Endothelins and venous tone in DOCA-salt hypertension

A role for the endothelin system in the pathogenesis of salt-dependent or low-renin forms of experimental hypertension, including the Dahl salt-sensitive and deoxycorticosterone-acetate (DOCA)-salt hypertensive rats has been well established [1]. In DOCA-salt hypertensive rats ET-1 gene and preproendothelin-1 (prepro ET-1) mRNA expression and immunoreactive ET-1 levels in mesenteric resistance arteries and the aorta are increased [2–4]. Resistance arteries of DOCA-salt hypertensive rats show substantial smooth muscle hypertrophy. This severe hypertrophy is almost completely prevented by administration of the combined ETA/ETB receptor antagonist bosentan when administered in the developmental phase of hypertension [5]. Interestingly, this antihypertrophic effect of bosentan is separated from its blood pressure-lowering effect, compatible with a direct effect of the endothelin system on vascular smooth muscle growth. Further support for the involvement of the endothelin system in the pathogenesis of hypertension in DOCA-salt and, more recently, in aldosterone-infused hypertensive rats is demonstrated by studies showing that selective ETA receptor antagonists can markedly attenuate or even completely abolish the development of hypertension in these experimental hypertensive models [6,7]. The demonstration of the involvement of the endothelin system in the development and maintenance of hypertension in DOCA-salt hypertensive rats has stimulated investigations into a potential role of this system at the venous site of the circulation, especially because in-vitro studies have consistently shown that the maximal vasoconstrictor response to, and potency of, endothelins in veins is greater compared to that in corresponding arteries [8–11]. The venous system is an important, yet infrequently considered part of the circulation. Changes in venous capacitance induced by alterations in venomotor tone can affect blood pressure through effects on venous return and cardiac output. In experimental animals, information about venous tone in vivo can be derived from the mean circulatory filling pressure (MCFP). The MCFP, essentially a measure of filling of the circulation, is the pressure that exists in the entire circulation when cardiac output is abruptly arrested and arterial and venous pressures are equalized [12]. Similar to vascular resistance, MCFP is increased in practically all forms of hypertension [13]. As blood volume in hypertension is not increased but, in contrast, is usually slightly reduced, the increase in MCFP in hypertension must be caused by a decrease in the compliance of the venous system, which in turn may be a consequence of an increase in venous tone, of structural venous changes or of the combination of these two effects [14]. In rats, MCFP compared to the MCFP in control rats is increased 3–4 weeks after DOCA-infusion and salt administration in their drinking water [15,16]. It has been shown that this increase in MCFP to some extent depends on an increased endogenous endothelin tone. Administration of an ETA-receptor antagonist to DOCA-salt hypertensive rats is associated with a decrease in both systemic arterial pressure and in MCFP, whereas only a minimal decease in systemic arterial pressure and no decrease in MCFP is seen in control rats [15]. It should be emphasized that the observed decrease in MCFP in response to ETA receptor blockade is relatively small (on average from 8.5 to 7.4 mmHg) compared to the decrease observed with ganglionic blockade with hexamethonium (from 8.5 to 5.5 mmHg). As ETB receptor activation of venous smooth muscles might also contribute to the increase in MCFP in DOCA-salt hypertensive rats, the effects of ETB-selective and mixed ETA/B endothelin receptor antagonists on MCFB have also been investigated. Similar to the ETA receptor antagonist, the combined ETA/B receptor antagonist is also associated with a decrease in MCFP, but no decrease in MCFP has been observed with a selective ETB-receptor antagonist [16]. These in-vivo findings indicate that the endothelin system does not act through ETB receptors to increase venous tone in the DOCA-salt hypertensive rat. A further exploration of the mechanism involved in the endothelin-mediated increase in venous tone in DOCA-salt hypertension is given in the study by Johnson et al. in this issue of the journal [17]. The main findings from their in-vitro studies are: (i) in contrast to the less sensitive mesenteric arteries as reported previously [11], mesenteric veins of DOCA-salt hypertensive as well as of control rats exhibit a similar sensitivity to the contractile actions of ET-1 and the selective ETB receptor agonist sarafotoxin; (ii) the ET-1 induced venoconstriction in DOCA-salt hypertensive and control rats is mediated by ETA receptors; (iii) preproET-1 mRNA levels in mesenteric veins from DOCA-salt hypertensive and control rats are not different; and (iv) preproET-1 mRNA levels are higher in veins compared to the corresponding arteries both in DOCA-salt hypertensive and control rats. Combining the results of the previous in-vivo studies and the present in-vitro findings, the conclusion is that the increase in venomotor tone in DOCA-salt hypertensive rats is not the result of a direct endothelin-mediated venoconstrictor response. What might be the explanation for the discrepancy between the in-vivo studies and the present in-vitro findings? One possibility, also mentioned by the authors, is the presence of an interaction between the endothelin system and other vasoconstrictor systems in vivo that is not seen in the in-vitro studies using isolated blood vessels. It has been reported that effects of ET-1 are potentiated by angiotensin II [18,19]. In the DOCA-salt hypertensive rat, such an interaction is not very likely, however, in the light of the suppression of the renin–angiotensin system in this experimental hypertension model. Interaction between the endothelin system and the sympathetic nervous system is another possibility. In addition to its direct vasoconstrictor effects, ET-1 amplifies the response to noradrenaline and, reciprocally, noradrenaline can potentiate the vasoconstrictor effects of ET-1 [10,20]. Furthermore, in hypertensive patients, ET-1 has been shown to potentiate sympathetically mediated venoconstriction [21]. It could be that the generalized up-regulation of the endothelin system in DOCA-salt hypertensive rats, although not demonstrable in isolated mesenteric veins, indirectly contributes to an increase in sympathetically mediated venoconstriction. Further support for this view is provided by the observation that sympathico-inhibition with the ganglion blocker hexamethonium results in a greater reduction in MCFP in DOCA-salt hypertensive compared to control rats [15]. Finally, the ETA-mediated increase in venous tone observed in DOCA-salt hypertensive rats may be a non-specific phenomenon related to the slightly elevated blood volume in this model resulting in enhancement of responses to vasoconstrictors. In conclusion, the role of the endothelin system in experimental salt-sensitive models of hypertension has been well established, but the mechanism by which it contributes to the increase in venomotor tone remains uncertain. Excitingly, the role of the endothelin system in experimental forms of salt-sensitive hypertension appears to have its counterpart in humans. Evidence for a role of the endothelium system in human salt-sensitive hypertension is emerging [22]. Black hypertensive patients, who characteristically have a salt-sensitive low-renin form of hypertension, demonstrate higher plasma ET-1 levels than White hypertensive patients. Furthermore, in response to mental and cold stress, plasma ET-1 levels increase more in Black than in White individuals, and this is accompanied by larger increments in blood pressure [23,24]. Finally, there is compelling evidence for an important role of the endothelin system in the regulation of growth of the adrenal cortex, as well as involvement in the pathogenesis of Conn's disease [25]. These findings further support a link between the endothelin system and salt-sensitivity in man, possibly being partly related to the action of endothelins on the synthesis of mineralocorticoids.