Comparison of vascular effects of ropivacaine and lidocaine on isolated rings of human arteries

Ropivacaine is a new local anaesthetic agent. Previous animal studies have indicated that vasoconstrictor effects are elicited by ropivacaine in vitro and subcutaneously and that it produces blanching of the skin if injected subcutaneously in humans.
Lidocaine is a widely used local anaesthetic reported to exert a biphasic effect on the microvasculature with contraction at low concentrations and relaxation at high concentrations. There is a need for pharmacologic tools able to counteract local arterial vasoconstriction. In this study, the contractile effect of ropivacaine and lidocaine were investigated in vitro on isolated human arteries.
Experiments were performed on 43 internal mammary artery (IMA) rings obtained from 22 patients and on 14 radial artery (RA) rings from 7 patients. The rings were mounted in organ baths and isometric contractile activity was measured. Experiments were conducted by cumulative adding ropivacaine or lidocaine (1.5X10^-5 M; 4.5X10^-5 M; 1.5X10^-4 M; 4.5X10^-4 M; 1.5X10^-3 M; 4.5X10^-3 M; 1.5X10^-2 M) to the organ baths. The endothelium was mechanically removed in 19 IMA rings and in 9 RA rings.
Ropivacaine and lidocaine produced a biphasic response with contraction at low concentrations (1.5X10^-5 1.5X10^-3 M) and release of the maximal contraction at higher concentrations. No statistically significant differences in contractile or relaxing effects were seen between the two drugs. Removal of the endothelium did not significantly affect contractile activity. In this study of human mammary artery preparations, ropivacaine is not a stronger vasoconstrictor than lidocaine.     

Propulsive activity of the isolated segmental colon of the guinea pig

Propulsive activity in segments of isolated distal colon of guinea-pig was investigated. Propulsive activity, as indicated by movements of the bolus (5 x 10 mm diameter) made of plastic with a steel wire, was recorded isometrically using a force-displacement transducer. Muscle tension of longitudinal axis was also recorded isometrically in the same preparation. In all preparations, spontaneous propulsive activity, which was due to combination of ascending excitation and descending inhibition, occurred periodically. The frequency of propulsive activity was 4.0 +/- 0.9/10 min (M +/- SE, n = 8) and the duration was 64.0 +/- 9.0 sec (M +/- SE, n = 9). The propulsive force was 16.4 +/- 3.4 g (M +/- SE, n = 10) at peak. The spontaneous propulsive activities were blocked by atropine (10(-5) g/ml). These activities were gradually decreased in frequency and in propulsive force within 2-3 hours. When spontaneous propulsive activities were negligible, carbachol (10(-9)-10(-7) g/ml) added to the bathing medium stimulated propulsive activity in a dose dependent manner.     

Comparison of nitroprusside and hydralazine in isolated uterine arteries from pregnant and nonpregnant patients

The purpose of the present study was to determine the relative potency of nitroprusside and hydralazine with respect to inhibition of norepinephrine-induced contraction of isolated, uterine arteries from pregnant and nonpregnant patients. The arteries, obtained after hysterectomy, were dissected free from surrounding tissue, and arterial rings were prepared and mounted in tissue chambers filled with Kreb's-bicarbonate solution. Isometric tension was recorded. At concentrations of 10(-9) M to 10(-5) M, both nitroprusside and hydralazine produced concentration-dependent inhibition of the contractile response to norepinephrine. Nitroprusside and hydralazine were more potent in relaxing arteries contracted by a lower concentration (3 X 10(-6) M) of norepinephrine than by a higher concentration (10(-5) M) of norepinephrine. Regardless of the concentration of norepinephrine, nitroprusside was considerably more potent than hydralazine. The concentrations of nitroprusside that produced 50% inhibition (IC50) of the contractile response to norepinephrine (3 X 10(-6) M) in uterine arteries from pregnant and nonpregnant patients were 3.2 +/- 0.5 X 10(-9) M (n = 5) and 1.2 +/- 0.1 X 10(-9) M (n = 6), respectively. The IC50 values for hydralazine acting against norepinephrine (3 X 10(-6) M) in the uterine arteries from pregnant and nonpregnant patients were 5.1 +/- 0.5 X 10(-7) M (n = 5) and 4.0 +/- 0.5 X 10(-7) M (n = 6), respectively. Nitroprusside (10(-6) M), compared to hydralazine (10(-5) M), produced the greater maximal inhibition of norepinephrine-induced contraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differences in the physiological response and ultrastructure of human and guinea pig vas deferens. Effects of prostaglandins, irradiation, and temperature

