mezerein and Hypertension

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(-8) mol/l) than in control arteries (TPA, 2.82 x 10(-8) mol/l; mezerein, 2.34 x 10(-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(-6) mol/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.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcium Channels; Desoxycorticosterone; Diterpenes; Enzyme Activation; Hypertension; Male; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Protein Kinase C; Rats; Rats, Inbred Strains; Sodium, Dietary; Terpenes; Tetradecanoylphorbol Acetate

Recent observations suggest that a phospholipid-sensitive, calcium-dependent protein kinase affects the contractile responses of vascular smooth muscle. Protein kinase C activators such as the tumor-promoting phorbol esters have been used as tools to study protein kinase C function in various intact cells. The present study characterizes vascular reactivity to protein kinase C activation in rats made hypertensive by coarctation of the abdominal aorta. Thoracic aortic strips from hypertensive rats developed greater force than arteries from normotensive rats in response to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). Thoracic aortae from hypertensive rats were more responsive (lower threshold dose) to the phorbol ester than those from normotensive rats. Additionally, arteries from hypertensive rats were more responsive to the contractile effects of mezerein, a non-phorbol ester activator of protein kinase C. Removal of the endothelium did not eliminate the difference in responsiveness to TPA in thoracic aortae from normotensive and hypertensive rats. The threshold dose of TPA in abdominal aortae from hypertensive rats was not different from that in normotensive rats. However, the maximal response to 10(-6) mol/l TPA after 60 min in abdominal aortae from hypertensive rats was significantly less than that in aortae from normotensive rats. Thus, contractile responses to TPA appear to be influenced by arterial pressure per se. The inhibitory effects of the calcium antagonist, verapamil, in thoracic aortae from hypertensive rats were greater than in those from normotensive rats. Verapamil inhibited TPA-induced contractions in abdominal aortae from hypertensive rats to the same extent as in those from normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aorta, Thoracic; Aortic Coarctation; Carcinogens; Diterpenes; Dose-Response Relationship, Drug; Hypertension; Male; Muscle, Smooth, Vascular; Phorbol Esters; Protein Kinase C; Rats; Rats, Inbred Strains; Terpenes; Tetradecanoylphorbol Acetate

Recent studies suggest that phospholipid-sensitive, Ca2+-dependent protein kinase C participates in contractile responses of vascular smooth muscle. This study characterizes vascular reactivity to protein kinase C activators in stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Helical strips of mesenteric arteries were mounted in organ chambers for measurement of isometric contractions (responses were normalized as a percentage of maximal force in response to 100 mM KCl; in SHRSP, 350 +/- 16 mg; in WKY, 335 +/- 21 mg). Arteries from SHRSP contracted faster and developed greater force than arteries from WKY (168 +/- 9% vs 143 +/- 3%) in response to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate. Arteries from SHRSP (0.6 X 10(-8) M) were more sensitive to the phorbol ester than those from WKY (2.2 X 10(-8) M), as indicated by the dose of the phorbol ester required to produce 50% of the maximal response to KCl. Additionally, SHRSP arteries were more sensitive to the contractile effects of mezerein, a non-phorbol ester activator of protein kinase C. Ca2+-free solution (1.0 mM EGTA) and verapamil (10(-7) M) caused relaxation (approximately -60%) of contractions in response to the phorbol ester (10(-6) M). Addition of 10(-6) M of the phorbol ester to arteries that were preincubated in Ca2+-free solution (1.0 mM EGTA for 30 minutes) elicited submaximal contractions (in SHRSP, 26 +/- 4%; in WKY, 38 +/- 7%). Upon addition of 1.6 mM Ca2+, arteries from SHRSP contracted faster (t1/2 = 2.7 +/- 0.6 minutes) than those from WKY (8.2 +/- 0.5 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Vessels; Calcium; Diterpenes; Enzyme Activation; Hypertension; Protein Kinase C; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Terpenes; Tetradecanoylphorbol Acetate; Vasoconstriction