Differential effects of propofol, ketamine, and thiopental anaesthesia on the skeletal muscle microcirculation of normotensive and hypertensive rats in vivo{dagger}

Z. L. Brookes*, C. S. Reilly and N. J. Brown

University of Sheffield, Division of Clinical Sciences (South), Academic Anaesthesia Unit and Microcirculation Research Unit, Royal Hallamshire Hospital, Sheffield S10 2JF, UK

* Corresponding author. E-mail: zoe.brookes{at}sheffield.ac.uk

Accepted for publication March 12, 2004.


    Abstract
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 Footnotes
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. This study utilized the dorsal microcirculatory chamber (DMC) model to determine differential effects of i.v. propofol, ketamine, and thiopental anaesthesia on the skeletal muscle microcirculation (10–180 µm) of normotensive (Male Wistar Kyoto, WKY) and hypertensive (spontaneously hypertensive Harlan, SHR) rats, importantly, comparing responses to a conscious baseline.

Methods. Three weeks following implantation of the DMC in WKY (n=8) and SHR (n=6) (130 g) 0.25 ml 100 g–1 FITC–BSA (i.v.) was administered and the microcirculation viewed using fluorescent in vivo microscopy for a 30 min baseline (t=0–30 min). This was followed by either propofol, thiopental, ketamine, or saline (i.v. bolus induction over 5 min (t=30–35 min)), then maintenance step-up infusion for 60 min (t=45–105 min), so that animals received all four agents 1 week apart (56 experiments).

Results. Dilation of A3 arterioles (15–30 µm) and V3 venules (20–40 µm) with propofol was greater in SHR (t=95 min, A3 36.7 (12)%, V3 15.5 (2.3)%) than WKY (t=95 min, A3 19.4 (7.4)%, V3 8.0 (2.3)%) (P<0.05). Constriction of A3 with ketamine was greater in SHR (t=95 min, A3 –29.1 (6.4)%) than WKY (A3 –17.5 (8.8)%) (P<0.05). This was accompanied by hypotension with propofol in SHR (–32% decrease in systolic arterial pressure), but not WKY (–6%) and hypertension with ketamine in WKY (–15%) and SHR (–24%) (P<0.05). During thiopental anaesthesia there was dilation of A1 (80–180 µm), A3, and V3 in WKY (P<0.05). Conversely, in SHR dilation of venules (29.2 (8.7)%) was accompanied by constriction of A1 and A3 (t=95 min, A1 –25.1 (5.9)%, A3 –45.2 (3.1)%) (P<0.05).

Conclusion. Within the skeletal muscle microcirculation of hypertensive rats there is enhanced dilation with propofol and constriction with ketamine, associated with exaggerated changes in arterial pressure. Thus, dysfunctional control mechanisms at the level of the microcirculation alter responses to anaesthesia during hypertension.

Keywords: anaesthetics i.v., ketamine ; anaesthetics i.v., propofol ; anaesthetics i.v., thiopental ; muscle, skeletal


    Introduction
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 Abstract
 Introduction
 Materials and methods
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In clinical practice, patients with hypertension are known to have an increased risk of morbidity and mortality during anaesthesia. Complications include an increased hypotensive response to agents such as propofol and an exaggerated hypertensive response to ketamine. Genetically hypertensive rats also exhibit exaggerated cardiovascular responses to anaesthesia.1 Hypertension alters extrinsic control mechanisms that affect the microcirculation, including increased sympathetic drive to skeletal muscle and increased release of norepinephrine.2 3 Hypertension also alters local intrinsic control mechanisms, for example increased sensitivity to norepinephrine acting at {alpha}-adrenoreceptors,2 4 and increased sensitivity of voltage dependent Ca2+ channels,5 both present on vascular smooth muscle of small arterioles and venules (<200 µm) in skeletal muscle.5 6 Propofol, thiopental, and ketamine also exert their respective hypo- or hypertensive effects via the same extrinsic and intrinsic mechanisms that are dysfunctional in hypertension.714 Thus, we propose that microvascular responses to anaesthesia will differ in hypertensives when compared with normotensives, reflecting changes in systemic arterial pressure. Greater reductions in blood flow to skeletal muscle occur during anaesthesia with the inhalation agent isoflurane in spontaneously hypertensive Harlan rats (SHR), as compared with Male Wistar Kyoto rats (WKY).15 However, the effects of the i.v. agents propofol, ketamine, and thiopental have not been studied previously.