Marked differences were observed in the mechanical reactions of human and guinea pig vas deferens to prostaglandins, irradiation, and cooling. In human preparations prostaglandin E1 (0.1-1 ng/ml) had an augmentory effect on the contractile response after electrical neurostimulation (10 Hz, 0.3 ms, 3 s), but no visible influence (at concentrations ranging from 1 ng to 10 micrograms/ml) on the contractile response after electrical muscle stimulation (10 Hz, 40 ms, 3 s). In contrast, in guinea pig preparations (PGE1 (0.1-1 ng/ml) had an inhibitory effect on the contractile response after electrical neurostimulation and an augmentory effect (0.1-1 micrograms/ml) on the contractile response after electrical muscular stimulation. Human vas deferens showed higher radiosensitivity than guinea pig preparations. The neurotransmitters acetylcholine and catecholamines increased the radiosensitivity of guinea pig preparations, but not of human ones. Vas deferens reacted to short-time (15-120 s) cooling with an immediate temporary contraction, at 25 degrees C of short (seconds), at 5 degrees C of long (minutes) duration; after rewarming (5-37 degrees C) a second contraction appeared in guinea pig preparations, but not in human ones. Whereas the contraction to electrical neurostimulation (10 Hz, 0.3 ms, 3 s) was abolished in human preparations by cooling, it was only inhibited in guinea pig vas deferens. Electron microscopy showed differences in the ultrastructure of human and guinea pig vas deferens. Muscle cells were more widely separated in human vas deferens (generally 400 nm or more) than in guinea pig (approximately 100-200 nm), and the intracellular space in human preparations contained more collagen. The axons in human preparations contained predominantly large granular and agranular vesicles, those in guinea pig preparations small granular and agranular vesicles. The possible correlation between the physiological response of human and guinea pig vas deferens and the ultrastructural differences is discussed. The results indicate the possibility that other pharmacophysiological and toxicological phenomena could be essentially different in human and guinea pig material.     

Effect of aminoglycoside antibiotics on the electrical stimulation-induced contractile response of the guinea-pig ureter

Using electrical stimulation, we first investigated whether the movement of ureteral smooth muscle of the guinea-pig was myogenic in its control, or neurogenic. We then investigated the effects of aminoglycoside antibiotics (kanamycin, bekanamycin and ribostamycin) on the movement of ureteral smooth muscle induced by electrical stimulation. In these investigations, each ureter removed from the animal was cut into three approximately equal-sized segments, which are an upper segment (kidney side), a middle segment and a lower segment (urinary bladder side). Each segment was mounted in an organ bath filled with Krebs solution and the mechanical response induced by electrical stimulation of each segment was recorded isometrically. Each one of the upper, the middle and the lower segments was stimulated with rectangular pulses (50 volt, 0.1-3 msec durations, 40 Hz) for a period of 2 sec. Of all segments tested (ten in each group), none showed any response to the stimulation with pulses below 0.5 msec duration. While 2-3 segments out of ten of the upper, the middle and the lower ureteral segments showed a contractile response to stimulation with pulses of 1 msec duration, the rest of the segments showed no response to the same stimulation. This contractile response was not inhibited by tetrodotoxin which is known to block the nerve-mediated response. And also, all the ten samples of each upper, middle and lower segment never failed to show a contractile response to stimulation with pulses of 2 msec and 3 msec duration. Various drugs which are already known to block the nerve-mediated response (i.e., atropine, guanethidine, phentolamine, propranolol and tetrodotoxin) were tried, but none of them had an inhibitory effect on the contractile response. On the other hand, each one of kanamycin (KM), bekanamycin (AKM) and ribostamycin (RSM) in concentrations of 1 x 10(-5) g/ml-1 x 10(-3) g/ml produced a concentration-dependent decreasing effect in the magnitude of the electrical stimulation-induced contractile response of the ureteral segment. In addition, the decreasing effects of these antibiotics were also observed in the tetrodotoxin. From these results, we concluded that the contractile response of the ureter may be myogenic in its control, and the aminoglycoside antibiotics, KM, AKM and RSM, may act directly on the ureteral smooth muscle so as to decrease its contractile response.     

