Background: Both propofol use and advanced age are predictors of intraoperative hypotension. We previously demonstrated that propofol enhances vasodilation in mesenteric arteries from aged rats, partly due to increased nitric oxide (NO) bioavailability. Patients chronically treated with angiotensin-converting enzyme (ACE) inhibitors may exhibit refractory hypotension under general anesthesia. We hypothesized that propofol enhances NO-mediated vasodilation in arteries from aged rats chronically treated with ACE inhibitors.
Methods: Sprague-Dawley rats aged 12 to 13 months were treated with or without captopril for 7 to 8 weeks, yielding a final age of 14 to 15 months at the time of experimentation. Before euthanasia, arterial blood pressures were obtained through carotid artery cannulation. Concentration-response curves to propofol (0.1-100 µM) or methacholine (MCh) (0.01-3 µM) were then assessed on isolated resistance mesenteric arteries (100-200 μm diameter) from both treatment (captopril) and control rats. MCh relaxation was also assessed after propofol pretreatment (1 and 10 µM). N(G)-nitro-l-arginine methyl ester (l-NAME) (100 µM) and meclofenamate (10 µM) were used to inhibit NO and prostaglandin synthesis, respectively. Concentration-response data were summarized as 50% of the maximum relaxation response or area under the curve.
Results: Mean arterial blood pressure in the captopril-treated rats was lower than in untreated rats (P = 0.049). When comparing relaxation in arteries from captopril-treated versus untreated rats, concentration-response curves revealed that captopril-treated rats display greater direct propofol relaxation (P = 0.018). MCh relaxation in the absence of propofol, however, was not different between captopril-treated and untreated rats (P = 0.80). Propofol pretreatment increased MCh relaxation in arteries from captopril-treated compared with untreated rats (P = 0.029 for 1 µM and P = 0.020 for 10 µM). Meclofenamate did not have an effect in this response (P = 0.22). l-NAME-dependent inhibition of MCh relaxation, however, was greater in arteries from control compared with captopril-treated rats (P = 0.0077). However, propofol increased the proportion of NO-dependent vasodilation to MCh similarly in both groups. This suggests that other vasodilatory pathways are involved in the differential response to MCh in the presence of propofol in captopril-treated rats.
Conclusions: Our results show that mesenteric arterial relaxation in response to propofol, both by direct stimulation and through modulation of endothelium-dependent mechanisms, is, in part, NO-dependent. In captopril-treated rats, propofol further increased arterial relaxation through a non-NO-dependent vasodilating pathway (e.g., endothelium-derived hyperpolarizing factor), which may account for enhanced vasodilation during propofol exposure in patients treated with ACE inhibitors.