The aim of this study therefore, is to determine the effects of induction and maintenance doses of i.v. propofol, ketamine, and thiopental anaesthesia on cardiovascular and microcirculatory variables in normotensive and genetically spontaneously hypertensive rats. The dorsal microcirculatory chamber (DMC) will be implanted chronically and fluorescent in vivo microscopy used to determine vessel diameter and macromolecular leak, a measure of vessel endothelial cell integrity,16 in conscious and anaesthetized animals. Our previous studies using the DMC demonstrated that i.v. anaesthetics produce different responses during induction and maintenance of anaesthesia in the skeletal muscle microcirculation of normotensive rats in vivo.17 A second aim of this study therefore, is to establish whether these differences are a dose-dependent phenomena by performing a controlled dose–response study during the maintenance period.


    Materials and methods
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 Footnotes
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Animals
Male Wistar Kyoto (WKY, n=8) and spontaneously hypertensive Harlan (SHR, n=6) rats were obtained from the Sheffield Field Laboratories at the University of Sheffield. Food in the form of a standard pelleted commercial diet (Diet, CRM, Labsure, Poole, UK) and tap water were available ad libitum and animals were exposed to a 12/12-h light/darkcycle. All procedures were performed with Home Office approval, Project Licence number PPL 40/2110.

Experimental design
In weeks 1 and 2 animals weighing 80–90 g (age 5 weeks, n=14) underwent daily training; being placed in a restraining device. Surgery was performed in week 3 and then animals were allowed 1 week to recover before recommencing training in weeks 4 and 5. At week 6 animals were entered into the experimental protocol, receiving saline, propofol, ketamine, and thiopental over a 3-week period (weeks 6–9, weight 220–350 g, age 11–13 weeks). It has been shown previously that at this age animals have developed hypertension.20 A total of 56 experiments were performed in total, but before commencing this study we randomized the use of anaesthesia so that agents administered first were: saline (n=3), propofol (n=4), ketamine (n=4), and thiopental (n=3).

Surgery
In week 3, rats weighing 130–140 g (7–8 weeks old) were anaesthetized with 0.1 ml 100 g–1 hypnorm/diazepam (1:1, hypnorm (0.315 mg ml–1 fentanyl citrate, 10 mg ml–1 fluanisone); Janssen-Cilag Ltd, High Wycome, Bucks, UK). Diazemuls (10 mg ml–1; Dumex Ltd, Tring, Herts, UK) was administered intraperitoneally (i.p.). The DMC was then implanted according to methods described previously in detail18 19 and modified by the authors. The DMC consists of two halves of light weight polycarbonate (Carolina Medical Electronics, King, NC, USA), which when implanted into the dorsal skinfold allows sufficient space to enclose one layer of cutaneous maximus muscle.

Experimental protocol
The experimental protocol (165 min) was repeated on four occasions in weeks 6–9 so that each animal randomly received saline, propofol, ketamine, and thiopental 1 week apart. The rat was placed in the restrainer and 0.25 ml 100 g–1 fluoroscein isothiocyanate conjugated to bovine serum albumin (FITC–BSA) administered into the tail vein using a winged needle infusion set (Venisystems, Butterfly, 25-short), followed by 30 min with no infusion (t=0–30 min, baseline). Anaesthesia or saline (i.v.) was then administered over 5 min (t=35–40 min, induction) followed by 60 min of a continuous saline or anaesthetic infusion (t=45–105 min, maintenance), which was increased in equal step-up increments over this period. The infusion was then stopped for the remainder of the study (t=105–165, recovery).

Animals were given sterile solutions of either: propofol (10 mg kg–1 i.v. induction, 10–60 mg kg–1 h–1 step-up maintenance; WKY, n=8; SHR, n=6 experiments), ketamine (30 mg kg–1, 40–90 mg kg–1 h–1; WKY, n=8; SHR, n=6), thiopental (30 mg kg–1, 40–90 mg kg–1 h–1; WKY, n=8; SHR, n=6), or saline (1 ml kg–1 bolus, 5–10 ml kg–1 h–1 infusion; WKY, n=8; SHR, n=6). Animals always received 3 ml kg–1 of fluid during induction and 5–9 ml kg–1 h–1 (step-up) during maintenance. We have determined previously that these anaesthetic doses maintain a surgical plane of anaesthesia with blood gases, pH, and plasma anaesthetic concentration all within the physiological range.21

During anaesthesia, air containing oxygen 30% was blown into a chamber positioned over the animal (1.5 litre min–1).21 The animal was also placed on a warming pad during unconsciousness to maintain body temperature at 36–37°C, which was monitored by an oesophageal thermistor probe. Cardiovascular variables (heart rate, SAP and DAP) were measured every 15 min non-invasively using a tail cuff.

