AngII (angiotensin II), ACE (angiotensin I-converting enzyme) and the AT1 receptor (AngII type 1 receptor) are associated with the inflammatory process and microvascular dysfunction of AKI (acute ...kidney injury) induced by renal I/R (ischaemia/reperfusion). However, Ang-(1-7) angiotensin-(1-7), ACE2 (angiotensin I-converting enzyme 2) and the Mas receptor also play a role in renal disease models. Therefore, in the present study, we have examined the renal profile of Ang-(1-7), ACE2 and the Mas receptor in renal I/R and compared them with that of AngII, ACE and the AT1 receptor. Male Wistar rats were submitted to left nephrectomy and ischaemia (45 min) followed by reperfusion (2 or 4 h) in the right kidney. At 4 h of reperfusion, renal AngII was increased (P<0.01) and renal Ang-(1-7) was decreased substantially (P<0.05), although plasma levels of both angiotensins were unchanged. In addition, renal I/R decreased the renal mRNA expression of renin (P<0.05), AT1 receptors (P<0.001) and ACE2 (P<0.05). At 2 and 4 h of reperfusion, renal ACE activity was reduced (P<0.05). On the other hand, renal expression of the Mas receptor was greatly increased at 4 h of reperfusion (P<0.01), which was confirmed by immunohistochemical and Western blot analysis. In conclusion, increased renal expression of the Mas receptor associated with changes in the RAS (renin-angiotensin system)-related peptidases support an important role for the ACE2-Ang-(1-7)-Mas axis in AKI.
Administration (3 to 100 microg/kg IV) of clonidine, rilmenidine, and an imidazoline derivative, 2-(2-chlorophenylamino)imidazoline, in pithed nonstimulated rabbits caused a dose-dependent increase ...in mean arterial pressure without affecting heart rate. Prazosin (0.1 mg/kg IV) almost abolished the pressor responses to 2-(2-chlorophenylamino)imidazoline, partially inhibited those induced by clonidine, but failed to affect those elicited by rilmenidine. In contrast, yohimbine (1 mg/kg IV) blunted the pressor responses of the 3 drugs. In sympathetically stimulated pithed rabbits, 2-(2-chlorophenylamino)imidazoline induced only pressor effects, whereas clonidine and rilmenidine caused a transient pressure increase followed by a dose-dependent depressor effect. Yohimbine abolished the depressor effect of both drugs, which may have involved presynaptic alpha(2)-adrenoceptors. In conclusion, peripheral effects of 2-(2-chlorophenylamino)imidazoline and clonidine involved at least alpha(1)- and alpha(2)-adrenoceptor activation, whereas pressor and depressor effects of rilmenidine were mediated by alpha(2)-adrenoceptors.
The ATP-sensitive potassium channel blocker glibenclamide prevents renal ischemia/reperfusion injury in rats.
Renal ischemia/reperfusion (I/R) is a complex neutrophil-mediated syndrome. ...Adenosine-triphosphate (ATP)-sensitive potassium (KATP) channels are involved in neutrophil migration in vivo. In the present study, we have investigated the effects of glibenclamide, a KATP channel blocker, in renal I/R injury in rats.
The left kidney of the rats was excised through a flank incision and ischemia was performed in the contralateral kidney by total interruption of renal artery flow for 45 minutes. Renal perfusion was reestablished, and the kidney and lungs were removed for analysis of vascular permeability, neutrophil accumulation, and content of cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-10 4 and 24 hours later. Renal function was assessed by measuring creatinine, Na+, and K+ levels in the plasma and by determination of creatinine clearance. Drugs were administered subcutaneously after the onset of ischemia.
Reperfusion of the ischemic kidney induced local (kidney) and remote (lung) inflammatory injury and marked renal dysfunction. Glibenclamide (20 mg/kg) significantly inhibited the reperfusion-associated increase in vascular permeability, neutrophil accumulation, increase in TNF-α levels and nuclear factor-κB (NF-κB) translocation. These inhibitory effects were noticed in the kidney and lungs. Moreover, glibenclamide markedly ameliorated the renal dysfunction at 4 and 24 hours.
