Increased Ca2+ sensitivity as a key mechanism of PKC-induced constriction in pressurized cerebral arteries.
The effects of activating protein kinase C (PKC) with indolactam V (Indo-V) and 1,2-dioctanoyl-sn-glycerol (DOG) on smooth muscle intracellular Ca2+ concentrations ([Ca2+]i) and arterial diameter were determined using ratiometric Ca2+ imaging and video edge detection of pressurized rat posterior cerebral arteries. Elevation of intraluminal pressure from 10 to 60 mmHg resulted in an increase in [Ca2+]i from 74 +/- 5 to 219 +/- 8 nM and myogenic constriction. Application of Indo-V (0.01-3 microM) or DOG (0.1-30 microM) induced constriction and decreased [Ca2+]i to 140 +/- 11 and 127 +/- 12 nM, respectively, at the highest concentrations used. In the presence of Indo-V, the dihydropyridine Ca2+-channel-blocker nisoldipine produced nearly maximum dilation and decreased [Ca2+]i to 97 +/- 7 nM. In alpha-toxin-permeabilized arteries, the constrictor effects of Indo-V and DOG were not observed in the absence of Ca2+. Both PKC activators significantly increased the degree of constriction of permeabilized arteries at different [Ca2+]i. We conclude that 1) Indo-V- or DOG-induced constriction of pressurized arteries requires Ca2+ influx through voltage-dependent Ca2+ channels, and 2) PKC-induced constriction of pressurized rat cerebral arteries is associated with a decrease in [Ca2+]i, suggesting an increase in the Ca2+ sensitivity of the contractile process.
Gokina
N I
NI
Department of Obstetrics and Gynecology, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA. gokina@salus.med.uvm.edu
Knot
H J
HJ
Nelson
M T
MT
Osol
G
G
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002273:Carcinogens / Q000494:pharmacology; D002536:Cerebral Arteries / Q000502:physiology*; D004075:Diglycerides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007211:Indoles / Q000494:pharmacology; D007769:Lactams / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D011921:Rats, Inbred WKY; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D002273:Carcinogens; D004075:Diglycerides; D007211:Indoles; D007769:Lactams; C044295:1,2-dioctanoylglycerol; C043969:indolactam V; D011493:Protein Kinase C; D002118:Calcium