In hypertensive subjects, angiotensin II and endothelin participate in a manner involving closely interwoven pathways in increasing blood pressure (BP) and inducing end organ damage. The primary objective of this study was to determine the effect of TRC120038, a novel dual AT1/ETA receptor blocker on BP, in obese Zucker spontaneously hypertensive fatty rats (ob-ZSF1), an animal model of moderate hypertension, diabetes with progressive renal and cardiac dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC120038 (11.8？mg/kg bid.) or candesartan cilexetil (0.3？mg/kg od.) or vehicle control. Blood pressure (by radio-telemetry) and renal functional markers were monitored throughout the study. Cardiac function was assessed terminally by pressure volume catheter. Markers for renal dysfunction were measured and changes were evaluated histopathologically. TRC120038 showed greater fall in both systolic and diastolic BP in comparison to candesartan at its maximum antihypertensive dose. TRC120038 also reduced the severity of renal dysfunction and preserved cardiac function in ob-ZSF1 rat. 1. Introduction Inspite of multihypertensive drug treatment, significant proportion of poorly controlled hypertensives exist [1–3]. Greater incidences of stroke, heart failure, and end stage renal disease are reported in these patients [4, 5]; rigorous blood pressure (BP) lowering treatment targets are recommended for these patient population [6, 7]. Hypertensive patients have upregulated endothelin and renin angiotensin system (RAS). This has been clearly shown by elevated plasma levels of endothelin-1 (ET-1) [8] and plasma renin activity [9] in such subjects. More recently, endothelin receptor blockers have shown to be effective in resistant hypertensives [10]. It is now well established that increased ET-1 activity is one of the contributors for increased incidence of hypertension in diabetics with insulin resistance [11–13]. Similarly, association of increased body mass index with enhanced-ETA-receptor-dependent vasoconstrictor activity in hypertensive subjects has been demonstrated [13–15]. A substantial part of the poor responders to current antihypertensive therapy is characterized by salt sensitivity and increased-ETA-receptor-dependent vasoconstrictor tone [16, 17]. Such evidence suggests that abnormality in the endothelin system (in addition to RAS) plays a role in the pathophysiology of poorly controlled/difficult to treat (obesity- and diabetic-related) hypertension and that targeting endothelin system in addition to the RAS is a useful treatment for
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