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Differentiation of intestinal smooth muscle relaxation caused by drugs that inhibit phosphodiesterase.

In this study a number of chemically unrelated smooth muscle relaxants were tested: a) for potency of phosphodiesterase (PDE)-inhibition, using guinea pig colon-PDE and rat erythrocyte-PDE, b) for potency and duration of relaxation of the isolated guinea-pig colon, c) for their interaction with NH4Cl and orciprenaline as well as with "high calcium". Compared with the spasmolytic effect inhibition of guinea pig colon-PDE or rat erythrocyte-PDE was strong for papaverine and some other relaxants but was low or virtually absent with verapamil, hexobendine and bencyclane. The spasmolytic effect of some PDE-inhibitors was found diminished by the PDE-activator NH4Cl. Most of these drugs enhanced the relaxant effect of the "cyclase activator" orciprenaline; the latter are designated A-type drugs. Verapamil, bencyclane, hexobendine and M 13 did not show this type of interaction with NH4Cl and orciprenaline; they are designated B-type drugs. With A-type drugs--but not with B-type drugs--a highly significant correlation was observed between potency of relaxation and inhibition of colon-PDE (r = 0.85) as well as rat erythrocyte-PDE (r = 0.77). The spasmolytic action of aminophylline and papaverine (A-type drugs) was not inhibited by elevation of extracellular calcium to 9 mM, whereas relaxation induced by verapamil and hexobendine (B-type drugs) at 1.8 mM calcium was found abolished by 9 mM calcium. It is concluded that A-type drugs relax guinea-pig colon by inhibition of PDE and accumulation of cAMP, and that B-type drugs in all probability act by (a) cAMP-independent mechanism(s).

3',5'-Cyclic-AMP Phosphodiesterases↗

Effects of narcotic analgesics, especially pethidine and norpethidine, on renal pelvic smooth muscle in patients with hydronephrosis.

Relaxation of the renal pelvic smooth muscle is usually attempted as a symptomatic treatment in painful colic of the upper urinary tract. The spasmolytic potency of morphine, pethidine, pentazocine, fentanyl, naloxone and papaverine was evaluated using noradrenaline-contracted pelvic strips from hydronephrotic patients. The order of spasmolytic potency was found to be fentanyl greater than pethidine = papaverine greater than pentazocine = naloxone. Morphine produced a dual effect, starting with contraction followed by relaxation. Norpethidine, which is the only metabolite of pethidine occurring in human plasma, had the same relaxing potency as its parent compound, pethidine. Thus, an active metabolite may play a role in the outcome of spasmolytic drug treatment.

Analgesics, Opioid↗

Clinical pharmacokinetics of ketobemidone. Its bioavailability after rectal administration.

The pharmacokinetic constants and rectal bioavailability of the narcotic analgesic ketobemidone were determined in six male patients after surgery. Plasma concentrations were measured following intravenous administration of Ketogin 2 ml, containing ketobemidone chloride 10 mg, and a spasmolytic compound N,N-dimethyl-3,3-diphenyl-1-methylallylamine chloride 50 mg, and following rectal administration of one suppository of Ketogin, containing ketobemidone chloride 10 mg and the spasmolytic component 50 mg. Following intravenous administration, the disposition of ketobemidone followed a biexponential pattern with a fast distribution phase and a slower elimination phase: the plasma half-life (t1/2) was 2.42 +/- 0.41 h (m +/- SD). After rectal administration, the disposition of ketobemidone fitted a one-compartment model. The elimination half-life was 3.27 +/- 0.32 h. The mean rectal bioavailability for ketobemidone was 44% +/- 9%. The pharmacokinetic constants of the spasmolytic component, N,N-dimethyl-3,3-diphenyl-1-methylallylamine, were also determined in five of the patients, both after intravenous and after rectal administration. The plasma half-life was 3.07 +/- 0.53 h and 3.79 +/- 1.14 h, respectively. The rectal bioavailability was estimated to be 33% +/- 14%.

Adult↗

Glucagon-(1-21)-peptide. Study of its action on sphincter of Oddi function by endoscopic manometry.

