The angiotensin???endothelin relationship

In the current issue of the journal, Rothermund et al. [1] provide new evidence regarding the important topic of whether endothelin-1 (ET-1) may mediate some of the actions of the renin–angiotensin system. The authors tested the potential nephroprotective effect of both ETA selective and ETA/ETB antagonists in a model of renin-dependent hypertension, the TGR (mRen2)27 transgenic rat. They were unable to find either a blood pressure-lowering action of either agent or improvement of renal damage, whereas an angiotensin receptor blocker lowered blood pressure and improved both renal damage and survival. They concluded that whereas renin–angiotensin blockade protects the kidney, endothelin receptor blockade does not have renal protective effects in primary renin-dependent hypertension, suggesting that endothelin is not mediating pathophysiological actions of angiotensin. A role in cardiovascular pathophysiology of an angiotensin–endothelin relationship was first proposed by Thomas Lüscher's group who demonstrated that cultured smooth muscle cells from the spontaneously hypertensive rat exhibited increased message for ET-1 after exposure to angiotensin II [2]. Shortly afterwards, we showed that ET-1 was overexpressed in the vasculature of experimental hypertensive rats with low or suppressed renin [3,4]. Furthermore, other studies performed by our group showed that, in the model of 2-K 1C Goldblatt hypertension, in which the renin–angiotensin system is activated, there was no upregulation of preproET-1 mRNA in the vasculature [5]. Only in the late phase of 2-K 1C Goldblatt hypertension, which is not renin-dependent, were we able to detect an upregulation of preproET-1 message. Moreover, when 2-K 1C Goldblatt hypertensive rats were treated with endothelin receptor antagonists, blood pressure was not reduced [6,7]. In addition, we showed that the vasculature of 2-K 1C hypertensive rats exhibited eutrophic remodelling of resistance arteries, whereas the signature of ET-1 effects on the resistance vasculature is hypertrophic remodelling, as found in desoxycorticosterone acetate-salt hypertensive rats [7,8] or Dahl salt-sensitive rats [9]. However, not long afterwards, it was demonstrated that exogenous angiotensin infusion was associated with endothelin overexpression and that endothelin receptor blockers reduced blood pressure and corrected vascular changes in angiotensin-infused rats [10,11]. Again, in partial contrast to these data, Hocher et al. [12] showed that an endothelin antagonist did not lower blood pressure of 2-K 1C Goldblatt hypertensive rats, but did reduce cardiac hypertrophy in these experimental animals. This is in agreement with data showing that, although preproET-1 mRNA was not overexpressed in most vessels in 2-K 1C Goldblatt hypertensive rats, the endothelin system was activated in the heart of 2-K 1C rats [13]. The development of a model in which human angiotensinogen and human renin are overexpressed, and which develops malignant hypertension, again allowed the relationship of ET-1 and angiotensin II to be explored in a renin-dependent model. Those studies demonstrated that renin-dependent renal inflammation could be blocked by bosentan, the ETA/ETB endothelin receptor antagonist [14]. Finally, some studies have shown that that blockade of AT1 angiotensin receptors, but not of endothelin receptors, prevents hypertension and cardiovascular disease in transgenic (mREN2)27 rats, another renin-dependent model, via adrenocortical steroid- independent mechanisms [15]. The findings in the study by Rothermund et al. [1] add to this long series of controversial data by showing that renal damage is not improved by endothelin receptor blockade in this same model of primary renin-dependent hypertension [1]. How can we put all this data together? How can such conflicting data suggesting that ET-1 is both stimulated and not stimulated by angiotensin II be interpreted? Can this be the result of using different endothelin receptor blockers such as ETA selective versus combined ETA/ETB antagonists? This does not appear to be the case because there is no systematic difference to suggest an association of endothelin activation with renin-dependent models depending on the type of antagonist used. We have ourselves repeated the exogenous angiotensin II experiments, and, as seen in Figure 1, the preproET-1 message as revealed by in situ hybridization, is overexpressed in the vascular wall in response to angiotensin II infusion. Over the last few years, we have suggested that, in severe hypertension, or when angiotensin II is infused exogenously