FPL 55712—An antagonist of slow reacting substance of anaphylaxis (SRS-A): A review

Compound FPL 55712 is a highly selective antagonist of SRS-A derived from guinea-pig, rat, man and dog. It equally antagonizes SRS (slow reacting substance) released by calcium ionophore from rat basophilic leukemia cells and peritoneal mono-nuclear cells and by compound 48/80 from cat paw. In comparatively high doses FPL 55712 significantly inhibits passive cutaneous anaphylaxis in rat and anaphylactic bronchoconstriction in guinea-pig and rat and acute anaphylactic shock in the monkey. It inhibits the antigen-induced rhythmic mechanical activity in chicken ileum and late phase of Schultz-Dale reaction in guinea-pig trachea and human bronchus. In addition, FPL 55712 inhibits the SRS-A-induced release of rabbit aorta contracting substance (RCS) from guinea-pig lung. FPL 55712 facilitates sputum clearance in allergic canine asthma. This compound also inhibits the guinea-pig ECF-A (eosinophil chemotactic factor of anaphylaxis)-induced eosinophil chemotactic response of guinea-pig eosinophils in vitro. Compound FPL 55712 is an invaluable pharmacological tool for the identification of SRS(A) and to help define the role of SRS-A in the pathophysiology of immediate hypersensitivity (e.g. anaphylaxis and allergic asthma). Clinical trials of FPL 55712 as an aerosol in allergic obstructive respiratory diseases in man and animals may help to further understand the mechanism(s) and chemical mediator(s) involved in these conditions.     

The effect of lipoxygenase inhibitors and leukotriene antagonists on anaphylaxis

The experiments whose results are reported here were carried out with the aim of showing a possible role for lipoxygenase products in the modulation of the Schultz-Dale reaction. For this purpose, the actions of nordihydroguaieretic acid (NDGA) and of FPL 55712 were tested during anaphylaxis in guinea-pig ileum and tracheain vitro. Isolated preparations from guinea-pigs, which had been subcutaneously sensitized with ovalbumin and incomplete Freund adjuvant, were challenged with increasing concentrations of antigen; in preparations isolated from the same animal an antigen-concentration anaphylactic-reaction curve was performed in the presence of the drugs. NDGA 3.3×10^–6 M was capable of inhibiting anaphylaxis in the trachea to a maximum extent of 40% but it did not affect anaphylactic reaction in the intestinal smooth muscle. FPL 55712 2×10⁶ M did not exert any activity on anaphylaxis in either preparations. The difference between SRS-A and histamine as mediators of anaphylaxis in the tissue preparations used could explain the fact that NDGA acted on the trachea alone.     

Effect of inhibition of arachidonic acid metabolism on anaphylaxis of guinea pig lung strips

The effect of inhibitors of the cyclooxygenase and/or lipoxygenase pathways of arachidonic acid metabolism on the anaphylactic contraction of lung parenchymal strips from ovalbumin sensitized guinea pigs was studied. Indomethacin, a selective cyclooxygenase inhibitor, significantly enhanced the anaphylactic contraction at 10^–6 M with no effect at 10^–5 or 10^–4 M. By contrast, nordihydroguaiaretic acid (NDGA, 10^–5 and 10^–4 M), a lipoxygenase inhibitor, and 1-phenyl-3-pyrazolidinone (phenidone, 10^–4 M), an inhibitor of both the cyclooxygenase and lipoxygenase markedly inhibited the anaphylactic contractile response. The pattern of inhibition was similar to that produced by FPL 55712, an antagonist of slow reacting substance of anaphylaxis (SRS-A), and was characterized by a decrease in the maximum tension and in the duration of the contraction. The results suggest that inhibition of the lipoxygenase pathway reduced anaphylactic contraction of guinea pig lung strips possibly by inhibiting the synthesis and release of SRS-A.     

