Anesthesia & Analgesia:
Cardiovascular Anesthesiology: Society of Cardiovascular Anesthesiologists: Research Reports
Propofol Increases Vascular Relaxation in Aging Rats Chronically Treated with the Angiotensin-Converting Enzyme Inhibitor Captopril
Gragasin, Ferrante S. MD, FRCPC*†‡§‖; Bourque, Stephane L. PhD‡§‖¶; Davidge, Sandra T. PhD†‡§‖¶
From the Departments of *Anesthesiology and Pain Medicine, †Physiology, and ¶Obstetrics & Gynecology, University of Alberta; ‡Women and Children’s Health Research Institute, §Cardiovascular Research Centre, and ‖Mazinkowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
Accepted for publication November 30, 2012.
Study funding information is provided at the end of the article.
The authors declare no conflicts of interest.
Reprints will not be available from the authors.
Address correspondence to Ferrante S. Gragasin, MD, FRCPC, Department of Anesthesiology and Pain Medicine, University of Alberta, 8-120 Clinical Science Building, 8440-112 St., Edmonton, Alberta, Canada T6G 2G3. Address e-mail to firstname.lastname@example.org.
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). NG-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.
Perioperative hypotension may be associated with unfavorable cardiovascular outcomes.1 Both increasing patient age as well as the use of propofol predict risk for intraoperative hypotension.2 We have previously shown that, in the aging rat, vasodilation is increased in the presence of propofol due in part to an increase in nitric oxide (NO)-mediated vasodilation.3 This may explain, at least in part, the intraoperative hypotension that can be seen in the aging population.
Hypertension occurs in up to 70% of the elderly population.4 Angiotensin II antagonists such as angiotensin-converting enzyme (ACE) inhibitors are frequently prescribed for treating hypertension in the elderly and for patients with impaired left ventricular function. It has been documented that patients receiving ACE inhibitors may develop greater hypotension during general anesthesia.5–8 However, the reasons have not been fully investigated, particularly in the aging population. Angiotensin II antagonism improves vascular function by increasing NO bioavailability and reversing oxidative stress.9–11 Therefore, given our functional findings in the aging vasculature, it is likely that the chronic use of ACE inhibitors may enhance arterial vasodilation in the elderly. Indeed, it is suggested that concomitant use of nitroglycerin with the perioperative use of ACE inhibitors can cause severe hypotension intraoperatively.12 Additionally, it has been reported that endothelial NO synthase “uncoupling” occurs with aging such that the enzyme produces superoxide rather than NO, and this uncoupling can be reversed with blocking the angiotensin II pathway with an ACE inhibitor to restore NO availability.13,14 Thus, we hypothesized that, in aging rats chronically treated with the ACE inhibitor captopril, the administration of propofol results in increased vascular relaxation compared with aging rats not treated with captopril. Moreover, endothelial-dependent, NO-mediated vasodilation is enhanced in the presence of propofol in these captopril-treated rats.
This study was approved by the University of Alberta Health Sciences Animal Policy and Welfare Committee and was in accordance with the Canadian Council on Animal Care and National Institutes of Health guidelines.
Sprague-Dawley rats aged 12 to 13 months were treated with the ACE inhibitor captopril (2 g/L) dissolved in drinking water, which was available ad libitum, for a duration of 7 to 8 weeks. Control animals received no treatment in their drinking water. The final age of the animals at the time of experimentation was 14 to 15 months; this would approximately equate to an age of 50 to 60 in human years.15 The concentration and duration of captopril treatment were chosen based on previous studies that showed a lowering of plasma angiotensin II levels with this dosage.16–18
Blood Pressure Measurement and Tissue Isolation
Rats were anesthetized by intraperitoneal injection of sodium pentobarbital (70 mg/kg). Once surgical anesthesia was achieved, the left carotid artery of each rat was exposed and invasively cannulated with an ultra-miniature Mikro-Tip® pressure transducer catheter (Millar Instruments, Houston, TX). The systolic and diastolic blood pressures were recorded continuously for 10 minutes. The peak blood pressures recorded during these time periods were considered as baseline arterial blood pressure. The mesentery was then rapidly excised and placed in iced HEPES-buffered physiologic saline solution (sodium chloride 142, potassium chloride 4.7, magnesium sulfate 1.17, calcium chloride 4.7, potassium phosphate 1.18, HEPES 10, and glucose 5.5 mM, pH 7.4, 4°C). The rats were then euthanized by exsanguination via puncturing of the inferior vena cava. Mesenteric arteries were carefully dissected using a binocular microscope, and arteries with internal diameters ranging from 100 to 200 μm were mounted in an isometric myograph system, as previously described.19 Separate tissue baths at 37°C were used to study arterial segments simultaneously. For this study, we assessed 7 control and 7 captopril-treated rats. After each rat was euthanized, the mesenteric artery segments were divided into subsegments. Each subsegment was randomized and subjected to receive one of the following: no inhibitor, NG-nitro-L-nitro arginine methyl ester (L-NAME), meclofenamate (meclo), or L-NAME + meclo, in separate wire myography baths (see Protocols for Vascular Reactivity below). Each subsegment was also subjected to the combination of propofol pretreatment and methacholine (MCh) relaxation, as well as direct vascular relaxation to propofol itself.
