Anesth Analg 2003;97:1639-1645
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Mechanisms of Propofol-Mediated Hyperpolarization of In Situ Rat Mesenteric Vascular Smooth Muscle
Tamotsu Nagakawa, MD*,
Mitsuaki Yamazaki, MD*,
Noboru Hatakeyama, MD*, and
Thomas A. Stekiel, MD
*Department of Anesthesiology, Toyama Medical and Pharmaceutical University, Toyama, Japan, and the
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin
Address correspondence and reprint requests to Mitsuaki Yamazaki, MD, Department of Anesthesiology, Toyama Medical and Pharmaceutical University, Toyama, 930–0194, Japan. Address e-mail to myama@ ms.toyama-mpu.ac.jp.
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Abstract
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Previously, we reported that propofol hyperpolarizes vascular smooth muscle (VSM) cells of small arteries and veins. The current study was designed to determine whether propofol-mediated hyperpolarization is the result of specific effects on potassium channels known to exist in VSM and on steps in the intracellular nitric oxide (NO), cyclic guanosine monophosphate (cGMP), and cyclic adenosine monophosphate (cAMP) second messenger pathways. VSM transmembrane potentials (Em) were measured in situ in sympathetically denervated, small mesenteric arteries and veins of Sprague-Dawley rats. Effects of propofol on VSM Em were determined before and during superfusion with specific inhibitors of VSM calcium-activated (KCa), adenosine triphosphate-sensitive (KATP), voltage-dependent (Kv), and inward rectifying (KIR) potassium channels and with endogenous mediators of vasodilation. Propofol significantly hyperpolarized VSM in small mesenteric vessels. This hyperpolarization was abolished on inhibition of KCa and KATP channel activity and on inhibition of NO and cGMP (but not cAMP). Assuming a close inverse correlation between the magnitude of VSM Em and contractile force, these results suggest that propofol induces hyperpolarization and relaxation in denervated, small mesenteric vessels by activation of KCa and KATP channels. Such channel activation may be mediated by activation of NO and cGMP, but not cAMP, second messenger pathways.
IMPLICATIONS: The results of this study indicate that propofol-mediated hyperpolarization in vascular smooth muscle can be attributed to the activation of calcium-activated, adenosine triphosphate-sensitive potassium channels, the nitric oxide, and cyclic guanosine monophosphate pathways.
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Introduction
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Propofol is a widely used IV anesthetic, but it sometimes produces relatively marked hypotension by a decrease in sympathetic activity (1) and direct vasodilation (2). Consistent with these actions, several studies have also demonstrated that in relatively large vessels in vitro, propofol inhibits calcium influx into vascular smooth muscle (VSM) cells (3,4), impairs the vasodilation induced by adenosine triphosphate-sensitive (KATP) channel potentiation (5), and inhibits the effects of endothelial-derived vasodilating substances (e.g., endothelium-derived hyperpolarizing factor, nitric oxide [NO], and prostacyclin) (6–9).
However, small blood vessels are the major regulators of peripheral vascular resistance and, hence, arterial blood pressure (10). In a previous study (11), we observed that a 30 mg · kg-1 · h-1 propofol infusion produced an in situ VSM hyperpolarization in small resistance-regulating arteries and capacitance-regulating veins. Such hyperpolarization was postulated to result from a propofol-induced attenuation of both sympathetic neural and non-neural regulation of VSM tone (11). However, the precise mechanisms of action of propofol at the level of the small blood vessel VSM cell membrane and the intracellular signaling pathways involved in the regulation of VSM tone and arterial blood pressure are not well understood.
Changes in resting membrane potential (Em) are closely coupled to corresponding alterations in VSM tone (12,13). Figure 1 illustrates some of the pertinent mechanisms regulating VSM tone in small blood vessels that may be modulated by anesthetics to produce hyperpolarization and vasodilation. A principal determinant of Em is the relatively large membrane permeability for four major types of potassium channels, viz., high conductance calcium-activated (KCa), voltage-dependent (KV), KATP, and inward rectifier (KIR) channels. The NO, cyclic guanosine monophos-phate (cGMP), and cyclic adenosine monophosphate (cAMP) second messenger pathways have been implicated in the regulation of potassium channel activities.
