VASCULAR SMOOTH MUSCLE PLASTICITY IN NITRIC OXIDE

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Effects of hypertension and impaired vascular endothelial function on smooth muscle contraction are not completely understood; particularly what molecular changes may take place. We are investigating the effects of nitric oxide deficiency and hypertension on the expression profile of ion channels in smooth muscle. Rats drink water containing Nw-nitro-L-arginine for 14 days to inhibit nitric oxide production and cause hypertension. Hypertension impairs endothelium-dependent relaxation and augments smooth muscle contraction. Smooth muscle membrane potential is depolarized by hypertension and may be the basis for increased contraction; however, mechanisms responsible are not known. We are testing the hypothesis that hypertension decreases the molecular and functional expression of ion channels in vascular smooth muscle that normally regulate membrane potential. RT-PCR, Western blot, and patch clamp electrophysiology techniques are used to assess ion channel expression at the gene, protein, and functional level. Our data indicate that hypertension decreases molecular and functional expression at least two major types of potassium channels: Ca2+-activated and voltage-dependent K+ channels. Expression of the BK alpha subunit protein, a Ca2+-activated K+ channel, is reduced. Further, this correlates with reduced Ca2+-activated K+ current. Expression of Kv1.5 protein, a voltage-dependent K+ channel, is reduced. This is also supported by reduced voltage-dependent K+ current. These findings suggest that reduced molecular and functional expression of smooth muscle K+ channels may lead to depolarization, augmented contraction, and contribute to the pathogenesis of hypertension. We are currently directing our efforts at determining molecular mechanisms governing these changes in K+ channel expression. This laboratory is uniquely positioned to address the hypothesis and the COBRE grant allows opportunities, resources, and infrastructure to ensure the development of the project and personnel.