Structure-activity relationships of triterpenoid derivatives extracted from Gymnema inodorum leaves on glucose absorption.

The leaves of Gymnema inodorum (GI) have been known to be effective for some diseases including diabetes mellitus, rheumatic arthritis and gout. The crude saponin mixtures extracted from GI leaves inhibited glucose absorption in the isolated intestinal tract and suppressed the increased blood glucose in rats. In this study, we examined the relationship between chemical structure and pharmacological activity of the four components from GI leave extracts (GiA-1, GiA-2, GiA-5 and GiA-7). These components were the derivatives of (3beta,4alpha,16beta)-16,23,28-trihydroxyolean-12-en-3-yl-beta-D-glucopyranosiduroic acid. GiA-2, GiA-5 and GiA-7 that have suppressive effects on the high K+-induced contraction, an increase in deltaPD and the increased blood glucose level in the glucose tolerance test have -H at the 21st position and -CH2OH at 4beta of aglycon. On the other hand, GiA-1 that does not have any effects on the three parameters mentioned above has -H at the 21st position and -CH3 at 4beta of aglycon. In conclusion, it is suggested that the inhibitory effect of triterpenoids in Gymnema leaves on glucose absorption from the intestinal tract relies on -CH2OH at 4beta.

Effect of herb supplement on hepatic enzyme activities in ddY mice.

Plasma glucose and lipid concentrations and hepatic enzyme activities were measured in male ddY mice supplemented with the herb, Echevaria glauca, to examine the effect of herbal treatment. In mice supplemented with the herb, plasma triglyceride (TG) and free fatty acid (FFA) concentrations decreased and hepatic glycolytic enzyme and glutathione peroxidase (GSHpx) activities increased significantly compared with those in the non-treated control mice. These increases in hepatic enzyme activities were not fully dose-dependent, however the higher dose and longer duration with herb supplement induced increases in the enzyme activities. It was found that dietary herb supplement caused an acceleration of hepatic function, judged by increased activities of glycolytic enzyme and GSHpx in ddY mice.

Mechanism of relaxant response to papaverine on the smooth muscle of non-pregnant rat uterus.

In the present paper, we examined a mechanism of the papaverine induced relaxation in the smooth muscle of non-pregnant rat uterus. The hyperosmotic 65 mM KCl (H-65K+)-or oxytocin-induced contraction in the uterus was inhibited by an addition of papaverine in a concentration-dependent manner. Papaverine did not increase both cAMP and cGMP contents in the uterus in the presence of H-65K+ or oxytocin. In fura 2 loaded muscles, papaverine did not affect an increase of [Ca2+]i level by high K+ or oxytocin. In permeabilized muscles, papaverine had no effect on the Ca2+-induced contraction. H-65K+ and oxytocin increased the rate of oxygen consumption 1.8 and 1.5 times higher than that in the resting condition, respectively. The increase of oxygen consumption in the H-65K+ or oxytocin was significantly inhibited by papaverine (1-100 microM). These results suggested that papaverine inhibits smooth muscle contraction mainly by inhibition of mitochondrial respiration in rat uterus as well as guinea pig ileum, which shows a highly spontaneous activity and a highly metabolic dependency of a contraction.

Inhibitory mechanism of papaverine on the smooth muscle of guinea pig urinary bladder.

In guinea pig urinary bladder, the hyperosmotic 65 mM KCI (H-65K+)- or carbachol (CCh)-induced contraction was inhibited by an addition of papaverine in a concentration-dependent manner. The cAMP content of the muscle in the presence of H-65K+ or CCh was increased by papaverine only at the higher concentration of 100 microM, but cGMP content was not affected by papaverine. Forskolin, compared with papaverine, increased cAMP content in a concentration-dependent manner, and nitroprusside did not significantly increase cGMP content. In a fura 2 loaded muscle, papaverine did not affect an increase of [Ca2+]i level by high K+ or CCh. The increase of oxidized flavoprotein (FPox) fluorescence and muscle contraction in the presence of H-65K+ or CCh was decreased by papaverine (1 - 100 microM), and the increase of pyridine nucleotide (PNred) fluorescence was not affected by papaverine. In summary, it was concluded that papaverine induced relaxation by inhibiting mitochondrial respiration in guinea pig urinary bladder as well as ileum. Moreover, it is proposed that the mechanism of papaverine-induced relaxation in the smooth muscle, which shows predominantly a metabolic dependency on its contraction, is an inhibition of mitochondrial respiration.