FPL 55712 — An antagonist of slow reacting substance of anaphylaxis (SRS-A): A review

Compound FPL 55712 is a highly selective antagonist of SRS-A derived from guinea-pig, rat, man and dog. It equally antagonizes SRS (slow reacting substance) released by calcium ionophore from rat basophilic leukemia cells and peritoneal mono-nuclear cells and by compound 48/80 from cat paw. In comparatively high doses FPL 55712 significantly inhibits passive cutaneous anaphylaxis in rat and anaphylactic bronchoconstriction in guinea-pig and rat and antigen-induced rhythmic mechanical activity in chicken ileum and late phase of Schultz-Dale reaction in guinea-pig trachea and human bronchus. In addition, FPL 55712 inhibits the SRS-A-induced release of rabbit aorta contracting substance (RCS) from guinea-pig lung. FPL 55712 facilitates sputum clearance in allergic canine asthma. This compound also inhibits the guinea-pig ECF-A (eosinophil chemotactic factor of anaphylaxis)-induced eosinophil chemotactic response of guinea-pig eosinophils in vitro. Compound FPL 55712 is an invaluable pharmacological tool for the identification of SRS(A) and to help define the role of SRS-A in the pathophysiology of immediate hypersensitivity (e.g. anaphylaxis and allergic asthma). Clinical trials of FPL 55712 as an aerosol in allergic obstructive respiratory diseases in man and animals may help to further understand the mechanism(s) and chemical mediator(s) involved in these conditions.     

Slow reacting substance as a preformed mediator from human lung.

Homogenates from human lung contained a preformed slow reacting substance (pSRS). The pattern of contraction on the guinea-pig ileum by pSRS was indistinguishable from that of SRS-A. The activity of pSRS could not be attributed to the presence of K+, Na+, Ca2+ and Mg2+ ions, or any prostaglandin including PGF2 or its 15-oxo derivative. As with SRS-A, pSRS could be absorbed onto Amberlite XAD-2 and silicic acid. Both were eluted from the former with 80 per cent ethanol and from the latter with a mixture of ethanol, ammonia and water. Both pSRS and SRS-A were resistant to the action of NaOH whereas their activities were destroyed by boiling in HCl. Arylsulphatase II B destroyed the activities of both pSRS and SRS-A. An antagonist of SRS-A, FPL55712, inhibited the action of pSRS at comparable concentrations to that of SRS-A. These experiments suggest that pSRS and SRS-A are identical. Thus SRS joins histamine and ECF-A as a preformed mediator. Although SRS was present in a preformed state the amount of material extractable was more than doubled by the anaphylactic reaction. The extraction of slow reacting substance from human lung without apparent requirement for antigen or antibody points to a possible role of this mediator in inflammatory reactions evoked by mechanisms independent of IgE and other tissue-sensitizing antibodies.     

The effect of Ro 21-7634 on the antigen-induced production of bronchoconstrictive arachidonic acid metabolites in the guinea pig lung

Ro 21-7634 has previously been shown to inhibit histamine and SRS-A release from actively-sensitized guinea pig lung fragments upon antigen challenge. In the studies described herein, it was observed that Ro 21-7634 does not decrease SRS-A release but instead acts to inhibit the synthesis of this mediator. This was confirmed by studying SRS-A synthesisin vitro in rat peritoneal cells after challenge with ionophore A23187. In the peritoneal cell system, Ro 21-7634 exhibited an IC₅₀ of 500 M, in comparison with 5,8,11,14-eicosatetraynoic acid, phenidone and BW755C (IC₅₀'s of 2, 100, and 100 M, respectively). When studied at 10^–4 and 10^–3 M in perfused guinea pig lung, Ro 21-7634 inhibited antigen-induced thromboxane A₂ production by 68 and 96%, respectively. In this system, antigen is believed to induce thromboxane A₂ production through the release of histamine and SRS-A from lung tissue. These mediators then interact at receptor sites in the lung parenchyma to induce thromboxane A₂ synthesis. Ro 21-7634 could thus be inhibiting thromboxane A₂ production by preventing the release of histamine and synthesis of SRS-A in the perfused lung system. Such a mechanism is suggested by the fact that although Ro 21-7634 was effective in inhibiting antigen-induced thromboxane production, it was ineffective in inhibiting thromboxane A₂ production induced in the guinea pig lung system by the direct perfusion of histamine or SRS-A through the lung.     

Effects of leukotrienes C4 and D4 on guinea-pig heart and the participation of SRS-A in the manifestations of guinea-pig cardiac anaphylaxis

Synthetic leukotrienes C₄ and D₄ (LTC and LTD) were found to possess potent coronary vasoconstrictor and cardiac depressant actions on isolated guinea-pig hearts. We therefore went further to investigate the possibility that endogenously released slow-reacting substance of anaphylaxis (SRS-A) might be responsible for the coronary vasoconstriction and negative inotropism in guinea-pig cardiac anaphylaxis. Results using time-course analysis as well as the specific SRS antagonist FPL 55712 have shown that SRS-A released during cardiac anaphylaxis was unlikely to be responsible for the early and most dramatic phase of coronary vasoconstriction that usually occurred at the 2nd min after antigen challenge, but could possibly be responsible for the latter and more prolonged phase occurring between the 6th and 14th min. This is because SRS-A release was found to peak at the 4th min after antigen challenge, 2 min after vasoconstriction had already peaked. Moreover, this early component of coronary vasoconstriction could not be blocked by FPL 55712, whereas the latter component was significantly reduced by the antagonist. The negative inotropism following cardiac anaphylaxis was also found to be significantly reduced by FPL 55712, thus suggesting SRS-A involvement. However, our experiments did not show whether the two actions were direct effects of SRS-A or whether contractility failure was a consequence of coronary vasoconstriction.     