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Figure 1. Diagram illustrating the non-neural, membrane, and intracellular mechanisms of control of vascular smooth muscle (VSM) vasodilation that are potential targets for anesthetic action. Persistent inhibitors and their sites of action are also illustrated. Nitric oxide (NO) is synthesized by NO synthase (NOS) in endothelium and diffuses across the VSM membrane to bind guanylate cyclase. Potassium channels (KCa, KV, KIR, KATP) contribute to the regulation of VSM transmembrane potential and thus to regulation of voltage-dependent Ca2+ channels. Protein kinase G (active) and protein kinase A (active) stimulate the transport of Ca2+ into the extracellular space and sarcoplasmic reticulum (S.R.). ATP = adenosine triphosphate; Ba = BaCl2; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; GLI = glibenclamide; Gs = guanine nucleotide-binding protein; GTP = guanosine triphosphate; IBX = iberiotoxin; L-NAME = NG-nitro-L-arginine methyl ester; ODQ = 1H-[1,2,4] oxadiazolo-4,3,-a-quinoxalin-1-one; PGI2 = prostacyclin; Rp-cAMPS = Rp-adenosine-3',5'-cyclic monophosphorothioate; Rp-8-pCPT-cGMPS = (Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate; 4AP = 4-aminopyridine.
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The first purpose of this study was to determine whether direct effects of propofol on small resistance and capacitance vessels include enhanced activation of VSM potassium channels leading to hyperpolarization. The second was to determine whether IV administration of propofol activates steps in the NO, cGMP, or cAMP second messenger pathways that are involved in the regulation of potassium channel activity.
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Methods
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The Animal Experiment Committee at Toyama Medical and Pharmaceutical University approved the present study. Fifty-four male Sprague-Dawley rats with body weights ranging between 200 and 300 g were studied. Each animal was sedated with 40 mg/kg intraperitoneal ketamine to facilitate weighing and presurgical preparation. Anesthesia was then induced with 20 mg/kg intraperitoneal pentobarbital. Surgical preparation included femoral arterial and venous cannulations for direct measurement of arterial blood pressure and medication infusion, respectively. In addition, a tracheotomy tube was placed and ventilation was controlled with a Harvard Model 683 ventilator (Harvard Apparatus, Cambridge, MA) to maintain end-tidal CO2 between 30 and 40 mm Hg. During all of the experiments the rats breathed an inspired oxygen concentration of 33% to reduce any possibility of hypoxia-induced effects on the VSM. Basal anesthesia was maintained with 5 mg · kg-1 · h-1 IV pentobarbital infusion.
Each animal was placed on a custom-made, movable microscope stage. A midline laparotomy was performed through which a loop of terminal ileum with its attached mesentery was externalized to expose small (200–300 µm od) branches of mesenteric arteries and paired veins. These vessels were cleared of perivascular fat without disturbing luminal flow. Surrounding connective tissue was fastened to the silastic rubber floor of a temperature-regulated tissue chamber with small stainless steel pins. A row of smaller stainless steel pins was placed immediately alongside the arteries and veins to separate them and to minimize pulsations that interfered with Em measurements. The preparation was continuously superfused with a physiologic salt solution (PSS) composed of NaCl 119 mM, KCl 4.7 mM, MgSO4 1.17 mM, CaCl2 1.6 mM, NaHCO3 24.0 mM, NaH2PO4 1.18 mM, and EDTA 0.026 mM (Sigma Chemical, St. Louis, MO). The PSS was maintained at 37°C and aerated with a gas mixture of N2, O2, and CO2 to maintain pH between 7.35 and 7.45, PCO2 between 35 and 45 mm Hg, and PO2 between 75 and 150 mm Hg.