After the final experiment at week 9, rats were killed with a lethal dose of i.v. thiopental.

In vivo microscopy
During the experimental protocol (t=0–165 min) animals were placed in the Perspex restrainer fixed to the stage of a modified horizontally mounted Nikon Optiphot microscope, equipped with transmitted and epi-illuminated blue fluorescent light (450–490 nm) to observe the microcirculation of the DMC, which protruded through a longitudinal slot. Images were displayed on a high-resolution monitor (Sony PVM-1443) via a black and white CCD camera (Hitachi, KP161, UK). Three to five areas were then pre-selected to include A1–A4 arterioles (10–120 µm) and V1–V4 venules (15–250 µm), classified according to their order of branching.22 Images were then recorded for 30 s every 10 min, and 5 min after induction, throughout the experiment on to VHS videotape (JVC E180-SX) for later off-line analysis.

Image analysis
Following completion of the study (after week 9) vessel diameters and macromolecular leak were determined off-line using computerized image analysis (Capiscope, KK Technology, UK) and the assessor was blinded to the drug administered. The system was calibrated to produce values in microns and diameters of arterioles and venules were measured from the outside edge of the vessel wall (<5% variability).23 Macromolecular leak from post-capillary venules (V3 and V4, <40 µm) was measured by placing three boxes (3 mm2 on screen) just outside the vessel wall and determining the mean of the grey levels obtained. Grey levels were determined using a software package (Capiscope) that assigned an integer value to the brightness of interstitial fluorescence (0, black; 255, white).

Statistical analysis
Changes in variables (Y), that is heart rate, arterial pressure, vessel diameter, and macromolecular leak are presented as mean (SEM) percentage change from baseline (t=30 min) (y): (Yy)/(yx100). In each group (WKY, n=8, 32 experiments; SHR, n=6, 24 experiments) raw data for saline, propofol, ketamine, and thiopental were compared with the pre-anaesthetic baseline (t=30 min) using a one-way ANOVA for repeated measures. Responses induced by each anaesthetic agent were also compared with conscious controls (six experiments, saline) using a two-way ANOVA for repeated measures. Post hoc analysis was performed using the Students–Newman–Keuls test. Results were considered statistically significant at P<0.05. A commercially available software package was used to perform the relevant statistical tests and regression analysis (Sigmastat, 2.0).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
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Controls
In the saline group there were no significant changes in heart rate (Table 1) or systolic arterial pressure (SAP, 127 (2), WKY; 153 (5) mm Hg, SHR) from baseline (t=30 min) values, following induction and during maintenance (Fig. 1A). However, in the S group heart rate was lower (Table 1) and SAP greater (Fig. 1AD) in SHR vs WKY (P<0.05). Conversely, diastolic arterial pressure (DAP) was lower in SHR (59 (2)) than WKY (66 (5) mm Hg). At baseline, arteriolar and venular diameters were greater in SHR than WKY (Table 2). All cardiovascular and microvascular variables remained stable between weeks 6 and 9.


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Table 1 Effects of propofol (P), ketamine (K), thiopental (T), and saline (S), on heart rate (beats min–1) in WKY (n=8) and SHR (n=6) during baseline (no saline or anaesthetic, t=30 min), after induction (bolus dose of saline or anaesthetic, t=45 min), during maintenance 10-min after each step-up infusion dose (t=55–105 min) and recovery (no saline or anaesthetic, t=105–165 min).

 


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Fig 1 SAP (SEM) at baseline (BL, no anaesthesia, t=30 min), following induction (IN, t=45 min), and during maintenance (MN, t=95 min) of saline (A), propofol (B), ketamine (C), or thiopental (D) in WKY (n=8) and SHR (n=6). *P<0.05 vs BL, {dagger}P<0.05 vs SHR.

