Propofol-induced Relaxation Research Articles

Propofol Relaxes Isolated Rat Aorta through BKCa Activation

Propofol is an intravenous anesthetic that can be used for the induction and maintenance of anesthesia. In the present study, it was aimed to investigate the mechanism of vasodilator action of propofol in the rat aorta (RA). The RA rings were suspended in isolated organ baths and tension was recorded isometrically. First, potassium chloride (KCl) and phenylephrine (PE) were added to organ baths to form precontraction. When the precontractions were stable, propofol (1, 10, and 100μM) was added cumulatively to the baths. The antagonistic effect of propofol on KCl (45mM), PE (1μM), 5-hydroxytryptamine (5-HT) (30μM), and calcium chloride (CaCl2) (10μM to 10mM) induced contractions in the vascular rings were investigated. Propofol-induced relaxations were alsotested in the presence of the K+ channel inhibitors tetraethylammonium (TEA, 1mM), glibenclamide (GLI, 10μM), 4-aminopyridine (4-AP, 1mM), and barium chloride (BaCl2, 30μM). Preincubation with propofol (1, 10, and 100μM) did not affect the basal tone but inhibited the contraction induced by KCl, PE, 5-HT, and CaCl2-induced contractions. Propofol-induced relaxation was not effected by 4-AP, GLI, and BaCl2. However, TEA inhibited propofol-induced relaxations significantly. The propofol induces relaxation in contracted RA and inhibits KCl, PE, 5-HT, andCaCl2-induced contractions. The results demonstrate that the mechanism of action of propofol-induced vasodilation in the RA may be related to large conductance Ca2+-activated K+ channel activation.

Propofol-Induced Vasodilation in Human Internal Mammary Artery: Role of Potassium Channels

The aim of this study was to investigate the vascular effects and mechanisms of propofol in the human internal mammary artery (IMA). In vitro experimental study. The study was conducted inthe research laboratory of a pharmacology department. IMA segments were obtained from 52 patients undergoing coronary artery bypass surgery. The IMA rings were suspended in isolated organ baths, and the changes in the tension were isometrically recorded. The antagonistic effect of propofol (1 μM, 10 μM, and 100 μM) on contractions induced by potassium chloride (45 mM), phenylephrine (1 μM), 5-hydroxytryptamine (30 μM), and calcium chloride (10 μM-10 mM) was investigated. The relaxations induced by propofol also were tested in the presence of the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (100 mM); the cyclooxygenase inhibitor, indomethacin (10 mM); and the potassium ion channel inhibitors, tetraethylammonium (1 mM), iberiotoxin (20 nM), glibenclamide (10 µM), 4-aminopyridine (1 mM), and barium chloride (30 µM). Propofol caused a significant concentration-dependent vasorelaxation, which was endothelium independent. It inhibited the contractions induced by potassium chloride, phenylephrine, 5-hydroxytryptamine, and calcium chloride (p < 0.001), but it did not affect the basal tension. Propofol-induced relaxation was significantly inhibited by iberiotoxin and tetraethylammonium (p < 0.001); however, it was not affected by 4-aminopyridine, glibenclamide, and barium chloride. This study clearly reveals that propofol relaxes the IMA, and propofol-induced vasodilation may be related to large conductance calcium ion-activated potassium ion channel activation. Propofol use in coronary artery bypass surgery can be valuable via its favorable vasodilator effect to overcome perioperative vasospasm of IMA.

Protein Kinase C Isoforms Distinctly Regulate Propofol-induced Endothelium-dependent and Endothelium-independent Vasodilation

Protein kinase C (PKC) isoforms improve endothelial nitric oxide synthase activity and contractile Ca sensitivity in blood vessels. These actions may have opposite effects on propofol-induced vasodilation. This study examines the hypothesis that propofol induces relaxation by enhancing the PKC-mediated nitric oxide synthesis in endothelium and/or inhibiting the PKC-regulated Ca sensitivity in vascular smooth muscle (VSM). Propofol (1-100 μM) induced greater relaxation in endothelium-intact rings compared with denuded rings, and this effect was antagonized by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). In contrast, treatment with the general PKC inhibitor GF-109203X augmented both the endothelium-dependent and endothelium-independent relaxation induced by propofol, and this enhancement was more profound in the intact rings at lower propofol concentrations. The enhancement was unaffected by L-NAME. Interestingly, calphostin C (an inhibitor of conventional and novel PKCs) and Gö-6976 (an inhibitor of conventional PKCs) had similar effects in augmenting propofol-induced relaxation in endothelium-denuded rings. Downregulation of novel isoforms not only reduced the norepinephrine-elicited contraction but also decreased the magnitude of propofol-induced relaxation. In vascular smooth muscle cells, propofol prevented norepinephrine-elicited phosphorylation of myosin light chain. Propofol can increase the PKC-mediated availability of nitric oxide but inhibit the novel PKC-regulated Ca-sensitization, which provides a novel explanation for the mechanism of propofol-induced vasodilation.