The amino acid sequence (1-21) of glucagon has been shown to have full spasmolytic action in animal studies but no metabolic effect. The motor activity of the sphincter of Oddi was measured during ERCP with manometric recordings of sphincter pressure. Then glucagon-(1-21)-peptide was given as a bolus intravenous injection; serial blood samples were taken to determine glucagon-like immunoreactivity. The spasmolytic effect of glucagon-(1-21)-peptide began 15 sec after injection and lasted up to 22 min at the higher doses. The basal pressure of the sphincter of Oddi was decreased by 31-56% after administration of glucagon-(1-21)-peptide. Phasic sphincter of Oddi pressure and wave frequency were also affected. In conclusion, glucagon-(1-21)-peptide has a relaxing effect on the human sphincter of Oddi and might emerge as an alternative to glucagon or other spasmolytic drugs for obtaining selective relaxation of the biliary tract.

Adult↗

Diclofenac and NS-398, a selective cyclooxygenase-2 inhibitor, decrease agonist-induced contractions of the pig isolated ureter.

Non-steroidal anti-inflammatory drugs (NSAIDs) are currently considered a first-line treatment of renal colic. Their action has been ascribed to the inhibition of renal prostaglandin synthesis, which decreases renal blood flow and diuresis, and consequently lowers the pressure in the renal pelvis and ureter. However, the effects of NSAIDs on induced contractions of ureteral smooth muscle have received little attention. Also, there is a lack of clinically relevant spasmolytic drugs for the ureter. Therefore, we studied the influence of the non-selective cyclooxygenase (COX) inhibitor diclofenac, a NSAID drug customarily used in the treatment of renal colic, and of NS-398, a selective COX-2 inhibitor, on induced contractions of the pig ureter. Serotonin (0.1-30 microM), norepinephrine (0.1-30 microM) and neurokinin A (0.03-10 microM) induced reproducible concentration-dependent contractions, which were inhibited by diclofenac and NS-398 (10-300 microM) in a concentration-dependent manner. The sensitivity of neurokinin A-induced contractions to diclofenac was 3-4 times greater than that of the amines. Depending on the concentration, inhibition ranged between 25 and 96% of the initially induced contractile activity. In the presence of inhibitors, supramaximal concentrations of agonists were unable to trigger recuperation of the initially induced contractions. Prostaglandin F2alpha did not reverse the effect of diclofenac on agonist-induced contractions. Removal of diclofenac or NS-398 from the organ baths showed that the inhibition was totally reversible. Thus, the non-selective COX inhibitor diclofenac and the selective COX-2 inhibitor NS-398 are almost equipotent in reducing agonist-induced contractions in the isolated porcine ureter. Although the clinical relevance of this spasmolytic effect remains to be demonstrated, the data suggest that patients suffering from renal colic may benefit not only from the anti-diuretic and analgesic effects of diclofenac, but also from its potential spasmolytic properties. Moreover, selective COX-2 inhibitors may have clinical potential, as they may cause fewer side effects.

Animals↗

Pharmacological basis for the medicinal use of ginger in gastrointestinal disorders.

Ginger (rhizome of Zingiber officinale) has been widely used for centuries in gastrointestinal disorders, particularly dyspepsia, but its precise mode of action has yet to be elucidated. This study was undertaken to study the prokinetic action of ginger and its possible mechanism of action. Prokinetic activity of ginger extract (Zo.Cr) was confirmed in an in vivo test when it enhanced the intestinal travel of charcoal meal in mice. This propulsive effect of the extract, similar to that of carbachol, was blocked in atropine-pretreated mice, a standard cholinergic antagonist. Likewise, Zo.Cr showed an atropine-sensitive dose-dependent spasmogenic effect in vitro as well as in isolated rat and mouse stomach fundus tissues. In atropinized tissue, it showed spasmolytic activity as shown by the inhibition of 5-HT- and K+-induced contractions. A spasmolytic effect was also observed in other gut preparations either as noncompetitive inhibition of agonist dose-response curves, inhibition of high K+(80 mM)-induced contractions, or displacement of Ca2+ dose-response curves to the right, indicating a calcium antagonist effect. Phytochemical analysis revealed the presence of saponins, flavonoids, and alkaloids in the crude extract. These data indicate that Zo.Cr contains a cholinergic, spasmogenic component evident in stomach fundus preparations which provides a sound mechanistic insight for the prokinetic action of ginger. In addition, the presence of a spasmolytic constituent(s) of the calcium antagonist type may explain its use in hyperactive states of gut like colic and diarrhea.

