Muscarinic type 1 receptors mediate part of nitric oxide’s vagal facilitatory effect in the isolated innervated rat right atrium

Hogan, Kieran; Markos, F.

doi:10.1016/j.niox.2006.05.005

Cited by 5 publications

(7 citation statements)

References 17 publications

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“…Furthermore, activation of M 3 muscarinic receptors produces heart rate deceleration associated with hyperpolarization of guinea pig atrial myocytes due to activation of a delayed rectifying K + current [40]. Nevertheless, blockade of M 3 muscarinic receptors had no impact on vagal chronotropic effects in rats [22].…”

Section: Introductionmentioning

confidence: 94%

“…Nevertheless, it is uncertain whether cardiac muscarinic cholinoreceptor subtypes other than M 2 contribute to vagal effects on cardiac pacemaker. In this regard, a reduction in negative chronotropic responses elicited by vagal stimulation [1,22,30,33] or exogenously applied acetylcholine [23] after infusion of subtype-selective (M 1 -M 3 ) muscarinic cholinergic receptor antagonists has been shown in some studies. Moreover, on the basis of IC 50 comparisons in the isolated canine right atrium, 4-DAMP, an M 3 muscarinic cholinoreceptor antagonist, may be more potent than AF-DX 116, an M 2 muscarinic cholinoreceptor antagonist, in inhibiting vagal chronotropic responses [1].…”

Section: Introductionmentioning

confidence: 99%

“…In this regard, M 1 and M 2 muscarinic cholinoreceptor antagonists are equipotent in inhibiting vagal chronotropic responses in anesthetized dogs [33]. Moreover, in the vagally innervated rat right atrium, parasympathetic chronotropic effects are inhibited by pirenzepine and synthetic MT7 toxin, M 1 muscarinic cholinoreceptor antagonists [22]. Furthermore, in isolated, perfused chicken hearts, M 1 muscarinic cholinoreceptors are involved in the presynaptic control of vagal stimulationevoked acetylcholine release [5,26].…”

Section: Introductionmentioning

confidence: 99%

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Subtype-selective blockade of cardiac muscarinic receptors inhibits vagal chronotropic responses in cats

Osadchii

2007

Pflugers Arch - Eur J Physiol

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This study was designed to determine if chronotropic responses induced by neurally released acetylcholine are modified by subtype-selective blockade of cardiac muscarinic cholinoreceptors. In anesthetized cats, a single burst of vagal stimulation was generated with an incremental time delay after the P wave of the atrial electrogram (P-Stimulus interval). The slope of the relationships between P-Stimulus and P-P intervals was used to assess changes in responsiveness of cardiac pacemaker to vagal effects throughout the cardiac cycle. An increase in P-Stimulus interval over the initial portion (approximately 120 ms) of the cardiac cycle produced a significant increment in lengthening of the P-P interval. Once the maximal negative chronotropic response was achieved, a further increase in P-Stimulus interval by only approximately 25 ms resulted in profound (by 80-90%) reductions in vagal effects, thus yielding a bimodal vagal phase response curve. Antagonists of M1 (pirenzepine), M2 (methoctramine and gallamine), and M3 (4-DAMP) muscarinic cholinoreceptors produced a reduction in the magnitude of maximal lengthening of cardiac cycle as well as an increase in latency of vagal effects. However, the increment in prolongation of P-P interval induced by a given change in timing of vagal stimulation during cardiac cycle was reduced by M1 and M2 muscarinic receptor blockers, but was unaffected by 4-DAMP. None of the antagonists modified the range of P-Stimulus intervals over which the maximum-to-minimum change of vagal responses occurred. Taken together, these data suggest different contribution of various subtypes of cardiac muscarinic receptors into the negative chronotropic responses induced by brief bursts of vagal stimulation.

