Vascular responsiveness to protein kinase C activators in mineralocorticoid-hypertensive rats

Abstract

This study characterizes vascular reactivity to protein kinase C activators, 12-O-tetradecanoylphorbol- 13-acetate (TPA) and mezerein, in normotensive sham and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Mesenteric arteries were excised, cut helically into strips and placed in a muscle bath for measurement of isometric force generation. Cumulative addition of TPA or mezerein to the bath caused an increase in tension in arteries from hypertensive and normotensive rats. Threshold values for TPA and mezerein (dose that produced a 5 mN/mm² response) were lower in arteries from DOCA-salt rats (TPA, 0.24 x 10 ^-8 mol/l; mezerein, 0.32 x 10^-8mol/l) than in control arteries (TPA, 2.82 x 10^-8mol/l; mezerein, 2.34 x 1O^-8 mol/l). Contractions to TPA in arteries from DOCA hypertensive rats were inhibited by the calcium-channel antagonist verapamil (10^-6 mol/l) to a greater degree than normotensive values. Arteries from rats undergoing DOCA-salt treatment for 5-7 days and from DOCA-treated rats drinking tap water for 4-6 weeks were less responsive to TPA than were arteries from the DOCA-salt hypertensive rats after 4—6 weeks of treatment. Furthermore, responsiveness to TPA in arteries from untreated rats was reduced compared with that in arteries from normotensive rats maintained on high-salt drinking water. Threshold responses to TPA did not differ between arteries incubated with 10^-6mol/l deoxycorticosterone and those incubated with the vehicle (ethanol). This study demonstrates that arteries from DOCA-salt hypertensive rats are more responsive to the contractile effects of TPA and mezerein than those from normotensive rats. The difference in sensitivity does not appear to be due to the direct effects of deoxycorticosterone on vascular smooth muscle. Differences in calcium mobilization via verapamil-sensitive channels may contribute to the increased vascular sensitivity to TPA in DOCA-salt rats. The duration of DOCA treatment and a high-salt water diet influence the responsiveness of arteries to protein kinase C activators. We conclude that enhanced activity of protein kinase C may be a component of altered vascular reactivity in mineralocorticoid-hypertensive rats.