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Article ; Online: Permeable Cornified Envelope Layer Regulates the Solute Transport in Human Stratum Corneum.

Zamani Zakaria, Afshin / Jepps, Owen G / Gould, Tim / Anissimov, Yuri G

2023 Volume 112, Issue 7, Page(s) 1939–1946

Abstract: To unravel the diffusion mechanisms of percutaneous drug delivery, suitable numerical analysis of stratum corneum structure is essential. In this research paper, we accounted for the permeable envelope layer in the brick-and-mortar finite element models ... ...

Abstract	To unravel the diffusion mechanisms of percutaneous drug delivery, suitable numerical analysis of stratum corneum structure is essential. In this research paper, we accounted for the permeable envelope layer in the brick-and-mortar finite element models of human stratum corneum. Both penetration and desorption experiments for tritiated water were simulated by transient finite element analysis. Rivet-shaped corneodesmosomes were included in the brick and mortar model. Results showed that cornified lipid permeability (P
MeSH term(s)	Humans ; Models, Biological ; Epidermis ; Diffusion ; Water ; Permeability ; Lipids
Chemical Substances	Water (059QF0KO0R) ; Lipids
Language	English
Publishing date	2023-03-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1016/j.xphs.2023.03.002
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Article ; Online: Acute, pro-contractile effects of prorenin on rat mesenteric arteries.

Rognant, Salomé / Baldwin, Samuel N / Pritchard, Harry A T / Greenstein, Adam / Calloe, Kirstine / Aalkjaer, Christian / Jepps, Thomas A

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2023 Volume 37, Issue 12, Page(s) e23282

Abstract: Prorenin and the prorenin receptor ((P)RR) are important, yet controversial, members of the renin-angiotensin-aldosterone system. The ((P)RR) is expressed throughout the body, including the vasculature, however, the direct effect of prorenin on arterial ... ...

Abstract	Prorenin and the prorenin receptor ((P)RR) are important, yet controversial, members of the renin-angiotensin-aldosterone system. The ((P)RR) is expressed throughout the body, including the vasculature, however, the direct effect of prorenin on arterial contractility is yet to be determined. Within rat mesenteric arteries, immunostaining and proximity ligation assays were used to determine the interacting partners of (P)RR in freshly isolated vascular smooth muscle cells (VSMCs). Wire myography examined the functional effect of prorenin. Simultaneous changes in [Ca
MeSH term(s)	Rats ; Animals ; Renin ; Muscle Contraction ; Myocytes, Smooth Muscle ; Mesenteric Arteries ; Adenosine Triphosphatases
Chemical Substances	Renin (EC 3.4.23.15) ; Adenosine Triphosphatases (EC 3.6.1.-)
Language	English
Publishing date	2023-11-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202301480
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Article ; Online: New ways of delivering the public health agenda--an evaluation of the Warm Homes, Healthy People 'Wrapped Up' project in Northamptonshire, England.

Adedeji, O T / Jepps, A

Public health

2014 Volume 128, Issue 1, Page(s) 101–104

MeSH term(s)	England ; Health Promotion/methods ; Health Status ; Heating ; Housing ; Humans ; Program Evaluation ; Public Health ; State Medicine/organization & administration
Language	English
Publishing date	2014-01
Publishing country	Netherlands
Document type	Evaluation Studies ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	427333-3
ISSN	1476-5616 ; 0033-3506
ISSN (online)	1476-5616
ISSN	0033-3506
DOI	10.1016/j.puhe.2013.09.016
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Article: The impact of an atrial septal defect on the progression of atrial tachypacing-induced atrial fibrillation in a Danish Landrace pig: A case report.

Saljic, Arnela / Norup Hertel, Julie / Leonhardt, Caroline / Dalgas Nissen, Sarah / Dobrev, Dobromir / Jepps, Thomas A / Jespersen, Thomas / Michael Sattler, Stefan

International journal of cardiology. Heart & vasculature

2022 Volume 40, Page(s) 101054

Language	English
Publishing date	2022-05-17
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	2818464-6
ISSN	2352-9067
ISSN	2352-9067
DOI	10.1016/j.ijcha.2022.101054
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Article: Crucial role for Sodium Hydrogen Exchangers in SGLT2 inhibitor-induced arterial relaxations.

