© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Endothelin-1 in angiotensin II-dependent hypertension
Answer to the Letter to the Editor
Department of Clinical and Experimental Medicine, Clinica Medica 4, University Hospital, Via Giustiniani 2, 35126 Padova, Italy
* Corresponding author. Tel.: +39-(0)49-821-3304 or 2301; fax: +39-49-880-2252 gprossi{at}ux1.unipd.it
Received 5 August 1999; accepted 5 August 1999
We are delighted that our paper [1] succeeded in generating interest and discussion. Gardiner and Bennett raised an important issue concerning the potential role of endothelin-1 (ET-1) in the high blood pressure (BP) of transgenic TGR(mREN-2)27 rats [2], a monogenic renin-dependent model of severe hypertension. As far as we can understand, they found a slow-onset hypotensive effect during an acute 8 hr infusion of a mixed ETA/ETB receptor antagonist (SB 209670) in male heterozygous TGR(mREN-2)27 rats, where they recorded invasively intra-arterial blood pressure [3]. This hypotensive effect was surpassed by that induced by losartan. Interestingly, a synergistic hypotensive effect of the two drugs was also noticed. Based on this evidence Gardiner and Bennett would seem to caution on our statement that ET-1 does not play a major role in this form of hypertension. In a previous study in female heterozygous TGR(mREN-2)27 rats we had also found that the BP in vivo and the aortic contractile responses in vitro followed parallel changes with ageing. We therefore suggested that ET-1 could play a role in this model of hypertension [4].
However, chronic studies with ET antagonists in younger rats have given opposite results. In 25 day-old male heterozygous HanRen2/Edin-rats, derived from crossing homozygous TGR(mREN-2)27 with Edinburgh SD rats, no effect of the mixed ETA/ETB endothelin antagonist bosentan (100 mg/Kg b.w.) on BP was seen [5]. More importantly, no effect on survival was noticed in this cross, which show a 73.5% incidence of the malignant phase of hypertension associated with an increased ET-1 mRNA content in the kidney. The lack of any BP lowering effect and of any prevention of cardiovascular mortality accords well with findings of a more recent study where we used both bosentan and the ETA selective antagonist BMS-182874, administered orally at dosages previously shown to abolish the pressor effect of exogenous ET-1 [6]. Four wk-old male heterozygous, TGR(mREN-2)27 rats were treated for 4 weeks; BP and target organ damage, as assessed from left ventricular hypertrophy and medial wall hypertrophy of the 100-200 µm mesenteric arterioles, were carefully determined. We found that neither ET antagonist had any effect on the development of hypertension and target organ damage, despite the fact that bosentan effectively lowered aldosterone secretion, as expected [7]. These findings were in sharp contrast with the efficacy of the angiotensin II AT-I receptor antagonist irbesartan in preventing both hypertension and hypertrophy of the heart and arterioles. The lack of efficacy of ET antagonists in preventing target organ damage is also in keeping with the result of an Australian study, where bosentan, although lowering to some extent BP, failed to prevent adverse histologic changes in the kidney in female heterozygous TGR(mREN-2)27 rats made diabetic with streptozocin [8].
The reasons for these different results are difficult to explain. It must be pointed out however, that Gardiner and Bennett's haemodynamic data were obtained under acute conditions, i.e. in a situation where stress and sympathetic activation are likely to occur, as suggested by the high heart rate shown in their own recordings [3]. Unfortunately, they did not measure plasma catecholamines in their study, but the fact that despite the marked fall in BP with either drugs, they did not see any further increase of heart rate, is consistent with the possibility of a marked sympathetic activation. This is not a trivial point since both catecholamines, vasopressin and possibly other mechanisms can stimulate ET-1 synthesis [9–11]. It is also possible that ET receptor antagonists lower BP only when given acutely and not chronically; however, in an acute studies where BP was recorded with telemetry, i.e. under conditions less stressful than those used by Gardiner et al. [3], bosentan did not exert any BP-lowering effect in hypertensive transgenic rats [6].
Furthermore, Gardiner et al. did not examine the effect of ET antagonist on target organ damage and thus could not draw any conclusion on the role of ET-1 in hypertension-induced cardiovascular damage in TGR(mREN-2)27. As already mentioned, we and others have not seen any protection with respect to target organ damage with long-term administration of different ET antagonists [5–8]. To reconcile these data, it does not seem unlikely that ET-1 could attain increasing importance in older animals, i.e. at a stage when both hypertension and target organ damage, including endothelial dysfunction, are fully developed, particularly if other conditions impairing endothelial function, such as diabetes, coexist.