Animals↗

Antagonism of glycerol trinitrate activity by an inhibitor of glutathione S-transferase.

The in vitro spasmolytic activity of glycerol trinitrate was measured on the KCl-contraction of aorta strips from the rabbit. In the presence of sulphobromophthalein, a known inhibitor of glutathione S-transferase, the dose-activity curve for the nitrate was displaced to the right. Much smaller displacements were obtained with the control spasmolytic substances--papaverine and S-nitroso-N-acetylpenicillamine. It was confirmed that sulphobromophthalein inhibits glutathione S-transferase activity in aorta homogenates. Aorta extracts did not detectably catalyze the reaction between glutathione and sulphobromophthalein and the glutathione level was not decreased by treating the intact aorta with sulphobromophthalein. It is concluded that sulphobromophthalein acts as a specific antagonist of the spasmolytic activity of glycerol trinitrate, probably as a result of its inhibition of glutathione S-transferase. It thus seems probable that glutathione and glutathione S-transferase are involved in the pharmacological activation of the organic nitrates.

Animals↗

Effects of three K+ channel openers on airways and pulmonary circulation in the isolated guinea-pig lung.

The antispasmodic and spasmolytic effects of levcromakalim (BRL 38227), aprikalim (RP 52891) and pinacidil were investigated in airways and pulmonary vessels of the isolated guinea-pig perfused lung. In airways, the three drugs exhibited modest antispasmodic properties, and pinacidil was more potent than levcromakalim and aprikalim against the contractions induced by carbachol (0.001-10 microM) or K+ (5-50 mM). Whereas levcromakalim and aprikalim acted only at low concentrations of K+, the rightward shift of the K+ concentration-effect curve produced by pinacidil was observed at all K+ concentrations (5-50 mM), suggesting that a mechanism of action other than K+ channel opening is involved in the effects of pinacidil. Pinacidil (0.3-100 microM) had the greatest spasmolytic effect in airways precontracted by carbachol (0.3 microM). The three K+ channel openers were equipotent against the sustained contractions of airways induced by 25 or 30 mM K+ and their spasmolytic activity was more marked against contractions induced by low rather low than high K+ concentrations. Levcromakalim and aprikalim were more effective as relaxant than as antispasmodic drugs. In K(+)-precontracted pulmonary vessels, the relaxant activity of pinacidil and levcromakalim was more pronounced than that observed in airways, suggesting a vascular selectivity of these drugs.

Animals↗

In vivo effects of different antispasmodic drugs on the rat bladder contractions induced by topically applied KCl.

The model originally proposed by Postius and Szelenyi for in vivo screening of spasmolytic compounds on the rat urinary bladder, has been modified and tested to verify its predictivity. The topically applied KCl induced reproducible contractions of the bladder that were dose dependently inhibited by i.v. administration of calcium antagonists like nifedipine, nicardipine, and verapamil. The other spasmolytics tested (oxybutynin, terodiline, flavoxate, and papaverine), showed a non-dose-related inhibition of the contractions. The in vivo potency of the calcium antagonists was related to their in vitro activity on the agonist-induced contractions of rat bladder strips, whereas the activity of the other spasmolytics appeared higher than that predicted on the basis of their in vitro efficacy. Nicardipine showed a dose-dependent inhibition of KCl-induced contractions also after oral administration, whereas oxybutynin and papaverine behaved as after i.v. administration. The described model represents, therefore, a good, quantitative, and reproducible tool of screening at the bladder level only for antispasmodic drugs endowed with strong calcium antagonistic activity.

Administration, Topical↗

Pharmacological basis for the use of Fumaria indica in constipation and diarrhea.

