Dhvanit I. Shah

Possible role of Akt to improve vascular endothelial dysfunction in diabetic and hyperhomocysteinemic rats.

The study has been designed to investigate the effect of demethylasterroquinone B1 (DAQ B1), an activator of Akt, in diabetes mellitus (DM) and hyperhomocyteinemia (HHcy)-induced vascular endothelial dysfunction. Streptozotocin (55xa0mgxa0kg−1, i.v.) and methionine (1.7% w/w, p.o., 4xa0weeks) were administered to rats to produce DM (serum glucose >140xa0mgxa0dl−1) and HHcy (serum homocysteine >10xa0µM), respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta and serum concentration of nitrite/nitrate. The expression of messenger RNA for p22phox and eNOS was assessed by reverse transcription-polymerase chain reaction. Serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion were estimated to assess oxidative stress. DAQ B1 (5xa0mgxa0kg−1, p.o.) or atorvastatin (30xa0mgxa0kg−1, p.o.) in diabetic and hyperhomocysteinemic rats significantly reduced serum glucose and homocysteine concentration. DAQ B1 or atorvastatin markedly improved acetylcholine-induced endothelium-dependent relaxation, vascular endothelial lining, serum nitrite/nitrate concentration and serum TBARS in diabetic and hyperhomocysteinemic rats. However, this ameliorative effect of DAQ B1 has been prevented by L-NAME (25xa0mgxa0kg−1, i.p.), an inhibitor of eNOS. Therefore, it may be concluded that DAQ B1-induced activation of Akt may activate eNOS and consequently reduce oxidative stress to improve vascular endothelial dysfunction.

Involvement of Rho-kinase in experimental vascular endothelial dysfunction

The present study has been designed to investigate the effect of fasudil (Rho-kinase inhibitor) in diabetes mellitus (DM) and hyperhomocyteinemia (HHcy) induced vascular endothelial dysfunction (VED). Streptozotocin (55 mg kg−1, i.v., once only) and methionine (1.7% w/w, p.o., daily for 4 weeks) were administered to rats to produce DM (serum glucose >140 mg dl−1) and HHcy (serum homocysteine >10 μM) respectively. VED was assessed using isolated aortic ring, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) concentration was estimated to assess oxidative stress. Atorvastatin has been employed in the present study as standard agent to improve vascular endothelial dysfunction. Fasudil (15 mg kg−1 and 30 mg kg−1, p.o., daily) and atorvastatin (30 mg kg−1, p.o., daily) treatments significantly attenuated increase in serum glucose and homocysteine but their concentrations remained markedly higher than sham control value. Fasudil and atorvastatin treatments markedly prevented DM and HHcy-induced (i) attenuation of acetylcholine induced endothelium-dependent relaxation, (ii) impairment of vascular endothelial lining, (iii) decrease in serum nitrite/nitrate concentration, and (iv) increase in serum TBARS. It may be concluded that fasudil prevented DM and HHcy-induced VED partially by decreasing serum glucose and homocysteine concentration due to inhibition of Rho-kinase. Moreover, inhibition of Rho-kinase by fasudil and consequent prevention of oxidative stress may have directly improved VED in diabetic and hyperhomocysteinemic rats. The Rho-kinase appears to be a pivotal target site involved in DM and HHcy-induced VED.

Design, synthesis, and evaluation of 5-sulfamoyl benzimidazole derivatives as novel angiotensin II receptor antagonists

A series of 5-alkylsulfamoyl benzimidazole derivatives have been designed and synthesized as novel angiotensin II (Ang II) receptor antagonists. The compounds have been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on isolated rat aortic ring and desoxycortisone acetate induced hypertensive rats, respectively. The activity is found related to size of alkyl group. The maximum activity is observed with a compact and bulky alkyl group like tert-butyl and cyclohexyl. The compounds 4g and 4h have shown promising both in vitro and in vivo activities. A receptor binding model is also proposed on the basis on the basis of structure-activity relationship in this study.