Forrester, Elizabeth A / Benítez-Angeles, Miguel / Redford, Kaitlyn E / Rosenbaum, Tamara / Abbott, Geoffrey W / Barrese, Vincenzo / Dora, Kim / Albert, Anthony P / Dannesboe, Johs / Salles-Crawley, Isabelle / Jepps, Thomas A / Greenwood, Iain A

bioRxiv : the preprint server for biology

2023

Abstract: Introduction: Sodium dependent glucose transporter 2 (SGLT2 or SLC5A2) inhibitors effectively lower blood glucose and are also approved treatments for heart failure independent of raised glucose. One component of the cardioprotective effect is reduced ... ...

Abstract	Introduction: Sodium dependent glucose transporter 2 (SGLT2 or SLC5A2) inhibitors effectively lower blood glucose and are also approved treatments for heart failure independent of raised glucose. One component of the cardioprotective effect is reduced cardiac afterload but the mechanisms underlying peripheral relaxation are ill defined and variable. We speculated that SGLT2 inhibitors promoted arterial relaxation via the release of the potent vasodilator calcitonin gene-related peptide (CGRP) from sensory nerves independent of glucose transport. Experimental approach: The functional effects of SGLT2 inhibitors (dapagliflozin, empagliflozin, ertugliflozin) and the sodium/hydrogen exchanger 1 (NHE1) blocker cariporide were determined on pre-contracted mesenteric and renal arteries from male Wistar rats using Wire-Myography. SGLT2, NHE1, CGRP and TRPV1 expression in both arteries was determined by Western blot and immunohistochemistry. Kv7.4/5/KCNE4 and TRPV1 currents were measured in the presence and absence of dapagliflozin and empagliflozin. Results: All SGLT2 inhibitors produced a concentration dependent relaxation (1µM-100µM) of mesenteric arteries that was considerably greater than in renal arteries. Cariporide relaxed mesenteric arteries but not renal arteries. Immunohistochemistry with TRPV1 and CGRP antibodies revealed a dense innervation of sensory nerves in mesenteric arteries that was absent in renal arteries. Consistent with a greater sensory nerve component, the TRPV1 agonist capsaicin produced significantly greater relaxations in mesenteric arteries compared to renal arteries. Relaxations to dapagliflozin, empagliflozin and cariporide were attenuated by incubation with the CGRP receptor antagonist BIBN-4096, the Kv7 blocker linopirdine and the TRPV1 antagonist AMG-517 as well as by depletion of neuronal CGRP. Neither dapagliflozin nor empagliflozin directly activated heterologously expressed TRPV1 channels or Kv7 channels. Strikingly, only NHE1 colocalised with TRPV1 in sensory nerves, and cariporide pre-application prevented the relaxant response to SGLT2 inhibitors. Conclusions: SGLT2 inhibitors relax mesenteric arteries by a novel mechanism involving the release of CGRP from sensory nerves following inhibition of the Na
Language	English
Publishing date	2023-12-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.05.570303
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Article ; Online: Molecular and functional characterization of Kv 7 channels in penile arteries and corpus cavernosum of healthy and metabolic syndrome rats.

Jepps, T A / Olesen, S P / Greenwood, I A / Dalsgaard, T

British journal of pharmacology

2016 Volume 173, Issue 9, Page(s) 1478–1490

Abstract: Background and purpose: KCNQ-encoded voltage-dependent potassium channels (Kv 7) are involved in the regulation of vascular tone. In this study we evaluated the influence of Kv 7 channel activation on smooth muscle relaxation in rat penile arteries and ... ...

