Protein kinase inhibitors and blood pressure control in spontaneously hypertensive rats.
Considerable evidence suggests that protein kinase C activation participates in the regulation of vascular smooth muscle tone. The objective of the current study was to examine the relations between inhibition of protein kinase C (PKC) and myosin light-chain kinase (MLCK) and vasorelaxation and blood pressure regulation in spontaneously hypertensive rats (SHR). Putative PKC inhibitors from two chemical classes, staurosporinelike (staurosporine and K252A) and isoquinolinesulfonamides (H7 and HA1004), were tested for their ability to 1) inhibit PKC and MLCK from SHR aorta, 2) relax isolated SHR aorta, and 3) lower blood pressure in conscious SHR. A rank order of potency for the inhibition of PKC and MLCK was established, with the staurosporinelike compounds (staurosporine PKC IC50 = 54 nM) clearly more potent than the isoquinolinesulfonamides (H7 PKC IC50 = 128 microM). The rank order of potency for inhibition of PKC was retained for inhibition of MLCK for all compounds. Staurosporine (EC50 = 75 nM) and H7 (EC50 = 2 microM) caused concentration-dependent relaxation of SHR aorta, but only staurosporine produced vasorelaxation at concentrations consistent with the inhibition of PKC or MLCK. Dose-dependent reductions in arterial pressure of SHR were demonstrated after intravenous injection of staurosporine and HA1004. A single intravenous injection of staurosporine (0.3 mg/kg) lowered blood pressure for more than 10 hours. Staurosporine also lowered blood pressure after oral administration. The depressor response to staurosporine was unaffected by sympathetic beta-adrenergic blockade. In conclusion, the vasorelaxant and antihypertensive actions of staurosporine in SHR are consistent with the inhibition of PKC but could also be equally related to inhibition of MLCK. Not all PKC inhibitors produce vasorelaxation and lower blood pressure. Moreover, the lack of correlation between in vitro vasodilation and PKC or MLCK inhibition for the isoquinolinesulfonamide protein kinase inhibitors H7 and HA1004 suggests that these agents do not cause vasorelaxation in SHR by inhibition of these enzymes.
Buchholz
R A
RA
Department of Cardiovascular Pharmacology, Sterling Research Group, Rensselaer, N.Y. 12144.
Dundore
R L
RL
Cumiskey
W R
WR
Harris
A L
AL
Silver
P J
PJ
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D026121:Indole Alkaloids; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D009568:Nitrendipine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D019311:Staurosporine; D013449:Sulfonamides; D014664:Vasodilation / Q000187:drug effects
D000470:Alkaloids; D002227:Carbazoles; D026121:Indole Alkaloids; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; C049985:staurosporine aglycone; D009568:Nitrendipine; D011493:Protein Kinase C; D009219:Myosin-Light-Chain Kinase; D019311:Staurosporine