptor blockers candesartan, irbesartan and losartan for inhibiting renal microvascular constriction.

Angiotensin II (Ang II) type 1 (AT1) receptor blockers differ in their affinity for the AT1-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 II-induced 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 locally-formed Ang II than losartan. The inhibitory effect of candesartan is more prolonged, suggesting a slow dissociation from the AT1-receptor. Additionally, candesartan was found to block the Ang II-induced constriction of renal microvessels in a surmountable manner.