Tetsuji Makita

A Comparative Evaluation of the Effects of Multiple Vasodilators on Human Internal Mammary Artery

Background Vasospasm of arterial grafts represents an unpredictable complication of coronary artery surgery and may compromise myocardial revascularization, and treatment is based on empirical therapy with nitroglycerin. Because of the potential for tolerance to nitroglycerin to occur, the authors studied different vasodilators acting through separate pathways on segments of human internal mammary artery. Methods Isolated vascular rings were precontracted with norepinephrine (1 [micro sign]M), KCl, or the thromboxane A2 analogue (U46619, 10 nM). Nitroglycerin (a nitrovasodilator), milrinone (a type III phosphodiesterase inhibitor), papaverine (a phosphodiesterase inhibitor), prostaglandin E1, and isradipine (a dihydropyridine calcium channel blocker) were added in a cumulative fashion. Results The analysis of the concentration ‐ response curves showed that vasodilators induced 90 ‐ 100% relaxation of the constricted segments with norepinephrine or the thromboxane A2 analogue, except prostaglandin E (1), which produced 73% relaxation at maximal concentrations. The effective concentrations of vasodilator agent that caused 50% relaxation for nitroglycerin and milrinone were within the range of the reported therapeutic concentrations in plasma. Isradipine was also effective at reversing receptor‐mediated contraction (maximal relaxation = 100% in internal mammary artery contracted with norepinephrine; maximal relaxation = 90% in internal mammary artery contracted with the thromboxane A2 analogue). Conclusions Vasodilator drugs acting through multiple pathways are effective at reversing in vitro vasoconstriction.

Sequential use of midazolam and propofol for long-term sedation in postoperative mechanically ventilated patients.

Acute withdrawal syndromes, including agitation and a long weaning time, are common adverse effects after long-term sedation with midazolam. We performed this study to determine whether the sequential use of midazolam and propofol could reduce adverse effects as compared with midazolam alone. We studied 26 patients receiving mechanical ventilation for three or more days after surgery. Patients were randomly assigned to two groups. In Group M, patients were sedated with midazolam alone. In Group M-P, midazolam was switched to propofol approximately 24 h before the expected stopping of sedation. The level of sedation was maintained at 4 or 5 on the Ramsay sedation scale. The sedation agitation scale was evaluated for 24 h after extubation. The recovery time from stopping of sedation to extubation was significantly shorter in Group M-P (1.3 ± 0.4 h) compared with Group M (4.0 ± 2.4 h). The incidence of agitation in Group M-P (8%) was significantly less frequent than that in Group M (54%). The results indicate that sequential use of midazolam and propofol for long-term sedation could reduce the incidence of agitation compared with midazolam alone.

Contractile and phosphatidylinositol responses of rat trachea to anticholinesterase drugs.

