Inhibition Of Contractile Activity Research Articles

Peppermint and caraway oils have muscle inhibitory and pro-secretory activity in the human intestine in vitro.

Herbal medicinal products with a broad activity spectrum may be promising alternatives to treat functional gastrointestinal disorders (FGD). Menthacarin® is a drug with a fixed combination of peppermint and caraway oils, which is clinically used to treat FGD-associated symptoms. We studied the effects of peppermint and caraway oils on contractile and secretory activity in 255 human small and large intestinal preparations derived from surgical resections (73 patients). Motility was recorded in circular smooth muscle strips and secretion with the Ussing chamber-voltage clamp technique. Electrical field stimulation evoked nerve induced contractile responses. KEYRESULTS: Peppermint and caraway oil concentrations dependently inhibited muscle contractility as indicated by sustained muscle relaxation and decrease in phasic contractility. These effects occurred in small and large intestinal preparations with IC50 values ranging between 17 and 90µg/mL for peppermint oil and between 7 and 127µg/mL for caraway oil. Neither peppermint nor caraway oil influenced the nerve evoked contractile response. The inhibition of contractile activity, but not the muscle relaxation, was prevented by the L-type calcium channel activator Bay K8644 but not by the neurotoxin tetrodotoxin. Both peppermint oil and caraway oil increased epithelial secretion, which remained in tetrodotoxin. The findings revealed a strong muscle inhibitory and pro-secretory action of peppermint and caraway oils at clinically relevant concentrations. Both actions were nerve-independent. The inhibition of contractility was mediated by inhibition of L-type calcium channels. The effects on muscle and epithelial activity may contribute to the beneficial effects observed in patients with FGD.

Su2040 Interaction Between GPR119 and CB1 Receptors in the Inhibition of Contractile Activity in Mouse and Human Gut

Su2040 Interaction Between GPR119 and CB1 Receptors in the Inhibition of Contractile Activity in Mouse and Human Gut

Changes in Contractile Activity of the Duodenum, Jejunum, and Ileum under Conditions of Psychogenic Stress in Rabbits

Psychogenic stress in rabbits caused by fixation of the animal to a frame was accompanied by an increase in duodenal contractile activity. In the jejunum, initial inhibition of motor activity gave way to activation more pronounced in the proximal part. In both parts of the ileum, inhibition of contractile activity was noted. A proximodistal gradient of the excitatory and inhibitory effects on the motility of the small intestine was demonstrated.

Inhibition of Contractile Activity During Postconditioning Enhances Cardioprotection by Restoring Sarcolemmal Dystrophin Through Phosphatidylinositol 3-Kinase

Although ischemic postconditioning (IPost) confers cardioprotection by protecting the mitochondria though the activation of phosphatidylinositol 3-kinase (PI3K), a potential drawback of IPost is impairment of aerobic ATP generation during reperfusion by repeated ischemia. This decrease in ATP might inhibit the restoration of sarcolemmal dystrophin, which is translocated during ischemia, and render cardiomyocytes susceptible to contraction-induced oncosis. Isolated rat hearts were subjected to 30 min ischemia and 120 min reperfusion. IPost induced by 20 cycles of 10-s reperfusion and 10-s ischemia enhanced the activation of PI3K as evidenced by the increased phosphorylation of Akt, but had no effect on myocardial ATP, restoration of sarcolemmal dystrophin, or cardiomyocyte oncosis during IPost. Administration of the contractile blocker, 2,3-butanedione monoxim (BDM), during IPost increased myocardial ATP and facilitated the redistribution of dystrophin to the sarcolemma. This led to reduced cardiomyocyte oncosis and infarct size, and improved the left ventricular function. The anti-oncotic effect of BDM occurred without changing the anti-apoptotic effect of IPost. The PI3K inhibitor, LY294002, prevented the phosphorylation of Akt, decreased the recovery of ATP and restoration of sarcolemmal dystrophin, and blocked the anti-oncotic and anti-apoptotic effects of IPost. These results suggest that the inhibition of contractile activity during IPost prevents cardiomyocyte oncosis and enhances cardioprotection through PI3K-dependent restoration of sarcolemmal dystrophin.