 

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Table 2 The mean (SEM) diameters of arterioles and venules (µm) in WKY (n=32 experiments) and SHR (n=24) at babseline (t=30min).

 
Cardiovascular variables
Propofol
Following induction and during maintenance heart rate decreased in WKY but increased in SHR (Table 1). SAP decreased following induction in both WKY and SHR, but during maintenance was decreased only in SHR (Fig. 1B). DAP decreased from 65 (7) and 62 (7) at baseline to 60 (4) and 40 (5) mm Hg during maintenance (t=95 min) in WKY and SHR, respectively (P<0.05).

Ketamine
Heart rate increased following induction and during maintenance, but was greater in SHR than WKY during maintenance. After induction and during maintenance SAP increased in both WKY and SHR (Fig. 1C) and this increase was greater in SHR during maintenance. DAP increased from 65 (5) and 50 (5) at baseline to 89 (9) and 78 (9) mm Hg following induction in WKY and SHR, respectively (P<0.05).

Thiopental
Following induction with thiopental heart rate decreased in WKY, but not in SHR, and no changes occurred during maintenance. Following induction and maintenance there was little change in SAP, with only the decreased SAP following induction in SHR reaching significance (P<0.05, Fig. 1D).

During the recovery period MAP did not return to baseline values in both WKY and SHR 1-h after all anaesthetic infusions were terminated (Fig. 1AD).

Microvascular variables
Diameter
Propofol: in WKY and SHR there was dilation of all arterioles and venules following induction and maintenance, but greater dilation of A3 and V3 in SHR was observed during maintenance (P<0.05, Fig. 2).



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Fig 2 Percentage change in the diameter of A1 (80–100 µm) and A3 (25–30 µm), and V3 venules (20–40 µm) from baseline (t=30 min) following induction (IN, t=45 min), during maintenance (t=95 min) and recovery (RC, t=165 min) of propofol, ketamine, and thiopental anaesthesia in WKY (n=8) and SHR (n=6). *P<0.05 vs BL, {dagger}P<0.05 vs SHR.

 
Ketamine: constriction of A1 and A3 and dilation of V3 occurred following induction in both WKY and SHR, but constriction of A1 and A3 was greater in SHR. During maintenance there was constriction of A1, A3, and V3 in WKY and SHR but greater constriction of A3 in SHR (P<0.05, Fig. 2).

Thiopental: following induction there was dilation of A1, A3, and V3 in WKY, but only dilation of A3 and V3 in SHR. During maintenance there was dilation of A1 and A3 in WKY, conversely there was constriction of these vessels in SHR (P<0.05, Fig. 2).

During the recovery period microvascular variables did not return to baseline values in both WKY and SHR 1-h after all anaesthetic infusions were terminated (Fig. 2).

Diameter: dose-dependent response
Dose-dependent responses were only assessed at the higher infusion rates as we considered that at t=55 min the induction dose would have been influencing the maintenance response.

Propofol: at higher infusion rates during maintenance there was a trend for increasing dilation of V3 with increasing dose in both WKY (r2=0.04, slope=0.79, P=0.05) (t=75–105) and SHR (r2=0.05, slope=0.45, P=0.01) (t=65–95 min) (Fig. 3).



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Fig 3 Dose-dependent percentage change in the diameter of A1 and A3 arterioles, and V3 venules, compared with baseline (t=30 min), during a step-wise increase in the maintenance dose between t=55 min and t=105 min during propofol, ketamine, and thiopental anaesthesia in WKY (n=8) and SHR (n=6). *P<0.05 vs BL.

 
Ketamine: during maintenance (t=65–105 min) there was a dose-dependent constriction of A1 (r2=0.51, slope=–0.74, P<0.000) in WKY. Constriction in SHR was of greater magnitude but did not demonstrate a dose-dependent response (Fig. 3).

Thiopental: during maintenance (t=65–105 min) in WKY there was a dose-dependent dilation of A1 (r2=0.3, slope=0.29, P=0.01), A3 (r2=0.11, slope=0.63, P=0.02) and V3 (r2=0.19, slope=0.48, P=0.008). Conversely, in SHR only A3 (r2=0.16, slope=–0.72, P<0.000) exhibited a dose-dependent constriction (Fig. 3).