Local sympathetic denervation of each paired mesenteric artery and vein preparation was accomplished by local superfusion with 300 µg/mL 6-hydroxydopamine for 20 min. This was followed by a 1-h washout with PSS. Before denervation, the preparation was superfused for 5 min with PSS containing 1 µM phentolamine to block the effect of released catecholamines (14).
Single-cell in situ VSM Em values were measured by advancing 3 M KCl-filled glass micropipettes into the VSM layer using a hydraulic micromanipulator (MHO-110; Narishige International, Tokyo, Japan). The potential difference between the intracellular microelectrode and a bath reference electrode was measured by using a microelectrode amplifier (MEZ 8301; Nihon Kohden, Tokyo, Japan). Micropipettes with impedances ranging between 40 and 60 megohms were pulled from borosilicate glass by using a model P-97 Brown-Flaming micropipette puller (Sutter Instruments, Novato, CA). Em and femoral arterial blood pressure were recorded simultaneously by using an RM-6000 polygraph system (Nihon Kohden) and a Superscope 2 digital data acquisition system (GW Instruments, Somerville, MA).
In all experiments, each animal was administered 30 mg · kg-1 · h-1 propofol or propofol intralipid vehicle (Pharmacia AB, Stockholm, Sweden) at the same concentration and rate as described before (11). The protocol for each experimental preparation included sequential measurement of arterial blood pressure and Em in artery and vein at the following times: 1) during intralipid vehicle infusion (control); 2) after 20 min local superfusion with the selected inhibitor (i.e., for K+ channel, NO-cGMP pathway, or prostacyclin-cAMP pathway) (inhibitor); 3) 30 min after washout of the inhibitor and infusion of propofol in its intralipid vehicle at a rate of 30 mg · kg-1 · h-1 (propofol); 4) after addition of the inhibitor to the superfusate together with the 30 mg · kg-1 · h-1 propofol infusion (propofol + inhibitor). The concentration of each potassium channel inhibitor used was between 0.5 and 2 orders of magnitude larger than the half maximum concentration (i.e., reported to produce a 50% block of channel activity) (15). Each NO, cGMP, or cAMP inhibitor concentration used was shown to be effective in our previous studies (11,16).
Three experimental series of measurements were performed. In the first, Em measurements were made in the presence and absence of selective inhibitors of each of 4 major types of potassium channels (i.e., 100 nM iberiotoxin, KCa inhibitor; 3 mM 4-aminopyridine, KV inhibitor; 10 µM BaCl2, KIR inhibitor; 1 µM glibenclamide, KATP inhibitor) to study propofol-induced potassium channel-mediated hyperpolarization.
The second experimental series evaluated the effect of NO-cGMP pathway inhibition on propofol-induced hyperpolarization in two separate studies. In the first, the effect of inhibition of NO synthesis on propofol-induced hyperpolarization was assessed by superfusion with 15 µM NG-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor. In the second study, the effect of an inhibition of two steps in the cGMP pathway on propofol-induced hyperpolarization was investigated with two inhibitors, 15 µM 1H-[1,2,4] oxadiazolo-4,3, -a-quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor, and 2.5 µM (Rp)-8-(para-chlorophenylthio)guano-sine-3',5'-cyclic monophosphorothioate (Rp-8-pCPT-cGMPS), a protein kinase G (PKG) phosphorylation inhibitor.
The third experimental series evaluated the effect of an inhibition of two steps in the cAMP pathway on propofol-induced hyperpolarization; this was investigated with two specific inhibitors, 410 µM SQ22536, an adenylate cyclase inhibitor, and 24.5 µM Rp-adenosine-3',5'-cyclic monophosphorothioate (Rp-cAMPS), a protein kinase A (PKA) phosphorylation inhibitor.
