Effects of Sarcoplasmic Reticulum Calcium Pump Inhibitors on Vascular Smooth Muscle

A dysfunctioning of Ca pump ATPase in the sarcoplasmic reticulum in vascular smooth muscle has been proposed as a contributing factor for the development of genetic hypertension. In this study, we determined whether in vitro inhibition of the sarcoplasmic reticulum Ca pump in vascular smooth muscle tissues and cultured cells isolated from aortas of spontaneously hypertensive rats (SHR) and Wistar- Kyoto (WKY) rats would elicit the known alterations of contractile function and cell growth. We found the following common vascular effects of thapsigargin and cyclopiazonic acid, which are known to be selective inhibitors of sarcoplasmic reticulum Ca-ATPase in a number of tissues including smooth muscle(1) Both sarcoplasmic reticulum Ca pump inhibitors diminished agonist-induced transient contraction in Ca-free medium (ie, contraction due to intracellular release of Ca) and enhanced nifedipine-sensitive contraction on readmission of Ca (ie, Ca influx via L-type channels); and (2) thapsigargin and cyclopiazonic acid inhibited the attachment of cultured aortic muscle cells to the substrate in a similar degree in both SHR and WKY cells, but SHR cells were more sensitive than WKY cells to the inhibition of cell proliferation by these two agents. The first effect may provide an explanation for several contractile abnormalities known to be associated with elevated cytosolic Ca concentration, whereas the second effect suggests that elevation of cytosolic Ca in aortic smooth muscle cells is not necessarily associated with or sufficient to account for the accelerated cellular proliferation in SHR. These results, however, further stress the functional importance of impairment of Ca regulation in vascular smooth muscle cells in genetic hypertension.