Effect of a nonselective endothelin antagonist on vascular remodeling in deoxycorticosterone acetate-salt hypertensive rats. Evidence for a role of endothelin in vascular hypertrophy.

Abstract

We have previously shewn that the endothelin content in arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats is increased. We designed this study to examine, using the new orally active nonselective endothelin receptor antagonist bosentan, whether this increase in vascular endothelin may contribute to elevated blood pressure and vascular hypertrophy in DOCA-salt hypertensive rats. Rats received bosentan (100 mg/kg body wt per day) for 3 weeks mixed with their food. Systolic blood pressure of DOCA-salt hypertensive rats rose to 197±5 mm Hg, and that of bosentantreated DOCA-salt hypertensive rats was 177±4 mm Hg (P<.01). Mesenteric resistance arteries were studied on a wire myograph. The media width, ratio of media width to lumen diameter, and cross-sectional area of the media of resistance arteries of bosentan-treated DOCA-salt hypertensive rats E ndothelins comprise a family of potent vasoconstrictor peptides 1 ' 2 endowed, as other similar peptides, with mitogenic properties. 3 The role of endothelins in hypertension is unclear. Endothelin-1 (ET-1) is one of the best-studied and possibly one of the more important members of this family of peptides in peripheral tissues. Several studies have demonstrated that the circulating concentrations of ET-1 exhibit little or no increase in most models of hypertension in animals or in human essential hypertension. "7 It has also been shown that the effects of ET-1 on blood vessels in experimental models of hypertension and in essential hypertensive humans are either normal or blunted.814 Thus, it has been difficult to postulate a role of ET-1 in hypertension.We have recently demonstrated that in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat the content of immunoreactive ET-1 is increased in aorta and mesenteric arteries despite normal circulating levels.15 Thus, endothelin secretion may occur abluminally, 16 and exaggerated vascular production may not result in elevated plasma levels. Histochemical staining for endothelin was enhanced in endothe- © 1994 American Heart Association, Inc.were significantly smaller than those of untreated DOCA-salt hypertensive rats. The lumen diameter and cross-sectional area of the media of vessels of bosentan-treated rats were not different from those of uninephrectomized control rats. Vasoconstrictor responses, which were altered in DOCA-salt hypertensive rats, approached control in the bosentan-treated rats. We conclude that these results with a nonselective endothelin receptor antagonist may suggest a role for endothelin in the elevation of blood pressure and vascular hypertrophy and remodeling in DOCA-salt hypertensive rats. Hal cells in these vessels. 15 In a subsequent study we found that the abundance of mRNA for ET-1 was significantly increased between three and five times in vessels of DOCA-salt hypertensive rats. 17 In contrast to DOCA-salt hypertensive rats, spontaneously hypertensive rats (SHR) did not exhibit an increased endothelin content in vascular tissues. 15 We were also impressed ...

Dual NEP/ECE inhibition improves endothelial function in mesenteric resistance arteries of 32-week-old SHR

“…Hypertrophic remodeling rather than eutrophic remodeling of resistance arteries, seems to occur in models associated with an upregulated ET system suggesting that ET-1 system upregulation leads to vascular hypertrophy. 42 In the current study, we observed no significant change in diameter, media thickness, cross-sectional area of the media, nuclear cell count or media-to-lumen ratio in first-order mesenteric resistance arteries of 32-week-old SHR caused by reducing blood pressure by means of a 4-week treatment with a vasodilator (hydralazine). This means that a decrease in blood pressure alone cannot reverse structural changes in these arteries.…”

Elevated mean arterial pressure in the ovariectomized rat was normalized by ETA receptor antagonist therapy: absence of cardiac hypertrophy and fibrosis

“…This observation was not unexpected since endothelin-1 is predominantly released abluminally from endothelial cells, and thus acts primarily as an autocrine/paracrine factor (Wagner et al, 1992). Consistent with this latter premise, plasma endothelin-1 levels were normal in the DOCA-salt hypertensive rat model, albeit the administration of a non-selective ET receptor decreased elevated blood pressure, and ameliorated vascular remodelling (Calderone et al, 1994;Li et al, 1994). In this regard, the potential paracrine role of locally released endothelin-1 on the underlying vasculature of the ovariectomized rat was examined.…”

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

“…55,66,67 These observations were extended by other laboratories and it can now be concluded that endothelin plays more of a vasoconstrictor and hypertrophy-promoting role in saltdependent (eg, DOC-salt, aldosterone-induced, Dahl SS, insulin-resistant, and 1K-1C Goldblatt models), 55,66,[68][69][70] than in salt-independent or renindependent forms of experimental hypertension (eg, SHR, 2K-1C Goldblatt, and L-NAME-induced hypertension). 55,56,67,70 The only exception seems to be the hypertension produced by exogenous administration of angiotensin II, in which endothelin participates in BP maintenance and vascular hypertrophy.…”