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Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats.

ABSTRACT: l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension.

SUBMITTER: Barawkar DA

PROVIDER: S-EPMC4018152 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats.

Barawkar Dinesh A DA Meru Ashwin A Bandyopadhyay Anish A Banerjee Abir A Deshpande Anil M AM Athare Chandrashekhar C Koduru Chandrasekhar C Khose Goraksha G Gundu Jayasagar J Mahajan Koshu K Patil Pradeep P Kandalkar Sachin R SR Niranjan Sanjay S Bhosale Shubhangi S De Siddhartha S Mukhopadhyay Sudit S Chaudhary Sumit S Koul Summon S Singh Umesh U Chugh Anita A Palle Venkata P VP Mookhtiar Kasim A KA Vacca Joseph J Chakravarty Prasun K PK Nargund Ravi P RP Wright Samuel D SD Roy Sophie S Graziano Michael P MP Singh Sheo B SB Cully Doris D Cai Tian-Quan TQ

ACS medicinal chemistry letters 20111007 12

l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitabl ...[more]

PMID: 24900281

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Project description:Recent studies demonstrate that there are sex differences in the expression of angiotensin receptor type 2 (AT2-R) in the kidney and that AT2-R plays an enhanced role in regulating blood pressure (BP) in females. Also, brain AT2-R activation has been reported to negatively modulate BP and sympathetic outflow. The present study investigated whether the central blockade of endogenous AT2-R augments deoxycorticosterone acetate (DOCA)/salt-induced hypertension in both male and female rats.All rats were subcutaneously infused with DOCA combined with 1% NaCl solution as the sole drinking fluid. BP and heart rate (HR) were recorded by telemetric transmitters. To determine the effect of central AT2-R on DOCA/salt-induced hypertension, male and female rats were intracerebroventricularly (icv) infused with AT2-R antagonist, PD123,319, during DOCA/salt treatment. Subsequently, the paraventricular nucleus (PVN) of the hypothalamus, a key cardiovascular regulatory region of the brain, was analyzed by quantitative real-time PCR and Western blot.DOCA/salt treatment elicited a greater increase in BP in male rats than that in females. Icv infusions of the AT2-R antagonist significantly augmented DOCA/salt pressor effects in females. However, this same treatment had no enhanced effect on DOCA/salt-induced increase in the BP in males. Real-time PCR and Western blot analysis of the female brain revealed that DOCA/salt treatment enhanced the mRNA and protein expression for both antihypertensive components including AT2-R, angiotensin-converting enzyme (ACE)-2, and interleukin (IL)-10 and hypertensive components including angiotensin receptor type 1 (AT1-R), ACE-1, tumor necrosis factor (TNF)-?, and IL-1?, but decreased mRNA expression of renin in the PVN. The central blockade of AT2-R reversed the changes in mRNA and protein expressions of ACE-2, IL-10, and renin, further increased the expressions of TNF-? and IL-1?, and kept higher the expressions of AT1-R, ACE-1, and AT2-R.These results indicate that endogenous AT2-R activation in the brain plays an important protective role in the development of DOCA/salt-induced hypertension in females, but not in males. The protective effect of AT2-R in females involves regulating the expression of brain renin-angiotensin system components and proinflammatory cytokines.

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Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats.

Publications

Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats.

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