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Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Subtype-selective blockade of cardiac muscarinic receptors inhibits vagal chronotropic responses in cats

Osadchii

2007

Pflugers Arch - Eur J Physiol

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“…This toxin was also used to show the major role of the M4 subtype in the inhibition of hippocampal and striatal adenylate cyclase activity as well as in the modulation of the neurotransmission of hippocampal neurons (Sánchez, et al, 2009a;Sánchez, et al, 2009b). The exceptional selectivity of MT7 for the M1 subtype was exploited to demonstrate that the potentiation of NMDA receptor currents in hippocampal CA1 pyramidal cells was mediated by the M1 receptor (Marino et al, 1998) or to confirm that the M1 receptor mediates part of nitric oxide's vagal facilitatory effect in the isolated innervated rat right atrium (Hogan and Markos, 2007). Finally, the group of Fernyhough has shown that, via ERK-CREB signaling activation, MT7 elevates neurite outgrowth and protects from small and large fiber neuropathy in adult sensory neurons (Sabbir and Fernyhough, 2018).…”

Section: Muscarinic Toxins: Muscarinic Receptorsmentioning

confidence: 99%

Structural and Functional Diversity of Animal Toxins Interacting With GPCRs

Baelen

Robin

Kessler

et al. 2022

Front. Mol. Biosci.

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Peptide toxins from venoms have undergone a long evolutionary process allowing host defense or prey capture and making them highly selective and potent for their target. This has resulted in the emergence of a large panel of toxins from a wide diversity of species, with varied structures and multiple associated biological functions. In this way, animal toxins constitute an inexhaustible reservoir of druggable molecules due to their interesting pharmacological properties. One of the most interesting classes of therapeutic targets is the G-protein coupled receptors (GPCRs). GPCRs represent the largest family of membrane receptors in mammals with approximately 800 different members. They are involved in almost all biological functions and are the target of almost 30% of drugs currently on the market. Given the interest of GPCRs in the therapeutic field, the study of toxins that can interact with and modulate their activity with the purpose of drug development is of particular importance. The present review focuses on toxins targeting GPCRs, including peptide-interacting receptors or aminergic receptors, with a particular focus on structural aspects and, when relevant, on potential medical applications. The toxins described here exhibit a great diversity in size, from 10 to 80 amino acids long, in disulfide bridges, from none to five, and belong to a large panel of structural scaffolds. Particular toxin structures developed here include inhibitory cystine knot (ICK), three-finger fold, and Kunitz-type toxins. We summarize current knowledge on the structural and functional diversity of toxins interacting with GPCRs, concerning first the agonist-mimicking toxins that act as endogenous agonists targeting the corresponding receptor, and second the toxins that differ structurally from natural agonists and which display agonist, antagonist, or allosteric properties.

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“…[32][33][34] This negative chronotropic effect in the atria is primarily mediated by mAChRs activation, including M1, and the anticholinergic activity of pirenzepine resumes the heart rate and rhythm. [32][33][34][35] We isolated the right atria from male mice and measured their spontaneous frequency of contraction (control), which was about 360 beats/min (see SI). Application of the muscarinic agonist carbachol (CCh, 1 µM) strongly reduces the frequency to around 200 beats/min (Figure 4) and addition of pirenzepine (PNZ, 1 µM) to the bath restores the frequency almost to control values (Figure 4).…”

Section: Competition Binding and Calcium Imaging Experiments At Muscarinic Receptorsmentioning

confidence: 99%

Rational Design of Photochromic Analogues of Tricyclic Drugs

et al. 2021

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Tricyclic chemical structures are the core of many important drugs targeting all neurotransmitter pathways. These medicines enable effective therapies to treat from peptic ulcer disease to psychiatric disorders. However, when administered systemically they cause serious adverse effects that limit their use. In order to obtain localized and on-demand pharmacological action using light, we have designed photoisomerizable ligands based on azobenzene that mimic the tricyclic chemical structure and display reversibly controlled activity. Pseudo analogs of the tricyclic antagonist pirenzepine demonstrate that this is an effective strategy in muscarinic acetylcholine receptors, showing stronger inhibition upon illumination both in vitro and in cardiac atria ex vivo.Despite the applied chemical modifications to make pirenzepine derivatives sensitive to light stimuli, the most potent candidate of the set, cryptozepine-2, maintained a moderate but promising M1 vs M2 subtype selectivity. These photoswitchable "crypto-azologs" of tricyclic drugs might open a general way to spatiotemporally target their therapeutic action while reducing their systemic toxicity and adverse effects.

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Muscarinic type 1 receptors mediate part of nitric oxide’s vagal facilitatory effect in the isolated innervated rat right atrium

Cited by 5 publications

References 17 publications

Subtype-selective blockade of cardiac muscarinic receptors inhibits vagal chronotropic responses in cats

Subtype-selective blockade of cardiac muscarinic receptors inhibits vagal chronotropic responses in cats

Structural and Functional Diversity of Animal Toxins Interacting With GPCRs

Rational Design of Photochromic Analogues of Tricyclic Drugs

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