The crude extract of Fumaria indica whole plant (Fi.Cr) and its fractions were studied in vitro for spasmogenic and spasmolytic effects to rationalize some of the traditional uses. Fi.Cr (1.0-5.0 mg/mL) caused a moderate degree of atropine-sensitive spasmogenic effect in guinea-pig ileum. In spontaneously contracting rabbit jejunum, Fi.Cr (0.03-0.3 mg/mL) caused a mild spasmogenicity followed by relaxation at the higher doses. In the atropinized preparations, Fi.Cr inhibited spontaneous and K(+)-induced contractions at the similar doses (0.1-1.0 mg/mL), which suggests calcium channel blockade (CCB). CCB effect was confirmed when pretreatment of the tissue with the Fi.Cr produced a dose-dependent shift in the Ca(2+) dose-response curves to the right, similar to that produced by verapamil. Activity-directed fractionation revealed that the spasmolytic effect is concentrated in the petroleum ether fraction, while dichloromethane fraction contains both spasmogenic and spasmolytic constituents. These data indicate that the presence of cholinergic and CCB constituents in Fi.Cr may explain the respective traditional use of Fumaria indica in constipation and diarrhoea.

Animals↗

Effects of rociverine on the human ureter: in vivo and in vitro experimental study.

An in vitro and in vivo study was conducted to verify the effects of rociverine--a new spasmolytic agent--on peristalsis in the human ureter. In vitro (human ureter strips), rociverine exerted a spasmolytic activity both on the baseline motility and on the spasm induced by direct contractants (eledoisin, KCl) or by histamine. It may therefore be concluded that rociverine is a predominantly myotropic spasmolytic. In the in vivo study, conducted in patients with cutaneous ureterostomy, the drug showed a marked inhibitory effect on the amplitude and frequency of the ureteral rhythmic spikes, without affecting the baseline tone.

Adult↗

Histamine receptor-independent muscle relaxation elicited by a series of histamine H2-receptor agonists on the isolated guinea pig duodenum: a study into the mechanism of action.

1. The histamine H2 receptor agonists, dimaprit, impromidine, amthamine, and several dimaprit- and impromidine-analogues were investigated for their spasmolytic activity on the guinea pig duodenum, precontracted with acetylcholine or KCl. 2. Almost all the H2 receptor agonists exerted a histamine H2 receptor-independent muscle relaxation, which was more evident on acetylcholine- than on KCl-precontracted preparations. 3. The relaxing activity of these compounds was independent of inhibitory receptors, like beta-adrenergic, GABA-ergic, serotoninergic, etc. Similarly, modifications of cyclic nucleotide metabolism and nitric oxide production did not appear to be involved. 4. The behavior of histamine H2-receptor agonists was shared only by the Na+-blocker procaine, the intracellular Ca2+-antagonist ruthenium red and, at least in terms of efficacy, by the protein kinase C inhibitor, chelerithrine. 5. This spasmolytic effect is probably due to an impairment of receptor-mediated depolarization at the plasma membrane level and/or an inhibitory activity on the protein kinase C-dependent activation of the contractile machinery. 6. Finally, our findings suggest that the histamine H2 receptor-independent muscle relaxation is a general feature shown by H2 receptor agonists endowed with different chemical structure and the putative spasmolytic "receptor" prefers a (substituted) thiazole over a (substituted) imidazole.

Animals↗

Pharmacological basis for the use of peach leaves in constipation.

The aqueous crude extract (PPL.Cr) of peach leaves (Prunus persica) was studied for the possible presence of gut stimulatory constituent(s) to rationalize the folkloric use of the plant in constipation. PPL.Cr at the dose of 1-10 mg/ml caused a moderate degree of spasmogenic effect in isolated guinea-pig ileum. Pretreatment of the tissue with atropine (1 M) completely abolished the contractile effect of the plant extract similar to that of acetylcholine which is suggestive of a cholinergic mechanism. In isolated rabbit jejunum preparations, PPL.Cr produced a week spasmogenic effect followed by relaxation of the spontaneous contractions at higher doses. Bioassay-directed fractionation revealed that the spasmogenic activity was separated in the aqueous fraction, while the spasmolytic activity was concentrated in the ethyl acetate fraction. When tested against K(+)-induced contraction, both PPL.Cr and its ethyl acetate fraction (PPL.EtAc) caused a dose-dependent inhibition, suggesting calcium channel blockade (CCB). The presence of CCB in peach leaves was confirmed when pretreatment of the tissue with PPL.EtAc caused a dose-dependent rightward shift in the Ca(2+) dose-response curves, similar to that produced by verapamil. These data indicate that the plant contains spasmogenic (cholinomimetic) and spasmolytic (calcium antagonist) constituents, which are concentrated in the aqueous and ethyl acetate fractions, respectively. Furthermore, the laxative effect of the plant reported in the traditional system of medicine may be partially due to the cholinergic action, which was dominant over the spasmolytic component.