Treatment with glibenclamide is associated with inhibition of neutrophil recruitment and amelioration of renal dysfunction following renal I/R. Glibenclamide may have a therapeutic role in the treatment of renal I/R injury, such as after renal transplantation.
Intestinal ischemia and reperfusion injury is dependent on the recruitment and activation of neutrophils. Glibenclamide, an ATP-sensitive potassium channel (K
ATP) blocker, has been shown to suppress ...neutrophil migration and chemotaxis during acute inflammatory responses by a mechanism dependent on its K
ATP channel blocking activity. In the present study, we evaluated whether the treatment with glibenclamide prevented local, remote and systemic injury following reperfusion of the ischemic superior mesenteric artery in rats. The artery was made ischemic for a period of 30 or 120 min followed by 30 (mild I/R) or 120 (severe I/R) min of reperfusion, respectively. Glibenclamide (0.8 to 20 mg/kg) or vehicle was administered subcutaneously 40 min prior to the reperfusion. Glibenclamide dose-dependently inhibited the reperfusion-associated increase in vascular permeability and neutrophil accumulation in mild I/R. In the severe injury model, glibenclamide inhibited inflammatory parameters, as assessed by Evans blue extravasation, neutrophil influx and haemoglobin content, and the increase in TNF-α (tumor necrose factor-α) and IL (interleukin)-6 levels in the intestine and lung. The drug did not affect the increase in IL-1β and IL-10 levels. TEA, a nonselective potassium channel blocker, also inhibited reperfusion injury in both intestine and lungs of animals submitted to mild and severe I/R. Our experiments suggest a role for K
ATP channels in mediating neutrophil influx and consequent reperfusion-associated injury in rats. The lack of effect of these drugs on the reperfusion-associated hypotension and lethality may limit their usefulness after severe reperfusion injury.
To find new compounds selective for purported I1 imidazoline receptors (I1Rs) over I2 imidazoline binding sites (I2BS) and α2-adrenoceptors (α2ARs), a series of pyrrolinic isosteres of rilmenidine ...has been prepared and their biological activity at I1Rs, I2BS, and α2ARs evaluated. This isosteric replacement provided us with compounds which still bound to I1Rs but not to I2BS nor to α2ARs. A limited structure−affinity relationship was generated around the heterocyclic moiety of these ligands. One compound in this series, LNP 509 (1e) cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine, had no detectable affinity at α2ARs yet was capable of lowering blood pressure after central administration. These pyrrolinic analogues constitute a new chemical class of imidazoline related compounds with high selectivity for the I1Rs. They could be used as new tools in the study of I1Rs and in the conception of new centrally acting hypotensive drugs.
The role of nitric oxide (NO), K
+ channels, and arachidonic acid metabolism, via cytochrome
P450 and cyclooxygenase pathways, in the renal vasodilatory effect of bradykinin was examined in the ...isolated rat kidney perfused ex situ with a blood-free solution. Bradykinin (BK, 0.25–1.0 μM) induced a dose-dependent reduction of 10–35% in the relative renal vascular resistance (rRVR) of isolated kidneys preconstricted with phenylephrine (PHE, 0.17–0.35 μM). The vasodilating effect of 0.5 μM bradykinin was significantly inhibited by the nitric oxide synthase inhibitors,
N
G-nitro-
l-arginine (95% inhibition) and
N
G-nitro-
l-arginine methyl ester (45–75% inhibition). Clotrimazole, an inhibitor of cytochrome
P450 pathway but not indomethacin, a cyclooxygenase inhibitor, reduced the renal vasodilator response to bradykinin by 84%. The nonspecific K
+ channel inhibitor, tetraethylammonium ion (TEA) and the selective inhibitor of Ca
2+-activated K
+ channels, charybdotoxin (ChTX) greatly attenuated the vasodilator response to bradykinin by approximately 84% and 79%, respectively. These two K
+ channel inhibitors showed similar effects on vasodilatation induced by
S-nitroso-acetyl-
d,
l-penicillamine (1 μM), a nitric oxide donor. The results suggest that bradykinin releases nitric oxide which, by opening potassium channels specifically the Ca
+-dependent type, mediates the renal vasodilator response to bradykinin in the isolated kidney perfused ex situ.
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