Abstract	Background and purpose: KCNQ-encoded voltage-dependent potassium channels (Kv 7) are involved in the regulation of vascular tone. In this study we evaluated the influence of Kv 7 channel activation on smooth muscle relaxation in rat penile arteries and corpus cavernosum from normal and spontaneously hypertensive, heart failure-prone (SHHF) rats - a rat model of human metabolic syndrome. Experimental approach: Quantitative PCR and immunohistochemistry were used to determine the expression of KCNQ isoforms in penile tissue. Isometric tension was measured in intracavernous arterial rings and corpus cavernosum strips isolated from normal and SHHF rats. Key results: Transcripts for KCNQ3, KCNQ4 and KCNQ5 were detected in penile arteries and corpus cavernosum. KCNQ1 was only found in corpus cavernosum. Immunofluorescence signals to Kv 7.4 and Kv 7.5 were found in penile arteries, penile veins and corpus cavernosum. The Kv 7.2-7.5 activators, ML213 and BMS204352, relaxed pre-contracted penile arteries and corpus cavernosum independently of nitric oxide synthase or endothelium-derived hyperpolarization. Relaxations to sildenafil, a PDE5 inhibitor, and sodium nitroprusside (SNP), an nitric oxide donor, were reduced by blocking Kv 7 channels with linopirdine in penile arteries and corpus cavernosum. In SHHF rat penile arteries and corpus cavernosum, relaxations to ML213 and BMS204352 were attenuated, and the blocking effect of linopirdine on sildenafil-induced and SNP-induced relaxations reduced. KCNQ3, KCNQ4 and KCNQ5 were down-regulated, and KCNQ1 was up-regulated in corpus cavernosum from SHHF rats. KCNQ1-5 transcripts remained unchanged in penile arteries from SHHF rats. Conclusions and implications: These data suggest that Kv 7 channels play a role in erectile function and contribute to the pathophysiology of erectile dysfunction, an early indicator of cardiovascular disease.
MeSH term(s)	Animals ; Arteries/metabolism ; Erectile Dysfunction/metabolism ; KCNQ Potassium Channels/genetics ; KCNQ Potassium Channels/metabolism ; Male ; Metabolic Syndrome/metabolism ; Penis/anatomy & histology ; Penis/blood supply ; Penis/metabolism ; Rats ; Rats, Mutant Strains ; Rats, Wistar
Chemical Substances	KCNQ Potassium Channels
Language	English
Publishing date	2016-02-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.13444
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Article ; Online: Effects of a novel selenium substituted-sugar (1,4-anhydro-4-seleno-d-talitol, SeTal) on human coronary artery cell lines and mouse aortic rings.

Zacharias, Triantafyllos / Flouda, Konstantina / Jepps, Thomas A / Gammelgaard, Bente / Schiesser, Carl H / Davies, Michael J

Biochemical pharmacology

2019 Volume 173, Page(s) 113631

Abstract: Chronic low-grade inflammation and oxidative damage are strongly associated with pathologies including cardiovascular disease. As a consequence, there is considerable interest in agents that mitigate damage. Selenium compounds can act as potent ... ...

Abstract	Chronic low-grade inflammation and oxidative damage are strongly associated with pathologies including cardiovascular disease. As a consequence, there is considerable interest in agents that mitigate damage. Selenium compounds can act as potent protective agents against oxidation due to the high reactivity and nucleophilicity of the selenium atom. 1,4-Anhydro-4-seleno-d-talitol (SeTal, a novel water-soluble selenium-based sugar) is a potent oxidant scavenger in vitro and in human plasma. Here we show that SeTal is highly stable in solutions that mimic biological fluids and the gastrointestinal tract, and is not rapidly degraded or metabolized unlike some other selenium-containing compounds. SeTal remains intact during extended storage, and it rapidly penetrates into, and effluxes from, primary human coronary artery endothelial and smooth muscle cells, but does not induce loss of metabolic activity, or modulate cell survival and growth rates at concentrations ≤2 mM. Steady-state intracellular concentrations can reach 2-10 μM. SeTal affords protection against H
MeSH term(s)	Animals ; Aorta/drug effects ; Aorta/metabolism ; Aorta/physiology ; Cell Line ; Cells, Cultured ; Coronary Vessels/cytology ; Coronary Vessels/drug effects ; Coronary Vessels/metabolism ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Glutathione Peroxidase/metabolism ; Hexoses/chemistry ; Hexoses/metabolism ; Hexoses/pharmacology ; Humans ; In Vitro Techniques ; Male ; Mice ; Middle Aged ; Molecular Structure ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/metabolism ; Organoselenium Compounds/chemistry ; Organoselenium Compounds/metabolism ; Organoselenium Compounds/pharmacology ; Oxidative Stress/drug effects ; Thioredoxin Reductase 1/metabolism ; Vasoconstriction/drug effects
Chemical Substances	1,4-anhydro-4-selenotalitol ; Hexoses ; Organoselenium Compounds ; glutathione peroxidase GPX1 (EC 1.11.1.-) ; Glutathione Peroxidase (EC 1.11.1.9) ; TXNRD1 protein, human (EC 1.8.1.9) ; Thioredoxin Reductase 1 (EC 1.8.1.9)
Language	English
Publishing date	2019-09-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2019.113631
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Article ; Online: One man's side effect is another man's therapeutic opportunity: targeting Kv7 channels in smooth muscle disorders.