Acetylcholine↗

Crystal structure of a disulfide-linked "trefoil" motif found in a large family of putative growth factors.

Porcine pancreatic spasmolytic polypeptide (PSP) belongs to a large family of homologous growth factor-like polypeptides characterized by a disulfide-linked "trefoil motif," duplicated and conserved in various family members. PSP contains two trefoil motifs, has several pharmacological actions on the gut, and has growth factor properties on epithelial cells in vitro. The human PSP analogue, human spasmolytic polypeptide, appears to be involved in many regenerative situations and, especially, in healing gastrointestinal ulcers. One member of the trefoil family, pS2, is secreted in approximately 50% of estrogen-dependent human breast carcinomas, which has led to its use as a tumor prognostic marker. Both pS2 and human spasmolytic polypeptide are also widely expressed in chronic gastrointestinal ulcerative conditions such as Crohn disease. Here we report the three-dimensional structure at 2.6-A resolution of a trefoil-containing protein, namely PSP, purified from porcine pancreas. The structure shows two homologous domains that share a supersecondary structure and disulfide bond pattern. The two domains pack asymmetrically giving rise to a number of protruding loops, exposed clefts, and an unusual electrostatic surface potential. Knowledge of the structure of PSP should allow the design of mutants to investigate further the function of PSP and other trefoil-containing peptides.

Amino Acid Sequence↗

Relaxant effect of ketamine and its isomers on histamine-induced contraction of tracheal smooth muscle.

The mechanism by which racemic (R(+/-)) ketamine relaxes airway smooth muscle is unclear and there is no information on the differential effects of ketamine and its isomers. In this study, we have examined the spasmolytic effect of R(+/-) ketamine and its isomers S(+) and R(-) ketamine and the role of intracellular calcium and opioid receptors in R(+/-) ketamine-induced relaxation. The tension of isolated guinea pig tracheal strips was measured isometrically with a force displacement transducer and contraction elicited with histamine 10(-5) mol litre-1. In histamine-preconstricted strips, the two ketamine isomers (4.5-18.0 x 10(-4) mol litre-1) produced equipotent relaxation. A subthreshold dose of each isomer of ketamine (10(-4) mol litre-1) which alone did not relax histamine-induced contraction (S(+), P < 0.01; R(+/-), P < 0.01; R(-), P < 0.05) significantly potentiated adrenaline 1.25-5.0 x 10(-9) mol litre-1-induced relaxation (potency: S(+) > R(+/-) > R(-)). Increase in extracellular Ca2+ (1.8-14.4 x 10(-3) mol litre-1) significantly reduced R(+/-) ketamine-induced relaxation. S(-) Bay K 8644, at concentrations up to 2.0 x 10(-6) mol litre-1, partially antagonized R(+/-) ketamine-induced relaxation whereas at 10(-5) mol litre-1 or higher it potentiated the response. Naloxone 1.5-6.0 x 10(-6) mol litre-1 did not affect the relaxation caused by R(+/-) ketamine. We conclude that although both ketamine isomers produced equipotent spasmolytic effects on airway smooth muscle precontracted with histamine, they differed in their ability to potentiate the relaxing effect of adrenaline. S(+) ketamine produced the greatest potentiation. Changes in intracellular Ca2+ level secondary to a reduction in the L-type Ca2+ current may partially mediate the spasmolytic effect of R(+/-) ketamine.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Cholinergic and purinergic responses in isolated human detrusor in relation to age.

