Renal endothelin in chronic angiotensin II hypertension

Abstract

To determine the influence of chronic ANG II infusion on urinary, plasma, and renal tissue levels of immunoreactive endothelin (ET), ANG II (65 ng/min) or saline vehicle was delivered via osmotic minipump in male Sprague-Dawley rats given either a high-salt diet (10% NaCl) or normal-salt diet (0.8% NaCl). High-salt diet alone caused a slight but not statistically significant increase (7 Ϯ 1%) in mean arterial pressure (MAP). MAP was significantly increased in ANG II-infused rats (41 Ϯ 10%), and the increase in MAP was significantly greater in ANG II rats given a high-salt diet (59 Ϯ 1%) compared with the increase observed in rats given a high-salt diet alone or ANG II infusion and normal-salt diet. After a 2-wk treatment, urinary excretion of immunoreactive ET was significantly increased by ϳ50% in ANG II-infused animals and by over 250% in rats on high-salt diet, with or without ANG II infusion. ANG II infusion combined with high-salt diet significantly increased immunoreactive ET content in the cortex and outer medulla, but this effect was not observed in other groups. In contrast, high-salt diet, with or without ANG II infusion, significantly decreased immunoreactive ET content within the inner medulla. These data indicate that chronic elevations in ANG II levels and sodium intake differentially affect ET levels within the kidney and provide further support for the hypothesis that the hypertensive effects of ANG II may be due to interaction with the renal ET system. dietary sodium chloride; blood pressure; kidney THE RENIN-ANGIOTENSIN SYSTEM plays an important role in the regulation of arterial pressure and renal function. It has traditionally been thought that ANG II exerts its vasoconstrictor and sodium-retaining actions via action on the angiotensin type 1 receptor (AT 1 ) and, therefore, directly participates in the pathogenesis of cardiovascular and renal diseases (10). However, recent studies indicate that ANG II may exert some of its effects via interaction with the endothelin (ET) system. One possible mechanism for this interaction is that ANG II may regulate ET-1 synthesis in the kidney. Several lines of evidence support this hypothesis. First, it has been reported that ANG II stimulates release of ET-1 by cultured vascular smooth muscle cells, endothelial cells, and mesangial cells (5,12,19). ANG II has also been shown to stimulate the expression of preproendothelin-1 mRNA in rat vascular smooth muscle cells and in rat and bovine endothelial cells (5, 9, 19). Second, in vivo studies showed that rats with chronic ANG II hypertension have elevated ET-1 levels in renal tissue but not in myocardial tissue and enhanced preproendothelin mRNA expression in the renal cortex and medulla (2, 4). Finally, the hypertension associated with chronic ANG II infusion can be attenuated by a mixed ET type A (ET A ) and ET type B (ET B ) receptor antagonist and by selective ET A -receptor antagonists (3,4,8,18). ET A -receptor antagonists have also been shown to prevent some of the changes in endothelial function obser...

Decreased Renal Cytochrome P450 2C Enzymes and Impaired Vasodilation Are Associated With Angiotensin Salt-Sensitive Hypertension

“…25,26 In the present study, the combination of a high-salt diet and angiotensin II infusion resulted in a greater increase in systolic blood pressure, which confirms salt sensitivity of angiotensin II-induced hypertension reported previously using radiotelemetry to measure arterial blood pressure. 27 It is generally accepted that excess dietary salt intake differentially modulates the activity of CYP450 enzymes in kidney. Precisely how increased circulating angiotensin II levels change the regulatory effect of a highsalt diet on CYP450 enzymes remains unclear.…”

“…This finding is in agreement with previous studies demonstrating impaired NO/cyclic guanosine monophosphate signaling in spontaneously hypertensive rats fed a high-salt diet and the increase of the NO synthase inactivator N G -N G -dimethyl-arginine in the kidney of angiotensin II-infused rats fed a high-salt diet. 27 Clearly, further investigation is required to delineate the role of EETs in the depressed vascular response to acetylcholine and sodium nitroprusside that develops in angiotensin II salt-sensitive hypertension.…”

Endothelin-Induced Increases in Ca 2+ Entry Mechanisms of Vascular Contraction Are Enhanced During High-Salt Diet

“…Recent studies have suggested a prominent role of ET in the control of renal plasma flow and renal sodium excretion and, thereby, the renal control mechanisms of arterial pressure. 13,16,17,25 However, the role of ET in the vascular control mechanisms of arterial pressure has not been clearly established.ET is one of the most potent vasoconstrictors described. 26…”

“…9 -12 Although the mechanisms of salt-sensitive hypertension have not been clearly identified, several studies point to a possible role of endothelin (ET). 7,[13][14][15][16][17] ET has been shown to interact with specific ET A and ET B receptors in tissues involved in the regulation of arterial pressure, particularly the kidney and the vasculature. 18 -24 Studies with specific ET A and ET B antagonists have suggested a possible role of ET as a mediator of angiotensin II-induced hypertension in rats, particularly during HS.…”

“…18 -24 Studies with specific ET A and ET B antagonists have suggested a possible role of ET as a mediator of angiotensin II-induced hypertension in rats, particularly during HS. 14,15,17 However, whether ET directly affects the control mechanisms of arterial pressure is less clear. Recent studies have suggested a prominent role of ET in the control of renal plasma flow and renal sodium excretion and, thereby, the renal control mechanisms of arterial pressure.…”