Interaction between irbesartan, peroxisome proliferator-activated receptor (PPAR-γ), and adiponectin in the regulation of blood pressure and renal function in spontaneously hypertensive rats

Abstract

Adiponectin exerts vasodilatory effects. Irbesartan, an angiotensin receptor blocker, possesses partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity and increases circulating adiponectin. This study explored the effect of irbesartan alone and in combination with adiponectin on blood pressure, renal hemodynamic excretory function, and vasoactive responses to angiotensin II and adrenergic agonists in spontaneously hypertensive rat (SHR). Irbesartan was given orally (30 mg/kg/day) for 28 days and adiponectin intraperitoneally (2.5 μg/kg/day) for last 7 days. Groups of SHR received either irbesartan or adiponectin or in combination. A group of Wistar Kyoto rats (WKY) served as controls. Metabolic data and plasma samples were taken on days 0, 21, and 28. In acute studies, the renal vasoconstrictor actions of angiotensin II (ANGII), noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) were determined. SHR control rats had a higher mean blood pressure than the WKY (132 ± 7 vs. 98 ± 2 mmHg), lower plasma and urinary adiponectin, creatinine clearance, urine flow rate and sodium excretion, and oxidative stress markers compared to WKY (all P < 0.05) which were progressively normalized by the individual drug treatments and to a greater extent by combined treatment. Responses to intrarenal administration of NA, PE, ME, and ANGII were larger in SHR (P < 0.05) than WKY by 20-25 %. Irbesartan enhanced (P < 0.05) responses to NA and PE, while adiponectin blunted responses to all vasoconstrictors (all P < 0.05). Combined treatment in SHR further decreased the renal vascular responses to ANGII. These findings suggest that an interactive relationship may exist between PPAR-γ, alpha adrenoceptors, and ANGII in the renal vasculature of the SHR.

Renoprotective and haemodynamic effects of adiponectin and peroxisome proliferator-activated receptor agonist, pioglitazone, in renal vasculature of diabetic Spontaneously hypertensive rats

“…Firstly, the natriuresis produced by adiponectin caused an increase in sodium and water excretion and could be contributory factor in reducing B.P. Secondly, adiponectin may inhibit Na+-K+-ATPase activity in renal proximal tubule cells of SHR diabetic rats, which supports our hypothesis that these drugs particularly adiponectin prevent the ANG II actions at various points along signaling pathway and in parallel with our previous findings (25).…”

“…We observed numerous significant findings in this experiment. Primarily, urinary excretion and plasma adiponectin concentrations were low in the diabetic SHRs, whereas, restored partially to those found in the WKY rats after pioglitazone administration which supports the previous findings, that through activation of PPAR-γ, adiponectin, prevents activation of the adrenoceptors and AT1 receptor (25). We administered adiponectin at a rate sufficient to increase its plasma concentration and urinary excretion as compared to normotensive rats.…”

Renoprotective and haemodynamic effects of adiponectin and peroxisome proliferator-activated receptor agonist, pioglitazone, in renal vasculature of diabetic Spontaneously hypertensive rats

“…Effect of exogenous pioglitazone, adiponectin, and a combination of pioglitazone and adiponectin on creatinine clearance (Cr.Cl), urinary creatinine (mg/ dl), urinary sodium concentration (urinary Na), absolute urinary sodium excretion (U Na V) fractional sodium excretion(FENa), urinary potassium (urinary K) and urinary sodium to potassium ratio (Na:K) in diabetic Spontaneously hypertensive rats. PLOS ONE adiponectin concentrations were low in the diabetic SHRs, whereas, restored partially to those found in the WKY rats after pioglitazone administration which supports the previous findings, that through activation of PPAR-γ, adiponectin, prevents activation of the adrenoceptors and AT1 receptor [25]. We administered adiponectin at a rate sufficient to increase its plasma concentration and urinary excretion as compared to normotensive rats.…”

Exogenous adiponectin with full Peroxisome proliferator-activated receptor agonists (pioglitazone) abrogates streptozotocin induced oxidative stress and vascular abnormalities in Spontaneously hypertensive rats.

“…The signi cance of NO in the kidney vasculature cannot be ruled out which performs various pivotal role including renal hemodynamics regulation, modulation of renal sympathetic neural activity and inhibition of tubular sodium reabsorptive mechanism (48). We observed that irbesartan @ (30 mg/kg/day) caused maximal dose for blockade of RAAS whilst its partial PPAR-γ agonistic activity also contributed in its B.P reduction and renoprotective characteristics in nondiabetic SHRs as observed previously in our ndings (49).…”