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.
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