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Cardiovascular Research 2000 48(3):365-366; doi:10.1016/S0008-6363(00)00239-X
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Chloride ions and the endothelium: their role in adrenoceptor-mediated vasoconstriction

M.Yvonne Alexander*

Department of Medicine and Therapeutics, University of Glasgow, Glasgow, G11 6NT, UK

* Tel.: +44-141-211-2111; fax: +44-141-211-1763 yalexander{at}clinmed.gla.ac.uk

Received 13 September 2000; accepted 27 September 2000

See article by Tabrizchi and Duggan [1] (pages 393–401) in this issue.

This report by Tabrizchi and Duggan [1] represents another link in the continuing effort to evaluate factors involved in the regulation of vascular tone. Much of the early work in this regard focussed on the findings by Furchgott and Zawadski [2] that endothelial derived relaxing factor (EDRF) is responsible for acetylcholine-induced vasodilation and the later independent reports of Ignarro and Moncada identifying EDRF as nitric oxide (NO) [3–4]. This led to a huge wealth of information drawn from in vitro and in vivo studies correlating hypertension or other cardiovascular disorders and a reduction in basal nitric oxide availability in certain rat models of hypertension [5–6] and patients with essential hypertension [7–9].

The study by Tabrizchi and Duggan described in this issue [1] was designed to investigate the participation of chloride ions and basal endothelial function in response to the {alpha}1-adrenoceptor agonist, cirazoline, in a rat model of hypertension.

The endothelium is an important regulator of vascular function, in that it responds to a variety of physiological stimuli, releasing vasoactive factors which have their affects on the underlying muscle layer. The endothelium produces nitric oxide which is a potent vasodilator [10] and is formed by the action of the enzymes NO synthase, of which there are three isoforms. The activity of the endothelial NOS is controlled by intracellular calcium/calmodulin, although in some cases, it exhibits calcium-independent activity [11–12]. This lends itself to the idea that nitric oxide may be produced at a continuous low level in cells, independent of alterations in calcium fluctuations. NO is the endogenous activator of the soluble form of guanylate cyclase, increasing cGMP levels, which causes a reduction in intracellular calcium and in turn causes smooth muscle relaxation [13].

The endothelium is also responsible for vasoconstriction induced by substances such as the {alpha}1-adrenoceptor agonists [14]. Agonists that elicit contraction, do so by increasing calcium, the delivery of which is governed by ion channels in the plasma membrane of both endothelial cells and vascular smooth muscle cells [15]. They may be voltage-dependent Ca2+ channels which open in response to depolarisation and is brought about by agonists acting on {alpha}1-adrenoceptors. Membrane potential is an important regulator of signal transduction, with changes in potential being controlled by K+, Cl–, and other non-selective cation channels [16]. Signal transduction pathways that lead to contraction and relaxation of smooth muscle involve an interplay of ion channels in the plasma membrane of vascular muscle cells, some of which are chloride channels. Several different types of chloride channels exist in endothelial cells [17].

Driven by the hypothesis that chloride ion handling by the endothelium represents an important component of vascular dysfunction, Tabrizchi and Duggan use the NOS inhibitor L-NAME to block NO production and evaluate the biological significance of the nitric oxide/arginine pathway on {alpha}1 adrenoceptor-mediated vasoconstriction in normal Krebs and chloride-free buffer using aorta from Dahl normotensive and hypertensive rats.

The SSR were placed on a 4% salt diet and systolic and diastolic blood pressure was measured before the aortas were removed from the experimental animals, Physiological contractile responses were determined in an organ bath. Cirazoline, an {alpha}1-adrenoceptor agonist, was used to induce aortic contractions and it was found, that in the presence of L-NAME, there was an increase in tension in the aortic rings from the normotensive rats but a lack of effect in aortic rings from salt-sensitive rats, which can be related to nitric oxide availability. This is in keeping with the findings of McIntyre et al. [5], who have shown that the stroke prone spontaneously hypertensive rat used in their study, also displays a lack of effect of L-NAME on phenylephrine-induced tension, when compared to the normotensive Wistar Kyoto strain, reflecting reduced basal nitric oxide availability in hypertensive compared to normotensive rats.

To confirm that chloride ions were involved in the response evoked by nitric oxide, Tabrizchi and Duggan used the chloride channel antagonist, IAA 94, and cirazoline-mediated contractions in aortic rings from both SRN and SSH rats were assessed in both normal Krebs and chloride-free buffer, in the presence and absence of L-NAME. Results from aortic rings of the SRN rats showed that chloride-free buffer potentiated contractions produced by cirazoline and did not show any further increase in tension in the presence of L-NAME and chloride-free buffer. This contrasted with the results from the SSH rats, where chloride-free buffer attenuated contractions to cirazoline, with no further inhibition in the presence of L-NAME. Since the SSH rat has a reduced bioavailability of nitric oxide compared to the SRN rat, these results suggest that basal release of NO has an effect on vasomotor tone via ion channels and chloride ions.

Tabrizchi and Duggan also examined the effect of chloride-free buffer on cGMP levels in both strains of rats. Results show no significant difference in cGMP levels between the strains, suggesting a lack of involvement of cGMP on the cirazoline-induced contractions. The fact that L-NAME did not enhance the response to ciazoline in chloride-free buffer and no difference in cGMP levels could imply an interplay with normal basal endothelial function and chloride ions independent of cGMP activity. This is an interesting finding in the light of their results linking nitric oxide availability and the presence of chloride ions on mechanical activity. As the authors rightly point out in reference to other work [18], this complex cellular regulation evoked by chloride channels in the vascular endothelium may be subject to another pathway, unrelated to the NO/cGMP-dependent pathway, which may contribute to adrenoceptor-mediated contraction, perhaps a Ca2+/Cl–-dependent process.

Recent findings, including those of Tabrizchi and Duggan, have emphasised new signalling aspects of contractile function, clearly a multifactorial process that involves a complex sequence of cellular events. The rapid progress being made in the molecular understanding of vascular pathophysiology and genetics will enable us to identify novel targets for therapeutic intervention in the foreseeable future.


   References
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