Propofol-induced relaxation of rat aorta is altered by aging.

Propofol causes vasodilation via endothelium-dependent and -independent mechanisms. Because endothelial function is impaired with aging, the effects of propofol on endothelium-dependent vasodilation might be altered by aging. The aim of this study was thus to determine the effects of aging on vascular responses to propofol. Young (4-6 weeks old) or adult (16-25 weeks old) rats were anesthetized with sevoflurane. The thoracic aorta was dissected and cut into pieces 3-4 mm in length. In some rings, the endothelium was deliberately removed. The ring segment of the aorta was mounted for isometric force recording at a resting tension of 0.5-1.0 g in a 2 ml organ bath, containing Krebs-Ringer bicarbonate buffer. Arteries were precontracted with phenylephrine, and the function of endothelium was confirmed with acetylcholine. Then, we studied the concentration-dependent effects of propofol in endothelium-intact (control group) and -denuded aortic rings (denuded group), as well as those treated with N(ω)-nitro-L-arginine methylester (L-NAME group). Relaxation due to propofol was observed in the control groups of both young and adult rats in a concentration-dependent manner, but the magnitude of relaxation was significantly greater in young rats. In addition, in young rats, relaxation due to propofol was significantly and equally reduced in both L-NAME and denuded groups at all propofol concentrations that we studied (10(-6)-10(-3) M). In adult rats, relaxation due to propofol was quite similar between control and L-NAME groups at all propofol concentrations, whereas it was significantly reduced in the denuded group. These results suggest that endothelium-derived nitric oxide plays an important role in propofol-induced vasodilation in young rats, but not in adult rats.

The Mechanisms of Propofol-Induced Vascular Relaxation and Modulation by Perivascular Adipose Tissue and Endothelium

Propofol causes hypotension due to relaxation of vascular smooth muscle cells through its direct or indirect vasodilator effects. Perivascular adipose tissue (PVAT) and endothelium attenuate vascular contraction, and the function of PVAT is altered in hypertension and diabetes. Whether PVAT affects the action of anesthetics on vascular function is unknown. We studied the mechanisms of propofol-induced relaxation in relation to the involvement of PVAT and endothelium. Thoracic aortic rings from Wistar rats were prepared with or without PVAT (PVAT+ and PVAT-), intact endothelium (E+), or both, or with the endothelium removed (E-) for functional studies. In phenylephrine precontracted vessels, propofol-induced relaxation was highest with both PVAT and E+ and lowest in vessels denuded of both PVAT and endothelium. Propofol-induced relaxation occurred via both endothelium-dependent and -independent mechanisms. The relaxation response induced by propofol was significantly reduced by nitric oxide synthase inhibitor (l-NNA), K(+) channel blockers (tetraethylammonium and glibenclamide) in E+ and E- vessels, and by soluble guanylyl cyclase inhibitor 1H-(1,2,4) oxadiazolo (4,3-A) quinazoline-1-one and hydrogen peroxide scavenger (catalase) in E- vessels. The presence of PVAT significantly enhanced the relaxation response induced by propofol. In contrast to phenylephrine precontracted vessels in which the presence of PVAT or endothelium had an effect, in vessels precontracted with KCl, propofol-induced relaxation was similar among the 4 types of vessel preparation. PVAT enhances the relaxation effect induced by propofol in rat aorta through both endothelium-dependent and endothelium-independent pathways thus highlighting the clinical importance of PVAT.