PurposeSome anticholinesterases (anti-ChE) such as neostigmine and pyridostigmine but not edrophonium, stimulate phosphatidylinositol (PI) response. Although a direct relationship was suggested between the increase in PI response and airway smooth muscle contraction, there are no data regarding the effects of anti-ChE drugs on airway smooth muscle. Thus, we examined the contractile properties and PI responses produced by anti-ChE drugs.MethodsContractile response. Rat tracheal ring was suspended between two stainless hooks in Krebs-Henseleit (K-H) solution. (I) Carbachol (CCh), anti-ChE drugs (neostigmine, pyridostigmine, edrophonium) or DMPP (a selective ganglionic nicotinic agonist) were added to induce active contraction. (2) The effects of 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP), an M3 muscarinic receptor antagonist, on neostigmineor pyridostigmine-induced contraction of rat tracheal ring were examined. (3) Tetrodotoxin (TTX) was tested on the anti-ChE drugs-induced responses.PI response. The tracheal slices were incubated in K-H solution containing LiCl and3[H]myo-inositol in the presence of neostigmine or pyridostigmine with or without 4-DAMP, an M3 muscarinic receptor antagonist.3[H]inositol monophosphate (IP,) formed was counted with a liquid scintillation counter.ResultsCarbachol (0.1 μM), neostigmine (1 μM), pyridostigmine (10 μM) but not edrophonium or DMPP, caused tracheal ring contraction. 4-DAMP, but not tetrodotoxin, inhibited neostigmine and pyridostigmineinduced contraction. Neostigmineor pyridostigmine-induced IP1 accumulation was inhibited by 4-DAMP.ConclusionsThe data suggest that anti-ChE drugs activate the M3 receptors at the tracheal effector site.RésuméObjectifCertains anticholinestérasiques (anti-ChE) comme la néostigmime et la pyridostigmine, mais non l’edrophonium, stimulent la réponse du phosphatidylinositol (PI). Bien qu’on ait évoqué une relation directe entre l’augmentation de la réponse PI et la contraction des muscles lisses du conduit aérien, il n’y a pas de données concernant les effets de médicaments anti-ChE sur les muscles lisses des voies aériennes. Donc, nous avons étudié les propriétés contractiles et les réponses du PI produites par les médicaments anti-ChE.MéthodeRéponse contractile. Des anneaux de trachée de rat ont été suspendus entre des crochets inox dans une solution de Krebs-Henseleit (K-H). (1) Du carbachol (CCh), des médicaments anti-ChE (néostigmine, pyridostigmine, edrophonium) ou DMPP (un agoniste nicotinique ganglionnaire sélectif) ont été ajoutés pour induire une contraction active. (2) Les effets du méthobromide 4-diphénylacétoxy-N-méthyl-pipéridine (4-DAMP), un antagoniste des récepteurs muscariniques M3, sur la contraction d’anneaux de trachée de rat induite par la néostigmine ou la pyridostigmine, ont été examinés. (3) La tétrodotoxine (TTX) a été évaluée lors des réponses induites par les médicaments anti-ChE.Réponse PI. Les tranches de trachée ont été mises en incubation dans la solution K-H contenant du LiCI et3[H]myo-inositol en présence de néostigmine ou de pyridostigmine, avec ou sans 4-DAMP, un antagoniste des récepteurs muscariniques M3. Le monophosphate3[H]inositol (IP1) ainsi formé a été mesuré à l’aide d’un compteur à scintillation liquide.RésultatsLe carbachol (0,1 μM), la néostigmine (1 μM), la pyridostigmine (10 μM) mais non l’edrophonium ou le DMPP ont causé des contraction des anneaux de trachée. La 4-DAMP contrairement à la tétrodotoxine, a inhibé les contractions induites par la néostigmine et la pyridostigmine. Laccumulation d’IP1 induite par la néostigmine ou la pyridostigmine a été inhibée par la 4-DAMP.ConclusionLes données indiquent que les médicaments anti-ChE activent les récepteurs M3 au site effecteur de la trachée.

The Vasodilator Effects of Clevidipine on Human Internal Mammary Artery

Endothelial dysfunction and platelet activation with thromboxane release may contribute to spasm or alterations in internal mammary artery (IMA) graft flow during coronary artery surgery.Clevidipine, an ultrashort-acting dihydropyridine calcium channel blocker, is undergoing clinical development, but there are little data regarding its effects on human vasculature. We investigated the effects of clevidipine on human IMA obtained during surgery. After precontracting IMA segments with an analog of thromboxane (U46619, 10-8 mol/L), acetylcholine and nitroglycerin were added cumulatively to examine endothelial function. Concentration-response curves to clevidipine were cumulatively obtained during submaximal contraction to the U46619 (10-8 mol/L) in rings with and without endothelium. In the IMA samples with endothelium, acetylcholine did not completely reverse the U46619-mediated contraction, which implies impaired endothelial function (40% +/- 6% maximal response). Both clevidipine and nitroglycerin completely reversed U46619-induced contraction (clevidipine (50% effective concentration [EC50] = 3.88 +/- 0.84 x 10-6 mol/L, nitroglycerin EC50 = 4.84 +/- 2.76 x 10-8 mol/L). The responses to clevidipine were similar in preparations with or without intact endothelium. Clevidipine is an endothelium-independent arterial vasodilator that offers a potential therapeutic option in the treatment of perioperative arterial graft vasospasm and/or hypertension. Implications: Clevidipine is a new ultrashortacting dihydropyridine calcium antagonist. In human internal mammary arteries precontracted with a thromboxane A2 analog, clevidipine was an effective vasodilator on vessel segments in the presence and in the absence of endothelium. (Anesth Analg 1997;85:1000-4)