Thus, while we are confident with our understanding of Gardiner's et al. data, we tend to maintain our view that in this form of severe Ang II-dependent hypertension ET-1 does not play any major role, at least in the early stages and in causing target organ damage.
Perhaps a more important issue which relates to Gardiner and Bennett's comment concerns the role of ET-1 in Ang Il-dependent forms of hypertension. As reviewed in detail in our paper, while there seems to be rather consistent results supporting a clear-cut participation of ET-1 in low-renin-hypertension, such as that induced by DOCA-salt, more controversial data exist in high renin- and Ang II-hypertension [1]. The potential reasons why ET-1 may take part in a hypertension induced by exogenously administered Ang II, but not in the models with an enhanced endogenous production of Ang II, were already discussed [1]. It is worth mentioning in this context that a recent paper, unpublished at the time of our review, has added further controversy to this area, In a two-kidney one-clip (2K-1C) rat model of renovascular hypertension Hocher et al. reported no significant BP lowering effect of bosentan, and of both an ETA– (BQ-123) and an ETB– (1RL1038) selective receptor antagonist [12]. This finding did not come unexpected since they found no evidence of activation of the ET system in heart tissue at any stage of the 2K-1C hypertension. However, long-term treatment with ET receptor antagonists effectively reduced fibrosis in the heart. Accordingly, the contention that ET-1 plays a role in target organ damage even when it does not play a major role in raising BP is intriguing and remains to be further tested.
Thus, the general issue of the role of ET-1 in Ang II-dependent forms of hypertension is still controversial and undoubtedly needs further intensive investigative efforts.
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- Rossi G.P., Sacchetto A., Cesan M., Pessina A.C. Interactions between endothelin-1 and the renin-angiotensin-aldosterone system. Cardiovasc Res I. (1999) 43:300–307.[CrossRef]
- Gardiner S.M., Bennett T. Interactions between endothelin-1 and the renin-angiotensin-aldosterone system. Cardiovasc Res (1999) 44:461.
- Gardiner S.M., March J.E., Kemp P.A., Mullins J.J., Bennett T. Haemodynamic effects of losartan and the endothelin antagonist, SB 209670, in conscious, transgenic ((mRen2)27), hypertensive rats. Br J Pharmacol. (1995) 116:2237–2244.[ISI][Medline]
- Cargnelli G., Rossi G.P., Pessina A.C., et al. Changes of blood pressure and aortic strip contractile responses to ET-I of heterozygous female transgenic rats, TGR(mRen2)27. Pharmacol Res. (1998) 37:207–211.[CrossRef][ISI][Medline]
- Whitworth C.E., Veniant M.M., Firth J.D., Cumming A.D., Mullins J.J. Endothelin in the kidney in malignant phase hypertension. Hypertension. (1995) 26:925–931.
[Abstract/Free Full Text] - Rossi G.P., Sacchetto A., Rizzoni D., et al. Endothelin-1 (ET-1) in renin-dependent hypertension and related cardiovascular disease. Am J Hypertens. (1999) 12:51A. (Abstract).
- Belloni A., Rossi G.P., Andreis P.G., et al. Endothelin adrenocortical secretagogue effect is mediated by the B receptor in rats. Hypertension. (1996) 27:1153–1159.
[Abstract/Free Full Text] - Wilkinson-Berka J., Kelly D., Cooper M., Skinner S. Bosentan normalizes blood pressure, but does not prevent renal pathology in the diabetic REN-2 rat. Hypertension. (1998) 32:608–608. (Abstract).
- Gray G.A., Webb D.J. The endothelin system and its potential as a therapeutic target in cardiovascular disease. Pharmacol Ther. (1996) 72:109–148.[CrossRef][ISI][Medline]
- Emori T., Hirata Y., Ohta K., et al. Cellular mechanism of endothelin-I release by angiotensin and vasopressin. Hypertension. (1991) 18:165–170.
[Abstract/Free Full Text] - Kaburagi S., Hasegawa K., Morimoto T., et al. The role of endothelin-converting enzyme-1 in the development of alpha1 adrenergic-stimulated hypertrophy in cultured neonatal rat cardiac myocytes. Circulation. (1999) 99:292–298.
[Abstract/Free Full Text] - Hocher B., George I., Rebstock J., et al. Endothelin system-dependent cardiac remodeling in renovascular hypertension. Hypertension. (1999) 33:816–822.
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