Analysis of Cyclic Adenosine-3',5'-Monophosphate Levels in Structures of the “Informational” and “Motivational” Systems of the Rat Brain during Acquisition of a Conditioned Active Avoidance Reaction

Cyclic adenosine-3',5'-monophosphate (cAMP) levels in structures of the informational and motivational systems of the brain were measured during acquisition of a conditioned two-sided active avoidance reflex in rats. cAMP levels were measured in three groups of animals – intact animals, trained animals, and an active control group (given uncombined presentations of the conditioned (light) and unconditioned (electric shock) stimuli) – immediately after reproduction of the acquired reflex. Significant accumulation of cAMP levels in brain structures was seen in animals of the active control group in the hypothalamus and in trained animals in the left and right hippocampus and the right frontal cortex. Positive correlations were found between cAMP levels in symmetrical parts of the frontal cortex, amygdala, and hypothalamus in animals of all study groups. In addition, active control rats and trained rats showed interhemisphere and intrahemisphere correlations between cAMP levels in brain macrostructures, whose patterns were specific for each group. The pattern of correlations observed here is assessed from the point of view of the role of the informational and motivational structures in the organization of adaptive behavior.     

Alteration of drug responsiveness in guinea-pig lung anaphylaxis using different antigen challenge concentrations

Antihistamine-resistant anaphylactic bronochospasm in guinea pigs is increased with increasing doses of antigen (ovalbumin, OA) challenge. This was observed in passively and actively sensitized animals, and by both i.v. and aerosol routes of antigen challenge. At a challenge concentration of 100 mg/kg OA, antihistamines were virtually inactive. Indeed, the resulting bronchospasm was inhibited by isoproterenol, theophylline and ketotifen but not any anticholinergics, anti-5HT, SRS-A antagonists, arachidonic acid lipoxygenase inhibitors or antiallergic drugs. However, in the presence of chlorpheniramine, the response was antagonized by SRS-A antagonists (FPL 55712 and isamoxole), but not the lipoxygenase inhibitors (BW 755C, ETYA, NDGA and phenidone). This suggests that the antihistamine-resistant bronchospasm produced in guinea pigs challenged with high antigen concentrations might be the result of SRS-A release. This is by no means certain since the currently available SRS-A antagonists possess other mechanisms of action; furthermore, the failure of lipoxygenase inhibitors to influence this response is not consistent with a role for SRS-A. Elucidation of the mechanism of the antihistamine-resistant bronchospasm awaits development of more specific SRS-A antagonists.     

Control of pulmonary vascular smooth muscle tone by sarcoplasmic reticulum ca2+ pump blockers: thapsigargin and cyclopiazonic acid

The effect of thapsigargin (TG) and cyclopiazonic acid (CPA) on the mechanical activity of the rat pulmonary artery were investigated. In chemically (-escin)-skinned arterial strips, application of TG (0.1–1 M) or CPA (0.5–10 M) prior and throughout the loading procedure of the internal Ca²⁺ stores (0.3 M free Ca²⁺ ions for 8–10 min) concentration dependently inhibited the subsequent contractile response induced by noradrenaline (NA, 10 M) or caffeine (25 mM). In intact strips repeatedly incubated in a Ca²⁺-containing solution (2.5 mM for 10 min), followed by incubation in a Ca²⁺-free solution 12 min before NA-stimulation, TG and CPA not only inhibited the NA-induced contraction but also increased the tension which appeared during the exposure time to Ca²⁺. The two phenomena developed with similar time courses. The increase in tension during the readmission of Ca²⁺ ions was not antagonized by verapamil (10 M) or nifedipine (1 M) but was blocked by La³⁺ (50 M) and Co²⁺ (1 mM) ions. The amplitude of the verapamil-insensitive TG (or CPA)-induced contraction was dependent on the external [Ca²⁺] [0.1–10 mM, concentration for half maximal effect (EC₅₀) =0.85 mM], not modified by the reduction of the external [Na⁺] (from 130 to 10 mM) and decreased by depolarization of the strip using K⁺-rich (30–120 mM) solutions. Under the latter condition, 38±9 and 83±4% reduction (n=5) was observed in the presence of 60 and 120 mM K⁺ respectively. This contraction was also concentration dependently inhibited by the tyrosine kinase inhibitors genistein (0.5–50 M) and tyrphostin (2–50 M). Sr²⁺ ions, which contracted both depolarized intact and skinned strips, failed to replace Ca²⁺ ions in the verapamil-insensitive contraction induced by TG or CPA (n=4). Finally, TG (1 M) and CPA (10 M) did not modify the pCa tension relationship in skinned strips (n=5). These results show that the main action of TG and CPA in rat pulmonary artery is to prevent the refilling of the internal Ca²⁺ store. TG and CPA also seem to facilitate a Ca²⁺ influx through a specific verapamil-insensitive pathway. The biophysical and molecular characteristics of this pathway remain to be elucitated, although it appears to involve a tyrosine kinase activity.     

