PubMed Health⌕ Search

Biomedical subjects

S Kigoshi

Publications and source records attributed to S Kigoshi.

At least 19 recordsLinked to original sources
PubMed1992

Neurogenic responses of urethra isolated from the dog.

Electrical transmural stimulation evoked contraction and relaxation in isolated urethral circular muscle of the dog. The responses were abolished by tetrodotoxin, indicating their neurogenic origin. The contractile force in the middle urethra was greater than that in the proximal and distal urethra. The contractions were not affected by atropine and propranolol, but were completely inhibited by phenoxybenzamine, prazosin and guanethidine. In preparations contracted with prostaglandin F2 alpha, electrical stimulation induced frequency-dependent relaxation in all urethral portions. Atropine, phenoxybenzamine, prazosin and guanethidine had no effect on the relaxation, while propranolol slightly attenuated the relaxation induced at the highest frequency used (5 Hz). The non-adrenergic, non-cholinergic relaxation was also not affected by ketanserin, methysergide, diphenhydramine, alpha,beta-methylene ATP or capsaicin. Exogenously applied phenylephrine and clonidine both produced contractions but the maximal response to clonidine was much smaller than that to phenylephrine. Acetylcholine produced no or feeble contractions. In the preparations contracted with prostaglandin F2 alpha, isoproterenol and vasoactive intestinal polypeptide (VIP) produced relaxation. These results suggest that the circular muscle of dog urethra is reciprocally innervated by sympathetic adrenergic and non-adrenergic, non-cholinergic nerves, and that the neurogenic responses are markedly affected by muscle tension and the portion of the urethra examined.

Animals↗
PubMed1992

5-Methylurapidil may discriminate between alpha 1-adrenoceptors with a high affinity for WB4101 in rat lung.

The alpha 1-adrenoceptors of rat lung with a high affinity for [3H]-prazosin were subdivided into two populations (high and low affinity sites) by WB4101 and 5-methylurapidil but the proportions were different between both drugs. After pretreatment with chlorethylclonidine, WB4101 recognized only high affinity sites, while 5-methylurapidil still detected high and low affinity sites. These results indicate that alpha 1-adrenoceptors with a high affinity for WB4101 are not homogeneous in the rat lung, suggesting the possible existence of a new alpha 1-adrenoceptor subtype in addition to alpha 1A and alpha 1B subtypes.

Adrenergic alpha-Antagonists↗
PubMed1992

Identification of alpha 1-adrenoceptor subtypes in the rat vas deferens: binding and functional studies.