Macromolecular leak
Macromolecular leak occurred during induction with propofol in WKY and then at higher infusion rates during maintenance (t=85–105 min, P<0.05, Fig. 4 at 95 min), with a trend to increase with increasing dose. Macromolecular leak was not observed with ketamine or thiopental in WKY. In SHR however, there was macromolecular leak with propofol, thiopental, and ketamine following induction and during maintenance (P<0.05, Fig. 4).



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Fig 4 Percentage change in macromolecular leak at t=95 min, during maintenance of propofol (P), ketamine (K), thiopental (T), and saline (S) in WKY (n=8) and SHR (n=6). *P<0.05 vs baseline (t=30 min), {dagger}P<0.05 vs WKY, {ddagger}P<0.05 vs saline.

 

    Discussion
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 Abstract
 Introduction
 Materials and methods
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The DMC model has been used to evaluate skeletal muscle microvascular responses to propofol, ketamine, and thiopental anaesthesia, for the first time in vivo utilizing both spontaneously hypertensive and normotensive rats, and importantly, compared with a conscious baseline. The microcirculation of hypertensives exhibited very different responses to anaesthesia, indicative of the altered microvascular control mechanisms that occur with this disease.

In normotensive and hypertensive rats, arterioles and venules dilated during induction and maintenance of propofol anaesthesia, which is in agreement with an increased vasodilation to propofol in aortic rings of SHR in vitro.24 In our study, concurrent with this vasodilation, we also observed an enhanced decrease in arterial pressure. Small arterioles and venules in SHR appeared more sensitive to the vasodilator effects of propofol, but the V3 in particular exhibited the most significant difference. An important mechanism of direct vasodilation by propofol is inhibition of L-type Ca2+ channels;12 13 25 most notably it is the small vessels (<40 µm) that receive greater control from such intrinsic mechanisms. In hypertension Ca2+ channels are known to be up-regulated in the cremaster muscle arterioles and the portal vein.5 26 The dihydropyridine sensitive calcium ion channel blocker felodipine also increases venular blood flow in SHR, but not WKY.26 In our in vivo study, venules in hypertensive rats were particularly sensitive to the vasodilator effects of propofol. Hence, it may be proposed that in the microcirculation of SHR, there is up-regulation of Ca2+ channels, which is greater on the venous side, and this in turn confers a greater sensitivity to the vasodilator and hypotensive effects of propofol.

During induction and maintenance of thiopental anaesthesia, there was dilation of arterioles and venules in WKY, but constriction of arterioles and dilation of venules in SHR. Similarly, in normotensive animals thiopental is known to cause arteriolar and venular dilation in both rat skeletal muscle and the bat wing in vivo when compared with a conscious baseline,17 27 an effect mediated by inhibition of L-type Ca2+ channels.14 In hypertensive rats, however, we observed greater dilation of venules with thiopental in SHR compared with WKY, mirroring responses to propofol. Conversely, dilation occurring in arterioles in WKY was completely reversed to a pattern of constriction in SHR (Fig. 5). It is probable that this compensatory constriction of arterioles contributed to the maintenance of SAP we observed in SHR (Figs 1C and 2). As a result of its apparent haemodynamic stability, thiopental is often the induction agent of choice in patients with hypertension. Interestingly, therefore, we have identified that this stability is not mirrored within the microcirculation; indeed, constriction of the arterioles supplying skeletal muscle would cause a decrease in blood flow and tissue perfusion.



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Fig 5 Percentage change in diameter of A3 arterioles vs V3 venules at t=95 min, during maintenance of propofol, ketamine, and thiopental anaesthesia in WKY (n=8) and SHR (n=6).

 
We observed that ketamine caused little change in the diameter of venules following induction, which is in agreement with previous studies in the bat wing.30 However, dilation was greater and reached significance in SHR thus, similar to propofol and thiopental, ketamine may cause this via an enhanced effect on inhibition of voltage gated Ca2+ channels.5 29 Nevertheless, constriction of venules prevailed during maintenance of ketamine anaesthesia and thus, intrinsically mediated vasodilation of venules via Ca2+ channels appeared to be over-ridden at this later stage. During maintenance of ketamine anaesthesia constriction of the arterioles and venules occurred in conjunction with an increase in arterial pressure, in both SHR and WKY. The increases in SAP and heart rate were greater in SHR and there was greater constriction of A3 arterioles. Within skeletal muscle microcirculation {alpha}-adrenoreceptors tend to predominate in arterioles compared to venules of a similar size.6 Ketamine can increase plasma norepinephrine concentration11 and in combination with the increased sensitivity of {alpha}-adrenoreceptors in SHR2 4 this extrinsic control mechanism would contribute to the exaggerated hypertensive response observed in A3 arterioles during maintenance.