Pharmacologic properties of FPL 55712 administered by aerosol

FPL 55712 was investigated by the aerosol route of administration for efficacy at protecting against leukotriene-induced bronchoconstrictions in guinea pigs and for mediator release inhibitory activity in passively sensitized rats. In the studies to investigate leukotriene antagonism; anesthetized, spontaneously breathing guinea pigs were pretreated with propranolol and were exposed via tracheal cannula to aerosols generated by a Monaghan nebulizer. Subsequently, the animals were artificially ventilated and challenged with LTD₄ or LTE₄ (25 g/kg, i.v.). FPL 55712 produced a concentration-dependent inhibition of LTD₄ and LTE₄-induced bronchoconstriction (IC₅₀'s 0.5% and 0.8%, respectively). Although the biologic half-life of FPL 55712, administered intravenously, was very short (1.7 minutes against LTD₄ and 1.2 minutes against LTE₄) after aerosol administration the biological half-life was surprisingly long (120 minutes against LTD₄ and 90 minutes against LTE₄). Aerosolized FPL 55712 also possessed weak antiallergic activity in comparison to disodium cromoglycate when measured as an inhibitor of IgE-mediated anaphylactic bronchoconstriction in rats (IC₅₀'s of 2.0% and 0.01%, respectively). Thus, these studies demonstrate that, when administered by aerosol, FPL 55712 is effective at protecting against leukotriene-induced bronchoconstrictions, exhibits a long duration of action and also possesses weak antiallergic activity.     

Regulation of ion transport via apical purinergic receptors in intact rabbit airway epithelium

We investigated purinergic receptors involved in ion transport regulation in the intact rabbit nasal airway epithelium. Stimulation of apical membrane P2Y receptors with ATP or UTP (200 M) induced transient increases in short-circuit current (I_sc) of 13 and 6% followed by sustained inhibitions to 8 and 17% below control level, respectively. Serosal application of nucleotides had no effect. The ATP-induced response appeared to involve additional activation of apical adenosine (P1) and P2X receptors. The inhibitory effect of ATP and UTP on I_sc was eliminated by pretreatment with amiloride (100 M), while the stimulatory effect was potentiated, indicating that ATP and UTP inhibit Na⁺ and stimulate Cl^– current. Ionomycin (1 M) induced responses similar to UTP and ATP and desensitized the epithelium to the nucleotides, indicating involvement of intracellular Ca²⁺ (Ca²⁺_i). Furthermore, ATP, UTP and ionomycin induced 21, 24, and 21% decreases, respectively, in transepithelial conductance. Measurements of unidirectional isotope fluxes showed a 39% decrease in the dominant net Na⁺ absorption in response to ATP, while the smaller net Cl^– secretion increased only insignificantly and unidirectional Cl^– fluxes decreased significantly. The results suggest that nucleotides released to the airway surface liquid exert an autocrine regulation of epithelial NaCl absorption mainly by inhibiting the amiloride-sensitive epithelial Na⁺ channel (ENaC) and paracellular anion conductance via a P2Y receptor-dependent increase in Ca²⁺_i, while stimulation of Cl^– secretion is of minor importance.     