1. The alpha 1-adrenoceptor subtypes of the prostatic and epididymal portion of rat vas deferens were characterized in binding and functional experiments. 2. In saturation experiments, [3H]-prazosin bound to two distinct affinity sites in the epididymal portion of rat vas deferens (pKD = 10.1 +/- 0.13 and 9.01 +/- 0.15, Bmax = 507 and 1231 fmol mg-1 protein, respectively). In the prostatic portion [3H]-prazosin bound to a single affinity site (pKD = 9.82 +/- 0.04, Bmax = 924 fmol mg-1 protein). 3. In the displacement experiments, unlabelled prazosin displaced biphasically the binding of 200 pM [3H]-prazosin to the epididymal portion; the resulting two pKI values were consistent with the affinity constants obtained in the saturation experiments. WB4101 (2-(2,6-dimethoxy-phenoxyethyl)-amino-methyl-1,4-benzodioxane) and benoxathian also discriminated the two affinity sites in the epididymal portion and the population of low affinity sites for the three antagonists was approximately 40%. On the other hand, the prostatic portion predominantly showed a single affinity site for prazosin, WB4101 and benoxathian, although the presence of a small proportion (less than 10%) of the low affinity site could be detected. HV723 (alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy)ethyl)-a min o)- propyl) benzeneacetonitrile fumarate) displaced the [3H]-prazosin binding monophasically with a low affinity in both halves. 4. Pretreatment with chlorethylclonidine (CEC) at concentrations higher than 1 microM inhibited 700 pM [3H]-prazosin binding to the prostatic portion by approximately 50%. However, the inhibition in the epididymal portion was much less (approximately 21% at 50 microM CEC).5. In the functional study, the contractile response to noradrenaline was competitively inhibited by prazosin, WB4101, benoxathian and HV723 with similar and low affinities (pKB value ranging from 8.0to 9.0) in the epididymal portion of rat vas deferens. In the prostatic portion of rat vas deferens,noradrenaline also produced a contraction, but the maximal amplitude of contraction developed was approximately one-fourth of that in the epididymal portion. Prazosin and WB4101 also inhibited the contractile response of the prostatic portion with the pKB values similar to those obtained in the epididymal portion. The contractions to noradrenaline in both portions were potently attenuated by 1 LM nifedipine but were not affected by pretreatment with 1O LM CEC.6. Under conditions where P2x-purinoceptors and prejunctional M2-adrenoceptors were blocked, electrical transmural stimulation produced a rapidly developing phasic contraction and a subsequent tonic contraction in the epididymal portion of rat vas deferens. The phasic and tonic contractions were inhibited in a concentration-dependent manner by prazosin (ICs = 25.7 and 25.9 nm, respectively),WB4101 (ICo= 7.27 and 7.58 nM), benoxathian (ICs = 10.9 and 8.66 nM) and HV723 (ICs = 15.9 and 14.9 nM). Nifedipine selectively attenuated the tonic contraction induced by electrical stimulation, and the residual phasic response was inhibited by the antagonists mentioned above with similar affinities to those in the absence of nifedipine. CEC (10 gM) had little effect on the adrenergic neurogenic contractions.7. The present results indicate the presence of two distinct alpha&-adrenoceptor subtypes in the rat vas deferens, which show respectively high and low affinities for each of prazosin, WB4101 and benoxathian,and presumably correspond to putative MIA and alL subtypes according to the recent am-adrenoceptorsubclassifications. The contractions induced by exogenous and endogenous noradrenaline seem to be predominantly mediated through the alL subtype. The heterogeneous distribution of the low affinity sites(alL subtype) may well explain differences in functional responsiveness between the two portions of rat vas deferens.

Acetonitriles↗
PubMed1992

Selectivity of bevantolol hydrochloride towards alpha- and beta-adrenoceptor subtypes in rat cerebral cortex.

Selectivity of bevantolol hydrochloride (NC-1400) towards alpha- and beta-adrenoceptor subtypes of rat cerebral cortex was examined in binding experiments and compared with propranolol. Bevantolol biphasically displaced the 3H-dihydroalprenolol binding. The affinity of bevantolol to beta 1-adrenoceptor was equal to that of propranolol. Bevantolol displaced 3H-prazosin binding monophasically but not 3H-p-aminoclonidine binding. These results suggest that bevantolol is a beta 1-adrenoceptor antagonist with a relatively high affinity to alpha 1-adrenoceptor subtypes.

Adrenergic beta-Antagonists↗
PubMed1992

In vitro pharmacological profile of the novel alpha 1-adrenoceptor antagonist HSR-175.

The pharmacological profile of HSR-175, a new alpha 1-adrenoceptor antagonist, was studied in vitro and compared with those of other alpha 1-antagonists. HSR-175, prazosin, bunazosin and yohimbine competitively antagonized the contractile responses induced by noradrenaline in the dog mesenteric arteries and the rabbit thoracic aorta. The pA2 values for HSR-175 in the dog mesenteric arteries and the rabbit aorta were 10.38 and 9.63, respectively, which were significantly higher than those for prazosin (8.39 and 8.80), bunazosin (8.44 and 8.75) and yohimbine (7.34 and 6.10). HSR-175 also inhibited the sympathetic adrenergic contraction induced by electrical transmural stimulation in the dog mesenteric arteries, and the inhibitory effect of HSR-175 was more potent than those of prazosin and bunazosin. Although HSR-175 also possessed competitive antagonist properties at pre- and postsynaptic alpha 2-adrenoceptors in the rat vas deferens and the dog saphenous veins, those affinities (pA2 = 6.41 and 7.05) were much lower than those at postsynaptic alpha 1-adrenoceptors. Furthermore, HSR-175 at concentration of 10(-6) M showed no inhibition on the contractile responses to 5-HT, histamine, KCl and angiotensin II in the rabbit thoracic aorta. These results indicate that HSR-175 is a very potent and selective alpha 1-adrenoceptor antagonist.