Mechanism for the Inhibition of Contractile Activity of the Gastric Antrum and Pylorus in Rabbits during Psychogenic Stress

Psychogenic stress in rabbits (fixation to a frame) was accompanied by the inhibition of contractile activity of the gastric antrum and pylorus. These changes persisted during blockade of muscarinic receptors, nicotinic receptors, alpha(2)-adrenoceptors, and beta(1)/beta(2) adrenoceptors. A stress-induced decrease in gastric motor activity was mediated by the nonadrenergic noncholinergic mechanism. It resulted from the influence of a hormonal stress factor on the stomach, which was probably realized through nonadrenergic inhibitory neurons of the enteric nervous system.

Excitatory and inhibitory 5-hydroxytryptamine (5-HT) receptors expressed in the isolated porcine uterine muscles

5-Hydroxytryptamine (5-HT) receptors mediating excitatory and inhibitory actions of 5-HT on contractility of uterine strips from non-pregnant pigs were characterized. Expression of 5-HT 2A and 5-HT 7 receptors was examined by molecular biological study. 5-HT-containing cells were observed immunohistochemically. In the spontaneously contracting uterine circular muscle layers, 5-HT caused inhibition of contractile activity. SB269970 (5-HT 7 receptor antagonist, 10 nM) shifted the concentration-inhibition curve of 5-HT to the right, but higher concentrations of SB269970 (100 nM–1 μM) changed the monophasic curve to a biphasic curve (mixture of excitatory and inhibitory responses to 5-HT). Addition of ketanserin (5-HT 2 receptor antagonist, 10 nM–1 μM) decreased the excitatory effects of 5-HT. 5-HT was less effective in inhibiting the spontaneous contraction in the longitudinal muscles. Ketanserin enhanced the inhibitory responses and SB269970 reversed the inhibitory responses to excitatory responses. In the presence of SB269970, α-methyl-5-HT was equipotent to 5-HT in increasing contractility of longitudinal muscle and ketanserin competitively inhibited the responses to α-methyl-5-HT (pK d = 8.78). Muscle layer-dependent expression of both 5-HT 2A receptor and 5-HT 7 receptor mRNAs in the porcine uterine muscle layers was demonstrated by RT-PCR and real-time PCR. 5-HT immunoreactivity was detected only in uterine gland cells, which were localized near the uterine circular muscle layers. In the longitudinal and circular muscle layers with endometrium, compounds 48/80 and ketanserin did not change the spontaneous contractility, but SB269970 significantly increased the contractile activity of the circular muscle. In conclusion, excitatory 5-HT 2A and inhibitory 5-HT 7 are present in the uterus of non-pregnant pigs. Endogenous 5-HT containing cells are mainly present in uterine glands of the pig. The possible roles of 5-HT and its receptors in regulation of porcine uterine spontaneous contractility are discussed.

Nitrergic mechanisms mediating inhibitory control of longitudinal smooth muscle contraction in mouse small intestine

Studies using genetic manipulation to investigate mechanisms of control of physiologic function often necessitate mouse models. However, baseline functional analysis of murine small intestinal motility has not been well defined. Our aim was to define nitrergic mechanisms regulating mouse small intestinal longitudinal muscle. Endogenous nitric oxide (NO) is an important neuroregulatory substance mediating inhibition of contractile activity in murine small bowel. Full-thickness muscle strips of jejunum and ileum from C57BL/6 mice (n > or =6 mice) cut in the direction of longitudinal muscle were studied. Numerous conditions of electrical field stimulation (EFS) and effects of exogenous NO and NO donors were studied in the absence or presence of inhibitors of nitric oxide synthase (NOS) and 1H-[1,2,4]-oxadiazaolo-[4,3-a]-quinoxalin-1-one (ODQ), a downstream inhibitor of guanylyl cyclase. EFS induced a frequency-dependent inhibition of contractile activity in both jejunum and ileum (P < 0.05). As the voltage of EFS was increased, inhibition turned to excitation in the jejunum; in contrast, the ileum demonstrated a voltage-dependent increasing inhibition (P < 0.05 each). EFS-induced inhibition was blocked by NOS inhibitors and ODQ. NO donors inhibited spontaneous contractile activity abolished by ODQ. NO appears to be an endogenous inhibitory neurotransmitter in murine longitudinal small bowel muscle. Nitrergic mechanisms mediate inhibitory control of murine longitudinal small intestinal muscle. Differences exist in neuroregulatory control between jejunum and ileum that may be related to their known difference in motor patterns.