Protocols for Vascular Reactivity
Cumulative doses of the α-adrenoreceptor agonist phenylephrine (PE) (0.1–100 µM) were administered at the start of each experiment to determine the 80% effective concentration (EC80) dose to be used for the remainder of each protocol. By using the value of percentage relaxation, we attempted to normalize the amount of absolute relaxation between the potential differing preconstrictions among different arteries. Vascular reactivity was compared between arteries from rats treated with and without captopril. Intact endothelium was confirmed with a relaxation response to MCh, the stable analog of acetylcholine. We assessed the reactivity after a 5-minute PE constriction under 2 conditions: (1) propofol alone (0.1–100 µM in cumulative doses added every 2 minutes), and (2) MCh (0.01–3 µM in cumulative doses added every 2 minutes) after a 10-minute pretreatment with and without propofol (1 and 10 µM). Vascular tone measurements were taken at the end of each time point. The propofol preparation we used in our study is that which is available clinically (i.e., Diprivan®; AstraZeneca Canada): 10 mg/mL propofol solubilized in a 10% Intralipid solution, which consists of 10% soybean oil, 1.2% egg phosphatide, 2.25% glycerol, 0.55% disodium edetate, and water with sodium hydroxide to adjust pH 6.5 to 8.5. Because we have previously shown that there is a significantly greater vasodilation with propofol compared with its vehicle Intralipid,3 we did not add an Intralipid arm in this study. To determine the contributions of endothelial-dependent pathways of relaxation to propofol and MCh, L-NAME (100 µM), an inhibitor of NO synthase, or meclo (10 µM), an inhibitor of prostaglandin H synthase, was added. The combination of L-NAME and meclo, which would result in residual relaxation attributed to endothelium-derived hyperpolarizing factor (EDHF), was also used. The inhibitors were allowed to incubate in the baths for 15 minutes. The doses to assess vascular reactivity are based on our previous work as well as the work of others.3,19–25
We have previously shown that vascular functional studies using this current experimental model have a standard deviation of <10%.19 Therefore, to detect a change of at least 15%, 7 animals per group were used based on a 2-tailed test with 80% power and an error of 0.05. GraphPad Prism 4 software (GraphPad Software Inc., San Diego, CA) on a Windows 7 platform was used for all statistical analyses. Values are expressed as mean (95% confidence interval). The logarithm of the drug concentration eliciting 50% of the maximum relaxation response (EC50) was calculated using nonlinear regression analysis by fitting the concentration-response for MCh to a sigmoidal-shaped curve. For data that did not resemble sigmoidal-shaped curves, area under the curve (AUC) was used to summarize the data. AUC was obtained by plotting the individual experimental traces into a relaxation curve, and the summation of the relaxations for each dose was calculated. Given our sample size of 7 control and 7 captopril-treated rats, there are 7 separate summarized data points (EC50 or AUC) each for no endothelial inhibitor, L-NAME, meclo, and L-NAME + meclo, in both groups (control and captopril). When assessing endothelial-dependent relaxation to MCh, because we repeated the measurements of relaxation after the addition of no propofol, 1 µM, and 10 µM propofol in succession, we used mixed models to address the correlation between observations over time. Specifically, we used a repeated-measures analysis of variance (ANOVA) with the covariance model of compound symmetry. To determine whether the data follow a normal distribution, we used the Shapiro-Wilk normality test to analyze the baseline data for MCh relaxation (before propofol exposure) and data for direct propofol relaxation in arteries from both control and captopril-treated rats. The data residuals were normally distributed for MCh relaxation (P values = 0.24 and 0.32 for control and captopril, respectively) as well as for propofol relaxation (P values = 0.18 and 0.12 for control and captopril, respectively). Intergroup differences were assessed using Student t test, or 1-way ANOVA with Tukey post hoc analysis or 2-way ANOVA with Bonferroni post hoc analysis, as appropriate, for multiple comparisons. The corresponding 95% confidence intervals obtained after post hoc analyses are reported as corrected confidence intervals. A value of P < 0.05 was considered statistically significant.