Adrenergic alpha-Antagonists↗
PubMed1992

Tizanidine may discriminate between imidazoline-receptors and alpha 2-adrenoceptors.

The selectivity of tizanidine to the imidazoline-receptor and alpha 2-adrenoceptor recognized by 3H-p-aminoclonidine was examined in rat kidney membranes and was compared with those of other imidazoline compounds. Tizanidine bound to the imidazoline-receptors with approximately 20 times higher affinity than the alpha 2-adrenoceptors. The order of relative selectivity to imidazoline receptor was tizanidine greater than oxymetazoline greater than clonidine greater than naphazoline, where clonidine showed an equal affinity to both receptors. Tizanidine may act more potently on the imidazoline-receptors than the alpha 2-adrenoceptors.

Animals↗
PubMed1992

Effect of pentazocine on the cytotoxicity of cortisone-resistant lymphocytes from mouse thymus.

Pentazocine and its related compounds were examined for their effect on the cytotoxicity of cortisone-resistant lymphocytes (CR lymphocytes) against Ehrlich carcinoma cells. The following compounds were used: pentazocine, naloxone, levallorphan, eptazocine and morphine. CR lymphocytes were obtained from the thymus or spleens of mice injected i.p. with hydrocortisone acetate (125 mg/kg) 2 days before harvesting the lymphocytes. The mixture of tumor cells and CR lymphocytes was inoculated s.c. into mice after incubation in the presence or absence of 10 microM drugs. Five weeks after inoculation, the percentage of mice developing a solid tumor among the recipients given the pentazocine-treated cell mixture of tumor cells and thymic CR lymphocytes was significantly smaller than the percentage in recipients given the cell mixture treated with or without other drugs (percent tumor takes: 21% and about 80%, respectively). Splenic CR lymphocytes did not show any cytotoxic effect, irrespective of the drug treatment. The pretreatment of CR lymphocytes or Ehrlich cells with 10 microM pentazocine did not affect the cytotoxicity of thymic and splenic CR lymphocytes. The proportion of the lymphocyte-conjugated tumor cells was significantly increased when the mixture of CR lymphocytes and tumor cells was incubated in the presence of pentazocine. The present results indicate that the cytotoxicity of thymic CR lymphocytes is enhanced by pentazocine possibly through the increase in the proportion of the lymphocyte-conjugated tumor cells but enhanced not by the other drugs.

Animals↗
PubMed1991

Supersensitivity to tetrodotoxin and lignocaine of sea anemone toxin II-treated sodium channel in guinea-pig ventricular muscle.

1. Sea anemone toxin II (ATX II, 20-30 nM) doubled the action potential duration in guinea-pig papillary muscles without affecting the maximum rate of rise of the action potential (Vmax) and the resting potential. 2. Tetrodotoxin and lignocaine shortened the prolonged action potential in the ATX II-treated papillary muscles in concentrations (30 nM - 3 microM) at which these drugs did not suppress the Vmax. 3. Whole-cell voltage-clamp experiments with single ventricular cells showed that ATX II produced a slowly decaying inward sodium current following a transient sodium current upon depolarization. 4. The ATX II-induced slowly decaying current was reduced by tetrodotoxin or lignocaine in concentrations (300 nM-1 microM for tetrodotoxin, 3-10 microM for lignocaine) at which these drugs failed to affect the Vmax in cells not treated with ATX II. 5. These results suggest that sodium channel modification by ATX II not only changes its kinetics but also increases the susceptibility of the channel to block by tetrodotoxin and lignocaine.

Action Potentials↗
PubMed1991

Three distinct binding sites for [3H]-prazosin in the rat cerebral cortex.

