Endothelial nitric oxide synthase polymorphisms affect the changes in blood pressure and nitric oxide bioavailability induced by propofol.

Propofol anesthesia is usually accompanied by hypotension, which is at least in part related to enhanced endothelial nitric oxide synthase (NOS3)-derived NO bioavailability. We examined here whether NOS3 polymorphisms (rs2070744, 4b/4a VNTR, rs3918226 and rs1799983) and haplotypes affect the changes in blood pressure and NO bioavailability induced by propofol. Venous blood samples were collected from 168 patients at baseline and after 10 min of anesthesia with propofol 2 mg/kg administered intravenously by bolus injection. Genotypes were determined by polymerase chain reaction and haplotype frequencies were estimated. Nitrite concentrations were measured by using an ozone-based chemiluminescence assay, while NOx (nitrites + nitrates) levels were determined by using the Griess reaction. We found that CT + TT genotypes for the rs3918226 polymorphism, the ba + aa genotypes for the 4b/4a VNTR and the CTbT haplotype were associated with lower decreases in blood pressure and lower increases in nitrite levels after propofol anesthesia. On the other hand, the TCbT and CCbT haplotypes were associated with more intense decreases in blood pressure and higher increases in nitrite levels in response to propofol. Our results suggest that NOS3 polymorphisms and haplotypes influence the hypotensive responses to propofol, possibly by affecting NO bioavailability.

Angiotensin converting enzyme inhibitors enhance the hypotensive effects of propofol by increasing nitric oxide production.

Propofol anesthesia is usually accompanied by hypotension. Studies have shown that the hypotensive effects of propofol increase in patients treated with angiotensin-converting enzyme inhibitors (ACEi). Given that both propofol and ACEi affect nitric oxide (NO) signaling, the present study tested the hypothesis that ACEi treatment induces pronounced hypotensive responses to propofol by increasing NO bioavailability. In this study we evaluated 65 patients, divided into three groups: hypertensive patients chronically treated with ACEi (HT-ACEi; n = 21), hypertensive patients treated with other antihypertensive drugs instead of ACEi, such as angiotensin II receptor blockers, ß-blockers or diuretics (HT; n = 21) and healthy normotensive subjects (NT; n = 23). Venous blood samples were collected at baseline and after 10min of anesthesia with propofol 2mg/kg administrated intravenously by bolus injection. Hemodynamic parameters were recorded at each blood sample collection. Nitrite levels were determined by using an ozone-based chemiluminescence assay, while NOx (nitrites+nitrates) levels were measured by using the Griess reaction. Additionally, experimental approaches were used to validate our clinical findings. Higher decreases in blood pressure after propofol anesthesia were observed in HT-ACEi group as compared with those found in NT and HT groups. Consistently, rats treated with the ACEi enalapril showed more intense hypotensive responses to propofol. The hypotensive effects of propofol were associated with increased NO production in both clinical and experimental approaches. Enhanced increases in nitrite levels after propofol anesthesia were observed in HT-ACEi patients compared with NT and HT groups. Accordingly, rats treated with enalapril showed increased vascular NO formation after propofol anesthesia compared with rats receiving vehicle. Our data show that ACEi enhance the hypotensive responses to propofol anesthesia and increase nitrite concentrations. These findings suggest that increased NO bioavailability may account for the enhanced hypotensive effects of propofol in ACEi-treated patients.