For a time-control study, and to determine the possible interfering effect of the propofol intralipid vehicle, VSM Em measurements were made in separate vessel preparations over the time period required for the four successive steps in each of the three experimental series of measurements. VSM Em did not change significantly with time, and the propofol intralipid vehicle did not affect VSM Em when administered over the two time periods during which propofol and propofol plus inhibitor would have been administered. Blood concentrations of propofol were measured commercially (BML, Tokyo, Japan) from samples taken at the end of the study. In the present study, a 30 mg · kg-1 · h-1 propofol IV infusion rate produced a plasma concentration ranging between 11 and 14 µg/mL. This was similar to that observed in our previous study (11). A 30 mg · kg-1 · h-1 propofol IV infusion rate was used to examine the mechanisms of propofol-mediated hyperpolarization. In our previous study (11), we found that at this rate (though not at slower rates, e.g., 10 mg · kg-1 · h-1), propofol significantly hyperpolarized both innervated and denervated small mesenteric arteries and veins.
The VSM Em value reported for each step in each of the experimental protocols is the mean ± SD of six average Em values (one average Em value per vessel and one vessel per animal preparation). An average Em value is the numerical average of at least 5 stable (5–10 s) individual VSM cell impalements in a single vessel preparation. For VSM Em, a one-way analysis of variance with repeated measures (StatView, Abacus Concepts, Berkeley, CA) was used to compare mean values between specific groups in each protocol. The significance of differences between mean values was evaluated using the post hoc least significance difference test. P 
0.05 was used to determine the significance of all differences.
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Results
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Mean arterial blood pressure (MAP) was measured simultaneously with VSM Em in the presence and absence of inhibitor and/or propofol infusion in each animal preparation. Inhibitor infusion alone did not produce a significant change in MAP in any animal group. However, propofol infusion caused an approximately 17% reduction in MAP in the animal groups. In each inhibitor + propofol group, propofol significantly reduced MAP by an amount similar to that observed during propofol infusion alone.
Superfusion with each of the four types of potassium channel inhibitors significantly depolarized arterial and venous VSM relative to the control condition (Table 1). When infused alone, propofol induced a significant arterial and venous VSM hyperpolarization compared with respective control values. Such propofol-induced hyperpolarization was abolished during superfusion with either the KCa or the KATP channel inhibitor, but not with the KV or KIR channel inhibitor.
The NO synthesis inhibitor significantly depolarized VSM in each vessel type (Table 2). In addition, superfusion with propofol plus L-NAME produced a depolarizing response when compared with propofol alone. Superfusion with the inhibitor of cGMP synthesis (ODQ) or inhibitor of PKG activation (Rp-8-pCPT-cGMPs) also significantly depolarized the arterial and venous VSM. Furthermore, the propofol-induced hyperpolarization was abolished in the presence of either the inhibitor of cGMP synthesis or PKG activation.
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Table 2. Effect of Nitric Oxide (NO) cyclic guanosine monophosphate (cGMP) Pathway Inhibitors and Propofol on Vascular Smooth Muscle Transmembrane Potentials
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Both arterial and venous VSM were significantly depolarized by both the inhibitor of cAMP synthesis (SQ22536) and the inhibitor of PKA activation (Rp-cAMPS) (Table 3). However, propofol-induced hyperpolarization was not significantly attenuated by either of these two inhibitors.
