Gene–gene interactions in the protein kinase C/endothelial nitric oxide synthase axis impact the hypotensive effects of propofol

Abstract

Anaesthesia with propofol is frequently associated with hypotension, which is at least partially attributable to increased nitric oxide (NO) formation derived from the activation of protein kinase C (PKC)/endothelial NO synthase (NOS3) axis. In this cross‐sectional study, we tested whether PRKCA (which encodes PKCα) polymorphisms, or haplotypes, and interactions among PRKCA and NOS3 polymorphisms affect the hypotensive responses to propofol. We collected venous blood samples from 164 patients before and 10 min after propofol administration. Genotypes were determined by PCR and haplotype frequencies were estimated. Nitrite and NOx (nitrites+nitrates) levels were measured by using an ozone‐based chemiluminescence assay and the Griess reaction, respectively. We used multifactor dimensionality reduction to test interactions among PRKCA and NOS3 polymorphisms. Propofol promoted enhanced blood pressure‐lowering effects and increased nitrite levels in subjects carrying GA + AA genotypes for the rs16960228 and TC + CC genotypes for the rs1010544 PRKCA polymorphisms, and the CCG haplotype. Moreover, genotypes for the rs1010544 PRKCA polymorphism were associated with higher or lower blood pressure decreases in response to propofol depending on the genotypes for the rs2070744 NOS3 polymorphism. Our findings suggest that PRKCA genotypes and haplotypes impact the hypotensive responses to propofol, possibly by modifying NO bioavailability, and that PRKCA‐NOS3 interactions modify the blood pressure‐lowering effects of propofol.

Features and mechanisms of propofol-induced protein kinase C (PKC) translocation and activation in living cells

“…Moreover, propofol modulates the functions of cardiomyocytes, vascular endothelial cells, and neurons via PKCs (Kurokawa et al, 2002;Kanaya et al, 2003;Lu et al, 2009;Li et al, 2021). In particular, propofol-activated PKC phosphorylates endothelial NO synthase (eNOS), possibly producing NO and dilating vessels, which may be involved in propofol-induced hypotension and vascular pain (Wang et al, 2010;Oliveira-Paula et al, 2022).…”

Nongenetic and genetic predictors of haemodynamic instability induced by propofol and opioids: A retrospective clinical study

“…ABCB1 rs1128503 has been found to be associated with a decrease in heart rate and blood pressure during sevoflurane‐remifentanil anaesthesia 22 . NOS3 rs2070744, rs3918226 and rs1799983 were found to be associated with propofol‐induced changes in blood pressure 23,24 …”

“…22 NOS3 rs2070744, rs3918226 and rs1799983 were found to be associated with propofol-induced changes in blood pressure. 23,24 Overall, pharmacogenetic studies of propofol and opioid-induced haemodynamic instability are not common and usually focus on the effect of a single gene on a single drug. Therefore, to investigate the factors that influence cardiovascular susceptibility of propofol and opioids anaesthesia in a more extensive and comprehensive manner, GABRA1, GABRA4, GABRB1, GABRG2, GABBR2, BDNF, OPRM1, P2RX4, CYP2B6, NR1I2, NR1I3, CYP3A4, CYP3A5, CES2, ABCB1, NOS3 and KCNH2 are all included in this study.…”