The difference in the inhibitory mechanisms of papaverine on vascular and intestinal smooth muscles.

Papaverine (0.3-100 microM) more potently inhibited phenylephrine (1 microM)-induced contraction than 65 mM K+-induced contraction of the aorta, while it equally inhibited contractions induced by 65 mM K+ and carbachol (1 microM) in ileal smooth muscle. In phenylephrine-treated aorta, papaverine (1-10 microM) increased the cAMP and cGMP content. However, in carbachol-treated ileum, 30 microM papaverine partially increased the cAMP content while it maximally relaxed the preparation. In fura2-loaded aorta, papaverine (0.3-10 microM) inhibited both the contraction and the increase in intracellular Ca2+ level ([Ca2+]i) induced by phenylephrine in parallel. However, papaverine inhibited carbachol-induced contraction with only a small decrease in [Ca2+]i. Papaverine (1-30 microM) inhibited the carbachol-induced increase in oxidized flavoproteins, an indicator of increased mitochondrial oxidative phosphorylation, in ileal smooth muscle whereas it did not change the phenylephrine-induced increase in the aorta. These results suggest that papaverine inhibits smooth muscle contraction mainly by the accumulation of cAMP and/or cGMP due to the inhibition of phosphodiesterase in the aorta whereas, in ileal smooth muscle, papaverine inhibits smooth muscle contraction mainly by the inhibition of mitochondrial respiration.

Suppression of glucose absorption by extracts from the leaves of Gymnema inodorum.

Gymnema sylvestre (GS) is one of the Asclepiad strains that grows in South-east Asia. Their therapeutic effects for treating diabetes mellitus, rheumatic arthritis and gout have been well known for a long time. However, the problem is that GS suppresses sweetness and tastes bitter. For this study, we chose Gymnema inodorum (GI) instead of GS, since it has an advantage that it does not suppress sweetness nor is it bitter in taste. In this paper, effects of glucose availability of some saponin fractions (F-I to F-IV) extracted from GI leaves, which were obtained by high-performance liquid chromatography were studied on a high K(+)-induced contraction of guinea-pig intestinal smooth muscle, O2 consumption on guinea-pig ileum, glucose-evoked transmural potential difference (delta PD) of guinea-pig everted intestine and blood glucose level in glucose tolerance tests on rats. The extracts of GI leaves suppressed the intestinal smooth muscle contraction, decreased the O2 consumption, inhibited the glucose evoked-transmural potential, and prevented the blood glucose level. Our studies suggest that the component of GI inhibits the increase in the blood glucose level by interfering with the intestinal glucose absorption process.

Effects of various selective phosphodiesterase inhibitors on muscle contractility in guinea pig ileal longitudinal smooth muscle.