Involvement of a nitric oxide-cyclic guanosine monophosphate pathway in control of Fallopian tube contractility

Fallopian tube smooth muscle contractions are physiologically related to transport of the ovum within the oviduct. Nitric oxide (NO) has proved to be a mediator of tubal contractility. The main pathway by which NO exerts its relaxing effect on tubal contractions has not been fully elucidated. NO-mediated effects may be cyclic guanosine monophosphate (cGMP)-dependent or cGMP-independent. The objective of the present study was to investigate whether a NO-cGMP pathway is present in the Fallopian tube and, if present, to examine whether this pathway is involved in tubal contractility. Tubal smooth muscle strips were mounted in organ baths for measurement of tissue cGMP and for isometric recording of contractile activity. Following administration of the NO donor spermine NONOate a more than three-fold increase in tissue levels of cGMP was measured. Pretreatment with inhibitors of cGMP production prior to administration of spermine NONOate resulted in similar levels of cGMP as found in strips exposed to only plain buffer solution. Administration of spermine NONOate to muscle baths resulted in a significant inhibition of contractile activity, while pretreatment with inhibitors of cGMP production almost eliminated the relaxing effect of the NO donor. This study showed that a NO-cGMP pathway is present in the Fallopian tube and that the pathway is involved in Fallopian tube contractility.

Localization of cardiac (alpha)-myosin heavy chain mRNA is regulated by its 3' untranslated region via mechanical activity and translational block.

We have altered the spontaneous contractile activity of neonatal cardiac myocytes in culture to investigate the re-lationship between mechanical forces, myofibril assembly, and the localization and translation of (alpha)-myosin heavy chain mRNA. Immunofluorescence and in situ hybridization techniques revealed that contracting myocytes display well aligned myofibrils and a diffuse distribution of (alpha)-myosin heavy chain mRNA. Inhibition of contractile activity with the calcium channel blocker verapamil (10 microM) resulted in myofibril disassembly and a perinuclear mRNA distribution within six hours. There was a significant decrease (P<0. 05) of mRNA levels, 5 to 15 micron away from the nucleus following 6 hours of verapamil treatment compared with control cells. Inhibition of protein synthesis with cycloheximide (10 microM) also resulted in perinuclear mRNA localization despite having little effect on contractile activity or myofibril assembly. To determine if the 3' untranslated region of (alpha)-myosin heavy chain mRNA was sufficient for localizing the entire message, a chimeric construct composed of beta-galactosidase coding region followed by (alpha)-myosin heavy chain 3' untranslated region sequences was made as a reporter plasmid and transfected into cultured myocytes. A perinuclear accumulation of ss-galactosidase was exhibited in many of the contractile arrested cells (48.3+/-2.4%, n=7). In contrast, significantly fewer (P<0.05) contracting control (29.1+/-3.3%, n=7) and strongly contracting, isoproterenol-treated cells (27.2+/-6.1%, n=3) exhibited a perinuclear localization of protein. The distribution of the reporter protein was not affected by the contractile state in cells transfected with a constitutively translated 3'UTR. We propose that mechanical activity of neonatal cardiac myocytes regulates the intracellular localization of alpha-myosin heavy chain mRNA via the 3' untranslated region mediated by an initial block in translation.

Effect of extrinsic denervation in a canine model of jejunoileal autotransplantation on mechanical and electrical activity of jejunal circular smooth muscle.

Little is known about the acute and chronic effects of the intestinal transplantation on smooth muscle contractile physiology. Our aim was to determine the effects of the denervation necessitated by jejunoileal autotransplantation on membrane potential and contractile activity. Six dogs underwent a model of jejunoileal autotransplantation that specifically avoids ischemia/reperfusion injury (by maintaining blood flow to the gut during the "transplantation" procedure). Strips of jejunal circular muscle were studied sequentially before and 2 and 8 weeks after denervation by recording mechanical and intracellular electrical activities in vitro. The amplitude of spontaneous contractions (X +/- SD) was increased (P < 0.05) at 2 compared to 0 weeks (126 +/- 19 vs 77 +/- 32 g/g; P < 0.05) but markedly decreased at 8 weeks (7 +/- 2 g/g). Contraction frequency, resting membrane potential, and amplitude of slow waves were unchanged across these time points. Bethanechol (10(-7)-10(-4) M) and substance P (10(-8)-10(-6) M) dose-dependently increased contractile activity at all time points, but the absolute change in amplitude was decreased at 8 weeks. The amplitude of inhibitory junction potentials (IJPs) and duration of inhibition of contractile activity in the presence of cholinergic and adrenergic blockade increased at 2 and 8 weeks; off-contraction amplitude was decreased at 8 weeks (P < 0.05). These effects may occur via changes in neurotransmitter release, changes in regulation of membrane receptors, or alteration of characteristics of the membrane threshold potential.