1. The putative alpha 1-adrenoceptor subtypes of rat cerebral cortex membranes were characterized in binding. 2. Specific binding of [3H]-prazosin was saturable between 20-5000 pm. Scatchard plots of the binding data were non-linear, indicating the presence of two distinct affinity sites for prazosin (pKD, high = 10.18, Rhigh = 308 fmol mg-1 protein; pKD, low = 8.96, Rlow = 221 fmol mg-1 protein). 3. In the membranes pretreated with chlorethylclonidine (CEC) two affinity sites for prazosin were also observed: the affinities were similar to those without CEC pretreatment, but the maximum numbers of binding sites were reduced by CEC pretreatment to 23 and 62% for prazosin-high (Rhigh) and low affinity sites (Rlow), respectively. 4. The prazosin-high affinity sites were further subdivided into two subclasses by WB4101(2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane) and phentolamine; the low affinity sites for WB4101 and phentolamine were more potently inactivated by CEC as compared with the high affinity sites. On the other hand, prazosin, HV723 (alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy)ethyl)- amino )-propyl)benzeneacetonitrile fumarate) and yohimbine inhibited [3H]-prazosin binding to prazosin-high affinity sites monophasically. 5. In addition to the high affinity sites, the prazosin-low affinity sites were labelled at high concentrations of [3H]-prazosin. Thus, prazosin and WB4101 showed shallow displacement curves. On the other hand, HV723 and yohimbine did not discriminate between prazosin-high and low affinity sites. 6. Two distinct alpha 1-adrenoceptor subclassifications have been recently proposed (alpha 1A, alpha 1B subtypes and alpha 1H, alpha 1L, alpha 1N subtypes). 5. In both motoneurones and dorsal root fibres, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) effectively depressed the depolarization induced by kainoids, and neither 3-[(+/-)-2-carboxypiperazin-4-yl]propyl-1- phosphonic acid (CPP) nor picrotoxin blocked or affected the depolarization, but there were some differences in pharmacological potencies of glutamate antagonists between both preparations.6. MFPA, HFPA and acromelic acids should provide valuable pharmacological tools for analysis of physiological functions of excitatory amino acids, in particular, as specific agonists for some subtypes of kainate receptors.

Adrenergic beta-Antagonists↗
PubMed1991

Pharmacological profile of the novel alpha-adrenoceptor antagonist KT-611 (naftopidil).

The pharmacological profile of a new alpha-adrenoceptor antagonist, KT-611 (naftopidil), was studied in vitro. In the dog mesenteric and carotid arteries and in the rabbit, guinea pig and rat thoracic aortae, KT-611 competitively inhibited alpha 1-adrenoceptor-mediated contractions induced by noradrenaline with pA2 values ranging from 6.73 to 8.15. KT-611 also inhibited the postjunctional alpha 2-adrenoceptor-mediated contractions in the dog saphenous vein (pA2 = 6.77) or dog basilar artery. However, the responses mediated through prejunctional alpha 2-adrenoceptors (rat vas deferens), beta-adrenoceptors (rat atria), muscarinic receptors (guinea pig ileum) and 5-HT2 receptors (dog mesenteric artery) were little affected by KT-611. KT-611 also inhibited the sympathetic adrenergic contraction evoked by electrical transmural stimulation in the dog mesenteric artery, and the inhibition was not relieved upon repetitive washing for 1 hour with the drug-free solution. 3H-prazosin and 3H-clonidine binding to the rat cortex membranes was inhibited by KT-611 with pKi values of 7.69 and 5.75, respectively. These results suggest that KT-611 is an alpha 1-adrenoceptor antagonist with a weak antagonistic activity to postjunctional alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1991

Subtypes of alpha 1-adrenoceptors involved in noradrenaline-induced contractions of rat thoracic aorta and dog carotid artery.

We tried to determine alpha 1-adrenoceptor subtypes involved in noradrenaline-induced contractions of rat thoracic aorta and dog carotid artery. Prazosin competitively antagonized the contractions induced by noradrenaline in both the arteries with a high pKB value (approximately 9.7). WB4101, benoxathian, phentolamine, HV723 and 5-methylurapidil also competitively antagonized the responses to noradrenaline in both the arteries: however, the affinities for the antagonists were significantly higher in the rat thoracic aorta than in the dog carotid artery. The affinities for the competitive antagonists were not changed by treatment with nifedipine. In the rat thoracic aorta, chlorethylclonidine (CEC) elicited either a persistent contraction with rhythmic activities before treatment with nifedipine or partial inactivation of alpha 1-adrenoceptors in the presence of nifedipine. On the other hand, CEC produced only inactivation of alpha 1-adrenoceptors in the dog carotid artery. These results suggest that noradrenaline-induced contractions of the rat thoracic aorta and dog carotid artery are respectively mediated through distinct alpha 1-adrenoceptor subtypes. According to the alpha 1A, alpha 1B subclassification, the alpha 1-adrenoceptor of dog carotid artery is like the alpha 1B subtype, while that of rat thoracic aorta is atypical. Both subtypes are also identified as a high affinity site for prazosin (alpha 1H subtype) in the alpha 1H, alpha 1L and alpha 1N subclassification.