The effects of various selective phosphodiesterase (PDE) inhibitors on muscle contractility in guinea pig ileal longitudinal smooth muscle were investigated. 1) 3-Isobutyl-1-methyl xanthine (IBMX) or zaprinast markedly inhibited the high K(+)- or carbachol (CCh)-induced contraction and increased cGMP content of the muscle strip in a concentration-dependent manner. However, these agents only slightly increased the cAMP content. Milrinone or Ro20-1724 also slightly inhibited the high K(+)- or CCh-induced contraction and increased the cAMP content, but did not increase cGMP. 2) In a fura2-loaded muscle, IBMX or zaprinast inhibited both contractions and the increase in intracellular Ca2+ ([Ca2+]i) level induced by high K+ or CCh, although the inhibitory effect on the [Ca2+]i level was smaller than that on muscle tension. 3) In alpha-toxin-permeabilized muscles, cGMP, IBMX or zaprinast significantly inhibited the Ca(2+)-induced contraction. These results suggest that IBMX and zaprinast inhibit muscle contraction in the ileal longitudinal smooth muscles mainly through an increase in cGMP and the inhibitory mechanism of IBMX or zaprinast is involved in the decreases in the [Ca2+]i level and sensitivity of contractile elements to Ca2+.

Suppression of glucose absorption by some fractions extracted from Gymnema sylvestre leaves.

Extracts containing gymnemic acids, which were extracted from the leaves of Gymnema sylvestre (GS) as nine fractions, were evaluated for their effects on a high K(+)-induced contraction of guinea-pig ileal longitudinal muscles, on glucose transport mediated by the difference of glucose-evoked transmural potential difference (delta PD) in the inverted intestine of guinea-pig and rat, and on blood glucose in rat. Among nine fractions obtained by high performance liquid chromatography from the extract, f-2 and f-4 strongly suppressed the high K(+)-induced contraction of the ileal muscle, f-3 and f-5 did so moderately, and f-8 and f-9 did so weakly, whereas the other fractions did not affect it. The degree of suppression of high K(+)-induced contraction by f-2 at 74% was almost the same as that of f-4 at 67%, at concentrations of 0.1 mg/ml. The suppressed contraction by f-2 or f-4 was recovered by adding 5.5 mM pyruvate. The delta PD increased by 5.5 mM glucose in the inverted intestines of guinea-pig and rat were equally suppressed by 0.1 mg/ml of f-2 or f-4 to 40%. In a rat sucrose tolerance test, f-2 and f-4 suppressed the elevation of blood glucose level. Both f-2 and f-4 suppressed the contraction of guinea-pig ileal longitudinal muscle, interfered with the increase in delta PD induced by glucose in the inverted intestines of guinea-pig and rat, and inhibited the elevation of blood glucose level. In conclusion, it is suggested that some of the extracts containing gymnemic acids from GS leaves suppress the elevation of blood glucose level by inhibiting glucose uptake in the intestine.

Decreased pulmonary arterial endothelium-dependent relaxation in heartworm-infected dogs with pulmonary hypertension.

OBJECTIVE: To investigate the contractility of pulmonary arterial smooth muscle and the relation between pulmonary hypertension and endothelium-derived relaxing factor in canine heartworm disease. ANIMALS: 18 noninfected control and 9 heartworm-infected dogs. PROCEDURE: Mean pulmonary arterial blood pressure was measured in vivo, and tension of pulmonary arterial strips was measured by use of the isometric tension method. RESULTS: After phenylephrine (10(-5)M)-induced contraction of the pulmonary vascular smooth muscle, carbamylcholine chloride (CCh, 10(-6)M) caused more relaxation of the vascular smooth muscle of noninfected, dogs than that of heartworm-infected dogs. Furthermore, the degree of CCh-induced relaxation was inversely correlated with mean pulmonary arterial blood pressure in the noninfected and the heartworm-infected dogs. The CCh-induced relaxation was inhibited by pretreatment with NG-nitro-L-arginine methyl ester hydrochloride (10(-5)M), and in reversed dose-dependent manner by L-arginine (10(-4) to 3 x 10(-2)M). Sodium nitroprusside (10(-8) to 10(-5)M) caused a dose-dependent relaxation in all vessels, and there was no significant difference in the relaxation responses in both groups except at 10(-7)M for vessels with intact endothelium from noninfected dogs. CONCLUSION: The depression of endothelium-dependent relaxation is correlated with the pulmonary arterial blood pressure in heartworm-infected dogs, suggesting that the decrease is one of the essential factors for the genesis of pulmonary hypertension in canine filariasis.