Effects of chloride and potassium channel blockers on apoptotic cell shrinkage and apoptosis in cortical neurons

K⁺ and Cl^– homeostasis have been implicated in cell volume regulation and apoptosis. We addressed the hypothesis that K⁺ and Cl^– efflux may contribute to apoptotic cell shrinkage and apoptotic death in cultured cortical neurons. CLC-2 and CLC-3 chloride channels were detected in cultured cortical neurons. The Cl^– channel blockers 4,4-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS), 4-acetamido-4-isothiocyanatostilbene-2,2-disulfonic acid (SITS) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) inhibited the outwardly rectifying Cl^– current, prevented apoptotic cell shrinkage, and mildly attenuated cell death induced by staurosporine, C₂-ceramide, or serum deprivation. Cl^– channel blockers, however, at concentrations that prevented cell shrinkage had no significant effects on caspase activation and/or DNA fragmentation. Cell death in the presence of a Cl^– channel blocker was still sensitive to blockade by the caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethyl ketone (z-VAD-fmk). Electron microscopy revealed that, although DIDS prevented apoptotic cell shrinkage, certain apoptotic ultrastructural alterations still took place in injured neurons. On the other hand, the K⁺ channel blocker tetraethylammonium (TEA), clofilium, or the caspase inhibitor z-VAD-fmk prevented cell shrinkage as well as caspase activation and/or DNA damage, and showed stronger neuroprotection against apoptotic alterations and cell death. The results indicate that neurons may undergo apoptotic process without cell shrinkage and imply distinct roles for Cl^– and K⁺ homeostasis in regulating different apoptotic events.     

Capsaicin and anaphylactic reactions in the giunea-pig airways

Further evidence is reported on the influence exerted by capsaicin on the anaphylactic reaction evoked in actively sensitized guinea-pigs. In Herxheimer microshock induced by ovalbumin aerosol, pretreatment of animals with 100 g/kg i. p. capsaicin prolonged the preconvulsion time when the drug was administered 3 h before antigen challenge. In contrast, the same dose of capsaicin injected 30 min before aerosol caused a shortening of latency of the respiratory symptomatology. The influence of the drug is no longer evident after 24 h. In in vitro experiments desensitization to capsaicin of tracheal preparations caused a reduction of histamine and SRS-A released during antigen challenge, in comparison to controls. Moreover, anaphylactic histamine release was increased in preparations perfused with 10^–8 M substanceP. In conclusion, our findings confirm that neuropeptides may be involved in the pathogenesis of asthma by affecting release of mediators.     

Role of histamine H2 receptors in the mechanism of formation of experimental gastric ulcers induced in rats by various stressors

Dystrophic lesions of the gastric mucosa were observed to be formed and the pepsinogen content was reduced by 57% in the gastric mucosa of rats exposed to various experimental stressors (immobilization with electrical stimulation, immobilization at 6°C, trauma to or ligation of the pylorus). and the changes correlated with the degree of injury to the stomach. Pharmacological blockade of H2 receptors by cimetidine (100 moles/kg) and methiamide (410 moles/kg) largely prevented the formation of experimental ulcers and the decrease in the pepsinogen level. The results indicate that endogenous histamine participates in the mechanism of formation of dystrophic gastric lesions.Department of Pharmacology, Institute of Experimental Medicine, Academy of Medical Sciences of the USSR, Leningrad. (Presented by Academician of the Academy of Medical Sciences of the USSR S. V. Anichkov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 88, No. 8, pp. 151–153, August, 1979.     

Inhibitory effect of famotidine on cat gastric secretion

The inhibitory effect of the novel H2 receptor antagonist famotidine was studied in conscious gastric fistula cats against dimaprit-induced hypersecretion, in comparison with ranitidine. On the secretory plateau induced by dimaprit (2 mol kg^–1 h^–1) famotidine (0.05–0.2 mol kg^–1 i.v.) exerted a dose-dependent inhibitory effect, being approximately 4.5 times as potent as ranitidine (ID₅₀ values were 0.067±0.015 and 0.30±0.025 mol kg^–1 for famotidine and ranitidine, respectively). No significant differences were found between the two drugs, as for the time-course of the inhibitory effect. Famotidine (0.01–0.32 mol kg^–1 h^–1) caused a parallel displacement of the dose-response curve to dimaprit to the right, without reducing the maximum response to the stimulant, thus behaving as a competitive antagonist, like ranitidine. pA₂ values for famotidine and ranitidine were 7.95 and 6.92, respectively. In the same range of doses famotidine dose-dependently reduced also the secretory response to histamine. From these data it was concluded that famotidine is a potent histamine H2 receptor antagonist in the cat gastric mucosa; moreover, conversely from in vitro data, the antagonism was surmountable even at the highest doses tested. In vivo experiment, therefore, did not reveal any particular feature of this compound, apart from the undoubtedly high potency, in comparison with other members of the family.     