PURPOSE: We investigated whether the contractility of isolated human detrusor muscle, responsiveness to commonly used spasmolytic drugs, and expression of selected muscarinic and purinergic (P2X) receptor subtypes (M2, M3, P2X1 and P2X3) change with age. MATERIALS AND METHODS: Tissues were taken from 63 patients 37 to 84 years old undergoing radical cystectomy. Specimens from 49 patients were used for contractility studies and those from 50 were used for mRNA analysis. RESULTS: Propiverine, oxybutynin, tolterodine and atropine decreased contractions evoked by electric field stimulation to different degrees. However, neither the efficacy nor potency of the drugs showed age related changes. Since human detrusor muscle shows atropine resistant noncholinergic responses, we also studied the putative age dependence of concentration-response curves to the muscarinic agonist carbachol, and the purinergic agonists adenosine triphosphate (ATP) and alpha-beta-methylene-ATP. Sensitivity to alpha-beta-methylene-ATP increased with age, while the efficacy and potency of spasmolytic drugs did not depend on age. In addition, mRNA detected for M2, M3, P2X1 and P2X3 receptors did not change with age. CONCLUSIONS: Our results do not provide evidence for age related contractile deterioration in human detrusor muscle strips, nor do they suggest that responses to anticholinergic spasmolytic drugs change substantially with age.

Adult↗

Cardiovascular effects at multi-detector row CT colonography compared with those at conventional endoscopy of the colon.

PURPOSE: To compare the cardiovascular effects of computed tomographic (CT) colonography and conventional endoscopy in a group of patients undergoing both procedures. MATERIALS AND METHODS: A total of 144 patients underwent CT colonography followed by flexible sigmoidoscopy (40 patients) or colonoscopy (104 patients). Pulse, blood pressure, and oxygen saturation were measured before, during, and after the procedures. Forty patients also underwent continuous Holter electrocardiographic (ECG) monitoring. Periprocedural pain was assessed by using a handheld counting device. Outcome variables were assessed by using a combination of paired t testing and multilevel linear regression. RESULTS: When a spasmolytic was not used, CT colonography was associated with only a small increase in oxygen saturation (P =.03), while use of a spasmolytic caused an increase in pulse (mean increase, 19.9 beats per minute; P <.001) and diastolic blood pressure (mean increase, 5 mm Hg; P <.001). Compared with that at CT, oxygen saturation decreased significantly during and after colonoscopy and sigmoidoscopy (mean decrease after colonoscopy with sedation, 1.0%; P <.001). Systolic and diastolic blood pressure also decreased during and after colonoscopy (mean systolic decrease after colonoscopy with sedation, 16.6 mm Hg, P <.001; mean diastolic decrease after colonoscopy with sedation, 7.5 mm Hg, P <.001). Patients were 30.3 times more likely to develop bradycardia after endoscopy (95% CI: 2.65, 346; P =.006). Ventricular couplets were significantly higher at endoscopy than at CT in patients with a history of cardiac disease (odds ratio: 72.5 and 95% CI: 4.56, 1,153 at CT vs odds ratio: 14.6 and 95% CI: 0.96, 222 at endoscopy; P =.002). Patients were 1.89 times more likely to register pain during colonoscopy than during CT (95% CI: 1.06, 3.38; P =.03). CONCLUSION: CT colonography had no significant cardiovascular effect other than spasmolytic-induced tachycardia. Endoscopy-and colonoscopy in particular-causes cardiovascular effects that are largely related to sedation. CT colonography is less painful than colonoscopy and is comparable to flexible sigmoidoscopy.

Adult↗

Buchu (Agathosma betulina and A. crenulata, Rutaceae) essential oils: their pharmacological action on guinea-pig ileum and antimicrobial activity on microorganisms.

The mode of action of essential oils from two buchu species (Agathosma betulina and A. crenulata, Rutaceae) from the Cape region of South Africa has been studied on smooth muscle in-vitro using guinea-pig ileum. At high concentration, the oils had an initial spasmogenic activity followed by spasmolysis. The spasmolytic action was post-synaptic, not atropine-like and did not involve adrenoceptor or guanylyl cyclase activation. In the presence of the phosphodiesterase inhibitor rolipram, the spasmolytic action of A. betulina was significantly increased whilst that due to A. crenulata was also increased but not to a significant level. These results suggested a mode of action for the oils involving cyclic adenosine monophosphate. In addition, A. betulina appeared to block calcium channels but this was not seen with A. crenulata, possibly because the initial spasmogenic activity complicated the study of its spasmolytic action. Neither essential oil (10 microL, undiluted) demonstrated antimicrobial action against Enterococcus hirae and Pseudomonas aeruginosa but very low activity was observed against Escherichia coli, Saccharomyces cerevisiae and Staphylococcus aureus, suggesting little potential for these oils as antimicrobial agents/preservatives.

Animals↗