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In vascular smooth muscles, the relaxation and constriction of arterioles and arteries constantly takes place in order to maintain the required arterial resistance, cardiac output and total peripheral resistance (TPR). Vasodilatation is not a direct process and therefore involves a number of initiating factors that lead to the changes causing the resistance vessels to dilate. The major mechanism of vasodilatation involves hyperpolarisation mediated dilation of vessels by weak rectifying ATP-sensitive K+ channels (KATP), the inwardly rectifying K+ channel (Kir) and depolarisation activated, calcium dependent K+ (BKCa) channels.
Figure , shows the molecular structure of the KATP channel. The proposed structure of the KATP channel consists of one SUR (sulphonylurea) and a Kir (inward rectifying) subunit. There are two nucleotide binding factors.
KATP channels have a Kir subunit and a sulphonylurea binding site as shown in figure 1. It was demonstrated that the activity of KATP is not dependent upon voltage changes and are also not time dependent (Yokushiki et al., 1998). Due to the presence of Kir subunits, KATP have weak rectifying properties as a result of a strong depolarisation stimulus. In response to strong depolarisation, KATP flickering within the decreases and they remain open. Single channel conductance is around 80ps in cardiac myocytes (Kakei et al., 1985), however their existence in the vascular smooth muscles is still controversial due their low expression density in these tissues.
Vasodilatation is important to raise blood flow to parts of the body where there is increased demand of oxygen, i.e during exercise. The initiation of vasodilatation pathway is through the fall in Cytosolic [Ca2+] which deactivates MLCK. Vasodilatation effects of KATP are exerted through decreasing the influx of calcium by inhibiting the voltage gated calcium channels (VDCC) through hyperpolarisation of the membrane. Membrane potential is important at regulating the influx of calcium. Therefore any shift from depolarisation to hyperpolarisation will lead to a decreased calcium entry as the open state probability of VDCC becomes low. Calcium is an important mediator of vasoconstriction as it contributes to the formation of Ca2+-calmodulin complex that activates myosin light chain kinase (MLCK). MLCK phosphorylates the MLC20 site of myosin head (Kam et al., 1985) in smooth muscles leading to the formation of actin-myosin cross-bridges and hence causing vasoconstriction. The latch state is maintained that lead to a prolonged crossbridges formation at a low energy expenditure. Dephosphorylation by myosin light chain phosphatase, a constitutively active enzyme, leads to vasodilatation. Therefore Ca2+ is an important mediator of the amount of activated MLCK available to form crossbridges. Thus the inhibition of VDCC by KATP during hypoxia and Kir in active myocardium leads to hyperpolarisation and hence vasodilatation. Studies in 2002, revealed KATP knockout mice having a hypercontractile arteries due to coronary artery spasm, leading to myocardial ischeamia followed by death through lethal arrhythmias (Miki et al., 2002). Moreover, kir6.1 subunit knockout mice had an elevation in ST segment of their ECG. On the other hand the Kiv trigger vasodilatation through their strong inward rectifying properties. This is caused merely through the existence of polyamines ions such as spermine and sperimidine in the pore of Kir. Their vasodilatation mechanism involveds the rise in [K+]o associated with the repolarisation state of the action potential. They exert K+ current in response to increase [K+]o at resting states and hence cause hyperpolarisation. This type of mechanism occurs predominately in the small arteries and arterioles to cause vasodilation.
As the name suggests, KATP channels are sensitive to the levels of intracellular ATP. These channels open as a result of the fall in ATP levels, i.e. decreased ATP/ADP ratio. This usually occurs during severe ischaemia where there is decreased oxygen availability or complete deprivation in oxygen supply to a particular tissue. Moreover, during periods of hypoxia, the rise in ADP, GDP, adenosine and H+ concentrations also increase the opening probability of these channels. These channels have been reported to contribute to its protective roles in vital organs such as the heart and brain and therefore gained a lot of attention. Vasodilatory effects of KATP are intervened through decreasing the influx of calcium by inhibiting the voltage gated calcium channels (VDCC) through hyperpolarisation of the membrane. Membrane potential is important at regulating the influx of calcium. Therefore any shift from depolarisation to hyperpolarisation will lead to a decreased calcium entry as the open state probability of VDCC becomes low as Calcium is an important mediator of vasoconstriction, as previously described.
Vasodilators such as calcitonin-gene related peptide and adenosine activate PKA and PKG causes the opening of the vascular KATP channels. PKA stimulates Ca2+ATPase pumps to reduce cytosolic [Ca2+], thus phosphorylating the KATP to cause hyperpolarisation leading to inactivation of MLCL and thus vasodilatation. Glibenclamide is a potent inhibitor of the KATP channel and through its application vasoconstriction occurs. Similarly, a recent study reported the vasodilatory effects of H2S a gas that also acts on KATP (Liang et al., 2011) in the smooth muscle cells of the cerebral arterioles. However, whether these channels remain active during normal physiological levels still remains controversial but their increased opening probability during hypoxic conditions make them a very important contributor to vasodilatation during periods of high oxygen demand where a raised blood flow to excerising muscles is required.