Leucotrienes,SRS-A and the vascular manifestations of PCA

In order to study possible mediators of the vascular manifestations of passive cutaneous anaphylaxis (PCA), several arachidonic acid metabolites were injected into guinea-pig skin. SRS-A, LTB4, LTC and LTD increased vascular permeability, responses to LTs being enhanced by PGE2. Mepyramine inhibited responses to histamine, but not those to SRS-A and LTs: the latter were inhibited by the SRS-A antagonist FPL-55712. Both mepyramine and FPL-55712 exert limited inhibitory effects on vascular permeability during PCA. Leukotrienes may contribute towards vascular permeability during PCA.     

Antagonism of histamine and leukotrienes by azelastine in isolated guinea pig ileum

The effects of azelastine on histamine- and leukotriene C₄ and D₄ (LTC₄, LTD₄)-induced contractile responses in isolated guinea pig ileum were investigated. Following a 2-min contact with the ileum, azelastine produced competitive antagonism of histamine (pA₂=8.24). Following a 15-min contact, azelastine at 2.5×10^–9 M exerted competitive antagonism, but at higher concentrations (10, 40 and 160×10^–9M) it not only shifted histamine concentration-effect curves to the right but also suppressed its maximum. Thus, azelastine exerts a dual (competitive/noncompetitive) antagonism of histamine depending upon the concentration and duration of contact. Azelastine and FPL 55712 (a known LT receptor antagonist) produced concentration-dependent antagonism of LTC₄ and LTD₄. Azelastine and compound FPL 55712 also exerted concentration-dependent reversal (relaxation) of pre-existing LTC₄-induced contractions. In conclusion, the potent H₁-histamine and leukotriene receptor blocking activities of azelastine may contribute to its antiasthmatic/antiallergic activities.     

Contractile properties and ultrastructure of three types of muscle fibre in the dogfish myotome

Summary Three main types of fibre can be differentiated in the adult dogfish myotome at the immediate post-anal level. An outer band of muscle consists of 80–90 pale multiply innervated fibres (superficial fibres). These fibres are 80–90 m in diameter, lack M-lines and have a low Ca²⁺-activated myosin ATPase activity. Volume densities of myofibrils (V_v(my,f)) and mitochondria (V_v(mt,f)) are respectively 76 and 9.5%. Beneath this layer are around 8000 red multiply innervated fibres. These have an average diameter of 25–40 m. V_v(my,f) and V_v(mt,f) are 62 and 21% respectively, and M-lines are present. Around 11000 white focally innervated twitch fibres lie beneath the red fibre zone. White fibres with an average diameter of 80–120 m have a high Ca²⁺-activated myosin ATPase activity and V_v(my,f) and V_v(mt,f) are 78 and 5% respectively.Contractile properties of single skinned fibres were determined at 12° C. Maximum Ca²⁺ activated tensions (kN m^–2) and unloaded contraction speeds (muscle lengths s^–1) were 49 and 0.5 for superficial, 70 and 1.4 for red and 180 and 4.4 for white muscle fibres.Superficial fibres have not been reported in other elasmobranchs with the exception of the closely related nursehound (Scyliorhinus stellaris L.) It is suggested that they are specialized for sustained force generation, having a tonic (postural) rather than a locomotor role.     

The “small” conductance chloride channel in the luminal membrane of the rectal gland of the dogfish (Squalus acanthias)

Besides the larger Cl^– channel with a single channel conductance of about 45 pS, a small channel was observed in the luminal membrane of the dogfish rectal gland [9]. In cell excised (inside out) patches with NaCl solution on both sides, the latter channel had a single channel conductance of 11±1 pS (n=21), and its current-voltage relationship was linear in the voltage range+90 to –90 mV. The open state probability increased moderately with negative clamp potentials. Ionic replacement studies revealed a high selectivity of Cl^– over gluconate, sulfate, and iodide, whereas bromide was permeable to some extent. Also the channel is impermeable for Na⁺. The Cl^– channel blocker 5-nitro-2-(3-phenylpropylamino)-benzoate did not affect this small conductance Cl^– channel. It can be concluded that the luminal membrane of stimulated rectal gland cells possesses two types of Cl^– channels, which differ markedly in their characteristics.Supported by Deutsche Forschungsgemeinschaft Gr 480/8 and by NSF and NIH grants to the MDIBL