Muscarinic stimulation and antagonism and glucoregulation in nondiabetic and obese hyperglycemic mice

Plasma glucose and insulin responses to a muscarinic agonist (bethanechol chloride) and a muscarinic antagonist (atropine) were evaluated in obese C57BL/6J ob/ob mice and in lean C57BL/6J + /? mice. In lean +/? mice, plasma glucose decreased in response to 1 and 2 micrograms/g bethanechol chloride, whereas insulin increased significantly. In ob/ob mice, insulin increased remarkably in response to bethanechol administration (saline, 632 +/- 80 microU/ml; 2 micrograms/g bethanechol chloride, 1794 +/- 97 microU/ml; n = 10), but surprisingly, plasma glucose also rose significantly (saline, 230 +/- 14 mg/dl; 2 micrograms/g bethanechol chloride, 363 +/- 18 mg/dl, n = 10). This exaggerated hyperglycemia in ob/ob mice was not associated with significant changes in plasma glucagon. Furthermore, administration of propranolol hydrochloride did not diminish bethanechol chloride-induced hyperglycemia in ob/ob mice. Administration of atropine (2.5, 5, and 10 mg/kg body wt) induced a significant decrease in plasma insulin without changes in plasma glucose in ob/ob mice, whereas neither plasma insulin nor plasma glucose changed in lean mice. Finally, conversion of [14C]alanine to glucose was increased in ob/ob mice after bethanechol chloride administration, indicating that muscarinic stimulation increases gluconeogenesis in an animal model of type II (non-insulin-dependent) diabetes.     

Low-sodium resistant non-adrenergic inhibitory neurotransmission in the guinea-pig duodenum

The evoked inhibitory potentials (i.p.s) in the longitudinal smooth muscle cells of the guinea-pig duodenum were recorded intracellularly. The i.p.s were not blocked by adrenergic blocking agents, guanethidine (10(-6) g/ml), propranolol (10(-6) g/ml) and phentolamine (10(-6) g/ml), and atropine (10(-6) g/ml). Tetrodotoxin (10(-7)-10(-6) g/ml) abolished the non-adrenergic non-cholinergic i.p.s evoked by single or repeated stimulation without changes in the resting membrane potential of the longitudinal smooth muscle. In the presence of atropine (10(-6) g/ml), acetylcholine (5 X 10(-9)-7 X 10(-7) g/ml) had no effect on the amplitude of the i.p.s d-tubocurarine (2 X 10(-5) g/ml) reduced the amplitude of the i.p.s and produced a small depolarization in the muscle membrane. The longitudinal muscle membrane was slightly depolarized by Li-solution and the i.p.s could be evoked in the Li-solution for a long period, accompanying with the slight decrease in the amplitude of the i.p.s. In the choline-solution, the depolarization of the muscle membrane and the slight increase in the amplitude of the i.p.s were obtained. The i.p.s were abolished in the Ca2+-free choline-solution. In the sucrose-solution, the decrease of the resting membrane potential of the longitudinal smooth muscle was observed and the amplitude of the i.p.s was gradually reduced during the perfusion of the sucrose-solution. Chloride deficiency had no considerable effect on the amplitude of i.p.s. The results obtained suggest that the non-adrenergic non-cholinergic inhibitory neurotransmission is low-sodium resistant and the excitation-secretion coupling in the non-adrenergic non-cholinergic inhibitory nerves is mainly dependent on the external calcium ions but not sodium ions.     

Comparison of vasoactive response of left and right internal thoracic arteries to isosorbide-dinitrate and nitroglycerin: an in vitro study

OBJECTIVE: The internal thoracic artery (ITA) is the most important graft in coronary artery bypass grafting. Its distal region is, however, prone to vasospasm. We studied the effects of nitroglycerin (NTG) and isosorbide-dinitrate (DSDN) on distal segments of left versus right ITA. METHODS: Rings of distal segments (6 to 9 mm proximal to bifurcation) of the human left and right ITA were studied. After baseline contraction of the rings, achieved using 60 mmol/L of KCl, they were exposed to increasing doses of ISDN and NTG (10 to 100 microg/ml), and dose-response curves were recorded. RESULTS: The contractile response of left ITA rings to KCl were significantly lower than those of right ITA rings (1.87 +/- 0.25 g versus 3.5 +/- 0.61 g, p < 0.005). Both nitrates inhibited the contractile response in a concentration-dependent manner, with relaxing effects of ISDN higher than those of NTG (p < 0.01) in both left and right ITA rings. CONCLUSIONS: The distal segment of the left ITA is less prone to vasospasm than that of the right. ISDN has a considerably higher relaxant effect on this segment than NTG. We therefore recommend favoring high doses of ISDN over NTG as an antispastic measure.     

