The effects of AF-DX 116, a cardioselective muscarinic antagonist, on the negative inotropic action of soman, a cholinesterase inhibitor

Baskin, S. I.; Thomsen, R H; Maxwell, Donald M.

doi:10.1016/s0024-3205(97)84352-4

Cited by 3 publications

(2 citation statements)

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“…ACh has a negative inotropic effect in addition to a negative chronotropic action and depresses norepinephrine release at adrenergic nerve terminals in the cardiovascular system via presynaptic muscarinic receptors (36,40). The positive inotropic action of AF-DX 116 is inhibited by propranolol, a b-adrenergic blocker (41). The strong positive inotropic action of AF-DX 116 in SART-stressed rats may thus be caused by an increased contraction of heart muscle due to norepinephrine release through blockage of M2 receptors at sympathetic nerve terminals.…”

Section: Discussionmentioning

confidence: 99%

Blood Pressure and Heart Rate Are Increased by AF-DX 116, a Selective M2 Antagonist, in Autonomic Imbalanced and Hypotensive Rats Caused by Repeated Cold Stress

Hata

Itoh

Funakami

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-Rats exposed to SART (specific alternation of rhythm in temperature) stress, which are ideal animal models for vagotonia-type dysautonomia, show various changes in cardiac and circulatory systems. In this study, attention was directed to cholinergic function in the SART-stressed rat heart and the effects of AF-DX 116, a specific muscarinic M 2 antagonist, on blood pressure and heart rate. The results were compared with those obtained for atropine and pirenzepine. In SART-stressed rats, systolic and diastolic blood pressures (SBP and DBP) were lower than in unstressed rats. Oral AF-DX 116 resulted in greater elevation of DBP than SBP in unstressed rats. In stressed rats, greater and more prolonged elevation of SBP than in unstressed rats was noted, particularly at higher doses. A dose-dependent SBP change in stressed rats, caused by intravenous AF-DX 116, was shifted upward in parallel with that in unstressed groups, unlike with oral administration. The positive chronotropic effect of this drug was smaller in stressed rats than in unstressed rats, in contrast to the pressor effect. SART-stressed rats may thus have an enhanced sympathetic tone in the heart, as well as changes in muscarinic M2 receptors at sympathetic nerve endings and at the heart muscle. The effects of AF-DX 116 on blood pressure and heart rate thus may arise from peripheral action and AF-DX 116 may be useful for treating hypotension related to autonomic imbalance of the vagotonia type.Keywords: Stress, Blood pressure, AF-DX 116, Hypotension, M2 antagonist Blood pressure (BP) is related to sympathetic tone and physical and/ or psychological stress (1 -7). In general, stress is thought to induce hypertension in humans and experimental animals. Rats subjected to SART (specific alternation of rhythm in environmental temperature) stress (8) showed hypotension (9) in a manner different from hypertension in animals subjected to other types of stress such as cold and restraint (10 -12).SART stress is induced through sudden drops in environmental temperature and is a type of repeated or intermittent cold stress in rodents. Experimental animals subjected to SART stress are accepted as animal models of vagotoniatype dysautonomia in consideration of the results of Aschner and Mecholyl tests (13). The stressed animals exhibit pathophysiological abnormalities such as an abnormal galvanic skin response (GSR) (8) and electroencephalogram (EEG) (14), hyperalgesia (15), thrombocytopenia (16), as well as hypotension (9). In cardiac and circulatory systems, the animals show tachycardia, short PQ and long QRS intervals and high voltage in R waves on electrocardiograms (ECG) (17), and blood flow either increases or decreases in the arteries (9, 18). In the cholinergic system, a decrease in acetylcholine (ACh) content and an elevation of the synthesis and hydrolysis of ACh in the brain (19) were noted in addition to an increase in ACh content, a decrease in ACh-esterase activity and the number of muscarinic ACh receptors in the small intestine (20).SART-stres...

