Endothelial vasoregulation and mechanosensitive ion channels in hypertension.

[9] and are involved in Ca2+ mobilization induced by Introduction mechanical stretch [10]. Stretch-activated ion channels were originally identified in chick skeletal myocytes by Haemodynamic forces associated with blood flow play use of the patch-clamp technique. They are involved a crucial role in the acute regulation of vascular tone in the mechanotransduction of various tissues in verand long-term changes of vascular structure and tebrates and non-vertebrates [11]. Pathophysioremodelling [1,2]. Alterations in endothelial function logically a dysfunction of mechanosensitive ion chanappear to be involved in the disturbed vasoregulation nels have been reported to be involved in stretchin hypertension and in the development of atherosclerinduced arrhythmias [12] and in muscular dystrophy otic lesions of the vessel wall [2]. Located at the [13]. These specialized ion channels are sensitive to interface between blood and vessel wall, the endothelium is directly subjected to haemodynamic forces changes in membrane tension or stretch which can be associated with blood flow and responds to haemoinduced under experimental conditions by suction dynamic stimulation with the secretion of vasoactive applied to the rear of the patch pipette. The activation mediators. Increases in blood flow induce a vasodilof the channels shows a graded increase of channel ation which depends on an intact endothelium and is activity with respect to the degree of membrane stretch mediated by endothelium-derived factors like nitric elicited by different strengths of pipette suction. The oxide (NO) or prostacyclin 2 Flow-dependent electrophysiological properties of the channel, i.e. ion vasodilatation is an important protective mechanism selectivity and channel conductance, remain unaffected to avoid damage of the vessel wall by frictional wall by membrane stretch. Endothelial stretch-activated shear stresses associated with flow. channels have a channel conductance between 25 and The mechanism by which the endothelium senses 45 pS and are impermeable for anions and permeable flow and the associated haemodynamic forces and for monoand divalent cations [9,14,15]. The channel transforms them into biochemical signals ultimately permeability for Ca2+ ions is 3–4 times lower than for leading to the secretion of endothelial mediators has monovalent cations e.g. K+ and Na+. However, indirbeen incompletely characterized so far. Activation of ect evidence showed that due to the large inwardly ion channels and changes in intracellular calcium directed electrochemical gradient for Ca2+ ions an homeostasis are involved in the acute response of the activation of the stretch-activated channels leads to a endothelium to mechanical stimulation [3]. This is sufficient Ca2+ influx into the endothelial cell and demonstrated by the observation that the flow-induced increases the intracellular Ca2+ concentration [14,16 ]. endothelium-dependent vasodilatation in perfused Stretch-activated ion channels are blocked by gadolinarteries depends on the activity of K+ channels [4 ] ium, a trivalent lanthanide, in concentrations of less and involves an increase in intracellular Ca2+ concenthan 30 mmol/l. tration [5]. It should be mentioned that in contrast to Furthermore, two K+-selective mechanosensitive ion previous reports [6,7] the Ca2+-dependent phase of channels have been observed in endothelial cells. An flow-induced NO production was recently reported to endothelial stretch-activated K+ channel K ) has be abolished in perfused isolated conduit arteries of been identified in freshly isolated rat aortic endothelial the rabbit after restoring the assumed in vivo length of cells [17]. This channel had a mean channel conductthe arteries [8 ]. ance in cell-attached patches of 70 pS and was selectively permeable for K+ ions with a permeability ratio Stretch-activated channels K+5Na+ of 1151. A shear-stress-activated K+ channel was observed in cultured bovine aortic endothelial cells Mechanosensitive, stretch-activated ion channels have [18]. The channel had a mean channel conductance of been postulated to act as endothelial mechanosensors 31 pS and was inwardly rectifying. The activation of these K+ selective mechanosensitive channels led to an Correspondence and offprint requests to: J. Hoyer, Department of Nephrology, UKBF, 12200 Berlin, Germany. efflux of K+ ions and subsequently to a hyperpolariz-