Analysis of the contractions evoked by sympathetic nerve stimulation, and thermal effect on the guinea-pig vas deferens--study as a model for the thermotherapy of benign prostatic hyperplasia

BACKGROUND: The present study was designed to investigate the mechanism of thermotherapy on benign prostatic hyperplasia (BPH), using the guinea-pig vas deferens as a model for BPH. The components of contractions elicited by electrical field stimulation and nicotine were analyzed, and the thermal effect on the vas deferens was examined. METHODS: The vas deferens was dissected, suspended vertically through two silver ring electrodes, and attached to an isometric transducer. The electrical stimulation of 10 constant current pulses (10 mA) with 0.3 msec in duration of 5, 10, and 40 Hz was achieved under air-gap condition. Drugs were added directly to a 5 ml Magnus tube containing Tyrode solution (36 degrees C) gassed with a 95% O2-5% CO2 mixture. The components of contractions evoked by electrical stimulation and nicotine were investigated by tetrodotoxin (TTX), and blocking agents of alpha 1-adrenoceptors and/or purinoceptors. Thermal effect on electrically evoked contractions was examined at incubation temperature of 25 degrees C (control), 43 degrees C, 45 degrees C, 46 degrees C and 47 degrees C for 1 hour. RESULTS: Nicotine (200 microM) elicited biphasic contractions, which were triggered by corelease of noradrenaline (NA) and ATP (N-ATP) from sympathetic nerve terminals by activation of prejunctional nicotine receptors. NA and N-ATP caused the corresponding contractions, alpha 1 and N-ATP components, respectively. Combined application of prazosin (1 microM) and suramin (50 microM) abolished these contractions. Activation of post-junctional alpha 1-adrenoceptors by NA caused release of ATP from muscle cells to produce the contraction (alpha 1-ATP component), which was sensitive to both suramin and prazosin. N-ATP and alpha 1 components attributed to fast and slow part of the contraction, respectively. Electrical field stimulation caused biphasic contractions which consisted of both neurogenic (TTX-sensitive) and non-neurogenic (TTX-insensitive) components. An increase in stimulation frequency (5 to 40 Hz) increased the neurogenic components, which contained alpha 1 and N-ATP components, as well as the case of nicotine. The non-neurogenic components consisted of alpha 1-ATP, muscle-derived ATP (m-ATP) and unknown substance 'X' components. Nifedipine (10 microM). L-type Ca2+ channel blocker, markedly reduced the contractions induced by bath applied phenylephrine (alpha 1-agonist, 100 microM) but only partially blocked the contractions produced by bath applied ATP (500 microM). The contractile force in amplitude and neurogenic components induced by electrical field stimulation did not change at 43 degrees C, but both declined significantly above 45 degrees C. The neurogenic components at 45 degrees C and 46 degrees C were suppressed to 22 +/- 6% and 14 +/- 3% (mean +/- SD) of control, respectively. All the contractile responses were abolished at 47 degrees C. CONCLUSION: The contractions of the guinea-pig vas deferens evoked by electrical field stimulation consisted of alpha 1, N-ATP, alpha 1-ATP, m-ATP and X components. Sympathetic nerve fibers in the muscles were completely inactivated by thermal exposure at 47 degrees C for 1 hour. The results suggest that the minimal temperature for thermotherapy of BPH should be 47 degrees C.     

Trimethaphan is a direct arterial vasodilator and an alpha-adrenoceptor antagonist

