Introduction: Endothelin-1 (ET-1) is a potent vasoactive peptide that acts on ETA and ETB receptors and has been implicated in hemorrhagic shock (HS). Centhaquin, a cardiovascular active agent, is a highly effective resuscitative agent and is currently undergoing phase II clinical trials (CTRI/2017/03/008184).
Hypothesis: Resuscitative effect of centhaquin may be mediated through ET receptors.
Methods: We determined the effect of HS and resuscitation by hypertonic saline (saline) or centhaquin on ETA and ETB receptor levels in the brain, heart, kidney, liver, lung and abdominal aorta. Sprague-Dawley rats (325±20g) were anesthetized and a pressure catheter SPR-320 was placed in left femoral artery. Hemorrhage was induced by withdrawing blood from right femoral artery, and mean arterial pressure (MAP) was maintained at 35 mmHg for 30 minutes then resuscitation was performed with SA or centhaquin. Arterial blood gases and cardiovascular parameters were determined before the induction of hemorrhage and at various times till 90 min after resuscitation. Tissues were collected to analyze ETA and ETB receptor expression using Western blot technique.
Results: Blood lactate level increased following HS; resuscitation with centhaquin produced a significant improvement in MAP and blood lactate compared to saline. No change in ETA or ETB receptor levels were observed in the brain, heart, lung and liver following HS or resuscitation with saline or centhaquin. HS produced an increase (140%) in ETA expression in the abdominal aorta which was attenuated by saline and centhaquin. ETB receptor levels were unaltered following HS, however, centhaquin significantly increased (79%) ETB receptor expression in the abdominal aorta. No change in ETA receptor expression was observed in the renal medulla following HS, however, centhaquin produced decrease (-61%) in ETA levels compared to HS. HS decreased (-34%) ETB receptor expression in the renal medulla which was completely reversed by centhaquin and not saline.
Conclusions: Centhaquin was found to be an effective resuscitative agent and induced an increase in ETB receptor expression in the renal medulla could lead to vasodilator effect and promote diuresis and natriuresis, preventing injury to the renal medulla.