Inhibition of contractile activity of cultured rat cardiomyocytes in response to reduced oxygenation

Hypoxia completely abolishes the spontaneous contractile activity of cardiomyocytes. Once the original oxygenation is restored, the cells regain their functional activity, which exceeds the control level (particularly after a 2-h hypoxia). It can be assumed that the rapid restoration of cardiomyocyte functional activity is due to the preservation of a sufficiently high oxygen content and to the compensatory activation of glycolysis.

Inhibitory and excitatory mechanisms of neurotensin action in canine intestinal circular muscle in vitro.

The effect of neurotensin on canine ileal circular muscle devoid of myenteric plexus was investigated using single and double sucrose gap techniques. Similar results were obtained with microelectrode techniques. Neurotensin caused a temperature-sensitive and dose-dependent biphasic response, an initial hyperpolarization associated with inhibition of contractile activity, followed by an excitatory phase, usually consisting of spike discharge and tonic and phasic contractions, for which depolarization was not required. Neither response was affected by tetrodotoxin, phentolamine, propranolol, or atropine. The hyperpolarization was associated with decreased membrane resistance, blocked by 10(-7) M apamin, and converted to tonic depolarization by apamin (10(-6) M). Tachyphylaxis to neurotensin occurred when the stimulation interval was less than 20 min. After Ca2+ depletion, depolarization was observed instead of the hyperpolarization; this depolarization was not affected by nitrendipine and was gradually abolished with repetitive stimulation at 20-min intervals. When Ca2+ was present, nifedipine did not alter the hyperpolarizing phase of the response but inhibited spiking and blocked all contractions. The excitatory phase of the response was enhanced by Bay K-8644. Neuromedin N elicited a response identical with that of neurotensin. The responses of the two peptides were completely cross tachyphylactic. Inhibitory junction potentials were not affected by neurotensin tachyphylaxis. It is concluded that neurotensin and neuromedin N activate apamin-sensitive, calcium-dependent potassium channels in circular muscle, causing membrane hyperpolarization and inhibition of muscle contraction. Release of intracellular calcium is involved in the activation of these potassium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Contractile activity modulates myosin heavy chain-beta expression in neonatal rat heart cells

To determine whether spontaneous contractile activity affected the expression of myosin heavy chain isoenzymes in cultured neonatal rat heart cells, ventricular myocytes were isolated from 2-day-old rat pups by collagenase digestion and cultured for 24-96 h in the presence and absence of verapamil (10 microM), KCl (50 mM), or dihydropyridine receptor antagonists that produced contractile arrest. Inhibition of spontaneous contractile activity was associated with significant reductions in total myosin heavy chain (MHC) content and synthetic rates. Electrophoretic analysis of MHC isoenzymes indicated that MHC-beta protein rapidly disappeared from arrested cells, whereas MHC-alpha isoenzyme levels were less affected. In association with these protein changes, mRNA transcript levels for MHC-beta were markedly reduced in quiescent cells, whereas mRNA transcript levels for several other contractile protein genes were relatively less affected. Inhibition of contractile activity and MHC-beta expression were reversible upon removal of the arresting agents. Furthermore, the decrease in MHC-beta mRNA levels in arrested myocytes could be prevented by direct activation of protein kinase C with phorbol 12-myristate 13-acetate (without restoration of contractile activity). Conversely, MHC-beta mRNA levels in beating cells were reduced by treatment with staurosporine (a selective protein kinase C inhibitor). Thus contractile arrest (produced by either L-channel blockade or membrane depolarization) inhibited the accumulation of MHC-beta in cultured neonatal rat heart cells via a pretranslational mechanism. These effects may occur in response to the modulation of signaling system(s) involving mechanical "stretch" transduced via protein kinase C.

