Endothelium derived relaxant factors (EDRFs)
Endothelium derived relaxant factor is produced and released by the endothelium to cause smooth muscle relaxation. The characterized EDRFs include nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarization factor (EDHF). By acting on endothelial membrane receptors, neurohumoral substances and shear stress cause a G-protein-mediated increase in calcium influx by opening non-selective cation channels. Increase in calcium influx hydrolyzes phosphotidyl inositol 4,5- bisphosphate (PIP2) yielding inositol triphosphate (IP3), which causes calcium efflux from intracellular stores. Thus, calcium enters cytosol, which activates the production of EDRFs.
Nitric oxide (NO)
NO is mainly found in coronary, pulmonary and cerebral arteries. NO is synthesized from L-arginine by endothelial isoform of NO synthase (eNOS) which is activated by Ca2+-calmodulin. Endothelial NO reaches vascular smooth muscle cell by diffusing across the endothelial cell membrane and activates soluble guanylate cyclase (sGC) to form cyclic GMP (cGMP) in the smooth muscle cell. NO has been found to induce relaxation by activating large-conductance Ca2+-activiated K+ channels (BKCa) and ATP-sensitive K+ channels (KATP) in smooth muscle cells, which suggest that NO hyperpolarize smooth muscle cells directly and indirectly via activation of sGC.
Prostacyclin (PGI2)
PGI2 is a metabolite of arachidonic acid by the action of cyclooxygenase enzyme (COX) in most blood vessels. Arachidonic acid is derived from membrane-bound phospholipids by phospholipase A2 (PLA2). Then arachidonic acid is converted to PGG2 by COX. PGG2 converts to PGH2 by hydroperoxidase. Consequently, PGH2 converted to vasoactive prostanoids such as protstacyclin (PGI2), prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), prostaglandin F2α (PGF2α) and thromboxane A2 (TXA2) by the action of various synthases. PGI2 induces relaxation of vascular smooth muscle by activating IP receptor-coupled BKCa channel and IP receptors coupled to adenylate cyclase (AC).
Endothelium-derived hyperpolarizating factors (EDHFs)
Endothelial cell releases an endothelium-derived vasodilator which is resistant to inhibitors of eNOS and COX enzyme. It causes relaxation by hyperpolarizing vascular smooth muscle cell. Hyperpolarization in endothelial cells is triggered by an increased concentration of Ca2+, then the endothelial small-conductance (SKCa) and intermediate-conductance (IKCa) Ca2+-activated K+ channels are activated, which causes the efflux and accumulation of K+ in the myo-endothelial space. The increased electrochemical gradient of Ca2+ enhances the influx of Ca2+ into the hyperpolarized cell by voltage-independent Ca2+ channels, which enhances EDRF synthesis, triggering EDHF-mediated responses in the endothelial cell. The possible EDHFs candidates include epoxyeicosatrienoic acid, K+ ions and gap junction.
Potassium channels (K+ channels)
K+ channels are suggested to be essential for maintaining the electrical potential across the surface membrane of smooth muscle cells and it plays an important role in regulating smooth muscle tone. In vascular smooth muscle cells, there are four types
of K+ channels including the large-conductance Ca2+-activated K+ (BKCa) channel, the voltage-gated K+ (Kv) channel, the inward rectifying K+ (KIR) channel and ATP-sensitive K+ (KATP) channel.
Calcium channel (Ca2+ channels)
In vascular smooth muscle cells, the major calcium channel is the L-type voltage-operated calcium channel, and this channel is activated by depolarization. It causes influx of Ca2+ to regulate intracellular Ca2+ concentration. The calcium entry mechanism is suggested to involve agonist-activated nonselective cation channel (NSCC). NSCC opening causes influx of Na+ and Ca2+, which results in depolarization in vascular smooth muscle cells and leads to further influx of Ca2+. Another calcium entry mechanism is associated with the stored-operate calcium channel (SOCC), which is activated by internal Ca2+ depletion. It causes vascular smooth muscle cells depolarization through Ca2+ influx.
Reference:
DENG, Yan. Cerebrovascular Effects of a Danshen and Gegen Formulation.