Gene–gene interactions in the protein kinase C/endothelial nitric oxide synthase axis impact the hypotensive effects of propofol
Gustavo H. Oliveira-Paula
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Wilf Family Cardiovascular Research Institute, Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, New York, New York, USA
Search for more papers by this authorDaniela A. Pereira
Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
Search for more papers by this authorLucas C. Pinheiro
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Search for more papers by this authorGraziele C. Ferreira
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Search for more papers by this authorWaynice N. Paula-Garcia
Department of Biomechanics, Medicine and Rehabilitation of the Locomotor System, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Search for more papers by this authorLuis V. Garcia
Department of Biomechanics, Medicine and Rehabilitation of the Locomotor System, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Search for more papers by this authorRiccardo Lacchini
Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil
Search for more papers by this authorMarcelo R. Luizon
Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
Search for more papers by this authorCorresponding Author
Jose E. Tanus-Santos
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Correspondence
Jose E. Tanus-Santos, Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil.
Email: [email protected]; [email protected]
Search for more papers by this authorGustavo H. Oliveira-Paula
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Wilf Family Cardiovascular Research Institute, Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, New York, New York, USA
Search for more papers by this authorDaniela A. Pereira
Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
Search for more papers by this authorLucas C. Pinheiro
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Search for more papers by this authorGraziele C. Ferreira
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Search for more papers by this authorWaynice N. Paula-Garcia
Department of Biomechanics, Medicine and Rehabilitation of the Locomotor System, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Search for more papers by this authorLuis V. Garcia
Department of Biomechanics, Medicine and Rehabilitation of the Locomotor System, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Search for more papers by this authorRiccardo Lacchini
Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil
Search for more papers by this authorMarcelo R. Luizon
Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
Search for more papers by this authorCorresponding Author
Jose E. Tanus-Santos
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Correspondence
Jose E. Tanus-Santos, Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil.
Email: [email protected]; [email protected]
Search for more papers by this authorFunding information: Conselho Nacional de Desenvolvimento Científico e Tecnológico; Fundação de Amparo a Pesquisa do Estado de São Paulo, Grant/Award Number: 2014-23946-0
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.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Supporting Information
| Filename | Description |
|---|---|
| bcpt13691-sup-0001-Supplementary figures_revised version_paper propofol PKC.docxWord 2007 document , 49.8 MB |
Figure S1. Correlation between changes in systolic blood pressure (SBP) and changes in nitrite levels after propofol anesthesia. r: Pearson correlation coefficient Figure S2. Effects of PRKCA genotypes on blood pressure (BP) before propofol anesthesia. (A) Effects of the CC (n = 61), CT (n = 83) and TT (n = 20) genotypes for the rs887797 polymorphism on systolic, mean, and diastolic BP. (B) Effects of the TT (n = 96) and TC + CC (n = 68) genotypes for the rs1010544 polymorphism on systolic, mean, and diastolic BP. (C) Effects of the GG (n = 124) and GA + AA (n = 40) genotypes for the rs16960228 polymorphism on systolic, mean, and diastolic BP. Data are shown as means ± SEM. Figure S3. Effects of PRKCA genotypes on nitrite and nitrate levels before propofol anesthesia. (A) Effects of the CC (n = 61), CT (n = 83) and TT (n = 20) genotypes for the rs887797 polymorphism on nitrite levels. (B) Effects of the TT (n = 96) and TC + CC (n = 68) genotypes for the rs1010544 polymorphism on nitrite levels. (C) Effects of the GG (n = 124) and GA + AA (n = 40) genotypes for the rs16960228 polymorphism on nitrite levels. (D) Effects of the CC (n = 61), CT (n = 83) and TT (n = 20) genotypes for the rs887797 polymorphism on nitrate. (E) Effects of the TT (n = 96) and TC + CC (n = 68) genotypes for the rs1010544 polymorphism on nitrate levels. (F) Effects of the GG (n = 124) and GA + AA (n = 40) genotypes for the rs16960228 polymorphism on nitrate levels. Data are shown as means ± SEM. Figure S4. Effects of PRKCA haplotypes on blood pressure (BP) and nitrite and nitrate levels before propofol anestesia. (A) Effects of CTG (n = 133), CCG (n = 65), TTG (n = 83), TTA (n = 29), and TCG (n = 11) PRKCA haplotypes on systolic, mean and diastolic BP. (B) Effects of CTG (n = 133), CCG (n = 65), TTG (n = 83), TTA (n = 29), and TCG (n = 11) PRKCA haplotypes on nitrite levels. (C) Effects of CTG (n = 133), CCG (n = 65), TTG (n = 83), TTA (n = 29), and TCG (n = 11) PRKCA haplotypes on nitrate levels. Data are shown as means ± SEM. |
| bcpt13691-sup-0002-Supplementary tables - revised version MS PRKCA-propofol.docxWord 2007 document , 37.9 KB |
Table S1. Effect of PRKCA genotypes on changes in blood pressure induced by propofol after adjustment for selected variables. Table S2. Effect of PRKCA genotypes on changes in nitrite and nitrate levels induced by propofol after adjustment for selected variables. Table S3. Effect of PRKCA haplotypes on changes in blood pressure induced by propofol after adjustment for selected variables. Table S4. Effect of PRKCA haplotypes on changes in nitrite and nitrate levels induced by propofol after adjustment for selected variables. Table S5. Genotype frequencies for PRKCA polymorphisms in patients with higher (H group) and lower (L group) decreases in blood pressure in response to propofol. Table S6. Genotype frequencies for NOS3 polymorphisms in patients with higher (H group) and lower (L group) decreases in blood pressure in response to propofol. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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