The endothelium of blood vessels plays a crucial role in the regulation of blood flow by controlling mechanical functions of underlying vascular smooth muscle. The regulation by the endothelium of vascular smooth muscle relaxation and contraction is mainly achieved via the release of vasoactive substances upon stimulation with neurohumoural substances and physical stimuli. Nitric oxide (NO) and prostaglandin I2 (prostacyclin, PGI2) are representative endothelium-derived chemicals that exhibit powerful blood vessel relaxation. NO action involves activation of soluble guanylyl cyclase and PGI2 action is initiated by the stimulation of a cell-surface receptor (IP receptor, IPR) that is coupled with Gs-protein-adenylyl cyclase cascade. Many studies on the mechanisms by which NO and PGI2 elicit blood vessel relaxation have highlighted a role of the large conductance, Ca2+-activated K+ (MaxiK, BKCa) channel in smooth muscle as their common downstream effector. Furthermore, their molecular mechanisms have been unravelled to include new routes different from the conventionally approved intracellular pathways. MaxiK channel might also serve as a target for endothelium-derived hyperpolarizing factor (EDHF), the non-NO, non-PGI2 endothelium-derived relaxing factor in some blood vessels. In this brief article, we review how MaxiK channel serves as an endothelium-vascular smooth muscle transducer to communicate the chemical signals generated in the endothelium to control blood vessel mechanical functions and discuss their molecular mechanisms.

The MaxiK channel is the large-conductance, voltage-dependent, and Ca²⁺-activated K⁺ channel. This channel is almost ubiquitously distributed among mammalian tissues including smooth muscles. The ability of MaxiK to work as a rheostat fine tuning membrane potential and intracellular Ca²⁺ enables it to mediate opposite functions: it facilitates contraction, but also acts as a negative feedback mechanism to restore tone after a contraction cycle. MaxiK activation mediates relaxations to a variety of physiological substances, whereas its inhibition plays a significant role in contractile responses. At the molecular level, MaxiK is a protein complex formed by at least two integral dissimilar membrane subunits, the pore-forming α-subunit and a regulatory β-subunit. In smooth muscles, β1 is the predominant subunit and most MaxiK seem to be assembled of α- and β1-subunits. The presence of the β1-subunit confers MaxiK with higher Ca²⁺/voltage sensitivity, which makes this channel an efficient tuner of smooth muscle functions in physiological conditions. The enhanced smooth muscle mechanical activities in mice lacking the β1-subunit gene support the principal role of this channel molecular component in tissue and whole animal functions. In this review, we discuss MaxiK channel roles as a tuner of smooth muscle contractility, especially focusing attention on the modulatory β1-subunit.

Prostaglandin I2 (PGI2, prostacyclin), an eicosanoid of the cyclooxygenase pathway, causes relaxation of vascular smooth muscle in most blood vessels and inhibits platelet aggregation. PGI2 and its stable analogues activate a specific cell-surface receptor (IP receptor, IPR), which is coupled to adenylyl cyclase through Gs-protein. Elevation of 3: 5-cyclic monophosphate (cyclic AMP, cAMP) levels has been considered to be a key cellular event to trigger blood vessel relaxation by IP agonists; however, its exclusive role has been recently challenged. Downstream effectors of the IP agonist metabolic cascade are plasma membrane K+ channels that upon activation would cause smooth muscle cell hyperpolarization and relaxation. The K+ channel candidates include ATP-sensitive K+ (KATP) channel and large conductance, Ca2+-activated K+ (MaxiK, BK) channel. The contribution of each K+ channel subtype would be governed by their relative expression and / or particular co-localization with different proteins of the IPR signaling cascade in each vascular bed. Scrutiny of the cellular mechanisms underlying IPR-activated vascular relaxation of a large conduit artery revealed that relaxation by an IP agonist, beraprost, is elicited through cAMP-independent pathway as well as by a cAMPdependent route. Both mechanisms include activation of MaxiK channels. The cAMP-independent vasorelaxant mechanism is partly attributed to a direct activation of MaxiK channel by Gs-protein. In this review article, we discuss cAMP-dependent and -independent mechanisms by which IPR stimulation activates MaxiK channel. Our recent work demonstrates a functional tight coupling between IPR and MaxiK channel through a cAMP-independent, Gs-protein mediated mechanism(s) in vascular smooth muscle.