Characterization of myometrial desensitization to β-adrenergic agonists

Continuous exposure of ovine myometrial strips exposed to isoproterenol (10 microM) resulted in only transient inhibition with contractions returning within 60 min. Rechallenging these strips with isoproterenol failed to induce inhibition, confirming the occurrence of desensitization. In contrast, exposure of myometrial tissue to isoproterenol for only 5 min did not result in desensitization. Myometrial strips exposed to isoproterenol demonstrated a significant increase in cAMP content associated with inhibition of contractile activity and a subsequent fall in cAMP content upon desensitization. Elevation of endogenous cAMP levels by either inhibition of cAMP-dependent phosphodiesterase activity (0.5 mM isobutylmethylxanthine, in ovine strips) or direct activation of adenylyl cyclase (10 microM forskolin, in rat strips) induced a rapid and significant inhibition of myometrial contractile activity in desensitized tissue. Scatchard analysis of the binding of the beta-adrenoceptor antagonist, [125I]iodocyanopindolol, revealed a significant reduction in the concentration of beta-adrenergic receptors (but no change in binding affinity) in desensitized myometrial tissue. Incubation of desensitized tissue with fresh buffer for 3 h induced only a partial recovery in responsiveness to isoproterenol. These data suggest that prolonged, but not acute, exposure of the myometrium to beta-adrenergic agonists induces a state of desensitization that is associated with a down-regulation of beta-adrenoceptors but maintenance of postreceptor function.

The inhibition of glandular kallikrein by peptide analog antagonists of bradykinin

Bradykinin sequence analog receptor antagonists exhibit at their carboxyl termini features which contribute to the affinity of peptide inhibitors of glandular kallikreins. These features include a preference for L-Arg over L-Lys at position P1 and bulky D-amino acids at P3. There is minimal steric restriction at P2. Three representative receptor antagonists were examined for their capacity to inhibit the amidolytic activity of human urinary kallikrein (HUK). The K i values for B4307 (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg), B4308 (Lys-Lys-Arg-Hyp-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg), and B3852 (Arg-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg) are 0.5, 0.3 and 2.5 μM, respectively. B4308 and B3852 were also shown to inhibit rat urinary kallikrein with K i's of 1.0 and 5.5 μM. In the estrous rat uterus assay, 0.4 to 1.6 μM quantities of B4308 gave 5 to 10 times as much inhibition of contractile activity when added at the beginning of the incubation of HUK with human low molecular weight kininogen than when added upon addition of the mixture to the organ bath. These antagonists may inhibit the kallikrein-kinin system not only by blocking the binding of kinins to their receptor(s) but also by inhibiting the release of kinins from kininogens.

Effects of prazosin and indomethacin on the alpha-adrenergic stimulation of rabbit myometrium.

The effect of norepinephrine (NE) stimulation of near-term pregnant rabbit myometrium was studied by comparing cumulative dose-response curves for NE and NE with prazosin or indomethacin. Prazosin blocked the stimulatory effects of NE. Indomethacin pretreatment resulted in attenuation, but not suppression of contractile activity. Myometrial activity was associated with a progressive increase in the synthesis of prostaglandin (PG) F2 alpha. Our observations suggest that alpha-adrenergic agonists have some myometrial stimulating effect independent of PG production.

Characterization of putative beta-adrenoceptors in the myometrium of the pregnant ewe: correlation between the binding of [3H] dihydroalprenolol and the inhibition of myometrial contractility in vitro.

beta-Adrenoceptors in the myometrium of the pregnant ewe were studied both functionally and by radioligand binding techniques using [3H] dihydroalprenolol (DHA). Spontaneous contractile activity in vitro was inhibited by beta-adrenoceptor agonists in a stereoselective manner; the order of potency suggested a beta 2-adrenoceptor was involved. The effects of salbutamol were antagonized competitively by propranolol but the antagonism demonstrated by atenolol and ICI 118,551 (beta 1- and beta 2-selective, respectively) was complex. DHA binding was saturable, rapidly reversible, stereoselective and appeared to occur to a single class of noninteracting sites with a Kd of 4.1 +/- 0.3 nM and a maximal capacity of 0.8 +/- 0.05 pmol/mg protein. Agonists demonstrated the same order of potency in competition for ligand binding sites as in inhibition of contractile activity. These data suggested that the DHA binding sites were part of the beta-adrenoceptor. Strong agonists occupied only 0.1% of all receptors to produce the full response. Competition experiments with antagonists produced complex curves which could be resolved into two components comprising approximately 70% and 30% of the total number of sites. It was suggested that these sites represented beta 2- and beta 1-adrenoceptors, respectively. The possibility of regulation of the relative numbers of beta 2- and beta 1-adrenoceptors in the myometrium was discussed.