Jepps, T A / Olesen, S P / Greenwood, I A

British journal of pharmacology

2012 Volume 168, Issue 1, Page(s) 19–27

Abstract: Retigabine is a first in class anticonvulsant that has recently undergone clinical trials to test its efficacy in epileptic patients. Retigabine's novel mechanism of action - activating Kv7 channels - suppresses neuronal activity to prevent seizure ... ...

Abstract	Retigabine is a first in class anticonvulsant that has recently undergone clinical trials to test its efficacy in epileptic patients. Retigabine's novel mechanism of action - activating Kv7 channels - suppresses neuronal activity to prevent seizure generation by hyperpolarizing the membrane potential and suppressing depolarizing surges. However, Kv7 channels are not expressed exclusively in neurones and data generated over the last decade have shown that Kv7 channels play a key role in various smooth muscle systems of the body. This review discusses the potential of targeting Kv7 channels in the smooth muscle to treat diseases such as hypertension, bladder instability, constipation and preterm labour.
MeSH term(s)	Animals ; Anticonvulsants/pharmacology ; Carbamates/pharmacology ; Constipation/drug therapy ; Female ; Humans ; Hypertension/drug therapy ; KCNQ1 Potassium Channel/drug effects ; KCNQ1 Potassium Channel/metabolism ; Membrane Potentials/drug effects ; Membrane Transport Modulators/pharmacology ; Muscle Tonus/drug effects ; Muscle, Smooth/drug effects ; Muscle, Smooth/metabolism ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; Muscular Diseases/drug therapy ; Muscular Diseases/metabolism ; Neurons/drug effects ; Obstetric Labor, Premature/drug therapy ; Phenylenediamines/pharmacology ; Potassium Channels, Voltage-Gated/drug effects ; Potassium Channels, Voltage-Gated/metabolism ; Pregnancy ; Urinary Bladder Diseases/drug therapy
Chemical Substances	Anticonvulsants ; Carbamates ; KCNQ1 Potassium Channel ; KCNQ1 protein, human ; Membrane Transport Modulators ; Phenylenediamines ; Potassium Channels, Voltage-Gated ; ezogabine (12G01I6BBU)
Language	English
Publishing date	2012-08-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/j.1476-5381.2012.02133.x
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Article ; Online: Dynein regulates Kv7.4 channel trafficking from the cell membrane.

van der Horst, Jennifer / Rognant, Salomé / Abbott, Geoffrey W / Ozhathil, Lijo Cherian / Hägglund, Per / Barrese, Vincenzo / Chuang, Christine Y / Jespersen, Thomas / Davies, Michael J / Greenwood, Iain A / Gourdon, Pontus / Aalkjær, Christian / Jepps, Thomas A

The Journal of general physiology

2021 Volume 153, Issue 3

Abstract: The dynein motor protein transports proteins away from the cell membrane along the microtubule network. Recently, we found the microtubule network was important for regulating the membrane abundance of voltage-gated Kv7.4 potassium channels in vascular ... ...