Effects of propofol on responses of rat isolated renal arteriole to vasoactive agents

Rat renal arterial rings were suspended in organ chambers for isometric tension recording. The effects of propofol on the resting tone, KCl-, norepinephrine (NE)-, serotonin- and thromboxane A 2 analog U46619-induced contractions were observed. The relaxation responses to propofol on KCl-, NE- and U46619-induced contractions were assessed in the absence or presence of cyclooxygenase inhibitor, nitric oxide synthetase inhibitor or specific K + channel inhibitors. Propofol did not significantly affect the resting tone, but inhibited the contractions induced by KCl-, NE-, serotonin- and U46619. Propofol (1–100 µM) concentration-dependently relaxed 60 mM KCl-, 10 µM NE-, and 1 µM U46619-induced contractions with the values of RC 50 (concentration to decline the precontraction by 50%) being 18.9 µM, 70.6 µM and 12.7 µM, respectively. Propofol-induced relaxation was attenuated by indomethacin, but not by either N G nitro- l-arginine methyl ester (L-NAME) or any K + channel specific inhibitors used. The vasorelaxations induced by acetylcholine, sodium nitroprusside and amrinone were not affected by the presence of propofol. The present results indicate that propofol antagonizes provoked contractions of the arteriole and suggest that inhibition of extracellular Ca 2+ influx and synthesis of vasodilator prostanoid may be involved in propofol-induced relaxation of the arteriole.

Investigation of Relaxant Effects of Propofol on Sheep Sphincter of Oddi

Background/Aims: Intravenous anesthetics are often used for conscious sedation in endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincter of Oddi (SO) manometry. This study was designed to investigate the effects of propofol on sheep SO. Methods: SO rings were mounted in a tissue bath and tested for changes in isometric tension in response to propofol (10^–8–10^–4M) in the presence or absence of L-NAME (3 × 10^–5M), a non-specific inhibitor of nitric oxide (NO) synthase; indomethacin (10^–5M), an inhibitor of cyclooxygenase; glibenclamide (10^–5M), an inhibitor of ATP-sensitive potassium channels; tetraethylammonium (3 × 10^–4M), inhibitors of calcium-activated potassium channels; 4-aminopyridine (10^–3M), a voltage-dependent potassium channel blocker. Furthermore, we investigated the Ca²⁺ antagonist feature of propofol in precontracted SO rings by CaCl₂. Results: Carbachol (10^–9–10^–5M) induced concentration-dependent contraction responses in the SO rings. Propofol (10^–8–10^–4M) produced concentration-dependent relaxation on isolated SO rings precontracted by carbachol (10^–6M). Preincubation of SO rings by L-NAME (3 × 10^–5M), indomethacin (10^–5M), glibenclamide (10^–5M), and 4-aminopyridine (10^–3M) did not produce a significant alteration on propofol-induced relaxation responses (p > 0.05), while preincubation by tetraethylammonium (3 × 10^–4M) significantly decreased the propofol-induced relaxation responses (p < 0.05). Propofol (10^–8–10^–4M) induced concentration-dependently relaxations in precontracted isolated SO rings by CaCl₂. Conclusion: The results suggest that propofol induced concentration-dependent relaxations in precontracted isolated SO rings. These relaxations are independent from NO, cyclooxygenase metabolites, and opened ATP-sensitive and voltage-dependent potassium channels. Opened Ca²⁺-sensitive K⁺ channels and inhibited L-type Ca²⁺ channels existing in smooth muscle by propofol can contribute to these relaxations. Propofol can be beneficial as alternative drugs for obtaining selective relaxation during SO manometry after controlled clinical studies.

Investigation of the relaxant effects of propofol on ovalbumin-induced asthma in guinea pigs

Because the incidence of asthma appears to be increasing, the importance of proper perioperative management of individuals with asthma will also continue to increase. Although its mechanism of smooth muscle relaxation is unknown, propofol has been associated with less bronchoconstriction during anaesthetic induction. The aim of this study was to investigate the possible mechanism of these effects and the effects of propofol on the isolated trachea preparations from control and ovalbumin-sensitized guinea pigs. Adult male guinea pigs, weighing 280-330 g, were randomly allocated to two experimental groups, each consisting of 10 animals. Ten guinea pigs were sensitized by intramuscular injections of 0.30 mL of a 5% (w/v) ovalbumin/saline solution into each thigh (0.6 mL total) on days 1 and 4, whereas the remaining 10 served as controls receiving a total of 0.6 mL distilled water on days 1 and 4 as placebo. The isolated trachea preparations were mounted in tissue baths with modified Krebs-Henseleit solution and aerated with 95% oxygen and 5% carbon dioxide. We tested the effects of propofol (10(-7)-10(-3) M) on resting tension and after precontraction with carbachol and histamine on isolated trachea preparations from control and ovalbumin-sensitized guinea pigs. We also tested the effect of propofol on isolated trachea preparations precontracted with carbachol and histamine in the absence and presence of different inhibitors or antagonists. We investigated propofol responses in tracheal smooth muscle precontracted with CaCl2. Propofol (10(-7)-10(-3) M) produced a concentration-dependent relaxation of isolated tracheal preparations precontracted by carbachol (10(-6) M) and histamine (10(-6) M) in both groups. Preincubation with N(w)-nitro L-arginine methyl ester (3x10(-5) M), indomethacin (10(-5) M) or propranolol (10(-4) M) did not produce a significant alteration on propofol-induced relaxation responses (P>0.05), while preincubation with tetraethylammonium (3x10(-4) M) significantly decreased the propofol-induced relaxation responses in both groups (P<0.05). Propofol (10(-7)-10(-3) M) induced concentration-dependently relaxations in isolated trachea rings precontracted with CaCl2 in both the control and ovalbumin-sensitized groups. Propofol induced concentration-dependent relaxations in precontracted, isolated trachea smooth muscle of guinea pigs in both the control and ovalbumin-sensitized groups. These relaxations were independent of epithelial function and stimulation of beta adrenergic receptors. Opened Ca2+-sensitive K+ channels and inhibited L-type Ca2+ channels can contribute to these relaxations.

