Cerebral Vascular Smooth Muscle Potassium Channels and their Possible Role in the Management of Vasospasm

Abstract

One of the promising therapeutic uses of the potassium channel openers is in the management of cerebral vasospasm, a prolonged vasoconstriction of major cerebral arteries which follows aneurysmal subarachnoid haemorrhage. In this review, we first summarize the properties of potassium channels in cerebral vascular smooth muscle. Calcium-activated and ATP-dependent potassium channels are the major potassium channels identified in the cerebrovascular smooth muscle and both are believed to play a role in the regulation of cerebrovascular smooth muscle tone. The calcium-activated potassium channels can be activated by depolarization, by elevation of internal calcium and by some vasodilators. Some neuropeptides and potassium channel openers open the ATP-dependent potassium channels and produce vasodilation. We then review the effects of both synthetic and endogenous potassium channel openers in the cerebrovascular system, discuss their efficacy in the management of models of cerebrovascular spasm, and outline the clinical promise of these agents.

Characterization of the potassium channels involved in EDHF‐mediated relaxation in cerebral arteries

“…Such a study is highly relevant, since these channels could serve as pharmacological targets in conditions, such as subarachnoid haemorrhage and cerebral ischaemia, which have been associated with loss of endothelium‐derived relaxing factors (Nakagomi et al , 1987; Mayhan et al , 1988; Hatake et al , 1992). It has also been suggested that drugs that cause cerebral vasodilatation by opening K‐channels and subsequent hyperpolarization may be of clinical value in situations where pathological vasospasm is caused by membrane depolarization (Zhang & Cook, 1994; Petersson et al , 1996a). The experimental approach adopted in the present study was to examine the effects of different K‐channel inhibitors on endothelium‐dependent relaxation in the presence of inhibitors of NO synthase and cyclo‐oxygenase in the guinea‐pig basilar artery and human pial arteries.…”

ACh-induced depolarization in inner ear artery is generated by activation of a TRP-like non-selective cation conductance and inactivation of a potassium conductance

“…If a component of the evoked EJP shows the same ionic mechanism and mediated by the same receptor(s) like the ACh-depolarization, and if both the EJP and the ACh-depolarization can be enhanced by a cholinesterase inhibitor, the collective evidence will satisfy the criteria (Jiang et al, 1982;Snyder, 1980) for establishing a neurotransmitter role of ACh in the vascular regulation. It will also be interesting to determine whether ACh-mediated depolarization/vasoconstriction plays a role in generation of cerebral vasospasm, possibly with a companion cochlear vasospasm, in aneurysmal subarachnoid haemorrhage cases where the EDHF mechanism is compromised (Zhang et al, 1994), and to determine the effectiveness of cholinergic and ion channel interventions. .…”

Modulation by the Endothelium of the Inhibitory Effects of Pinacidil and Nimodipine on Endothelin‐Induced Contraction in Cerebral Arteries

“…Pinacidil and cromakalim have been shown to attenuate vasoconstriction in cerebral arteries from man and different animal species as well as in a rabbit model of subarachnoid haemorrhage (Toda et al 1985;Nakajima & Ueda 1987;Cain & Nicholson 1989;Wahl 1989;Ksoll et al 1991;Zhang et al 1992;Ryman et al 1993;Zuccarello et al 1996). Although there is ample evidence that potassium channel openers can protect the heart in experimental models of myocardial ischaemia, an effect that may in part be related to improvement of the microcirculation (Andersson 1992;Hearse 1995), only few studies have attempted to evaluate the potential value of these drugs in cerebral ischaemia (Heurteaux et al 1993;Zhang & Cook 1994).…”

“…ischaemia, an effect that may in part be related to improvement of the microcirculation (Andersson 1992;Hearse 1995), only few studies have attempted to evaluate the potential value of these drugs in cerebral ischaemia (Heurteaux et al 1993;Zhang & Cook 1994).…”