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Table 3. Effect of cyclic guanosine monophosphate (cAMP) Pathway Inhibitors and Propofol on Vascular Smooth Muscle Transmembrane Potentials
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Discussion
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The first important result in the present study is that propofol-induced hyperpolarization was abolished by selective inhibition of KCa and KATP channels but not KV and KIR channels. In a previous study, we observed that KCa and KATP channels were also activated by isoflurane to produce in situ VSM hyperpolarization in rat mesenteric arteries and veins (17). The present data suggest that propofol-induced VSM hyperpolarization (and coupled vasorelaxation) in denervated small arteries and veins results from enhanced activity of KCa and KATP channels (or mechanisms that regulate them) but not of KV and KIR channels, similar to the isoflurane-induced hyperpolarization. Erdemli et al. (18) have demonstrated that the activation of KATP channels is probably the major mechanism of the vasodilator effect of propofol in the rat lung. In contrast, Park et al. (19) have shown that the vasodilator effect of propofol in rat distal coronary arteries is not mediated by opening of KATP channels. Possible reasons for this difference might be the vessel VSM specificity for propofol. Moreover, potassium conductance influences transmembrane Ca2+ influx and therefore VSM relaxation (20). Some investigators have shown coupling of VSM Em with active Ca2+-dependent VSM force generation (12,13). Previously, we demonstrated that propofol attenuates Ca2+ influx through the mesenteric VSM membrane (3). These observations suggest that K+ channel activation and consequent closure of voltage-dependent Ca2+ channels by propofol are one of the mechanisms of VSM relaxation in small mesenteric vessels.
Table 1 shows that the magnitude of VSM depolarization (in either artery or vein) produced by the specific inhibitor of the KCa channel (iberiotoxin) did not differ significantly from that produced by the specific inhibitor of the KATP channel (glibenclamide). In addition, both inhibitors blocked propofol-induced hyperpolarization. This strongly suggests that both channel types contribute to the regulation of VSM Em in rat small mesenteric arteries and veins. This conclusion is in agreement with our previous studies of the effect of isoflurane on VSM Em in rat small mesenteric artery and vein (17). However, the experimental design and VSM Em measurements in the present study do not provide a means of quantitatively assessing the relative magnitudes of the contribution of KATP and KCa channel activation to propofol-mediated VSM hyperpolarization in these vessels.
The second important result in the present study is the observed significant VSM depolarization as well as the elimination of a propofol-induced VSM hyperpolarization in both types of small mesenteric vessel after inhibition of NO synthesis. This result suggests that NO contributes to the tonic regulation of VSM tone in these vessels and that propofol can enhance the activity of endothelial-derived NO. However, Miyawaki et al. (6) have reported that propofol inhibits endothelial NO-mediated vasorelaxation in aorta. Park et al. (7) have also shown that propofol inhibits endothelium-derived relaxing factor production in aorta and pulmonary artery. The elimination of propofol-induced VSM hyperpolarization by inhibition of NO suggests that the action of propofol on the NO vasodilator pathway in these small mesenteric vessels may be different from that in large vessels.
The third important result in the present study is the observed elimination of the propofol-induced hyperpolarization by inhibition of cGMP synthesis or cGMP-mediated activation of PKG. Such elimination suggests that at least a portion of the vasodilator action of propofol results from an enhanced activity of NO and/or intracellular components of the cGMP second messenger system. A significant body of electrophysiological and pharmacological evidence supports the series of sequential steps for small vessel vasodilation beginning with endothelium-derived NO and including the VSM cytosolic cGMP cascade (Fig. 1). The activated PKG in this cascade phosphorylates several proteins involved in the relaxation of VSM. Such phosphorylation can also activate VSM membrane K+ channels, leading to hyperpolarization and reduced activity of voltage-dependent Ca channels (21,22).
A wide variety of studies indicate that the specific type of K+ channel activated by the NO-cGMP cascade varies with the type of physical or chemical stimulus for NO production (e.g., blood flow-generated shear stress, acetylcholine, and various neurohumoral and circulating humoral agents) and with the vessel location in a specific vascular bed. Most studies implicate either the KCa and KATP channel or both (21–24). Liu et al. (25) have also shown that propofol increases cGMP content in cultured bovine smooth muscle cells and soluble guanylate cyclase inhibitors, such as methylene blue and LY83583, attenuate this effect. In the present study, the elimination of propofol-induced VSM hyperpolarization by inhibitors of the cGMP pathway indicates that at least a portion of propofol’s vasodilator action results from enhanced activity of intracellular components of the cGMP-mediated second messenger system, which, in turn, may open VSM potassium channels. Results of the previous study (16) showed that either inhibitor of NO-cGMP pathway in the rat mesenteric vessels did not significantly attenuate isoflurane-induced hyperpolarization. Thus, the different results from the previous isoflurane study suggest a different action by propofol on NO synthesis, PKG activation, and cGMP synthesis.
