ETA Receptor Blockade Attenuates Hypertension and Decreases Reactive Oxygen Species in ETB Receptor-Deficient Rats

Abstract

We hypothesize that endothelin-A receptor stimulation contributes to the elevated blood pressure and superoxide production in endothelin-B receptor-deficient rats on a high salt diet. Experiments were conducted on homozygous endothelin-B-deficient (sl/sl) and wild-type rats (wt) fed a high salt diet (8% NaCl) for 3 weeks. Separate groups were given normal drinking water or water containing the endothelin-A receptor antagonist, ABT-627 (5 mg/kg per day; n = 8-9 in all groups). On a normal salt diet, (sl/sl) rats had a significantly elevated systolic blood pressure compared with wt (138 +/- 3 vs 117 +/- 4 mmHg, respectively; P < 0.05). High salt diet caused a significant increase in systolic blood pressure in (sl/sl) rats compared with wt (158 +/- 2 vs 138 +/- 3 mmHg, respectively; P < 0.05). Endothelin-A receptor blockade decreased systolic blood pressure in (sl/sl) rats on high salt (125 +/- 5 mmHg; P < 0.05 vs without antagonist) without affecting the systolic blood pressure in wt (119 +/- 4 mmHg). Aortic superoxide production (lucigenin chemiluminescence) and plasma 8-isoprostane were elevated in sl/sl rats and were significantly reduced by endothelin-A receptor blockade in sl/sl, but not in wt rats. These findings suggest that endothelin-1, through the endothelin-A receptor, contributes to salt-induced hypertension and vascular superoxide production in endothelin-B-deficient rats.

Extrarenal ET B Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats

“…9,32,33 Despite these effects, this and previous studies demonstrate that rats genetically deficient in ET B or undergoing chronic ET B blockade exhibit saltsensitive hypertension responsive to ET A blockade, suggesting that Na retention and hypertension under these conditions results not from a lack of ET B -mediated natriuresis or diuresis in the kidney but from an increase in ET A signaling. 11,15 This study goes further to demonstrate that although intrarenal ET B plays a significant role in determining BP in these animals on DNa diet, it plays a relatively minor role in determining BP in these animals on HNa diet. The absence of ET B outside of the kidney significantly contributes to salt-induced hypertension in rats.…”

“…However, these rats are also sensitive of ET A blockade, suggesting that hypertension in these rats is due to increased activation of ET A . 11 To evaluate these possibilities, we looked at the regulation of renal and vascular ET1 and ET A expression in response to dietary Na. We also examined the effect of chronic ET A blockade on cardiovascular and renal function.…”

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

“…51 This increase in oxidative stress can be attributed to the resulting elevations in ET levels because ET A receptor blockade can prevent the increase in blood pressure and oxidative stress in this model. 51 Similarly, chronic ET-1 infusion is associated with Despite mixed results using the antioxidant tempol, there is clear evidence that ET stimulates superoxide production through an NADPH oxidase-dependent manner in DOCA-salt hypertensive rats.…”

“…51 This increase in oxidative stress can be attributed to the resulting elevations in ET levels because ET A receptor blockade can prevent the increase in blood pressure and oxidative stress in this model. 51 Similarly, chronic ET-1 infusion is associated with elevations in reactive oxygen species, although reports disagree as to the extent to which oxidative stress contributes to the associated hypertension. 36,52 Whereas hypertension associated with chronic ET B receptor blockade can be inhibited by ET A receptor antagonists, evidence for a role of oxidative stress, or specifically superoxide, is not straightforward.…”

“…51 This increase in oxidative stress can be attributed to the resulting elevations in ET levels because ET A receptor blockade can prevent the increase in blood pressure and oxidative stress in this model. 51 Similarly, chronic ET-1 infusion is associated with Despite mixed results using the antioxidant tempol, there is clear evidence that ET stimulates superoxide production through an NADPH oxidase-dependent manner in DOCA-salt hypertensive rats. 55,56 Because ET A receptor blockade and superoxide scavenging can attenuate the hypertension associated with DOCA-salt treatment, it is reasonable to hypothesize that ETdependent hypertension could be inhibited by disruption of NADPH oxidase subunit assembly with the inhibitor, apocynin.…”