[Inhibitory effects of glucose utilization by gymnema acids in the guinea-pig ileal longitudinal muscle].

Two substances identified as ((3 beta, 4 alpha, 16 beta, 21 beta, 22 alpha)-21-tigloxy-16, 22, 23, 28-tetrahydroxyolean-12-en-3-yl-beta D-glucopyranosiduronic acid) (GA1) and ((3 beta, 4 alpha, 16 beta, 21 beta, 22 alpha)-21-(2-methylbutyroxy)-16, 22, 23, 28-tetrahydroxyolean-12-en-3-yl-beta-D-glucopyranosiduronic acid) (GA2) identified among the gymnemic acids are triterpene glycosides extracted from Gymnema sylvestre leaves. We examined the effects of GA1 or GA2 on high K(+)-induced contraction in the guinea-pig longitudinal muscle. A sustained muscle contraction induced by hyperosmotically added 65.4 mM KCI (H-65K+) was suppressed by GA1 or GA2 (7.7 x 10(-5) M). Simultaneous measurements of reduced pyridine nucleotide (PNred) or oxidized flavin protein (FPox) by the fluorescence technique and of contractile force revealed that GA1 and GA2 reduced the increase of PNred fluorescence and contractile force induced by H-65K+, whereas FPox fluorescence induced by it further increased. Reduced muscle contraction induced by GA1 or GA2 was restored by 5.5 mM pyruvate. Simultaneous measurements of intracellular Ca2+ [Ca2+]1 level and contractile force indicated that [Ca2+]1 level, which increased by H-65K+, hardly changed with GA1 and GA2. In summary, both GA1 and GA2, which are among the gymnemic acids, suppressed high K(+)-induced contraction in the guinea-pig ileal longitudinal muscle. The difference between these two gymnemic acids was not significant. The inhibitory effect of GA1 and GA2 on smooth muscle were assumed to be a result of inhibiting glucose uptake, which is an energy source of the muscle, whereas the inhibitory mechanisms were probably not mediated by Ca2+.

Effect of phorbol ester, 12-deoxyphorbol 13-isobutylate (DPB), on muscle tension and cytosolic Ca2+ in rat anococcygeus muscle.

Effects of phorbol ester, 12-deoxyphorbol 13-isobutyrate (DPB), on muscle tension and cytosolic Ca2+ ([Ca2+]i) level was investigated in rat anococcygeus muscle in comparison with other smooth muscles. 1) DPB (10(-6) M) induced a large contraction and an elevation of [Ca2+]i level in rat aorta and small and rhythmic changes in tension and [Ca2+]i level in guinea pig ileum. However, DPB did not change either of the parameters in rat anococcygeus muscle. 2) DPB caused tension development without changing the [Ca2+]i level elevated by high K+, ionomycin or beta-escin in the anococcygeus muscle. 3) In the beta-escin permeabilized muscles of guinea pig ileum and urinary bladder, rabbit mesenteric artery and rat anococcygeus muscle, DPB enhanced the Ca(2+)-developed tension. Moreover, the enhancement was inhibited by H-7 (3 x 10(-5) M). 4) DPB did not cause muscle tension to develop in the muscle of rat aorta, guinea pig ileum and rat anococcygeus muscle, pretreated with phorbol 12-myristate 13-acetate for 24 hr. In conclusion, DPB showed different contractile effects on the aorta, ileum and anococcygeus muscle, respectively. The initiation of muscle tension by DPB probably requires [Ca2+]i and the DPB-induced enhancement may be due to a Ca2+ sensitization of contractile elements in the anococcygeus muscle. Therefore, the difference between the DPB-induced response of the anococcygeus muscle and those of the other muscles seems to be due to a different Ca2+ movement caused by DPB. Moreover, it is suggested that DPB develops muscle tension by increasing [Ca2+]i and enhances it through the mediation of protein kinase C in the anococcygeus muscle as well as the other smooth muscles.