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Section: Discussionmentioning

confidence: 99%

Blood Pressure and Heart Rate Are Increased by AF-DX 116, a Selective M2 Antagonist, in Autonomic Imbalanced and Hypotensive Rats Caused by Repeated Cold Stress

Hata

Itoh

Funakami

et al. 2001

Japanese Journal of Pharmacology

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“…These ligands are structural congeners, and of all the compounds tested, NGD-3350 shows the highest binding affinity to pM 2 . 16 The AS-MS-based binding experiments revealed that all the ligands show saturable single-site binding to pM 2 like the M 2 -specific control antagonist AF-DX-116 29,30 (Fig. 3B).…”

Section: Discovery Of Novel Pm 2 Achr Ligands By Screening Small-molementioning

confidence: 94%

Discovery and Characterization of Orthosteric and Allosteric Muscarinic M2 Acetylcholine Receptor Ligands by Affinity Selection–Mass Spectrometry

Whitehurst¹,

Nazef²,

Annis³

et al. 2006

SLAS Discovery

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Screening assays using target-based affinity selection coupled with high-sensitivity detection technologies to identify smallmolecule hits from chemical libraries can provide a useful discovery approach that complements traditional assay systems. Affinity selection-mass spectrometry (AS-MS) is one such methodology that holds promise for providing selective and sensitive high-throughput screening platforms. Although AS-MS screening platforms have been used to discover smallmolecule ligands of proteins from many target families, they have not yet been used routinely to screen integral membrane proteins. The authors present a proof-of-concept study using size exclusion chromatography coupled to AS-MS to perform a primary screen for small-molecule ligands of the purified muscarinic M 2 acetylcholine receptor, a G-protein-coupled receptor. AS-MS is used to characterize the binding mechanisms of 2 newly discovered ligands. NGD-3350 is a novel M 2 -specific orthosteric antagonist of M 2 function. NGD-3366 is an allosteric ligand with binding properties similar to the allosteric antagonist W-84, which decreases the dissociation rate of N-methyl-scopolamine from the M 2 receptor. Binding properties of the ligands discerned from AS-MS assays agree with those from in vitro biochemical assays. The authors conclude that when used with appropriate small-molecule libraries, AS-MS may provide a useful high-throughput assay system for the discovery and characterization of all classes of integral membrane protein ligands, including allosteric modulators. (Journal of Biomolecular

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Observation of the effect of posterior scleral reinforcement combined with orthokeratology and 0.01% atropine in the treatment of congenital myopia: a case report

Yan,

Zhao,

Gao

et al. 2023

BMC Ophthalmol

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Background Myopia has recently emerged as a significant threat to global public health. The high and pathological myopia in children and adolescents could result in irreversible damage to eye tissues and severe impairment of visual function without timely control. Posterior scleral reinforcement (PSR) can effectively control the progression of high myopia by limiting posterior scleral expansion, improving retrobulbar vascular perfusion, thereby stabilizing the axial length and refraction of the eye. Moreover, orthokeratology and low concentrations of atropine are also effective in slowing myopia progression. Case presentation A female child was diagnosed with binocular congenital myopia and amblyopia at the age of 3 and the patient’s vision had never been rectified with spectacles at the first consultation. The patient’s ophthalmological findings suggested, high refractive error with low best corrected visual acuity, longer axial length beyond the standard level of her age, and fundus examination suggesting posterior scleral staphyloma with weakened hemodynamics of the posterior ciliary artery. Thereby, PSR was performed to improve fundus health and the combination of orthokeratology and 0.01% atropine were performed to control the development of myopia. Following up to 8 years of clinical treatment and observations, the progression of myopia could be well controlled and fundus health was stable. Conclusion In this report, 8-year of clinical observation indicated that PSR could improve choroidal thickness and hemodynamic parameters of the retrobulbar vessels, postoperative orthokeratology combined with 0.01% atropine treatment strategy may be a good choice for myopia control effectively.

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The effects of AF-DX 116, a cardioselective muscarinic antagonist, on the negative inotropic action of soman, a cholinesterase inhibitor

Cited by 3 publications

References 0 publications

Blood Pressure and Heart Rate Are Increased by AF-DX 116, a Selective M2 Antagonist, in Autonomic Imbalanced and Hypotensive Rats Caused by Repeated Cold Stress

Blood Pressure and Heart Rate Are Increased by AF-DX 116, a Selective M2 Antagonist, in Autonomic Imbalanced and Hypotensive Rats Caused by Repeated Cold Stress

Discovery and Characterization of Orthosteric and Allosteric Muscarinic M2 Acetylcholine Receptor Ligands by Affinity Selection–Mass Spectrometry

Observation of the effect of posterior scleral reinforcement combined with orthokeratology and 0.01% atropine in the treatment of congenital myopia: a case report

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