Blood Pressure Is Decreased in Rats Chronically Treated with Captopril
Mean arterial blood pressures were significantly lower in rats treated with captopril compared with control rats (77 [58–97] mm Hg vs 98 [85–110] mm Hg, P = 0.049). Despite this lower blood pressure, the rats did not have changes in behavior while housed in our animal facility, which would have suggested the presence of symptomatic hypotension.
Effects of Propofol Alone in Mesenteric Arteries from Rats Treated With and Without Captopril
Results of the arterial relaxation experiments are shown in Figure 1. Cumulative doses of propofol resulted in greater arterial relaxation in rats pretreated with captopril compared with control animals (Fig. 1A). The AUC revealed that the captopril dose-arterial relaxation response to propofol was greater than the control response (520 [410–630] vs 670 [590–760], P = 0.018; Fig. 1B). An unpaired t test of maximal arterial relaxation also revealed that it was greater when comparing rats treated with captopril versus without (98% [96%–99%] vs 64% [36%–92%], P = 0.011; difference between captopril and control was 34 [9–58]). Maximal relaxation refers to that elicited by the highest respective propofol dose used (100 µM), i.e., the percent reversal of PE-induced constriction back toward baseline tension before constriction. When assessing endothelial-derived mediators involved in this response, statistical significance was achieved with the addition of L-NAME and L-NAME + meclo, but not meclo alone, regarding decreased relaxation in arteries from captopril-treated but not from control rats (Fig. 1, C and D; Tables 1 and 2).
Effects of Propofol on MCh-Induced Relaxation in Arteries from Rats Treated With and Without Captopril
In the absence of propofol, there was no difference in relaxation in response to MCh in rats treated with captopril versus control rats (EC50 84 [42–130] nM vs 78 [43–110] nM; unpaired t test P = 0.80; difference between captopril and control was 6 [−54 to 22]; Fig. 2A). Upon the addition of 1 or 10 µM propofol to the tissue bath, the sensitivity to MCh relaxation in captopril-treated rats versus control rats was increased (unpaired t test P = 0.029 and 0.020, respectively; differences between captopril and control were −48 [−91 to −6] for 1 µM propofol and −61 [−110 to −11] for 10 µM propofol; Fig. 2, B and C, and Table 3). To correlate the repeated measurements over time (i.e., MCh relaxation in the absence of propofol, followed by MCh relaxation in the presence of 1 µM and subsequently 10 µM propofol), we analyzed the data using mixed models with the covariance model of compound symmetry. The P value for captopril was 0.035 and for propofol pretreatment (time) was 0.081. The interaction P value was 0.053. However, it is not reasonable to report significance for captopril alone because there may indeed be a significant interaction between captopril and propofol because of the low power for the study.
The contribution of endothelial-derived mediators to MCh relaxation in arteries from aging rats treated with or without captopril was investigated by assessing relaxation in control and captopril-treated animals in the presence of L-NAME and meclo as shown in Figure 3. The presence of L-NAME decreased relaxation in arteries from both control and captopril-treated rats compared with meclo. However, L-NAME decreased relaxation to MCh only in the control group compared with no inhibitor (Fig. 3A). With propofol pretreatment, we hypothesized that the contribution of NO to vascular relaxation is increased in both control and captopril-treated rats. In the presence of propofol, the contribution of NO to vascular relaxation was increased in both control and captopril-treated rats. Propofol pretreatment at a dose of 1 µM resulted in a decrease in relaxation to MCh in the presence of L-NAME in control and captopril-treated rats compared with no inhibitor or meclo. L-NAME + meclo inhibition of MCh relaxation reached statistical significance in only the control group when compared with meclo. Propofol pretreatment at a dose of 10 µM also resulted in a decrease in relaxation to MCh in the presence of L-NAME in control and captopril-treated rats when compared with no inhibitor or meclo (Fig. 4). In the presence of L-NAME + meclo, there was decreased relaxation to MCh in the control group only when compared with meclo, whereas it was decreased in the captopril-treated group when compared with either no inhibitor or meclo (Fig. 4). Arteries from both control and captopril-treated rats were not affected in the presence of meclo when compared with no inhibitor in the presence or absence of propofol. These data are summarized in Tables 4 and 5.