In helically cut strips of dog cerebral, mesenteric, and femoral arteries contracted with prostaglandin(PG)F2 alpha, trimethaphan (10(-5)-10(-3)M) caused a dose-related relaxation that was not influenced by atropine, propranolol, diphenhydramine, cimetidine, aminophylline, or indomethacin. Trimethaphan-induced relaxation was greater in extracerebral than in cerebral arteries. The relaxation was greater in phenylephrine-contracted arteries than in PGF2 alpha-contracted arteries. On the other hand, hexamethonium did not relax the arteries. Trimethaphan (10(-4)-10(-3)M) shifted the dose-response curve for norepinephrine in mesenteric arteries to the right, but failed to influence the contractile response to 25 mM KCl. Treatment with trimethaphan (10(-4)-10(-3)M) protected alpha-adrenergic receptors from persistent blockade by phenoxybenzamine. Trimethaphan (10(-7)-3 X 10(-6)M) and hexamethonium (3 X 10(-8)-10(-6)M) significantly attenuated the contractile response of mesenteric arteries to nicotine in a dose-dependent manner, but did not alter the response to transmural electrical stimulation. The antinicotinic potency of trimethaphan was approximately one-fourth that of hexamethonium. It is concluded that, unlike hexamethonium, trimethaphan acts directly on vascular smooth muscle to induce vasodilation, more prominently in extracerebral arteries than in cerebral arteries. In high concentrations, trimethaphan appears to possess an alpha-adrenergic blocking action.     

Induction of contraction in isolated rat aorta by cyclosporine

Cyclosporine (CsA) is a new immunosuppressive agent that has adverse effects of nephrotoxicity and de novo appearance of hypertension. It has been hypothesized that the mechanism of the contrary effects is through an action of CsA on vascular smooth muscle. To test this hypothesis, thoracic aortas were isolated from Wistar Kyoto rats and ring segments prepared for measurement of tension. CsA (5 X 10(-6) M) induced a slow increase in tone of the isolated rings with a response at 3 hr of 0.70 +/- 0.17 N/m2 X 10(4). This contraction was significantly inhibited by the Ca2+ channel blocker verapamil (0.30 +/- 0.08 N/m2 X 10(4) after 3 hr, P less than 0.05) and by the noncompetitive alpha-antagonist phenoxybenzamine (0.06 +/- 0.07 N/m2 X 10(4) after 3 hr, P less than 0.05). The competitive alpha-antagonist phentolamine had mixed effects. CsA does not irreversibly alter vascular smooth muscle contractile ability since a 3 hr exposure to the agent had no effect on either the maximal contractile response or sensitivity to KCl. We conclude that CsA can directly induce contraction in vascular smooth muscle, perhaps by inducing a release of norepinephrine from adrenergic nerve terminals. The data are consistent with the hypothesis that CsA induces nephrotoxicity and de novo hypertension through a contractile effect on vascular smooth muscle.     

Vasoactive response of different parts of human internal thoracic artery to isosorbide-dinitrate and nitroglycerin: an in-vitro study.

OBJECTIVE: The left internal thoracic artery (LITA) is the most important graft for coronary artery bypass grafting (CABG). Its distal region is, however, prone to vasospasm. The effect of nitroglycerin (NTG) and isosorbide-dinitrate (ISDN) on different segments of this region was studied. METHODS: Rings of three segments of the LITA were studied: 6-9 mm proximal to the bifurcation (part A); 1-3 mm proximal to the bifurcation (part B); and 3-6 mm distal to the bifurcation (part C). After baseline, maximal contraction of the rings was achieved using 60 mmol/l of KCl, they were exposed to increasing doses of ISDN and NTG (10-100 microg/ml), and dose-response curves were recorded. RESULTS: The contractile response of part A to KCl was significantly lower than that of parts B and C (1.87+/-0.25 versus 4.05+/-0.39 and 7.64+/-0.54 g, respectively; P<0.001). Both nitrates inhibited the contractile response in a concentration-dependent manner. The relaxing effects of both nitrates on part A was most pronounced (P<0.01), with the effect of ISDN being higher than that of NTG (P<0.01). CONCLUSIONS: The region 6-9 mm proximal to the LITA bifurcation is less prone to vasospasm, and has greater relaxation responses to ISDN and NTG than the more vasospastic distal parts of the LITA. We recommend avoiding the use of the very distal part of this artery during CABG, and to use high doses of ISDN rather than NTG as an anti-spastic measure.     