If we consider the dose-dependent responses in WKY and SHR during maintenance, first during propofol anaesthesia, there was increasing dilation of V3 with increasing dose. This is in agreement with previous studies in WKY reporting greater dilation after a prolonged (4 h) as opposed to a short i.v. infusion of propofol.13 There was also a dose-dependent dilation in SHR, but earlier in the maintenance period, perhaps suggesting that the venules of SHR are more sensitive to propofol and reach their maximal dilation at a lower dose.

Thiopental, however, demonstrated the most convincing evidence for dose-dependent responses. In WKY, there was increasing dilation of A1, A3, and V3 with increasing dose. Consequently the dilation we have reported previously following induction with thiopental, could be a dose-dependent phenomenon.17 Interestingly, dose-dependent vasodilation with pentobarbital and thiopental also occurs in the bat wing.27 Our previous studies of the microcirculation in WKY observed constriction of arterioles during maintenance.17 This is not a discrepancy, rather in our previous study the most frequently used maintenance infusion doses throughout the entire study were 40 and 50 mg kg–1 h–1. Constriction was observed in the present study at the same doses (t=55 and 65 min) and only at the higher infusion rates (t=95 and 105 min) did significant dilation emerge. Confirmation of dose-dependent dilation not only explains differential responses to induction and maintenance, but may also explain why both contraction and relaxation of vascular smooth muscle in response to anaesthesia are reported in the literature.31 32

We describe diameters of arterioles and venules in skeletal muscle that are greater in SHR than WKY, which appears surprising in a hypertensive disease state. However, previous studies do demonstrate increased diameters of arterioles in skeletal muscle in SHR during the early stages of hypertension, between 6 and 18 weeks.20 33 Our studies were performed in this time frame (aged 11–13 weeks). Struijker Boudier and colleagues, also reported increased diameters of V3 venules in SHR using the DMC in rats.20 In the present study venodilation was not a result of tissue damage, as vessels were vasoactive and vessel integrity was not compromised in the control animals. These observations are therefore in agreement with rarefaction as the mechanism of increased peripheral resistance in the early stages of hypertension, as opposed to decreases in resting diameter.34

In WKY, macromolecular leak occurred during propofol anaesthesia. A known side effect of Ca2+ antagonist drugs is oedema.35 36 Indeed, inhibition of dihydropyridine sensitive Ca2+ channels by nifedipine increases extravasation of albumin from postcapillary venules in skeletal muscle in vivo.35 36 It is possible therefore, that propofol also causes increases in venular permeability via inhibition of this mechanism. However, it must not be ignored that propofol may also have a number of pro-inflammatory effects, including up-regulation of leukocyte–endothelial interactions, which increase venular permeability and therefore, macromolecular leak.37 In hypertensive rats macromolecular leak occurred with all three anaesthetic agents indicating that post-capillary venules in these animals are more sensitive to the mechanisms that affect endothelial integrity possibly, including increased sensitivity of L-type Ca2+ channels.5 24

In conclusion, the skeletal muscle microcirculation in normotensive and hypertensive rats exhibits very differing responses to propofol, ketamine, and thiopental anaesthesia. We appreciate that a limitation of this study is its lack of direct mechanistic insight. However, having identified substantial differences between WKY and SHR these data will form the foundation of future research to confirm the precise mechanisms involved. In hypertensive rats we elucidated that thiopental causes dilation of venules compensated for by intense constriction of arterioles, and whilst this may explain its ability to maintain a stable arterial pressure in hypertension, this agent has very potent effects within the microcirculation. In hypertensive rats we also identified increased sensitivity to dilation with propofol and increased sensitivity to constriction with ketamine, responses that were in agreement with their respective exaggerated hypotensive and hypertensive effects on arterial pressure. It appears that dysfunctional control mechanisms at the level of the microcirculation (10–180 µm) contribute to altered responses to i.v. anaesthesia during hypertension.