Prostaglandins and the contractile function of the human oviductal ampulla.

Millimeter-wide muscle strips were prepared from the circular and longitudinal musculature of the oviductal ampulla of fertile women. These specimens were mounted in organ baths for isometric recording of contractile activity. The two types of strips exhibited similar rhythmic spontaneous activity which was found to be present in all phases of the menstrual cycle. Prostaglandin E2 (PGE2) caused an inhibition of contractile activity in both the circular and longitudinal layers, whereas PGF2 alpha induced a marked excitatory response in the specimens. Administration of prostacyclin (PGI2) also elicited an excitatory effect although much less pronounced that that of PGF2 alpha. Pretreatment with ETA, a blocker of endogenous prostaglandin synthesis, abolished the spontaneous contractile activity in a concentration-dependent manner. It is concluded that the ampullary portion of the human oviduct possesses pharmacological properties which differ in certain important respects from those of the isthmus. A shift in the tissue levels of endogenous prostaglandin levels may occur in sequence with ovulation and the pattern of the prostaglandins synthesized seems to be appropriate for the contractile function of the various tubal segments during ovum transport in women.

Levels of Cyclic AMP and Electrical Events during Inhibition of Contractile Activity in Vascular Smooth Muscle

The possible relationship between changes in electrical and mechanical activity and in tissue levels of cyclic AMP (cAMP) during relaxation of the myogenical active rat portal vein has been elucidated in response to different inhibitory stimuli. Isoproterenol, 10(-5) M, caused an initial pronounced inhibition of spike discharge and contractions followed by a partial recover over the 15 min exposure period. This inhibitory response was associated with doubling of tissue cAMP after 1 min and a less pronounced increase in later measurements (5 and 15 min). Papaverine, 10(-4)M, caused, in contrast, an inhibition of electrical and mechanical activity which developed gradually over the entire 15 min exposure period. The levels of cAMP at 1,5 and 15 min all exceeded the corresponding values obtained with isoproterenol. The two drugs in combination gave a biphasic inhibitory response associated with a sustained large increase in the level of cAMP. These drug induced inhibitions were thus accompanied by increased levels of cAMP, but the different time courses of the electromechanical responses could not be rlated to corresponding variations in the content of cAMP. Hyperosmolality (+150 mM sucrose) and mechanical vibration (100 Hz) elicited differentiated inhibitions of smooth muscle activity without changes in tissue cAMP. The mechanical effects elicited by isoproterenol, papaverine and hyperosmolality were accompanied by approximately parallel changes in electrical spike discharge. It is concluded that increased levels of cAMP are not indispensible for vascular smooth muscle relaxation, and that the magnitude of pharmacologically induced inhibitions are not always closely related to the total tissue content of the nucleotide.

Cell volume as a factor influencing electrical and mechanical activity of vascular smooth muscle.

ABSTRACTThe effects of variations in the extracellular osmolarity on the electrical and mechanical activity of the isolated rat portal vein were studied. Addition of sucrose or xylose (20–100 mmoles/l) to the “normal” solution caused inhibition of contractile activity which could be ascribed to changes in the electrical discharge pattern. Increasing osmolarity with urea produced transient inhibition, return to control activity, and, on return to normal solution, a transient excitation. Reducing osmolarity by 30–60 mOsm/l by decreasing the [Na+] and [Cl] of the medium caused sustained excitation with continuous spike discharge and tetanic contraction. Comparable decreases in the ionic concentrations but with osmotic substitution by sucrose or xylose had little influence on muscle activity. Substituting Na+ and Cl with urea on an equiosmolar basis caused excitation resembling that in hypoosmotic solution. If the smooth muscle cells are looked upon as osmotic cells with membranes that are freely permeable to H2O and urea but less permeable to sugar and ions, the results indicate a consistent correlation between cell volume and state of activity; shrinkage associated with inhibition, swelling with excitation. Changes in the transuiembrane concentration gradients for K+, Na+ and Cl‐, caused by the cellular volume changes, are not sufficient to explain the electrical responses. Changes in ionic membrane permeability are assumed to occur.