The differences in contribution of endothelial-derived mediators in the captopril-treated animals and controls were evaluated by observing the EC50 shift in the presence of L-NAME, meclo, and L-NAME + meclo as shown in Figure 5. We found that in the presence of meclo, there was no shift in EC50 when comparing captopril treatment to control or in the presence or absence of propofol. In the presence of L-NAME, the EC50 shift was different in control rats compared with captopril-treated rats. Additionally, the presence of propofol achieved a statistically significant alteration of the EC50 shift of L-NAME. A similar response is seen in the presence of L-NAME + meclo in these arteries.
The primary finding of our study is that, based on the concentration-response curves, vasodilation is increased in the presence of propofol in arteries from aging animals chronically treated with captopril compared with those not treated. This relaxation to propofol can be seen both by its direct stimulation and by its modulation of endothelium-dependent relaxation to MCh. It seems that NO was the primary endothelial-derived mediator involved in the enhanced relaxation to propofol in the captopril-treated group, because L-NAME inhibited the effects on direct propofol-induced relaxation. Interestingly, in contrast to our previous study,3 L-NAME was not found to modulate propofol’s effects in the vasculature of the control group. It is difficult to reconcile this disparity, although it is noteworthy that L-NAME was found to attenuate the relaxation at the lowest doses of propofol (i.e., before the onset of the second phase constrictor response after 1 µM; paired t test P = 0.030). These findings suggest that NO may modulate propofol-mediated vascular effects depending on the dose. We must acknowledge that a multitude of others factors may also account for these differences that we see between the 2 studies. These include the dose ranges of drugs used including the number of cumulative doses and time intervals between doses, and the use of EC90 versus EC80 of PE constriction. In addition, a notable difference in the present study was that sodium pentobarbital was used for anesthesia whereas isoflurane was previously used. Sodium pentobarbital has different effects compared with isoflurane, including differential gene expression profiles and alterations in second messenger systems26–28; future studies are needed to assess the role of anesthetic drugs on vascular reactivity to fully test this hypothesis. Notwithstanding this disparity, it should be noted that for this current study, there is a clear differential response between control and captopril-treated rats in this current group of animals.
When assessing the modulation of endothelial-dependent vasodilation (i.e., dilation to MCh), it is intriguing to see that a difference was not achieved between control and captopril-treated groups in relaxation to MCh in the absence of propofol (similar to what has been previously reported).29 However, the addition of propofol increased the relaxation to MCh in captopril-treated rats compared with controls. When assessing the endothelial-dependent vasodilators involved in this response, propofol increases NO modulation in both groups as evidenced by the EC50 shift to L-NAME. However, the enhanced relaxation to MCh in the presence of propofol in the captopril-treated animals was not attributed to NO because there was a similar increase in the proportions of the EC50 shift to L-NAME in both groups as each dose of propofol was increased. Therefore, a non–NO-dependent vasodilation likely accounts for this differential increase in MCh-induced relaxation in the presence of propofol in the captopril-treated group. It has been shown that ACE inhibition improves endothelium-dependent impairment of relaxation in hypertension,30 and this effect may be a result of improving EDHF-dependent relaxation, which declines with increasing age.31 Indeed, our data suggest that, in the absence of propofol, control rats possessed more NO-dependent vasodilatory capacity than captopril-treated rats, but given that there was similar overall relaxation, this may have been attributable to enhanced EDHF in captopril-treated rats to compensate for this. Moreover, the fact that there was little effect of L-NAME + meclo on relaxation in the absence of propofol suggests that the majority of baseline relaxation was attributed to EDHF in arteries from captopril-treated rats.
