Pressure-dependent myogenic constriction of cerebral arteries occurs independently of voltage-dependent activation.
Pressure-induced decreases in arterial diameter are accompanied by membrane depolarization and Ca(2+) entry via voltage-gated Ca(2+) channels. Recent evidence also suggests the involvement of Ca(2+) sensitization of the contractile proteins. Both PKC and Rho kinase are candidate second messengers for the mediation of the sensitization process. We investigated the signaling pathways of pressure-induced decreases in rat cerebral artery diameter in vessels that were depolarized with a 60 mM potassium-physiological salt solution (KPSS). Arteries were mounted on a pressure myograph, and pressure-induced constrictions were recorded. In some experiments simultaneous changes in intracellular Ca(2+) concentration ([Ca(2+)](i)) were recorded by using fura 2 fluorescence photometry. Pressure increases induced constriction with significant changes in [Ca(2+)](i) at high pressures (60-100 mmHg). The ratio of the change in diameter to change in [Ca(2+)](i) was greater for pressure-induced constriction compared with constriction produced by depolarization with 60 mM KPSS, suggesting that in addition to increases in [Ca(2+)](i), enhanced myofilament Ca(2+) sensitivity occurs during pressure-induced decreases in arterial diameter. Depolarizing the membrane with 60 mM KPSS increased [Ca(2+)](i) via a Ca(2+) influx pathway insensitive to PKC inhibition. Cerebral arteries were able to maintain their diameters in the continued presence of 60 mM KPSS. Pressure-induced constriction under these conditions was not associated with further increases in Ca(2+) but was abolished by selective inhibitors of PLC, PKC, and Rho kinase. We report for the first time that in rat cerebral arteries, pressure-induced decreases in arterial diameter are not only due to increases in voltage-gated Ca(2+) influx but also to accompanying increases in myofilament sensitivity to Ca(2+) mediated by PKC/Rho kinase activation.
Lagaud
G
G
Department of Pharmacology, Faculty of Medicine, Vancouver, British Columbia, Canada V6T 1Z3.
Gaudreault
N
N
Moore
E D W
ED
Van Breemen
C
C
Laher
I
I
D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009129:Muscle Tonus / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D014654:Vascular Patency / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D054460:rho-Associated Kinases
D002121:Calcium Channel Blockers; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases; D011188:Potassium; D002118:Calcium