Adrenergic alpha-Antagonists↗
PubMed1991

Differing susceptibilities to cold preservation of rat atria and ventricles.

The susceptibilities of atria and ventricles to cold preservation were studied in rat hearts. Rat hearts were stored in Collins' solution at 4 degrees C for 0, 12, or 24 hours, and the atrial and ventricular function was measured in a working heart model and in isolated atrial and papillary muscle preparations. In working heart preparations, cardiac output decreased to 0 ml/min and other parameters of ventricular function (systolic and end-diastolic pressure and dP/dt of the left ventricle) markedly deteriorated after 12 hours of preservation. After 24 hours, no contraction of the left ventricle was observed despite the presence of atrial contraction. In isolated atrial muscle preparations, the rate of spontaneous beating of the right atrium was not affected by cold preservation. The twitch contractions of right and left atria were attenuated but elicited after 24 hours. In electrically driven papillary muscles, twitch contractions were also markedly attenuated by 12 hours of preservation and were abolished after 24 hours. The positive inotropic effect of isoproterenol was also markedly attenuated in the atrial preparations by cold preservation. However, the positive chronotropic response to isoproterenol and the negative chronotropic and inotropic responses to carbachol were little affected by cold preservation. Intramural cholinergic and adrenergic nerve stimulation produced first negative and then positive effects on the beating rate and twitch contraction in the isolated right atria. Cold preservation selectively attenuated and finally abolished the adrenergic responses. In the ventricles, the adenosine triphosphate and creatine phosphate content significantly decreased and the lactate content increased with an increase in the preservation period. On the other hand, changes of such metabolites in the atria were either not observed or were much smaller. These results suggest that atrial function is maintained better than ventricular function in the cold-preserved heart.

Animals↗
PubMed1990

Supersensitivity to tetrodotoxin and lidocaine of anthopleurin-A-treated Na+ channels in crayfish giant axon.

Anthopleurin-A produced two distinct responses in crayfish giant axons: depolarization and prolongation of action potentials. The depolarization was prominent at low concentrations of anthopleurin-A, while a remarkable prolongation of the action potential was produced by higher concentrations of anthopleurin-A. Both effects of anthopleurin-A were inhibited by pre- or posttreatment with tetrodotoxin or lidocaine at concentrations which had not effect on the normal sodium channel. The prolongation of the action potential was more sensitive to tetrodotoxin and lidocaine than the depolarization was. These results suggest that sodium channels of the crayfish giant axon are modified by anthopleurin-A in at least two ways, thereby resulting in sensitization to tetrodotoxin and lidocaine.

Action Potentials↗
PubMed1990

Effects of TYB-3823, a new antiarrhythmic drug, on the electrophysiological properties of guinea-pig ventricular muscles.

1. The effects of TYB-3823 (B-GYKI 38233), a new antiarrhythmic drug, were electrophysiologically examined in the guinea-pig ventricular muscles. 2. TYB-3823 at concentrations of 1-3 x 10(-7) M significantly prolonged the action potential duration (APD) of the papillary muscle. However, the resting potential, action potential amplitude and maximum rate of depolarization (Vmax) were unaffected by the drug at such concentrations. At a higher concentration (1 x 10(-4) M) TYB-3823 reduced Vmax. 3. Voltage clamp experiments with single ventricular cells revealed that TYB-3823 at concentrations higher than 1 x 10(-7) M reduced the outward potassium currents, especially the time-dependent outward current, but that TYB-3823 failed to affect the calcium current. 4. These results suggested that TYB-3823 at low concentrations reduces the outward potassium current to give rise to a prolongation of APD and that at higher concentrations it additionally inhibits the sodium channels; both the effects may be related to the antiarrhythmic action of this drug.

Action Potentials↗
PubMed1990

Electrophysiological and mechanical effects of calcitonin gene-related peptide on guinea-pig atria.

