NA+ H+ EXCHANGE AND VASCULAR SMOOTH-MUSCLE PROLIFERATION/

Abnormal growth of vascular smooth muscle (VSM) is seen in various pat hologic conditions such as hypertension and atherosclerosis. Many clas sic vasoconstrictors have now been shown to be mitogenic, either by th emselves or in conjunction with other cofactors, such as insulin. The mitogenic effects of vasoconstrictors may be due, in part, to activati on of similar second messenger pathways, including stimulation of the Na+/H+ antiporter. It has been suggested, therefore, that an enhanced proliferation rate may be, in part, the consequence of elevated Na+/H exchange. This hypothesis is supported by several observations of the close association between Na+/H+ exchange activity and DNA synthesis in some cell types including fibroblasts and VSM. Stimulation of Na+/H + exchange may play a permissive role in optimal growth by preventing H+ accumulation (a fall in intracellular pH [pHi]) due to the increase d metabolic activity during cell stimulation. Enhancement of Na+/H+ ex change activity increases Na+ influx into the cell, and secondarily in creases K+ entry through activation of Na+/K+ ATPase activity. Althoug h the Na+/H+ antiporter may influence cell proliferation through vario us ionic mechanisms, it is not clear that enhanced proliferation is th e consequence of overactivity of this antiporter. In VSM, there are al so differences in the pattern of activation of the Na+/H+ antiporter b y hyperplastic and hypertrophic agents. Although pHi is increased in r esponse to both acute and chronic stimulation by hyperplastic factors, such as platelet-derived growth factor, a hypertrophic agonist such a s angiotensin II increases pHi acutely but lowers it chronically. Like wise, hyperplastic factors increase the Na+/H+ antiporter (NHE-1) mRNA levels, whereas angiotensin II does not. Clearly, much remains to be learned about the role of the Na+/H+ antiporter in the regulation of n ormal and exaggerated growth of vascular smooth muscle.