In contrast the Kir channels are present only in certain small diameter and submucousal arterioles and in coronary arterial smooth muscle (Park et al., 2008). Mechanism through it how it causes vasodilatation is similar to that of KATP, major difference being that the KATP is sensitive to ATP. Increase in [K+]o leads to an increased Ek of about -80 to -56mV. At basal conditions, the membrane potential of the arterial smooth muscle is -50mV to -40mV, which is more positive than the EK. This rightward shifting in the conductance-voltage relationship of the inward rectifier would increase the outward K+ current, leading to membrane hyperpolarisation to reach a new EK (Standen et al., 1996).
On the other hand, BKca channel is a specialised form of volatage dependent K+ channel (Kv) that is activated by depolarisation. They are large conductance channels and conversely are activated by increased intracellular Ca2+. At basal conditions, they are activated as a result of Ca2+ sparks exerted from the sarcoplasmic reticulum (SR) and hence generating a spontaneous transient outward current (STOC). In contrast, Kir channels produce an inward current. These STOCs contribute to the membrane potential. Their main role is to reduce vascular excitability and vasospasm. In addition, as calcium enters the myocytes, BKca activation makes the membrane more negative, which reduces the VDCCâ€™s open probability. Vessels with high BKCa expression channels do not possess action potential. BKca channel knockout mice had a raised vascular tone and blood pressure (Ledoux et al., 1989).
The maintenance of cellular [K+] is very important as these ions play a significant role in generating a negative membrane potential of about -70mV. Intracellular [K+]o is about 165mM and extracellular is ~5mM. During periods of cellular stress, i.e. ischaemia and hypoxia, [K+]o can rise to >10mM (Somjen GG 1987). As a result of increased energy demand, a brake in the â€œmyogenic toneâ€Â (pressure-induced constriction) is introduced by BKca channels. In vivo studies have revealed that the myogenic tone is the major contributor of vascular resistance and regulation of blood flow (Nelson et al., 1995). Therefore the opened and closed state status of the [K+] channel is very important. Opening of K+ channels during hypoxia controls the voltage-senstive Ca2+ channels (VDCC). The hypoxic environment increases the open state probability of K+ channels and hence hyperpolarisation causes the closure of VDCC. The net effect is the reduction in Ca2+ influx and hence vascular relaxation. (The roles of different K+ channels that contribute to vasodilatation is described above).
Theoretically, a large increase in [K+]o will cause depolarisation of the membrane as the membrane potential is shifted towards the equilibrium potential of K+ (EK). However paradoxically, it is evident that elevation in [K+]o to about 10mM to 16mM can hyperpolarise the membrane potential in the arterial smooth muscle (knot et al., 1996, Edwards et al) and hence vasodilatation. This type of paradoxity was recently tested through that two hypotheses that involved Na+/K+ ATPase (Webb et al.,1978) and Kir (Knot et al., 1996). A slight elevation in [K+] from 0mM to <5mM was seen to cause transient vasodilatations that was lost upon the application of Na+/K+ ATPase inhibitor, ouabain (McCarron and Halpern 1990). Thus stimulation of Na+/K+ ATPase causes transient membrane potential hyperpolarisations which decays with time as Na+ is extruded and membrane starts to depolarise to resting potentials (Joshua et al., 2000).
Another theory is through the activation of Kir that causes the hyperpolarisation of membrane towards the Ek, as a result of increased [K+]o. At a pressurised state cardiac myocytes have a membrane potential of about +40mV positive to Ek (Knot et al., 1996). An increased activity of Kir was reported as the [K+]o was raised to 15mM causing a sustained membrane hyperpolarisation and hence vasodilation.
In conclusion, most research on potassium channels involves the cerebral and coronary circulation. K+ channels are an important set of channels that contribute to the normal functioning of the cardiovascular system. Therefore, they are becoming a centre of attention and can now be therapeutically targeted to treat diseases related to the malfunctioning of the vascular tone. One of the most widely used vasodilator is nicorandil that cause the activation of KATP via the release of guanylyl cyclase stimulated rise in cGMP (kukovetz et al., 1992) causing hyperpolarisation and hence, vasodilatation. It is used for the treatment of angina. The exact mechanisms of how K+ channels exert their vasodilatory effects still remain to be controversial and therefore as research goes on the exact phenomenon of their mechanism will soon be revealed.