In contrast, no differences were observed in Em responses to propofol before and during block of selective steps in the cAMP-PKA pathway. In human platelets, propofol potentiated the NO-cGMP pathway but not the cAMP pathway (26). The results in the present study suggest that propofol-induced hyperpolarization appears to be independent of the cAMP pathway. However, Yamashita et al. (9) have reported that propofol inhibits the synthesis of prostacyclin and thus attenuates acetylcholine-induced, endothelium-dependent response. Therefore, the effect of propofol on the VSM cell membrane may be different from that on vessel endothelium. Moreover, the lack of a dependence of propofol-induced hyperpolarization on the cAMP pathway observed in the present study differs from our isoflurane result (16). Results in the present study showing that propofol-induced hyperpolarization involves the NO-cGMP pathway but not the cAMP pathway suggest significant differences in the VSM membrane and intracellular mechanisms underlying the vasodilator action between propofol and isoflurane.
In agreement with previous studies (27,28), in the present study propofol significantly reduced MAP. Therefore, it is possible that the hyperpolarization induced by propofol in the small artery is a result of the accompanying hypotension produced by propofol (i.e., a myogenic effect). In a previous unpublished study we measured a negative slope of 0.05 mV reduction of VSM Em magnitude (i.e., depolarization) per mm Hg intraluminal pressure increase (between approximately 50 and 200 mm Hg) in in vitro, isolated, perfused, segments of rat small mesenteric artery. Thus, a myogenic mechanism may contribute to the hyperpolarization of arterial VSM induced by this anesthetic. However, indirect evidence suggests that a myogenic mechanism cannot be the sole cause of the VSM hyperpolarization. For example, 97%–99% of propofol in vivo is bound to plasma proteins (29). In preliminary studies designed to eliminate hypotension by superfusion of in situ mesenteric vessels with a 5-µM concentration of propofol (which is 3 or 4 times larger than that attained in blood at an IV infusion rate of 30 mg · kg-1 · h-1), we have observed VSM hyperpolarization similar to those reported in this study.
In summary, 30 mg · kg-1 · h-1 propofol IV infusion hyperpolarizes VSM and attenuates control of VSM tone in mesenteric small resistance-regulating arteries and capacitance-regulating veins by enhancing the activity of membrane-bound KCa and KATP channels. The absence of additional VSM hyperpolarization by propofol after inhibition of endothelial-derived NO and the related cGMP pathway suggest that propofol acts in part through activation of endothelial-derived NO and the intracellular components of the cGMP-mediated second messenger system. In contrast, propofol-induced VSM hyperpolarization in small resistance-regulating arteries and capacitance-regulating veins does not appear to involve activation of steps in the cAMP pathway.
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Acknowledgments
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Supported, in part, by a grant from the Ministry of Education, Science Sports, and Culture of Japan (14770762).
The authors thank Dr. Zeljko J. Bosnjak, Professor, and Dr. William J. Stekiel, Professor, Departments of Anesthesiology and Physiology, Medical College of Wisconsin for their critical comments and suggestions concerning this study.
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Footnotes
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Presented, in part, at the 47th annual meeting of the Japan Society of Anesthesiologists, Tokyo, Japan, April, 2000; at the 48th annual meeting of the Japan Society of Anesthesiologists, Kobe, Japan, April, 2001; and at the 49th annual meeting of the Japan Society of Anesthesiologists, Fukuoka, Japan, April, 2002.
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Accepted for publication July 3, 2003.
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Abstract
Introduction