Effects of variations in extracellular osmolality on spontaneous contractile activity and response to nerve stimulation in rat detrusor muscle in vitro

The effects of hyperosmolar (390, 590 mosm/kg) and hypoosmolar (260 mosm/kg) solutions on myogenic spontaneous contractile activity and response to nerve stimulation were studied on strips of rat detrusor muscle in vitro. In isotonic (290 mosm/kg) solution the mean spontaneous contractile activity was 2.1 +/- 0.6% and the amplitude of the largest spontaneous contractions was 9.8 +/- 3.0% of maximal response to nerve stimulation. In 390 mosm/kg the frequency of spontaneous contractions decreased, but due to a fourfold increase of contraction amplitude a threefold increase of mean contractile activity was recorded. In 260 mosm/kg a similar contraction pattern as in 290 mosm/kg was seen. The spontaneous contractions were resistant to tetrodotoxin (10(-5) g/ml) in all osmolalities. In 590 mosm/kg the spontaneous activity had ceased, and a continuous contracture (resistant to tetrodotoxin) was observed with an amplitude of 41 +/- 1% of the maximal response to nerve stimulation at 290 mosm/kg. Similar maximal responses to nerve stimulation were obtained in 260, 290, and 390 mosm/kg. The frequency-response relation in 390 mosm/kg had a leftward shift at low frequencies. In 590 mosm/kg no response to nerve stimulation or acetylcholine was noted, but the preparations contracted vigorously following depolarization with high-K+ solution.     

Effects of aminobenzyl penicillin (AB-PC), methylchlorophenyl isoxazolyl penicillin (MCI-PC) and 6-aminopenicillanic acid (6-APA) on the contractile response of guinea-pig urinary bladder

The present study was undertaken to investigate the effects of aminobenzyl penicillin (AB-PC), methylchlorophenyl isoxazolyl penicillin (MCI-PC), and 6-aminopenicillanic acid (6-APA) on the contractile response of guinea-pig urinary bladder. AB-PC, MCI-PC, and 6-APA, respectively, diminished the intramural electrical stimulation-induced contractile response. AB-PC had almost no effect on the contractile response to exogenous acetylcholine, while MCI-PC remarkably reduced it. The reducing effect of MCI-PC was greater on the intramural electrical stimulation-induced contractile response than it is on the exogenous acetylcholine-induced contractile response. 6-APA slightly reduced the exogenous acetylcholine-induced contractile response. The reducing effect of 6-APA was a little weaker on the exogenous acetylcholine-induced contractile response than it is on the intramural electrical stimulation-induced contractile response. By the addition of AB-PC, the amplitude of spontaneous contractile response of the tissue was reduced gradually with light lowering of the tonus level of the tissue was almost prevented with a little lowering of the tonus level of the tissue. The effects of AB-PC and MCI-PC on the spontaneous contractile response of the tissue mentioned above were also observed in the presence of tetrodotoxin. On the other hand, by the addition of 6-APA, the reducing effect on the amplitude of spontaneous contractile response of the tissue and increasing effect on its frequency were recognized with remarkable raise of the tonus level of the tissue. These phenomena which were induced by 6-APA were also observed in the presence of tetrodotoxin. From these results, the conclusion comes as follows: 1) AB-PC may affect not only on the muscle but also on the intramural cholinergic nerves. 2) MCI-PC may affect on the muscle, but its effect on the intramural nerves is also not likely to be negligible at this time. 3) 6-APA may affect mainly on the muscle.     

Atropine sulphate enhances neuromuscular transmission in the rat

The effect of atropine (0.001-10 mumol.l-1) on neuromuscular transmission in the rat hemidiaphragm preparation was investigated by analysing its effects on directly and indirectly-elicited twitch, tetanic, post-tetanic twitch responses and on the phenomenon of post-tetanic twitch potentiation. The effect of atropine on contractions produced by endogenous acetylcholine (ACh) or exogenous ACh (added directly into organ bath containing muscle) was studied in rat ileum. The results showed that atropine in low concentrations (1 mumol.l-1 or less), enhanced the indirectly-elicited twitch, tetanic and post-tetanic twitch responses in the rat diaphragm preparation. The mean EC50 value of atropine-induced increase in twitch tension was 0.08 +/- 0.01 mumol.l-1 (mean +/- s.e. mean, n = 6). Atropine had little effect on directly-elicited twitch tension, but in high concentrations (10 mumol.l-1 or more), it reduced the directly, and indirectly-elicited twitch contractions and produced a neuromuscular block in the rat diaphragm preparation. Atropine increased the contraction produced, in rat ileum, by endogenous ACh, i.e. ACh released from the phrenic nerve stimulated at 50 Hz for 20 s duration (control contraction: 1.3 +/- 0.1 g, contraction in atropine: 1.7 +/- 0.2 g). In contrast, atropine significantly reduced the contraction produced by exogenous ACh in the same preparation (control contraction: 3.0 +/- 0.5 g, atropine: 2.0 +/- 0.1 g), suggesting that a different mechanism may be involved in the latter effect of atropine. It was concluded that atropine, in low concentration, enhanced neuromuscular transmission, possibly via a presynaptic mechanism. In high concentration, atropine may reduce and then block transmission, possibly via pre- and postsynaptic mechanisms.     