Propofol Attenuates Ovalbumin-induced Smooth Muscle Contraction of the Sensitized Rat Trachea: Inhibition of Serotonergic and Cholinergic Signaling

Propofol is considered suitable for induction of anesthesia in patients with bronchial asthma. However, the mechanisms of its action on bronchi are not fully understood. We examined the effects of propofol on ovalbumin (OA)-induced contraction of OA-sensitized rat trachea. Male Wistar rats were sensitized by a single intraperitoneal injection of OA 10 &mgr;g mixed with aluminum hydroxide, 10 mg, as adjuvant. Fourteen days later, the experiment was performed using the tracheal rings. We observed the effects of ketanserin, a 5-HT2 receptor antagonist, and atropine on OA-induced contraction. Next, the effects of propofol on OA-, serotonin (5-HT)-, acetylcholine-, or electrical field stimulation-induced contractions were observed. OA-induced contraction was 90% attenuated by the combination of ketanserin and atropine. Propofol significantly attenuated OA-induced contraction in a dose-dependent manner. Propofol abolished 5-HT-induced contraction, attenuated acetylcholine-induced contraction, and also almost completely attenuated the enhancement by 5-HT of electrical field stimulation-induced contraction. These results suggest that the mechanism involved in the attenuation by propofol of OA-induced contraction is inhibition of the actions of 5-HT. Propofol should be a useful anesthetic in patients with immunoglobulin E-related asthma.

A dose-response study of anticholinesterase drugs on contractile and phosphatidylinositol responses of rat trachea.

We investigated whether anticholinesterase drugs in large doses inhibit muscarinic receptors of airway smooth muscle. In vitro measurements of isometric tension and [3H]inositol monophosphate (IP1) that formed were conducted by using rat tracheal rings or slices. Neostigmine and pyridostigmine caused muscular contraction and IP1 accumulation in small doses (10 &mgr;M and ≤100 &mgr;M, respectively), but they attenuated muscular contraction and IP1 accumulation in larger doses (1000 &mgr;M). Edrophonium did not affect the smooth muscle tone and IP1 levels. Neostigmine, pyridostigmine, and edrophonium attenuated the carbachol (5.5 &mgr;M)-induced smooth muscle contraction and IP1 accumulation, when administered in large doses (1000 &mgr;M). The attenuation of contraction by neostigmine at large doses was not affected by methoctramine, an M2 muscarinic receptor antagonist, but was reversed by washing with fresh Krebs-Henseleit solution. The results suggest that anticholinesterase drugs have dual effects on the tension and phosphatidylinositol responses of rat trachea. Large doses of anticholinesterase drugs cause airway smooth muscle relaxation, which may be seen in patients with myasthenia gravis who have received excessive anticholinesterase therapy. Implications Neostigmine and pyridostigmine, but not edrophonium, have dual effects on the tension and phosphatidylinositol responses of rat trachea. Large doses of anticholinesterase drugs cause airway smooth muscle relaxation, which may be seen in patients with myasthenia gravis who have received excessive anticholinesterase therapy.

Carbachol, norepinephrine, and hypocapnia stimulate phosphatidylinositol turnover in rat tracheal slices.