Background/Aims: Effects of docosahexaenoic acid (DHA) on blood vessel contractions to various constrictors were investigated in rat mesenteric artery and compared with those of eicosapentaenoic acid (EPA) and linoleic acid (LA). Methods: Tension changes in mesenteric ring segments were isometrically recorded. Results: On sustained contractions induced by a thromboxane A2 mimetic (U46619), DHA exerted a strong inhibitory effect. This inhibitory effect of DHA on U46619 appeared both in endothelium-intact and endothelium-denuded preparations. Although the inhibitory effect of DHA on prostaglandin F2α (PGF2α)-induced contractions was also significant, contractions to phenylephrine (PE) and high-KCI were not affected by DHA. As well as DHA, EPA strongly diminished U46619- and PGF2α-induced contractions without showing a substantial inhibition of PE- and high-KCl-induced contractions. By contrast, LA did not show any significant inhibitory effects on any contractions. The DHA-induced inhibitory actions exerted on U46619 and PGF2α also emerged if ring preparations were pretreated with this ω-3 polyunsaturated fatty acid (PUFA). Conclusion: DHA and EPA are found to more pronouncedly inhibit prostanoid receptor-mediated contractions than other constrictor responses of the mesenteric artery via endothelium-independent mechanisms. These inhibitory effects of ω-3 PUFAs on prostanoid receptor-mediated contractions may partly underlie the mechanisms by which these ω-3 PUFAs elicit protective actions against circulatory disorders.

We examined the contribution of large-conductance, Ca(2+)-sensitive K+ (MaxiK) channel to beta2-adrenoceptor-activated relaxation to isoprenaline in guinea-pig tracheal smooth muscle focusing on the role for cAMP in the coupling between beta2-adrenoceptor and MaxiK channel. Isoprenaline-elicited relaxation was confirmed to be mediated through beta2-type of adrenoceptor since the response was antagonized in a competitive fashion by a beta2-selective adrenoceptor antagonist butoxamine with a pA2 value of 6.56. Isoprenaline-induced relaxation was significantly potentiated by a selective inhibitor of cyclic AMP-specific phosphodiesterase, Ro-20-1724 (0.1-1 microM). cAMP-dependent mediation of MaxiK channel in the relaxant response to isoprenaline was evidenced since the potentiated response to isoprenaline by the presence of Ro-20-1724 (1 microM) was inhibited by the channel selective blocker, iberiotoxin (IbTx, 100 nM). This concept was supported by the finding that the relaxation to a membrane permeable cAMP analogue, 8-bromo-cAMP (1 mM), was susceptible to the inhibition by IbTx. On the other hand, isoprenaline-induced relaxation was not practically diminished by an adenylyl cyclase inhibitor SQ 22,536 (100 microM). However, isoprenaline-induced relaxation in the presence of SQ 22,536 was suppressed by IbTx. Characteristics of isoprenaline-induced relaxant response, i.e., impervious to SQ 22,536 but susceptible to IbTx, were practically mimicked by cholera toxin (CTX, 5 microg/ml), an activator of adenylyl cyclase coupled-heterotrimeric guanine nucleotide-binding regulatory protein Gs. These findings indicate that in guinea-pig tracheal smooth muscle: 1) MaxiK channel substantially mediates beta2-adrenoceptor-activated relaxation; 2) both cAMP-dependent and -independent mechanisms underlie the functional coupling between beta2-adrenoceptor and MaxiK channel to induce muscle relaxation; and 3) direct regulation of MaxiK channel by Gs operates in cAMP-independent coupling between beta2-adrenoceptor and this ion channel.