Effects of phenylephrine on the contractile tension and cytosolic Ca2+ level in rat anococcygeus muscle.

A contractile property of phenylephrine (PE), alpha 1 agonist, on rat anococcygeus muscle was compared with that on rat aorta by simultaneously measuring changes in intracellular Ca2+ ([Ca2+]i) level and muscle tension. (1) PE (0.1-30 microM) and high K+ induced a sustained increases in [Ca2+]i level and muscle tension of both the muscles. (2) An application of verapamil (10 microM) and EGTA (4 mM) decreased the PE- or high K(+)-increased tension and [Ca2+]i level in both the muscle, respectively. (3) A cumulative application of PE or high K+ to anococcygeus muscle and aorta exhibited a positive relationship between [Ca2+]i and developed tension. The developed tension by PE was greater than that by high K+ at the same level of [Ca2+]i only in the aorta. A difference of regression slopes in the relationship between [Ca2+]i level and muscle tension under PE- and high K(+)-treatments in aorta was significant, but that in anococcygeus muscle was not. (4) An application of PE to anococcygeus muscle in Ca2+ free medium elicited a small transient contractile tension and increase in [Ca2+]i level, but that to aorta showed a large and transient increase in both the parameters. (5) Phorbol ester, DPB (1 microM), did not affect muscle tension or [Ca2+]i level in anococcygeus muscle, but DPB induced greater increases in aorta. (6) An application of PE (10 microM) with GTP produced a left shift in the pCa-tension curve in the beta-escin-permeabilized fiber of the anococcygeus muscle. In summary, it is suggested that the sustained contraction induced by PE in anococcygeus muscle is involved with the increases in [Ca2+]i which is due to Ca2+ influx mediated by alpha 1 receptor, but scarcely to Ca2+ release from the intracellular storage, and that an increase in Ca2+ sensitivity to PE is found only in the permeabilized anococcygeus muscle. The Ca(2+)-independent contractile mechanism in PE response as seen in aorta is probably to be absent in anococcygeus muscle. Moreover, it seems that the effect of the drug acting protein kinase C on anococcygeus muscle is extremely lesser than that on aorta.

The inhibitory effect of Li+ on contractile elements of intestinal smooth muscle.

The mechanism of the inhibitory effect of Li+ on contraction was examined in guinea pig ileal longitudinal smooth muscle. Li(+)-substitution (68.4 mM) reversed contractions induced by high K+ (45.4 mM), carbachol (1 microM) and histamine (1 microM) without changing the cytosolic Ca2+ level. Li+ also had no effect on the increase in 45Ca2+ uptake stimulated by high K+. High K+ transiently increased myosin light chain (MLC) phosphorylation, reaching a peak at 6-9 sec. Li(+)-substitution inhibited the high K(+)-induced MLC phosphorylation. In permeabilized ileal strips, contraction induced by 1 microM Ca2+ was inhibited by 10 mM Li+. The inhibitory effect was antagonized by increasing the concentration of Ca2+ or calmodulin. In the permeabilized muscle in which MLC was previously thiophosphorylated with 1 mM ATP gamma S and 3 microM Ca2+, ATP induced contraction in Ca2+ free buffer. Li+ added during this contraction did not show an inhibitory effect. In contrast, when 30 mM Li+ was added during the thiophosphorylation, the contraction induced by the subsequent addition of ATP was inhibited. Li+ (30 mM) changed neither the rate of relaxation induced by removing external Ca2+ in permeabilized muscle nor the rate of dephosphorylation of MLC induced by crude phosphatase extracted from the ileum. Li+ (15 mM), on the other hand, inhibited the rate of phosphorylation of MLC caused by crude MLC kinase extracted from the ileum. Li+ did not inhibit the calmodulin activity as measured with the (Ca2+ +Mg2+)-ATPase activity of the erythrocyte membrane. These results suggest that the inhibitory effect of Li+ on contractions is attributable to the inhibition of MLC kinase in guinea pig ileum.