Effect of bis(maltolato) oxovanadium on experimental vascular endothelial dysfunction

The study has been designed to investigate the effect of bis(maltolato) oxovanadium (BMOV), a protein tyrosine phosphatase inhibitor, on hypercholesterolemia and hypertension-induced vascular endothelial dysfunction. High fat diet (8xa0weeks) and deoxycorticosterone acetate (DOCA; 40xa0mgxa0kg−1, s.c.) were administered to rats to produce hypercholesterolemia and hypertension (mean arterial blood pressure >120xa0mmHg) respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) were estimated to assess oxidative stress. BMOV (0.2xa0mg/ml in drinking water) or atorvastatin (30xa0mgxa0kg−1, p.o.) markedly improved acetylcholine-evoked endothelium-dependent relaxation, lining of vascular endothelium, serum nitrite/nitrate concentration, and serum TBARS in hypercholesterolemic and hypertensive rats. However, this ameliorative effect of BMOV has been prevented by L-NAME (25xa0mgxa0kg−1, i.p.), an inhibitor of NOS, or by glibenclamide (5xa0mgxa0kg−1, i.p.), a blocker of ATP-sensitive K+ channels. It may be concluded that BMOV-induced inhibition of PTPase may improve vascular endothelial dysfunction.

Activation of Protein Kinase A Improves Vascular Endothelial Dysfunction

The study has been designed to investigate the effect of 8-Br-cAMP, an activator of protein kinase A (PKA), in diabetes mellitus- and hyperhomocysteinemia-induced vascular endothelial dysfunction. Streptozotocin (55 mg kg-1, i.v.) and methionine (1.7% w/w, p.o., 4 weeks) were administered to rats to produce diabetes mellitus (serum glucose >200 mg dL-1) and hyperhomocysteinemia (serum homocysteine >10 microM), respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. The expression of mRNA for p22phox and endothelial nitric oxide synthase (eNOS) was assessed by using reverse transcriptase-polymerase chain reaction (TBARS) (RT-PCR). Serum thiobarbituric acid-reactive substances (TBARS) concentration and aortic superoxide anion concentration were estimated to assess oxidative stress. 8-Br-cAMP (5 mg kg-1, i.p.) or atorvastatin (30 mg kg-1, p.o.) prevented diabetes mellitus- and hyperhomocysteinemia-induced attenuation of acetylcholine-induced endothelium-dependent relaxation, impairment of vascular endothelial lining, decrease in expression of mRNA for eNOS, serum nitrite/nitrate concentration, and increase in expression of mRNA for p22phox, superoxide anion, and serum TBARS. The ameliorative effect of 8-Br-cAMP was prevented by N omega-nitro-L-arginine methyl ester (L-NAME) (25 mg kg-1, i.p.) and glibenclamide (5 mg kg-1, i.p.). Therefore, it may be concluded that 8-Br-cAMP-induced activation of PKA may improve vascular endothelial dysfunction.

Possible role of exogenous cAMP to improve vascular endothelial dysfunction in hypertensive rats

The study has been designed to investigate the effect of 8‐Br‐cAMP, an activator of protein kinase A, in hypertension‐induced vascular endothelial dysfunction. Rats were uninephroctomized and desoxycortisone acetate (DOCA) (40u2003mg/kg, s.c.) was administered to rats to produce hypertension (mean arterial blood pressureu2003>u2003140u2003mmHg). Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta and serum concentration of nitrite/nitrate. The expression of mRNA for p22phox and eNOS was assessed by using reverse transcriptase‐polymerase chain reaction. Serum thiobarbituric acid reactive substances concentration and aortic superoxide anion concentration were estimated to assess oxidative stress. 8‐Br‐cAMP (5u2003mg/kg, i.p.) or atorvastatin (30u2003mg/kg, p.o.) prevented hypertension‐induced attenuation of acetylcholine‐induced endothelium‐dependent relaxation, impairment of vascular endothelial lining, decrease in expression of mRNA for endothelial nitric oxide synthase (eNOS), serum nitrite/nitrate concentration and increase in expression of mRNA for p22phox, superoxide anion and serum TBARS. The ameliorative effect of 8‐Br‐cAMP was prevented by N‐nitro‐l‐arginine methyl ester (25u2003mg/kg, i.p.) and glibenclamide (30u2003mg/kg, i.p.). It may be concluded that 8‐Br‐cAMP may stimulate expression and activity of eNOS and suppress expression of p22phox subunit of NADPH oxidase to reduce oxidative stress and subsequently improve vascular endothelial dysfunction.