at a high and steady rate, there is overexpression of ET-1 by the systemic vasculature and the kidney vessels and glomeruli [16]. When angiotensin II is generated endogenously and hypertension is not malignant, ET-1 is not stimulated by the circadian variations that occur with endogenously generated angiotensin II. Although unproven, this hypothesis appears to explain all the situations described above. The exceptions are certain vascular beds, such as the coronary circulation, in which the endothelium may be particularly sensitive to stimulation by angiotensin II, resulting in enhanced expression of ET-1 in situations where endogenously generated angiotensin II is increased in the absence of severe or malignant hypertension [13].Fig. 1: In situ hybridization showing upregulation of the message of preproendothelin-1 in the aorta of rats in response to subcutaneous angiotensin II infusion at a rate of 120 ng/kg body weight per min for 1 week by osmotic minipump, receiving (or not) the angiotensin AT1 receptor blocker losartan (10 mg/kg per day) in drinking water. Controls were sham infused with vehicle only. (a) Control, (b) angiotensin II and (c) angiotensin II + losartan, showing the hybridization with the preproendothelin-1 antisense oligonucleotide. (d) Control, (e) angiotensin II and (f) angiotensin II + losartan, showing hybridization with the preproendothelin-1 sense oligonucleotide, confirming the specificity of the hybridization.Where does this leave the relative roles of angiotensin and endothelin in cardiovascular and renal disease and in hypertension? The renin–angiotensin and endothelin systems appear to be parallel ones that function in series only under specific and very particular conditions. Because the endothelin system is activated secondary to severe elevations of blood pressure [17,18], regardless of whether angiotensin is elevated in the blood or not, endothelin expression will be enhanced in the vasculature and in the heart and kidney in severe forms of hypertension. In these cases, endothelin will play a role in cardiovascular and renal damage. An angiotensin-dependent model that responds to these characteristics is the double transgenic rat overexpressing human angiotensinogen and human renin [14]. Another condition in which angiotensin will stimulate endothelin is when the levels of angiotensin II are high and steady rather than exhibiting the normal circadian variations. Variable concentrations may be less effective than constant steady concentrations in their ability to stimulate target tissues. Finally, the stimulating effect of angiotensin II infusion on aldosterone production is another physiological variable that needs to be considered. We have shown that some of the effects attributed to direct action of angiotensin II are in fact mediated by the angiotensin II-stimulated increase in plasma aldosterone [19]. In a number of studies, we have demonstrated that mineralocorticoids [17], including aldosterone [20], stimulate the expression of ET-1. Thus, during angiotensin II infusion, or in some of the models in which angiotensin II is severely elevated, increased concentrations of aldosterone may stimulate the expression of endothelin, whereas under other circumstances, lower concentrations of aldosterone will not achieve this. This possibility remains to be explored. Whether subtle relationships exist in vivo between angiotensin and endothelin that result in some degree of mediation of the effects of angiotensin directly by endothelin remains to be established. At present, from the data in the literature, and the study by Rothermund et al. [1], it appears as if the effects of angiotensin are not mediated by endothelin in the kidney, as shown by very mild upregulation of preproET-1 mRNA, and the absence of changes in endothelin converting enzyme-1 activity and endothelin receptors [1]. However, the situation may be different in the heart, and here endothelin may indeed mediate angiotensin actions [12–14,21]. Rothermund et al. [1] raise a final important point in their study. Many investigations in different models of renal disease have shown that endothelin antagonists exert renal protective effects [22,23]. In many of these models, activation of the endothelin system has been demonstrated, and renal protection has been accompanied by blood pressure reduction. The absence of renal protection by endothelin antagonists in the absence of a lowering of blood pressure in primary renin-dependent hypertension underlines the critical role played by blood pressure reduction in the preservation of renal function.

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