Inhibitory effects of tiamulin on contractile and electrical responses in isolated thoracic aorta and cardiac muscle of guinea-pigs.

The inhibitory effect of tiamulin, an antibiotic produced by Pleurotus mutilis, on contractile and electrical responses in isolated thoracic aorta and cardiac muscle of guinea-pigs was studied. In the thoracic aorta, tiamulin with an IC50 of 9.7 x 10(-6) M inhibited sustained contractions induced by isosmotically added 60 mM KCl. The inhibitory effect of tiamulin on a Ca(2+)-induced contraction in a depolarized muscle was competitively antagonized by raising external Ca2+ concentration. Bay K 8644 (10(-7) M) antagonized tiamulin's inhibition of the Ca(2+)-induced contraction. Tiamulin (2 x 10(-5) M) decreased the elevated cytoplasmic Ca2+ level measured by the fura 2 AM method in the depolarized muscle. In high K(+)-isoprenaline-treated left atria, tiamulin (2 x 10(-5)-2 x 10(-4) M) produced negative inotropic effects. On the other hand in the membrane action potential of papillary muscles, tiamulin (2 x 10(-6)-2 x 10(-4) M) produced decreases in action potential and durations and 2 x 10(-4) M tiamulin depressed the slow response action potential in depolarized muscles. Tiamulin produced prolongations of the PR interval in ECG, negative chrono- and inotropic effects, and an increase in perfusion flow in guinea-pig isolated and perfused hearts. These effects of tiamulin on the aorta or cardiac muscle were similar to those of verapamil and nifedipine. These results suggest that both the inhibitory action of tiamulin on the high K(+)-induced contraction in the aorta and the negative inotropic effect of tiamulin on the cardiac muscle are due to an inhibition of Ca2+ entry through the voltage-dependent Ca2+ channels of cells of both these muscles.

The inhibitory effect of tiamulin on high K(+)-induced contraction in guinea pig intestinal smooth muscle.

Tiamulin with an IC50 of 1.7 x 10(-6) M inhibited both the rapid and sustained contractions induced by hyperosmotically added 60 mM K+ (Hyper 60 K+) without changing the membrane potential in the intestinal muscle. Tiamulin inhibition (2 x 10(-6)-2 x 10(-5) M) of the Ca(2+)-induced contraction in depolarized muscle was competitively antagonized by raising external Ca2+. Tiamulin (2 x 10(-5) M) slightly affected the Hyper 60 K(+)-induced phasic contraction under hypoxia and the carbachol-induced phasic contraction. Moreover, tiamulin (2 x 10(-5) M) inhibited the Hyper 60 K(+)-induced contraction with decreasing [Ca2+]cyt level. Although the inhibitory effect of 10(-7)-10(-5) M monesin, an inhibitor of mitochondrial respiration, on the Hyper 60 K(+)-induced contraction was reduced under hypoxia, the effect of tiamulin (2 x 10(-7)-2 x 10(-4) M) was not modified. Tiamulin changed neither the intracellular Na+ and K+ content of the depolarized muscle nor the Ca(2+)-induced contraction in the chemically skinned preparations. These results suggest that the inhibitory action of tiamulin on the Hyper 60 K(+)-induced tonic contraction is possibly due to the competitive inhibition of Ca2+ entry through the voltage-dependent Ca2+ channel of the intestinal smooth muscle cell.

Decrease in muscle tension and reduced pyridine nucleotides of the guinea pig ileal longitudinal smooth muscle in high K+,Na(+)-deficient solution.

