ANGIOTENSINS DIFFERENTIALLY ACTIVATE PHOSPHOLIPASE-D IN VASCULAR SMOOTH-MUSCLE CELLS FROM SPONTANEOUSLY HYPERTENSIVE AND WISTAR-KYOTO RATS

We previously showed that angiotensin (Ang) II activates phospholipase D (PLD) through AT(1) receptors in vascular smooth muscle cells (VSMC ) isolated from Sprague-Dawley rats [Freeman and Tallant, Biochem J. 3 04:543-548, (1994)]. In the present study, we compared activation of P LD by angiotensin peptides in VSMC from spontaneously hypertensive rat s (SHR) and their normotensive controls, Wistar-Kyoto (WKY) rats. Ang II caused a dose-dependent increase in PLD activity in VSMC from both rat strains. However, the response to Ang II in VSMC from hypertensive rats was approximately three times higher than that observed in VSMC from normotensive controls. Furthermore, Ang II-induced activation of PLD in VSMC from hypertensive rats was significant within 1 min, where as significant increases in PLD activity in cells from normotensive ra ts were not seen until 10 min after exposure to Ang II. Ang-(2-8) caus ed a similar increase in PLD activity which was three times higher in SHR VSMC than in WKY controls. In contrast, Ang-(1-7) did not affect P LD activity in either smooth muscle cell population. The Ang II-mediat ed increases in PLD activity in VMSC from both rat strains were comple tely blocked by AT(1) receptor antagonists (EXP 3174 or L-158,809). Co nversely, the AT(2) receptor antagonist PD 123177 (1 mu mol/L) was ine ffective. Thus Ang II stimulation of PLD in VSMC derived from both the hypertensive and normotensive rat aorta and the accumulation of its m etabolites (eg, phosphatidic acid and diacylglycerol) is coupled to ac tivation of AT(1) receptors predominantly and occurs in response to An g II or Ang-(2-8) but not Ang-(1-7). Moreover, activation of PLD by an giotensins in VMSC from the SHR is significantly more robust than that observed in VSMC from the normotensive WKY rat. We conclude that incr eased activation of PLD by Ang II in genetically-induced hypertension may reflect an additional mechanism linking enhanced contractile respo nses to enhanced growth.