Room E, 10/17/2000 9: 00 AM - 11: 00 AM (PS) Propofol-Induced Relaxation of Rat Aorta Is Altered by Aging

<b>Room E, 10/17/2000 9: 00 AM - 11: 00 AM (PS) Propofol-Induced Relaxation of Rat Aorta Is Altered by Aging</b>

Propofol-induced relaxation of rat mesenteric arteries: evidence for a cyclic GMP-mediated mechanism.

Experiments were designed to evaluate whether guanosine 3',5'-cyclic monophosphate (cGMP)-mediated mechanisms contribute to vasodilation via propofol in rat mesenteric resistance arteries. Ring segments were suspended in the myograph system for isometric tension recording, and responses to propofol were tested in the presence and absence of methylene blue (MB), an inhibitor of guanylate cyclase. At concentrations > or = 1 microM, propofol caused concentration-dependent relaxation of vessel rings precontracted with U46619 (a thromboxane analog). The effect was not affected by N-monomethyl-L-arginine (L-NMMA; 50 microM). MB (5 microM) reversed propofol-induced vasodilation by 30% (p < 0.001). In contrast, MB has no effect on nifedipine-inhibited vasocontraction. The propofol-induced relaxation was further tested in rings incubated in Ca2+-free solution. U46619-induced contractions were significantly reduced by propofol (40 microM) but not by nifedipine (1 microM). Propofol reduced to a similar degree the contractions obtained to exogenously added calcium chloride in the absence and the presence of MB. Furthermore, propofol (10-100 microM) increased cGMP content in cultured bovine vascular smooth-muscle cells. Soluble guanylate cyclase inhibitors, such as MB and LY83583, attenuated this effect. This investigation suggests that propofol-induced relaxations in small arteries, in addition to inhibition of calcium influx, are mediated by increases of cGMP in the smooth muscle cells.

Effect of propofol on norepinephrine-induced increases in [Ca2+]i and force in smooth muscle of the rabbit mesenteric resistance artery.

Propofol (2,6-diisopropylphenol) possesses vasodilating activity in vivo and in vitro. The propofol-induced relaxation of agonist-induced contractions in small resistance arteries has not been clarified. The effect of propofol was examined on the contractions induced by norepinephrine and high K+ in endothelium-denuded rabbit mesenteric resistance artery in vitro. The effects of propofol on the [Ca2+]i mobilization induced by norepinephrine and high K+ were studied by simultaneous measurement of [Ca2+]i using Fura 2 and isometric force in ryanodine-treated strips. Propofol attenuated the contractions induced by high K+ and norepinephrine, the effect being greater on the high K+-induced contraction than on the norepinephrine-induced contraction. In Ca2+-free solution, norepinephrine produced a transient contraction resulting from the release of Ca2+ from storage sites that propofol attenuated. In ryanodine-treated strips, propofol increased the resting [Ca2+]i but attenuated the increases in [Ca2+]i and force induced by both high K+ and norepinephrine. In the presence of nicardipine, propofol had no inhibitory action on the residual norepinephrine-induced [Ca2+]i increase, whereas it still modestly increased resting [Ca2+]i, as in the absence of nicardipine. In smooth muscle of the rabbit mesenteric resistance artery, propofol attenuates norepinephrine-induced contractions due to an inhibition both of Ca2+ release and of Ca2+ influx through L-type Ca2+ channels. Propofol also increased resting [Ca2+]i, possibly as a result of an inhibition of [Ca2+]i removal mechanisms. These results may explain in part the variety of actions seen with propofol in various types of vascular smooth muscle.