Pinacidil Pretreatment Improves Vascular Reactivity After Shock Through PKCα and PKC[Latin Small Letter Open E] in Rats

Abstract

We investigated the beneficial effect of pinacidil pretreatment on vascular reactivity, calcium sensitivity, and animal survival after hemorrhagic shock, its relationship to protein kinase Cα (PKCα), protein kinase Cε (PKCε), and adenosine. Using hemorrhagic shock rats, the protective effects of different extents of pinacidil pretreatment on vascular reactivity and in which the roles of PKCα, PKCε, and adenosine were observed. Pinacidil pretreatment significantly improved shock-induced decrease of vascular reactivity of superior mesenteric artery, which was antagonized by the PKCα antagonist Gö-6976 (5 × 10 mole/L) and PKCε pseudosubstrate inhibitory peptide (1 × 10 mole/L). Pinacidil pretreatment induced the translocation of PKCα and PKCε from the cytoplasm to the membrane. This translocation of PKCα and PKCε was eliminated by adenosine A1 receptor antagonist DPCPX (1 × 10 mole/L). As compared with simple fluid resuscitation, combination with pinacidil pretreatment significantly improved the vascular reactivity and survival rate of hemorrhagic-shocked rats. These results suggested that pinacidil pretreatment could induce good protective effects on vascular reactivity and calcium sensitivity after hemorrhagic shock mainly through the activation of PKCα and PKCε via adenosine A1 receptor, and this protective effect made an important contribution to the overall outcome of shock therapy.

Involvement of connexin 43 phosphorylation and gap junctional communication between smooth muscle cells in vasopressin-induced ROCK-dependent vasoconstriction after hemorrhagic shock

“…Refractory hypotension due to vascular hyporeactivity to catecholamine is a major cause of death in severe trauma, shock, or sepsis (20,25,29). It has long been known that under these pathological conditions, AVP still has systemic vasoconstrictor and vasopressor effects (3,4,17,24).…”

“…Protein kinase C (PKC) constitutes a family of serine/threonine kinases that serve as central signaling molecules and regulators of multiple cellular processes (5). Our previous study demonstrated that both ROCK and PKC play critical roles in the regulation of vascular reactivity (reflected by norepinephrine-induced vasoconstriction) after hemorrhagic shock (15,16,29). Furthermore, we found that AVP enhances the vasoconstrictive effect of norepinephrine via the ROCK and PKC pathways (30,32).…”

Pinacidil protects osteoblastic cells against antimycin A-induced oxidative damage

“…In a previous study, pinacidil prevented subarachnoid hemorrhage-induced vasospasm by the restoration of large-conductance Ca 2+ -activated K + channel activities (3). Furthermore, pinacidil pre-treatment was able to exert significant protective effects following hemorrhagic shock, mainly by the activation of protein kinase C (PKC)α and PKCε via adenosine receptor A1, which restored vascular reactivity and calcium sensitivity and influenced the success of hemorrhagic shock therapy (4). Pinacidil was also demonstrated to enhance the survival of cryopreserved human embryonic stem cells (hESCs) (5).…”

“…Following plating of thawed hESCs, pinacidil significantly enhanced cell attachment capacity. Previous studies have focused on investigating the function of pinacidil in the heart and coronary artery in order to elucidate the mechanism underlying its protective effects (4). It was hypothesized that the activation and opening of the mito-KATP (6) and the sarcolemmal KATP channel (7) may be beneficial in the restoration of mitochondrial energy metabolism by closing the mitochondrial transition pore (MTP), which stabilizes the mitochondrial membrane potential (MMP) and reduces intracellular Ca 2+ levels (8).…”