Rhythmicity in arterial smooth muscle

Abstract

Many arteries and arterioles exhibit rhythmical contractions which are synchronous over considerable distances. This vasomotion is likely to assist in tissue perfusion especially during periods of altered metabolism or perfusion pressure. While the mechanism underlying vascular rhythmicity has been investigated for many years, it has only been recently, with the advent of imaging techniques for visualizing intracellular calcium release, that significant advances have been made. These methods, when combined with mechanical and electrophysiological recordings, have demonstrated that the rhythm depends critically on calcium released from intracellular stores within the smooth muscle cells and on cell coupling via gap junctions to synchronize oscillations in calcium release amongst adjacent cells. While these factors are common to all vessels studied to date, the contribution of voltage-dependent channels and the endothelium varies amongst different vessels. The basic mechanism for rhythmical activity in arteries thus differs from its counterpart in non-vascular smooth muscle, where specific networks of pacemaker cells generate electrical potentials which drive activity within the otherwise quiescent muscle cells.

Figure 1. Membrane potential oscillations underlying vasomotion in rat irideal arterioles and basilar arteries

While depolarizations precede constrictions in both vessels, the most negative membrane potential reached in the iris is less than −60 mV while that in the basilar is considerably more positive and less stable. Note also that the oscillations in the iris are slower than those in the basilar artery. Part B reproduced with permission of Blackwell Publishing from Haddock & Hill (2002).

Figure 2. The voltage-independent coupled oscillator in iris arterioles

Constitutive activity of phospholipase C (PLC) leads to the production of IP₃ and basal release of Ca²⁺ from the IP₃-sensitive Ca²⁺ store. Simultaneous activation of protein kinase C (PKC) stimulates phospholipase A₂ (PLA₂) and breakdown of arachidonic acid via the lipoxygenase (LOX) pathway. The resultant metabolites further stimulate the PLC pathway resulting in cyclical oscillations in [Ca²⁺]_i due to the biphasic regulation of the IP₃ receptor by Ca²⁺. This also produces coincident cyclical depolarizations of the cell membrane through opening of a Ca²⁺-dependent chloride channel (Cl_Ca). Synchronization results from passage of Ca²⁺ through gap junctions. Voltage-dependent Ca²⁺ channels are not activated.

Figure 3. The voltage-dependent coupled oscillator in rat small mesenteric arteries

Application of agonist induces Ca²⁺ release from intracellular stores. This is oscillatory and, in combination with cGMP, produced by the action of endothelially derived nitric oxide (NO), activates a Ca²⁺- and cGMP-dependent chloride channel (Cl) which intermittently depolarizes the membrane potential. If sufficient cells depolarize together the depolarization opens voltage-dependent Ca²⁺ channels (VDCC) causing extracellular Ca²⁺ influx into the cells. As the cells are all electrically coupled, this Ca²⁺ entry is simultaneous and it synchronizes the intermittent Ca²⁺ release from ryanodine receptors (RyR) in adjacent cells.

Figure 4. The voltage-dependent membrane oscillator in rat basilar arteries

Constitutive activity of phospholipase C (PLC) leads to the production of IP₃ and release of Ca²⁺ to activate a Ca²⁺-dependent chloride channel (Cl_Ca). This current depolarizes the membrane potential and opens voltage-dependent Ca²⁺ channels (VDCC) causing extracellular Ca²⁺ influx. This Ca²⁺ influx activates ryanodine receptors (RyRs) causing further Ca²⁺ release which opens intermediate conductance K_Ca channels and the membrane hyperpolarizes, thereby closing the VDCCs. Coupling between adjacent smooth muscle cells is poor but the oscillating membrane voltage acts to synchronize adjacent cells due to electrical coupling via the endothelium. Closure of the VDCCs following SMC hyperpolarization ensures the vasodilatory part of the cycle while the tonic depolarization through the Cl_Ca channels ensures that the VDCCs reopen and the cycle oscillates.

Figure 5. The voltage-dependent membrane oscillator in rat mesenteric arteries

Application of agonist induces Ca²⁺ release from intracellular stores and activation of a depolarizing current. The resulting Ca²⁺ influx through VDCCs synchronizes and augments release from intracellular stores. Either Ca²⁺ or IP₃ passes through myoendothelial gap junctions into the endothelial cells to activate K_Ca channels. The ensuing hyperpolarization is then transferred electrotonically back into the SMCs where it reduces Ca²⁺ entry due to the closure of VDCCs.