Alterations in renal endothelin-1 production in the spontaneously hypertensive rat.

Abstract

Endothelin-1 inhibits sodium and water transport systems in the inner medullary collecting duct Endothelin-1 levels are reduced in the medulla of spontaneously hypertensive rats (SHR), raising the possibility that decreased inner medullary collecting duct production of endothelin-1 could contribute to inappropriate sodium and water retention. In the current study, immunoreactive endothelin-1 was measured in the urine, blood, and eluates from cortex and outer and inner medulla of SHR before (age 3-4 weeks) and after (age 8-9 weeks) the development of hypertension and in age-matched Wistar-Kyoto (WKY) controls. There was no difference in endothelin-1 levels between prehypertensive SHR and WKY rats. In contrast, 8-9-week-old SHR had significantly reduced endothelin-1 in the urine and outer and inner medulla, but not in the cortex or serum compared with those of WKY controls. Furthermore, inner medullary collecting duct cells from 8-9-week-old SHR, either acutely isolated or cultured, released less endothelin-1 than did those from WKY rats. Finally, the level of endothelin-1 messenger RNA was only reduced in the inner medulla and in inner medullary collecting duct cells from 8-9-week-old SHR. In summary, renal medullary, and in particular terminal collecting duct, endothelin-1 production is reduced in SHR only after the development of hypertension. Such decreases in inner medullary collecting duct endothelin-1 production may contribute to the hypertensive state in SHR. and causes a natriuresis and diuresis. 4 These renal actions of ET-1, however, clearly do not cause the same biological responses. For instance, ET-1-induced vasoconstriction reduces glomerular filtration rate, thereby reducing sodium and water excretion, 2 and ET-1 directly inhibits sodium and water reabsorption by the collecting duct. 5 -6 The reasons for this apparent lack of coordinate effects of ET-1 are unknown; however, it probably reflects the independent actions of locally produced ET-1. At least two such locally acting systems exist for ET-1 in the kidney. The first, that of endothelial cell-derived ET-1 modulation of vascular smooth muscle tone, may play a role in the pathogenesis

Nephroprotection of an ET A -Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats

“…3,25 This is true even in humans with kidney disease. 26 In our study, plasma ET-1 levels were not elevated in untreated UNX-SHRsp on a normal or high salt diet, but this finding must be interpreted with caution because circulating ET-1 levels do not necessarily reflect local ET production, 21 which is known to be increased in renal-damage models despite there being no elevation in circulating ET-1. 2 In one study on SHRsp with untouched kidneys, salt loading had no effect on the renal expression but increased cardiac expression of the preproET-1 mRNA.…”

“…Systolic BP was somewhat lower in treated animals beyond the 10th week of the high salt experiment, but this finding does not necessarily indicate an antihypertensive action; it may merely reflect progression of renal damage in untreated salt-loaded rats, leading to a further increase in systolic BP. Thus, although renal ET-1 production is increased in SHR, 21 ETs apparently play no major role in BP elevation, in contrast to other models of hypertensive renal damage, eg, deoxycorticosterone-salt hypertension, in which specific ET A receptor blockade, as well as nonspecific ET A/B receptor blockade, normalizes BP. 22 However, the ET system may play a role in the genesis of progressive renal damage even in the absence of systemic hypertension, as illustrated by the fact that normotensive rodents transgenic for ET-1 and ET-2 develop progressive renal damage.…”

Role of endothelin‐1 and the ETA receptor in the maintenance of deoxycorticosterone acetate‐salt‐induced hypertension

“…However, circulating ET-1 levels do not reflect the local production of the peptide. Indeed, the change in ET-1 content of tissues occurs without change in circulating ET-1 levels (Hughes et al, 1992;Lariviere et al, 1993).…”

Participation of renal and circulating endothelin in salt-sensitive essential hypertension

“…An analogous mechanism has been proposed in SHR, since this strain exhibits impairment of renomedullary synthesis of endothelin. 98,99 Inability to confirm decreased absolute levels of endothelin excretion in hypertensive patients by other authors 93,97 may reflect differences in endothelin plasma levels and renal function of the studied subjects. When these parameters are taken into consideration, it is unequivocal that fractional excretion of endothelin is reduced almost three-fold in essential hypertensive patients compared to normotensive controls.…”