Abstract	The dynein motor protein transports proteins away from the cell membrane along the microtubule network. Recently, we found the microtubule network was important for regulating the membrane abundance of voltage-gated Kv7.4 potassium channels in vascular smooth muscle. Here, we aimed to investigate the influence of dynein on the microtubule-dependent internalization of the Kv7.4 channel. Patch-clamp recordings from HEK293B cells showed Kv7.4 currents were increased after inhibiting dynein function with ciliobrevin D or by coexpressing p50/dynamitin, which specifically interferes with dynein motor function. Mutation of a dynein-binding site in the Kv7.4 C terminus increased the Kv7.4 current and prevented p50 interference. Structured illumination microscopy, proximity ligation assays, and coimmunoprecipitation showed colocalization of Kv7.4 and dynein in mesenteric artery myocytes. Ciliobrevin D enhanced mesenteric artery relaxation to activators of Kv7.2-Kv7.5 channels and increased membrane abundance of Kv7.4 protein in isolated smooth muscle cells and HEK293B cells. Ciliobrevin D failed to enhance the negligible S-1-mediated relaxations after morpholino-mediated knockdown of Kv7.4. Mass spectrometry revealed an interaction of dynein with caveolin-1, confirmed using proximity ligation and coimmunoprecipitation assays, which also provided evidence for interaction of caveolin-1 with Kv7.4, confirming that Kv7.4 channels are localized to caveolae in mesenteric artery myocytes. Lastly, cholesterol depletion reduced the interaction of Kv7.4 with caveolin-1 and dynein while increasing the overall membrane expression of Kv7.4, although it attenuated the Kv7.4 current in oocytes and interfered with the action of ciliobrevin D and channel activators in arterial segments. Overall, this study shows that dynein can traffic Kv7.4 channels in vascular smooth muscle in a mechanism dependent on cholesterol-rich caveolae.
MeSH term(s)	Cell Membrane ; Dyneins ; KCNQ Potassium Channels ; Muscle, Smooth, Vascular ; Myocytes, Smooth Muscle
Chemical Substances	KCNQ Potassium Channels ; Dyneins (EC 3.6.4.2)
Language	English
Publishing date	2021-02-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.202012760
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Article ; Online: TMEM16A is implicated in the regulation of coronary flow and is altered in hypertension.

Askew Page, Henry R / Dalsgaard, Thomas / Baldwin, Samuel N / Jepps, Thomas A / Povstyan, Oleksandr / Olesen, Søren P / Greenwood, Iain A

British journal of pharmacology

2019 Volume 176, Issue 11, Page(s) 1635–1648

Abstract: Background and purpose: Coronary artery disease leads to ischaemic heart disease and ultimately myocardial infarction. Thus, it is important to determine the factors that regulate coronary blood flow. Ca: Experimental approach: We performed mRNA and ... ...

Abstract	Background and purpose: Coronary artery disease leads to ischaemic heart disease and ultimately myocardial infarction. Thus, it is important to determine the factors that regulate coronary blood flow. Ca Experimental approach: We performed mRNA and protein analysis, electrophysiological studies of coronary artery myocytes, and functional studies of coronary artery contractility and coronary perfusion, using novel inhibitors of TMEM16A. Furthermore, we assessed whether any changes in expression and function occurred in coronary arteries from spontaneously hypertensive rats (SHRs). Key results: TMEM16A was expressed in rat coronary arteries. The TMEM16A-specific inhibitor, MONNA, hyperpolarised the membrane potential in U46619. MONNA, T16A Conclusions and implications: In conclusion, TMEM16A is a key regulator of coronary blood flow and is implicated in the altered contractility of coronary arteries from SHRs.
MeSH term(s)	15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology ; Acetamides/pharmacology ; Animals ; Anoctamin-1/antagonists & inhibitors ; Anoctamin-1/genetics ; Anoctamin-1/physiology ; Coronary Circulation/drug effects ; Coronary Vessels/drug effects ; Coronary Vessels/physiology ; Hydrazones/pharmacology ; Hypertension/physiopathology ; Male ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/physiology ; Pyrimidines/pharmacology ; Rats, Inbred SHR ; Rats, Wistar ; Serotonin/pharmacology ; Thiazoles/pharmacology ; Vasoconstrictor Agents/pharmacology ; ortho-Aminobenzoates/pharmacology
Chemical Substances	ANO1 protein, rat ; Acetamides ; Ani9 compound ; Anoctamin-1 ; Hydrazones ; N-((4-methoxy)-2-naphthyl)-5-nitroanthranilic acid ; Pyrimidines ; T16AInh-A01 ; Thiazoles ; Vasoconstrictor Agents ; ortho-Aminobenzoates ; Serotonin (333DO1RDJY) ; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (76898-47-0)
Language	English
Publishing date	2019-04-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.14598
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