    Acknowledgments
 
The Trustees of the former United Hospitals of Sheffield funded this work.


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{dagger} This work has been presented in part at the meetings of Experimental Biology (Orlando, USA, 2002) and European Society of Anaesthesiologists (2002). Back


    References
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 Footnotes
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 De Lano FA, Zweifach BW. Anaesthesia and microvascular dynamics in spontaneously hypertensive rats. Am J Physiol 1981; 245: H821–8

2 Bohlen HG. Arteriolar closure mediated by hyperresponsiveness to norepinephrine in hypertensive rats. Am J Physiol 1979; 236: H157–64[ISI][Medline]

3 Korner P, Bobik A, Oddie C, et al. Sympathoadrenal system is critical for structural changes in genetic hypertension. Hypertension 1993; 22: 243–52[Abstract]

4 Joshua IG, Wiegman DL, Harris PD, et al. Progressive microvascular alterations with the development of renovascular hypertension. Hypertension 1984; 6: 61–7[Abstract]

5 Arii T, Ohyanagi M, Shibuya J, et al. Increased function of the voltage-dependent calcium channels, without increase of Ca2+ release from the sarcoplasmic reticulum in the arterioles of spontaneous hypertensive rats. Am J Hypertens 1999; 12: 1236–42[CrossRef][ISI][Medline]

6 Marshall JM. The influence of the sympathetic nervous system on individual vessels of the microcirculation of skeletal muscle of the rat. J Physiol 1982; 332: 169–86[ISI][Medline]

7 Sellgren J, Ejnell H, Elam M, Ponten J, Wallin G. Sympathetic muscle nerve activity, peripheral blood flows, and baroreceptor reflexes in humans during propofol anaesthesia and surgery. Anesthesiology 1994; 80: 534–44[ISI][Medline]

8 Robinson BJ, Ebert TJ, O’Brien TJ, et al. Mechanisms whereby propofol mediates peripheral vasodilation in humans. Sympathoinhibition or direct vascular relaxation? Anesthesiology 1997; 86: 64–72[CrossRef][ISI][Medline]

9 Ebert TJ, Kanitz DD, Kampine JP. Inhibition of sympathetic neural outflow during thiopental anaesthesia in humans. Anesth Analg 1990; 71: 319–26[Abstract]

10 Ivankovich AD, Miletich DJ, Reimann C, et al. Cardiovascular effects of centrally administered ketamine in goats. Anesth Analg 1974; 53: 924–33[ISI][Medline]

11 Kienbaum P, Heuter T, Michel MC, et al. Racemic ketamine decreases muscle sympathetic activity but maintains the neural response to hypotensive challenges in humans. Anesthesiology 2000; 92: 94–101[CrossRef][ISI][Medline]

12 Chang KS, Davis RF. Propofol produces endothelium-independent vasodilation and may act as a Ca2+ channel blocker. Anesth Analg 1993; 76: 24–32[Abstract]

13 Holzmann A, Schmidt H, Gebhardt MM, et al. Propofol-induced alterations in the microcirculation of hamster striated muscle. Br J Anaesth 1995; 75: 452–6[Abstract/Free Full Text]

14 Yakushiji T, Nakamura K, Hatano Y, et al. Comparison of the vasodilator effects of thiopentone and pentobarbitone. Can J Anaesth 1992; 39: 604–9[Abstract]

15 Seyde WC, Durieux ME, Longnecker DE. The hemodynamic response to isoflurane is altered in genetically hypertensive (SHR), as compared with normotensive (WKY), rats. Anesthesiology 1987; 66: 798–804[ISI][Medline]

16 Miller FN, Joshua IG, Anderson GL. Quantitation of vasodilator-induced macromolecular leakage by in vivo fluorescent microscopy. Microvasc Res 1982; 24: 56–67[ISI][Medline]

17 Brookes ZL, Brown NJ, Reilly CS. Intravenous anaesthesia and the rat microcirculation: the dorsal microcirculatory chamber. Br J Anaesth 2000; 85: 901–3[Abstract/Free Full Text]

18 Smith TL, Osborne SW, Hutchins PM. Long-term micro- and macrocirculatory measurements in conscious rats. Microvasc Res 1985; 29: 360–70[ISI][Medline]