Background The intracellular mechanisms involved in the alpha‐adrenoceptor‐ or hyperventilation‐induced bronchoconstriction remain unknown. Because there is a direct relationship between phosphatidylinositol (PI) metabolism and airway smooth muscle contraction induced by muscarinic agonists, the authors examined the effects of carbachol (CCh), norepinephrine (NE), and hypocapnia on PI turnover in the airway smooth muscle. Methods Rat tracheal slices were incubated in Krebs‐Henseleit solution containing LiCl and [sup 3 Hydrogen]myo‐inositol in the presence of NE, CCh, or neither. The PCO2 in the solution was 36 plus/minus 3 mmHg (normocapnia), 19 plus/minus 2 mmHg (moderate hypocapnia), or 5 plus/minus 2 mmHg (severe hypocapnia), respectively. [sup 3 Hydrogen]inositol monophosphate (IP1) formed was counted with a liquid scintillation counter. Results Basal IP1 formed was greater at severe hypocapnia than at normocapnia. Norepinephrine‐ and CCh‐induced IP1 formation were also greater at hypocapnia than at normocapnia. Conclusions These results indicate that CCh, NE, and hypocapnia stimulate PI turnover in the airway smooth muscle, which would cause bronchoconstriction, and hypocapnia also augments NE‐ and CCh‐induced PI turnover, which could cause worsening of exercise‐induced asthma and vagotonic asthma, respectively.

Total intravenous anesthesia with propofol is associated with a lower rate of postoperative delirium in comparison with sevoflurane anesthesia in elderly patients

STUDY OBJECTIVE Postoperative delirium (POD) is a common complication of anesthesia. The incidence of POD in elderly patients ranges from 37% to 53%, and POD increases the morbidity and mortality of elderly patients. However, the effects of anesthetics on POD are not well known. The present study aimed to compare the incidence of POD resulting from propofol and sevoflurane anesthesia. DESIGN Double-blind prospective study. SETTING Operating room and postoperative recovery area. PATIENTS Thirty patients in the sevoflurane anesthesia group and 29 in the propofol anesthesia group. MEASUREMENTS Statistical analyses were performed using Microsoft Excel 2010 for Windows 7 (Microsoft Corporation, Redmond, Wash). Statistical analysis was performed using Fisher exact test and Student t test. MAIN RESULTS The incidence of POD in the propofol anesthesia (6.9%) was significantly less than that observed in the sevoflurane anesthesia (26.7%; 038). CONCLUSION In comparison with sevoflurane anesthesia, propofol anesthesia is associated with a lower incidence of POD in elderly patients.

Clonidine Attenuates the Carbachol‐induced Contractile and Phosphatidylinositol Responses of Rat Trachea

Although Clonidine is known to affect vascular smooth muscle, its effects on airway smooth muscle are not fully understood. This study was designed to examine the effects of Clonidine on carbachol‐induced contractile and phosphatidylinositol responses of rat trachea.

The effects of prolonged controlled hypotension induced by prostaglandin E1 on renal tubular function.

The effects of the prolonged 3-hour and 6-hour controlled hypotension induced by prostaglandin E1 (PGE1) on renal tubular function have been comparatively studied with trimethaphan (TMP; 3-hour hypotensive anesthesia) and enflurane deep anesthesia (6-hour hypotensive anesthesia), using the urine N-acetyl-β-D-glucosaminidase (NAG index) and the serum and urine N-acetyl-β-D-glucosaminidase (fractional clearance ofβ2-m; Fc-β2-m) as markers. During 3-hour and 6-hour controlled hypotension PGE1 , NAG index and Fc-β2-m and urine volume could be maintained without remarkable changes. In the group with TPM, NAG index and Fc-β2-m significantly increased. The increasing trend was also noted over time in deep anesthesia with enflurane. On 1st postoperative day, Fc-β2-m significantly increased in PGE1 group in both 3-hour and 6-hour hypotensive anesthesia, whereas it restored to normal on 2nd postoperative day. Also, in TMP and enflurane deep anesthesia, Fc-β2-m significantly increased on 1st postoperative day. With the latter, significant increase was also observed on 2nd postoperative day. These results suggest that, in 3-hour and 6-hour controlled hypotension induced by PGE1 , renal tubular function is normally maintained and that it is useful for prolonged controlled hypotensive anesthesia. However, further study is necessary because tubular dysfunction might appear on 1st postoperative day.