Vascular reactivity, tissue levels, and binding sites for endothelin: a comparison in the spontaneously hypertensive and Wistar–Kyoto rats

Abstract

The role of endothelin (ET-1) in mediating the development of blood pressure was investigated in the spontaneously hypertensive (SHR) rat using the Wistar-Kyoto (WKY) rat as the normotensive control. The following were characterized in both rat strains: age-dependent changes in mean arterial blood pressure (MAP), tissue (blood, lung, heart, and kidney) levels of immunoreactive ET-1 like related peptides (ET-1RP), aortic ring responses to ET-1, and specific high-affinity tissue (lung, atrium, ventricle, aorta, and kidney) binding sites for 125I-labelled ET-1. Commencing at age 10 weeks through to 12 weeks, SHR rats but not WKY rats developed a significant increase in MAP (from 152 +/- 7 to 189 +/- 3 mmHg) (1 mmHg = 133.32 Pa). However, in both WKY and SHR rats immunoreactive levels of ET-1RP increased (100 and 80%, respectively) throughout the same measurement period. The potency of ET-1 to contract aortic rings from SHR rats was slightly but not significantly greater than that for aortic rings from WKY rats, although aortic rings from SHR rats contracted in the presence of 0.5 nM ET-1, while those from WKY rats did not. The levels of immunoreactive ET-1RP were significantly reduced (32%) in the kidney and unchanged in the heart and lung of SHR rats compared with WKY rats. Specific 125I-labelled ET-1 binding sites displayed an increase and a significant decrease (24%) of density in the atrium and ventricle, respectively, a significant increase (31%) of affinity in the lung, and were unchanged in the kidney and aorta of SHR rats compared with WKY rats following the development of hypertension. The lack of a correlation between circulating levels of immunoreactive ET-1RP and the development of hypertension coupled with a lack of significant differences in vascular reactivity suggest that ET-1 is not the sole mediator of hypertension in this animal model. However, the tissue-specific changes in immunoreactive ET-1RP and 125I-labelled ET-1 binding sites suggest that ET-1 may be a partial mediator of hypertension and is subject to compensatory changes in response to the increased total peripheral resistance in SHR rats.

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

“…It is possible that alterations in medullary blood flow, 28 interstitial pressures, 29 or local hormonal changes 30 could affect production of ET-1 by IMCD cells in SHR, although no such relation between these factors and ET-1 synthesis by IMCD cells has been described. Reduced IMCD ET-1 production could conceivably be due to alterations in circulating plasma ET-1 concentration; however, neither the present study nor previous ones 13 - 14 detected changes in plasma ET-1 in SHR. It is also possible that the reduced ET-1 production is caused by an intrinsic change in IMCD cells.…”

“…Such a possibility has not been directly investigated; however, a previous study has detected no difference between SHR and WKY rats in whole kidney K,,, or B^, for 125 I-ET-1. 13 Furthermore, in this same study, whole kidney ET-1 was also found to be markedly reduced in hypertensive SHR compared with WKY controls. It is also possible that ET-1 receptor activation results in an altered signal in the IMCD of SHR.…”

Evidence for altered ETB receptor characteristics during development and progression of ventricular cardiomyocyte hypertrophy

“…Evidence that bosentan causes some regression of LVH without an appreciable reduction in blood pressure indicates that ET-1 may exert a local influence on cardiomyocyte hypertrophy independent of systemic pressor effects (20). For this reason, it is important to examine expression of the peptide and alterations in ET receptors and/or responsiveness within SHR hearts: conflicting evidence has been obtained in this regard depending on the approach used, tissue source, and sampling time (5,18,32), and little evidence exists of effects on isolated cardiomyocytes (10).…”

Responsiveness of Aortic Rings of Cadmium-Hypertensive Rats to Endothelin-1

“…The mean arterial blood pressures of the animals were recorded before and after completion of the intraperitoneal injections. The mean blood pressure recordings were made using the 'tail cuff method as described before [ 15] using a Harvard Rat Tail Blood Pressure Monitor, (Cat. No.…”