19 Hutchins PM, Marshburn TH, Maultsby SJ, et al. Long-term microvascular response to hydralazine in spontaneously hypertensive rats. Hypertension 1988; 12: 74–9[Abstract]

20 le Noble JL, Smith TL, Hutchins PM, et al. Microvascular alterations in adult conscious spontaneously hypertensive rats. Hypertension 1990; 15: 415–9[Abstract]

21 Brookes ZL, Brown NJ, Reilly CS. Response of the rat cremaster microcirculation to haemorrhage in vivo: differential effects of intravenous anaesthetic agents. Shock 2002; 18: 542–8[CrossRef][ISI][Medline]

22 Hutchins PM, Goldstone J, Wells R. Effects of hemorrhagic shock on the microvasculature of skeletal muscle. Microvasc Res 1973; 5: 131–40[ISI][Medline]

23 Brookes ZL, Brown NJ, Reilly CS. The dose-dependent effects of fentanyl on rat skeletal muscle microcirculation in vivo. Anesth Analg 2003; 96: 456–62[Abstract/Free Full Text]

24 Samain E, Clichet A, Bouillier H, et al. Propofol differently alters vascular reactivity in normotensive and hypertensive rats. Clin Exp Pharmacol Physiol 2002; 29: 1015–7[CrossRef][ISI][Medline]

25 Hirota K, Lambert DJ. I.V. anaesthetic agents inhibit dihydropyridine binding to L-type voltage-sensitive Ca2+ channels in rat cerebrocortical membranes. Br J Anaesth 1996; 77: 248–53[Abstract/Free Full Text]

26 Rivas-Cabanero L, Rodriguez-Barbero A, Macias-Nunez JF, et al. Effect of felodipine on systemic hemodynamics of spontaneous mild-hypertensive aged rats. Arch Physiol Biochem 1995; 103: 87–90[ISI][Medline]

27 Harris PD, Hodoval LF, Longnecker DE. Quantitative analysis of microvascular diameters during pentobarbital and thiopental anaesthesia in the bat. Anesthesiology 1971; 35: 337–42[ISI][Medline]

28 Grounds RM, Twigley AJ, Carli F, et al. The haemodynamic effects of intravenous induction. Comparison of the effects of thiopentone and propofol. Anaesthesia 1985; 40: 735–40[ISI][Medline]

29 Ratz PH, Callahan PE, Lattanzio FA,jr. Ketamine relaxes rabbit femoral arteries by reducing [Ca2+]i and phospholipase C activity. Eur J Pharmacol 1993; 236: 433–41[CrossRef][ISI][Medline]

30 Longnecker DE, Miller FN, Harris PD. Small artery and vein response to ketamine HCl in the bat wing. Anesth Analg 1974; 53: 64–8[ISI][Medline]

31 Klockgether-Radke AP, Frerichs A, Kettler D, et al. Propofol and thiopental attenuate the contractile response to vasoconstrictors in human and porcine coronary artery segments. Eur J Anaesthesiol 2000; 17: 485–90[CrossRef][ISI][Medline]

32 Mousa WF, Enoki T, Fukuda K. Thiopental induces contraction of rat aortic smooth muscle through Ca(2+) release from the sarcoplasmic reticulum. Anesth Analg 2000; 91: 62–7[Abstract/Free Full Text]

33 Bohlen HG, Lobach D. In vivo study of microvascular wall characteristics and resting control in young and mature spontaneously hypertensive rats. Blood Vessels 1978; 15: 322–30[ISI][Medline]

34 Struijker-Boudier HA, Crijns FR, Stolte J, et al. Assessment of the microcirculation in cardiovascular disease. Clin Sci (Lond) 1996; 91: 131–9[Medline]

35 Taherzadeh M, Warren JB. Comparison of diltiazem and verapamil on rat microvascular permeability. Microvasc Res 1997; 54: 206–13[CrossRef][ISI][Medline]

36 Lacolley P, Poitevin P, Koen R, et al. Different effects of calcium antagonists on fluid filtration of large arteries and albumin permeability in spontaneously hypertensive rats. J Hypertens 1998; 16: 349–55[CrossRef][ISI][Medline]

37 Valeski JE, Baldwin AL. Effect of early transient adherent leukocytes on venular permeability and endothelial actin cytoskeleton. Am J Physiol 1999; 277: H569–75[ISI][Medline]





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