In the present experiment, we studied the inhibitory mechanism of Na+ depletion on high K(+)-induced contraction by simultaneously measuring reduced pyridine nucleotides (PNred) or oxidized flavoproteins (FPox) fluorescence and contractile tension of the guinea pig ileal longitudinal muscle. Tension, PNred and FPox were all reversibly increased by the addition of hyperosmotic 65 mM KCl (H-65K+). A high K+, Na(+)-deficient (Iso-154K+) solution induced a contraction followed by a gradual relaxation and gradually decreased PNred fluorescence. A hyperosmotic addition of NaCl to the Iso-154K+ solution prevented the decreases in tension and PNred fluorescence. Addition of pyruvate or oxaloacetate restored the decrease in Iso-154K(+)-induced contraction, but not the decrease in PNred fluorescence. In contrast to the PNred fluorescence, an application of the Iso-154K+ solution increased the FPox fluorescence which was not significantly changed by an addition of NaCl, pyruvate or oxaloacetate. These results suggest that the inhibitory mechanism of Na+ depletion on the Iso-154K(+)-induced contraction is an inhibition of glucose utilization.

A change in inhibitory mechanism of Na+ deficiency on high K(+)-induced contraction in rat uterus with the progress of pregnancy.

In the present paper, effects of high K+/Na+ deficient solution on the rat uterus with the progress of the pregnancy were examined on the mechanical response and wet weight. The progress of pregnancy was divided in four stages, early stage (Day 4 and 5 of pregnancy), middle stage (Day 8-10), late stage (Day 14 and 15) and end stage (Day 21). In the early stage muscle, an isosmotically substituted high K+/Na+ deficient (iso-154K+) solution induced a large contraction followed by a decrease in tension level, though a hyperosmotic KCI addition induced a large sustained contraction. Similar results were shown in muscles of the middle and late stages. However, a maximum tension level and a subsequent inhibition by the iso-154K+ solution in the end stage muscle were smaller than those of other stages. On the other hand, iso-154K+ solution remarkably increased the relative cellular water content in the early or middle stage muscle, but moderately in the late or end stage one. In the muscle of all stages, a hyperosmotic addition of sucrose reversed the inhibition of muscle tension and the cell swelling by the iso-154K+ solution. Moreover, a substitution of more impermeable anion (C2H5COO-) for Cl- in the iso-154K+ solution decreased the inhibition of the contraction in the early stage muscle, but increased it in the end stage one. The substitution for Cl- with more permeable anion (NO3- or I-) produced a greater inhibition of contraction in all stage muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory effect of lithium on muscle contractions caused by various stimulants in guinea-pig ileum.

The tonic contractions induced in the guinea-pig ileal longitudinal muscle by 60 mM KCl, carbachol, histamine or A23187 were inhibited similarly by Li+-substituted solution. There was a good correlation between the Li+-induced inhibition of contractions induced by these stimulants and the intracellularly accumulated Li+ content. In the experiment with fura-2, Li+-substituted solution inhibited the high-K+-induced contraction without decreasing the cytosolic Ca2+ level elevated by high-K+ solution. The concentration-response curve for Ca2+ in the skinned fiber was shifted to the right by pretreatment with Li+-substituted solution. These results suggest that the inhibitory mechanism of Li+ on the contractions by various stimulants partly involves the direct inhibition of the contractile proteins in the guinea-pig ileal longitudinal muscle.

The effect of trifluoperazine on muscle tension and cytoplasmic Ca2+ level in guinea pig ileum.

In guinea pig ileal muscle strips, trifluoperazine (TFP) inhibited the high K+-induced contraction with an IC50 of 1.9 microM and the Ca2+-induced contraction in skinned fiber with an IC50 of 44 microM. TFP decreased the high K+-induced increase in cytoplasmic Ca2+ level at the concentration 3 microM, which did not inhibit the contraction in skinned fiber. It is suggested that the inhibitory effect of TFP on the high K+-induced contraction is mainly due to the decrease in cytoplasmic Ca2+.