Interstitial cells of Cajal in the plane of the myenteric plexus (ICC-MY) serve as electrical pacemakers in the stomach and small intestine. A similar population of cells is found in the colon, but these cells do not appear to generate regular slow wave potentials, as characteristic in more proximal gut regions. Ca²⁺ handling mechanisms in ICC-MY of the mouse proximal colon were studied using confocal imaging of muscles from animals expressing GCaMP6f exclusively in ICC. ICC-MY displayed stochastic, localized Ca²⁺ transients that seldom propagated between cells. Colonic ICC express ANO1 channels, so Ca²⁺ transients likely couple to activation of spontaneous transient inward currents (STICs) in these cells. The Ca²⁺ transients were due to Ca²⁺ release and blocked by cyclopiazonic acid (CPA), thapsigargin and caffeine, but unaffected by tetracaine. Antagonists of L- and T-type Ca²⁺ channels and reduction in extracellular Ca²⁺ had minimal effects on Ca²⁺ transients. We reasoned that STICs may not activate regenerative Ca²⁺ waves in ICC-MY because voltage-dependent Ca²⁺ conductances are largely inactivated at the relatively depolarized potentials of colonic muscles. We tested the effects of hyperpolarization with pinacidil, a K_ATP agonist. Ca²⁺ waves were initiated in some ICC-MY networks when muscles were hyperpolarized, and these events were blocked by a T-type Ca²⁺ channel antagonist, NNC 55-0396. Ca²⁺ waves activated by excitatory nerve stimulation were significantly enhanced by hyperpolarization. Our data suggest that colonic ICC-MY are conditional pacemaker cells that depend upon preparative hyperpolarization, produced physiologically by inputs from enteric inhibitory neurons and necessary for regenerative pacemaker activity.

01 Jan 2025·The Journal of Clinical Hypertension

Dissecting Causal Relationships Between Antihypertensive Drug, Gut Microbiota, and Type 2 Diabetes Mellitus and Its Complications: A Mendelian Randomization Study

Article

Author: Zheng, He ; Wang, Wenbin ; Qiu, Weida ; Wu, Shiping ; Feng, Yingqing

ABSTRACTLimited research has investigated the impact of antihypertensive medications on type 2 diabetes mellitus (T2DM) and whether gut microbiome (GM) mediates this association. Thus, we conducted a two‐sample Mendelian randomization (MR) analysis to estimate the potential impact of various antihypertensive drug target genes on T2DM and its complications. Genetic instruments for the expression of antihypertensive drug target genes were identified with expression quantitative trait loci (eQTL) in blood, which should be associated with systolic blood pressure (SBP). Sensitivity analysis, including reverse causality detection, horizontal pleiotropy, phenotype scanning, and Bayesian colocalization, was used to validate our findings. We performed a two‐step MR to detect the mediating role of GM. A 1‐standard deviation (SD) decrease of KCNJ11 (acting on arteriolar smooth muscle, e.g., Pinacidil) gene expression was associated with lower SBP of 1.12 (95% confidence interval [CI], 0.93–1.31) mmHg, and a decreased risk of diabetic retinopathy (odds ratio [OR], 0.63; 95% CI, 0.52–0.76). Similarly, a 1‐SD decrease of SLC12A2 (genetically a proxy for diuretics, for example, Torasemide) gene expression was correlated with a reduced risk of T2DM (OR, 0.88; 95% CI, 0.83–0.92). Interestingly, this causal effect was influenced by a decrease in the gut microbiota abundance of the genus Ruminococcus (effect proportion = 11.2%). Colocalization supports these results (KCNJ11: 98% for diabetic retinopathy; SLC12A2: 99% for T2DM). Findings provide novel targets for the treatment of T2DM and its complications, emphasize the importance of KCNJ11 and SLC12A2 in future drug development, and highlight the significant mediating role of the genus Ruminococcus.

01 Oct 2024·Heart Rhythm

Origin of ventricular fibrillation triggers in a model of localized repolarization heterogeneity

Article

Author: Renard, Estelle ; Bear, Laura R. ; Haïssaguerre, Michel ; Bear, Laura R ; Bernus, Olivier

BACKGROUNDHeterogeneities in ventricular repolarization contribute significantly to the genesis of ventricular fibrillation (VF). Although clinical arrhythmias are spontaneously triggered by premature ventricular complexes, these triggers are difficult to document and little is known about their site of origin.OBJECTIVESThe purpose of this study was to characterize spontaneous VF initiation in an experimental model of repolarization heterogeneity and to identify the origin of triggers in relation to the spatial dispersion of repolarization.METHODSSpatially limited repolarization heterogeneity was created in isolated perfused porcine right ventricles (N = 16) by local administration of pinacidil (20 μM) in a terminal branch of the right coronary artery. High-resolution optical mapping and pseudo-electrocardiography were performed under control conditions and after pinacidil perfusion.RESULTSNo arrhythmia occurred at baseline, but 74 VF episodes were observed in 13 hearts (82%) after pinacidil perfusion and were most often initiated by a ventricular trigger with a short coupling interval (297 ± 66 ms). Sixteen VF initiations were optically mapped in 4 hearts. Mapping showed triggers originating in all cases from the border zone between altered and normal repolarization areas where local action potential duration and repolarization time gradients were steep (15.9 and 15.8 ms/mm vs 1.5 and 3.0 ms/mm at nontrigger sites). Optical action potential traces were compatible with a phase 2 reexcitation mechanism. The subsequent VF cycles were driven by activities located in the same region.CONCLUSIONThis model of localized repolarization heterogeneity is able to produce spontaneous VF initiation. Our study demonstrates that VF triggers originate consistently from the border zone of repolarization dispersion.

100 Deals associated with Pinacidil

External Link

KEGG	Wiki	ATC	Drug Bank
D05482	Pinacidil	C02LX01	DB06762

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