Influence of sufentanil on cerebral metabolism and circulation in the rat

The authors examined the effects of large intravenous doses of sufentanil (5-160 micrograms/kg) on cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) in rats. CBF and CMRO2 were measured by a modified Kety-Schmidt technique using 133Xenon washout. Progressive decreases in CBF and CMRO2 occurred in animals receiving sufentanil. The maximum decrease was 53% and 40% for CBF and CMRO2 respectively, at a dose of 80 micrograms/kg. The values for CBF and CMRO2 in this group were 105 +/- 10 ml X 100 g-1 X min-1 (mean +/- SEM) and 6.5 +/- 0.5 ml X 100 g-1 X min-1, respectively, compared with 226 +/- 28 ml X 100 g-1 X min-1 and 10.9 +/- 1 ml X 100 g-1 X min-1 in the control group, which received N2O 70% in oxygen. Larger doses of sufentanil did not cause further significant changes in CBF and CMRO2. Sharp waves appeared on the electroencephalogram (EEG) of all the animals following sufentanil injection, and some animals had EEG changes develop consistent with seizure activity. This seizure-like activity appeared to consist of a single episode of short duration in the groups receiving 5, 10, and 20 micrograms/kg sufentanil. The incidence and frequency of seizure activity increased in the groups receiving higher doses of sufentanil, although the duration of seizures was still short. The results of this study indicate that sufentanil causes a significant decrease in CBF and CMRO2 similar to that previously reported for fentanyl, and high doses of sufentanil may cause frequent seizure-like patterns appearing on EEG.     

The effects of morphine, nalbuphine, and butorphanol on adrenergic function in canine saphenous veins

Saphenous vein rings mounted in organ chambers containing Krebs-Ringer solution were used to determine if the venodilator effects of morphine, nalbuphine, and butorphanol are the result of interference with adrenergic neurotransmission or are caused by direct depressant actions on venous smooth muscle cells. Morphine (5 X 10(-5) M and 2 X 10(-4) M) caused a dose-dependent depression of the contractile response to transmural electrical stimulation. H1- and H2- histamine antagonists did not attenuate the inhibitory effect of morphine. Concentrations of morphine and nalbuphine lower than 5 X 10(-5) M had no effect, whereas 5 X 10(-6) M butorphanol significantly depressed the evoked tension response to electrical stimulation. The contractile responses of the veins to exogenous norepinephrine (NE) were not altered by morphine, indicating a presynaptic site of action rather than a direct action on the venous smooth muscle. Transmural electrical stimulation was used to evoke release of endogenous NE. Morphine (5 X 10(-5) M and 2 X 10(-4) M), nalbuphine (2 X 10(-4) M), and butorphanol (4 X 10(-6) M) significantly decreased release of NE. Naloxone did not alter NE release and did not attenuate the inhibition of NE release observed with the opiates, indicating that the effect of morphine on this neuroeffector junction is not mediated by a naloxone-sensitive opiate receptor. Blockade of presynaptic alpha receptors by phenoxybenzamine or phentolamine augments NE release caused by transmural electrical stimulation; morphine inhibited this augmentation. The results of these experiments indicate that high concentrations of morphine may decrease NE release, an effect that may contribute to the venodilation and hypotension observed following administration of high doses of morphine in humans. In the usual analgesic doses, the venodilatory effects of morphine cannot be explained by local action on either NE release or venous smooth muscle contractility.     

Glomerular filtration response to acute ureteral obstruction in the dog

In order to assess the glomerular filtration responses to acute ureteral obstruction in the dog we employed an established method that does not require timed urine collections. Our results show a 57 per cent increase in renal blood flow (baseline: 203.8 +/- 50.9 vs. 319 +/- 69.4 ml./min. at 105 minutes; no. = 7) that was associated with a monophasic decrease in filtration fraction to -70 per cent at 120 minutes (0.26 +/- 0.025 vs. 0.08 +/- 0.007) and an increase in ureteral pressure to 63.1 +/- 6.1 mm. Hg at 120 minutes. A biphasic GFR response was noted with an initial small increase (baseline: 32.5 +/- 7.5 vs. 36.3 +/- 11.0 ml./min. at 2 minutes) followed by a continual decline to -55 per cent at 120 minutes (to 14.5 +/- 2.6 ml./min.). This investigation has confirmed the results of micropuncture studies showing maintenance of GFR early after complete ureteral ligation.     