1. The effects of calcitonin gene-related peptide (CGRP) on mechanical and electrophysiological responses were studied in the guinea-pig atrial muscle preparations and in single cells. 2. CGRP (greater than 10(-9) M) enhanced the twitch contraction in a concentration-dependent manner in electrically driven left atria and increased heart rate in spontaneously beating right atria. The positive inotropic and chronotropic effects of CGRP were not inhibited by propranolol but were attenuated by reduction of the calcium concentration in the bathing medium. 3. In single left atrial cells, CGRP slightly hyperpolarized the resting potential but did not affect the other action potential parameters significantly. 4. Under whole-cell voltage-clamp conditions, CGRP increased the calcium inward current. The peptide also increased the steady inward current elicited by hyperpolarization and the late outward current by depolarization. 5. These results suggest that CGRP may produce the positive inotropic and presumably chronotropic effects by increasing calcium inward current. CGRP also increases the potassium permeability. Such effects on ionic currents may not produce any apparent change in the action potential conformation, due to their opposite directional actions and relatively weak potencies.

Action Potentials↗
PubMed1990

Somatostatin decreases the calcium inward current in guinea-pig atria.

1. The effects of somatostatin on mechanical and electrophysiological responses were studied in guinea-pig atrial muscle preparations and single cells. 2. Somatostatin (greater than or equal to 10(-8) M) decreased the twitch contraction in a concentration-dependent manner in electrically driven left atria and spontaneously beating right atria. However, the beating rate was not affected. 3. The negative inotropic effect of somatostatin was transient. Desensitization to this agent developed slowly during continuous exposure to the peptide. 4. In single atrial cells, somatostatin significantly shortened the action potential duration, but the resting potential and action potential amplitude were not affected. 5. Under whole cell voltage-clamp conditions, somatostatin decreased the calcium inward current without affecting the sodium and potassium currents. 6. These results suggest that somatostatin selectively acts on the calcium channel of guinea-pig atrial cells to reduce the calcium inward current, which in turn gives rise to the negative inotropic effect.

Action Potentials↗
PubMed1990

Two distinct alpha 1-adrenoceptor subtypes involved in noradrenaline contraction of the rabbit thoracic aorta.

1. Recently, alpha 1-adrenoceptors in blood vessels have been classified into three subtypes (alpha 1H, alpha 1L and alpha 1N). We examined which subtype (or subtypes) is involved in the noradrenaline-induced contraction of rabbit thoracic aorta. 2. Noradrenaline produced a concentration-dependent contraction in the rabbit isolated thoracic aorta. Prazosin antagonized the contractions to noradrenaline, resulting in a rightward displacement of the concentration-response curve. However, the shift was not proportional to the concentration of prazosin; Schild plots showed that the inhibition by prazosin was biphasic, implying that noradrenaline acted through two receptor populations. Two affinity constants (pKB values of 10.02 and 8.83) were determined for prazosin at these sites. 3. However, under continuous treatment with 1 nM prazosin, or in strips pretreated with chlorethylclonidine (CEC; an alpha 1H inactivating agent) to remove the contribution of one receptor population, prazosin showed a single pKB or pA2 value of approximately 8.3. 4. Yohimbine also produced biphasic antagonism of noradrenaline-induced contractions, resulting in two affinity constants (pKB = 6.52 and 6.17). However, a monophasic Schild plot was obtained for yohimbine either in the presence of 1 nM prazosin (pA2 = 6.08) or in strips pretreated with CEC (pA2 = 6.03). 5. The Schild plot for HV723 (a selective alpha 1N-antagonist) yielded a monophasic slope (pKB = 8.47) and the inhibition was not affected by 1 nM prazosin or CEC-pretreatment. 6. [3H]-prazosin bound to alpha 1-adrenoceptors of the aortic membrane preparations with two different affinities (pKD = 9.94 and 8.37). The high but not the low affinity site was completely masked by 1 nM prazosin and inactivated by pretreatment with CEC. 7. These results strongly suggest that noradrenaline-induced contraction of the rabbit thoracic aorta is mediated through two distinct alpha l-adrenoceptor subtypes, designated alpha 1H and (alpha lL*

Acetonitriles↗