OBJECTIVETo determine whether chronic angiotensin (AngII) type I receptor (AT1R) blockade inhibits cardiomyocyte (CM) apoptosis and attenuates left ventricular (LV) dysfunction after ischemia-reperfusion (IR) in the isolated working rat heart.METHODSPostischemic recovery of LV developed pressure, the apoptotic index (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP in situ nick end labeling or TUNEL assay), and changes in expression of apoptotic markers Bcl-2, Bax, p53 and caspase-3 (Western immunoblots) were measured after IR (50 min aerobic perfusion; 25 min global ischemia; 40 min reperfusion) in working rat hearts that were randomized to five groups of six each along 1 week or 3 week pretreatment arms: sham (no drug, no perfusion); no drug, aerobic perfusion; and oral AT1R blockers losartan (30 mg/kg per day) or UP269-6 (3 mg/kg per day), or no drug before IR.RESULTSCompared to the no drug group after IR, losartan (not UP269-6) preserved functional recovery in 1 and 3 week groups. However, both losartan and UP269-6 reduced the apoptotic index and normalized the increase in Bax, decrease in Bcl-2 and increase in p53 and caspase-3 after IR. A bell-shaped relation between apoptosis and functional recovery after IR was flattened by AT1R blockade.CONCLUSIONThe results indicate that IR is associated with LV dysfunction and CM apoptosis involving activation of p53, caspase-3, and increased Bax/Bcl-2 ratio in the working rat heart. Importantly, chronic AT1R blockade inhibited the apoptosis and changes in expression of the markers without improving functional recovery, implying that decrease in apoptosis does not necessarily translate into decreased LV dysfunction.

01 Jun 2001·Journal of Cardiovascular Pharmacology and TherapeuticsQ4 · MEDICINE

Effect of Chronic AT1 Receptor Antagonism on Postischemic Functional Recovery and AT1/AT2 Receptor Proteins in Isolated Working Rat Hearts

Q4 · MEDICINE

Article

Author: Jugdutt, Bodh I. ; Xu, Yi ; Menon, Vijayan ; Moudgil, Rohit

To determine whether chronic angiotensin II (Ang II) type I receptor (ATR) antagonism improves recovery of left ventricular (LV) function after ischemia-reperfusion (IR) and increases AT,R and Ang II type 2 receptor (AT2R) protein expression in isolated working rat hearts, rats were randomized to pretreatment with either losartan (30 mg/kg/day) or UP269-6 (3 mg/kg/day), or no drug (control), for 1 week or 3 weeks before IR (50 min perfusion, 25 min ischemia, 40 min reperfusion). In vitro LV work and power and ex vivo AT,R and AT2R proteins (immunoblots) were measured. Compared to baseline perfusion, LV work and power showed variable recovery in control, losartan, and UP269-6 groups. Compared to control, losartan preserved recovery of LV work and power while UP269-6 showed less recovery after IR at both 1 week and 3 weeks. Both antagonists increased AT2R but not AT,R protein. The duration of pretreatment did not affect the expression of ATR or AT2R proteins. The results indicate that chronic AT,R blockade over 1 or 3 weeks increases AT2R (not ATIR) protein expression and may preserve but not improve postischemic functional recovery compared to controls in isolated working rat hearts.

01 Jun 2000·Journal of the Renin-Angiotensin-Aldosterone System

Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-ε in acutely reperfused myocardial infarction in the dog

Article

Author: Yi Xu ; Menon, Vijayan ; Jugdutt, Bodh I

To determine whether cardioprotection after chronic angiotensin II (Ang II) type 1 (AT1) receptor blockade involves Ang II type 2 (AT2) receptor expression and protein kinase C-ε (PKCε) activation, we measured in vivo haemodynamics and left ventricular (LV) remodelling and dysfunction (echocardiogram/ Doppler) and ex vivo AT1/AT2-receptor expression, IP 3R (1, 4, 5-inositol trisphosphate type 2 receptor) and PKCε proteins in dogs with acutely reperfused (90 minutes ischaemia, 90 minutes reperfusion) myocardial infarction (MI) following seven days of AT1-receptor blockade with oral losartan or UP269-6. The animals were randomised to sham; sham + losartan or UP269-6; MI alone; MI + losartan; MI + UP269-6. More marked AT1-receptor blockade with UP269-6 (greater inhibition of Ang II pressor responses) was associated with a smaller increase in preload, less systolic and diastolic dysfunction, less infarct expansion, and smaller LV diastolic and systolic volumes. However, both AT1-receptor antagonists decreased infarct size. Importantly, MI decreased AT1-receptor and AT2-receptor expression while MI after AT1-receptor antagonism increased AT1-receptor (mRNA, not protein) and AT 2-receptor (mRNA and protein) expression as well as IP3R and PKCε proteins and cyclic guanosine 3', 5' monophosphate (cGMP). These results suggest that cardioprotection induced by chronic AT1-receptor antagonism involves enhanced AT2-receptor expression and possibly downstream signalling through IP3R, PKCε and cGMP.

100 Deals associated with Ripisartan

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Indication	Highest Phase	Country/Location	Organization	Date
Atherosclerosis	Phase 2	FR	UPSA SAS	-
Coronary Restenosis	Phase 2	FR	UPSA SAS	-
Heart Failure	Phase 2	FR	UPSA SAS	-
Hypertension	Phase 2	-	Arisyn Therapeutics Inc	-
Hypertension	Phase 2	FR	UPSA SAS	-

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