Cholinergic and purinergic contribution to the micturition reflex in conscious rats with long-term bladder outlet obstruction

The urethra of female Wistar rats was partially obstructed for 15 weeks. The effects of atropine (1 mg/kg i.v.), suramin (100 mg/kg i.v.), and a combination of atropine and suramin on the peak micturition pressure (MP) were compared during cystometry in conscious rats controls or subjected to outlet obstruction. On the isolated bladder dome, we studied the inhibitory effect of 1 micromol/L atropine, 1 mmol/L suramin, and the combination of the two drugs on contractions induced by electrical field stimulation (EFS). We studied also the contractile response to 80 mmol/L KCl and the concentration-response curves to noradrenaline, phenylephrine, and carbachol on the bladder dome and bladder neck and alpha, beta-methylene adenosine triphosphate on the bladder dome. In conscious rats, the MP, bladder capacity, and micturition volume were significantly higher in obstructed rats than in controls. Suramin induced the same inhibition in the two groups of animals (-30.7 +/- 13.3% in controls and -29.2 +/- 8.5% in obstructed rats). Atropine decreased the MP, but this effect was twofold greater in obstructed animals (-28.1 +/- 3.1% and -65.1 +/- 6.9% in control and obstructed animals, respectively). However, the combined effect of atropine and suramin was additive in controls but not in obstructed (-56.7 +/- 5.4% and -55.9 +/- 9.4%, respectively). Similar results were obtained in vitro using 1 micromol/L atropine and 1 mmol/L suramin. In the obstructed bladder dome and bladder neck, we found a great reduction in KCl- and carbachol-induced contractility but no difference in the response to EFS. Responses to noradrenaline and phenylephrine were moderately reduced in the bladder neck only, whereas responses to alpha, beta-methylene adenosine triphosphate in the bladder dome were not reduced except at the concentration of 300 micromol/L. We conclude that long-term obstruction in rats could induce cholinergic nerve fiber proliferation as suggested by the decrease in M(3) muscarinic receptor contractility (desensitization) and by a greater sensitivity of the MP to atropine.     

Chronic extrinsic denervation after small bowel transplantation in rat jejunum: Effects and adaptation in nitrergic and non-nitrergic neuromuscular inhibitory mechanisms

BACKGROUND. Extrinsic denervation of the transplanted small bowel could play a substantial role in motor dysfunction of the transplanted gut. We attempted to determine the effect of chronic extrinsic denervation on intestinal contractility. METHODS. Jejunal longitudinal muscle strips were obtained from rats 1 week and 8 weeks after (1) syngeneic small bowel transplantation, (2) ischemia/reperfusion, or (3) gut transection/reanastomosis. Nonoperated rats (naive controls) and sham-operated rats (sham controls), 1 week after celiotomy/gut manipulation, served as controls. We evaluated the effects of exogenous nitric oxide, increasing doses of cholinergic and adrenergic agonists, and electrical field stimulation (EFS) in the presence or absence of N(G)-monomethyl-l-arginine, methylene blue, tetraethylammonium, or tetrodotoxin. RESULTS. Spontaneous contractile activity (_chi +/- SEM), when compared with the naive controls (11.3 +/- 2.0 g.5 min/mg), was increased in all 4 groups at 1 week (15.9 +/- 10 to 19.4 +/- 2 g.5 min/mg; P < or =.03 each) but not at 8 weeks postoperatively. The inhibition of contractile activity by nitric oxide was increased in small bowel transplantation in naive controls at 8 weeks to 80% +/- 10% versus 50% +/- 7% (P <.02). EFS induced an inhibition of contractile activity that was tetraethylammonium- and tetrodotoxin-sensitive but N(G)-monomethyl-l-arginine- and methylene blue-insensitive; the maximal EFS-induced inhibition was increased at 1 week and 8 weeks but only in the small bowel transplantation groups to 103% +/- 5% and 95% +/- 7%, respectively, versus 72% +/- 8% in naive controls (P 相似文献