Endothelin binding and calcium signalling in hypertension

The endothelium is central to the regulation of vascular tone. Amongst the many vasoactive substances synthesized by the endothelium, endothelin (with three isoforms, namely ET-1, ET-2 and ET-3, with ET-1 by far being the most potent) is one of the most powerful vasoconstrictors known [1]. However, endothelin, similar to the renin–angiotensin–aldosterone system (RAAS) and cathecholamines, has been pathophysiologically linked to cardiovascular disorders, including hypertension and heart failure. As we progressively unravel the mysteries of the RAAS, and attack its adverse effects with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and spironolactone, the endothelin system still remains shrouded with mystery, and established roles for interventions with the endothelin receptor antagonists remain elusive. Perhaps the answer lies in the endothelin receptor(s), that mediates the action(s) of endothelin. Indeed, ET-1 acts on two subtypes of the endothelin receptor, ET(A) and ET(B) [2], and both are present on vascular smooth muscle and mediate vasoconstriction. However, ET(B) is also present on vascular endothelium and stimulates the production of nitric oxide, resulting in vasodilatation [1]. The precise role of endothelin in hypertension is complex, and is thought to depend on an imbalance between ET(A) and ET(B) receptor function secondary to dysfunction of the nitric oxide pathway [2]. However, further insights into the subsequent mechanisms post-receptor binding are required. Indeed, cyclooxygenase seems to be involved in the pathophysiology of endothelin in hypertension [2]. Endothelin also induces proliferation of vascular smooth muscle, cardiac hypertrophy and (as mentioned above) has been implicated in the pathogenesis of heart failure [3]. Perhaps calcium may have a role and, in this issue of the journal, Molero et al. [4] demonstrate decreased endothelin binding and calcium signalling in microvessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Using a video analyser, thereby avoiding inter-observer variation, they found reduced ET-1-induced contraction in small mesenteric arteries. Endothelial receptor binding determined using [125I] ET was reduced by 50% in the DOCA rats. Importantly, Western immunoblotting for the ET(A) receptor showed that the latter effect was secondary to receptor modification rather than down-regulation. Finally, they demonstrated that the DOCA rats do not show the usual ET-1-induced [Ca2+]I increase in the small mesenteric arteries, probably due to a change in the calcium channel function, rather than loss of calcium channels [4]. Thus, their study elegantly demonstrates that, in the DOCA-salt hypertensive rat, endothelin function is attenuated because of ET(A) and L-type Ca2+ channel receptor modulation. The change in receptor function may perhaps be negative feedback as a potentially protective mechanism. What does this mean in a clinical context? Hypertension is a common condition, and is a major risk factor for cardiovascular morbidity and mortality. The aetiology of essential hypertension is still poorly understood and is multifactorial. Whilst the enthusiasts and cynical clinical pharmacologists would say that the RAAS may be all we need to know for human hypertension, the endothelin system could be a key link between vascular function and hypertension. Certainly, some evidence would suggest that endothelin activates local RAAS [5]. It is hoped that endothelin receptor antagonists, such as bosentan, would offer a new class of antihypertensive agents [6]. However, optimism and reality are different things, as illustrated by recent data on the vasopeptidase inhibitor, omapatrilat [7]. Many unanswered paradoxes remain. For example, circulating levels of ET-1 in hypertensive animals, and in humans with essential hypertension, were found to be in the low to normal range [8]. If endothelin ‘vasoconstricts’ blood vessels and increases peripheral resistance, and hence blood pressure, should levels not be high in hypertension? Furthermore, using immunohistochemical techniques, increased levels of ET-1 were demonstrated in the blood vessels of DOCA-salt hypertensive rats, but not spontaneously hypertensive rats [9], suggesting a greater(?) role for ET-1 in mineralocorticoid hypertension, rather than essential hypertension. Indeed, endothelin may produce a ‘salt sensitive’ rise in blood pressure. Perhaps ET-1 is exerting a paracrine effect, which may be likely because of a very short half-life of approximately 7 min. Intriguingly, could endothelin-induced hypertension be a form of secondary hypertension? Furthermore, while the blood vessels are exposed to high pressures in hypertension, paradoxically, the main complications of hypertension (i.e. stroke and myocardial infarction) are thrombotic rather than haemorrhagic, which is the so-called thrombotic paradox of hypertension (or ‘Birmingham paradox') [10], and whether the endothelin system contributes to the prothrombotic state in hypertension remains an unanswered question. Finally, is it possible to extrapolate data from the hypertensive rat (DOCA-salt type, or otherwise) to the upright two-legged human model? The rats in the study by Molero et al. [4] were hydrated with 0.9% saline solution, and received a uninephrectomy and the implantation of subcutaneous DOCA pellets. Whilst this is an entirely acceptable experimental model, more cynical clinical hypertensiologists would ask how does this compare with human hypertension. The rat mesentery may not necessarily be ideal for studying the effects of systemic hypertension, but Molero et al. [4] elegantly demonstrate their experiments in small vessels < 150 μm (which must be difficult to perform!), and these are the vessels that are thought to determine vascular resistance. We have only just begun to unravel some of the complexities of the RAAS in hypertension, and to learn how to modulate them to our advantage. With the endothelins, we have much to understand before we are fully confident of our progress, although therapeutic agents may not be too far away.