Although the agents responsible for production of vasospasm have not yet been clearly identified, the author reviews the molecular mechanisms involved in development of vasospasm mainly based on the experimental data in a canine two-hemorrhage model.
The blood products after subarachnoid hemorrhage most likely stimulate many cell membrane receptors, such as G protein–coupled receptors and receptor tyrosine kinases, to activate the tyrosine kinase pathway of the vascular smooth muscle cells. The activation of the tyrosine kinase pathway is associated with continuous elevation of intracellular Ca++ levels and activation of μ-calpain; the former may result mainly not from Ca++ release but from Ca++ influx from outside the cells. The increased intracellular Ca++ concentrations stimulate Ca++/calmodulin (CaM)–dependent myosin light chain kinase to phosphorylate myosin light chain continuously during vasospasm. A topical application of genistein, ethylene-glycol-bis(β-aminoethylether) N,N'-tetraacetic acid, or various L-type Ca++ channel blockers likely induces reversal of vasospasm as a result of a decrease in intracellular Ca++ levels. The blood products also activate the rho/rho-associated kinase pathway during vasospasm most likely via G protein–coupled receptors, and the activated rho-associated kinase inhibits myosin phosphatase through phosphorylation at its myosin-binding subunit to induce Ca++-independent development of vasospasm. The enhanced generation of arachidonic acid during vasospasm may also contribute to inhibition of myosin phosphatase, at least in part, through the rho/rho-associated kinase pathway. The activity of myosin phosphatase in vasospam can also be inhibited by activated protein kinase C independently of the rho/rho-associated kinase pathway, but the inhibition may play a minor and transient role in contractile regulation. The protein levels of thin filament–associated proteins, calponin and caldesmon, are progressively decreased in vasospasm, whereas their phosphorylation levels are increased. Both changes probably contribute to the enhancement of smooth muscle contractility. Contractile and cytoskeletal proteins appear to be degraded in vasospasm by proteolysis with activated μ-calpain, suggesting that the intracellular devices responsible for smooth-muscle contraction are severely degraded in vasospasm.
It remains to be determined the extent to which Ca++-dependent and -independent contractile regulations, proteolysis and phosphorylation of thin filament–associated proteins, and degradation of contractile and cytoskeletal proteins are involved in the development of vasospasm.