Previous clinical studies and meta-analysis suggest that patients receiving preoperative ACE inhibition are more likely to develop hypotension requiring intervention intraoperatively than patients for whom ACE inhibitors are withheld immediately before surgery.32 Perioperative angiotensin antagonism has also been associated with increased 30-day mortality in patients undergoing abdominal aortic aneurysm repair.33 The authors of this latter study speculate that perioperative hypotension may be a possible contributing factor. Regarding propofol specifically, a small study has suggested that hypotension with the use of propofol is more marked in patients treated with the ACE inhibitor enalapril.34 It has also been suggested that increasing induction doses of propofol in patients taking chronic ACE inhibitors leads to an increased number of hypotensive episodes requiring intervention.35 It has been suggested that patients taking chronic ACE inhibitor therapy receiving ACE inhibitors less than 10 hours before surgery are at risk of developing hypotension intraoperatively.6 It would be interesting to assess a change at the vascular level that may account for this finding. Therefore, a potential future direction of study would be to determine whether removing the availability of captopril the day before experimentation in these rats would reverse the enhanced vasodilation we observed in the presence of propofol.
Although our data suggest that direct vasodilation induced by propofol may indeed be affected by medications interacting with the NO pathway, the system is more complex when assessing the modulation of endothelial-dependent relaxation by propofol in the presence of ACE inhibition. ACE inhibitors are kininase inhibitors,36 so enhancement of endothelial-derived vasodilation via NO and non-NO (i.e., EDHF) pathways is a strong possibility in contributing to acute vascular responses to propofol in vivo. ACE inhibition may increase relaxation by increasing H2O2 in the wake of increased endothelial NO synthase expression37 or by increasing epoxyeicosatrienoic acids,38 2 substances that have been identified as mediators involved in EDHF-dependent relaxation. Nonetheless, further investigation is required to determine the reasons for propofol’s differential response between control and captopril treatment.
A limitation of this study is that it was completed in an ex vivo system and may not completely reflect what happens in vivo. The dose range of propofol used in this study was based on our previous work.3 It has been estimated that plasma concentrations of propofol in humans range from 2 to 10 μg/mL,39,40 which is similar to that reported in rats (up to 14 μg/mL in whole blood, ~80 μM).41 Protein binding of propofol may be in the range of 97% to 98%,42 thereby bringing the concentration of the free fraction to ~2.5 μM. However, it has been suggested that the peak plasma concentration of propofol may approach 35 μg/mL (~200 μM), yielding a free fraction of 6 μM.43 Nevertheless, one should not immediately assume that this ex vivo system behaves like an intact system in vivo. Indeed, in vivo studies would consider the interplay of multiple factors in the control of vascular tone (e.g., sympathetic nervous system,44 perivascular adipose tissue23). Chronic ACE inhibition can also decrease blood pressure by increasing angiotensin-(1–7) production,45 which may have a role in the in vivo response to propofol.
In summary, chronic ACE inhibition in aging rats results in an alteration in vascular reactivity in resistance mesenteric arteries that makes them more sensitive to propofol’s vasodilating effects, both directly and through modulation of endothelial-dependent vasodilation. Surprisingly, NO has more of a role in endothelial-dependent vasodilation in rats not receiving chronic ACE inhibition, and the increased relaxation in the presence of propofol observed in the captopril-treated animals may have been attributable to an upregulation of an EDHF-like response. This may be one of the mechanisms underlying hypotension that can be observed in patients chronically treated with ACE inhibitors.
This study was supported by the Canadian Institutes for Health Research. F. S. Gragasin, S. L. Bourque, and S. T. Davidge are supported by Alberta Innovates-Health Solutions as an Alberta Heritage Foundation for Medical Research Clinical Fellow, Fellow, and Scientist, respectively. S. L. Bourque is also supported by a Canadian Institutes for Health Research Fellowship. S. T. Davidge is a Tier I Canada Research Chair in Women’s Cardiovascular Health.
Name: Ferrante S. Gragasin, MD, FRCPC.
Contribution: Ferrante Gragasin helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript.
Attestation: Ferrante Gragasin attests to the integrity of the original data and the analysis reported in this manuscript, and approved the final manuscript. Ferrante Gragasin is the archival author.
Name: Stephane L. Bourque, PhD.
Contribution: Stephane Bourque helped analyze the data and prepare the manuscript.
Attestation: Stephane Bourque approved the final manuscript.
Name: Sandra T. Davidge, PhD.
Contribution: Sandra Davidge helped design the study, analyze the data, and prepare the manuscript.
Attestation: Sandra Davidge attests to the integrity of the original data and the analysis reported in this manuscript, and approved the final manuscript.
This manuscript was handled by: Charles W. Hogue, Jr., MD.
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