Crucial role for sensory nerves and Na/H exchanger inhibition in dapagliflozin- and empagliflozin-induced arterial relaxation

Abstract Aims Sodium/glucose transporter 2 (SGLT2 or SLC5A2) inhibitors lower blood glucose and are also approved treatments for heart failure independent of raised glucose. Various studies have showed that SGLT2 inhibitors relax arteries, but the underlying mechanisms are poorly understood and resp...

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Veröffentlicht in:Cardiovascular research 2024-11, Vol.120 (14), p.1811-1824
Hauptverfasser: 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
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container_end_page 1824
container_issue 14
container_start_page 1811
container_title Cardiovascular research
container_volume 120
creator 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
description Abstract Aims Sodium/glucose transporter 2 (SGLT2 or SLC5A2) inhibitors lower blood glucose and are also approved treatments for heart failure independent of raised glucose. Various studies have showed that SGLT2 inhibitors relax arteries, but the underlying mechanisms are poorly understood and responses variable across arterial beds. We speculated that SGLT2 inhibitor-mediated arterial relaxation is dependent upon calcitonin gene-related peptide (CGRP) released from sensory nerves independent of glucose transport. Methods and results The functional effects of SGLT1 and 2 inhibitors (mizagliflozin, dapagliflozin, and empagliflozin) and the sodium/hydrogen exchanger 1 (NHE1) blocker cariporide were determined on pre-contracted resistance arteries (mesenteric and cardiac septal arteries) as well as main renal conduit arteries from male Wistar rats using wire myography. SGLT2, CGRP, TRPV1, and NHE1 expression 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. All SGLT inhibitors (1–100 µM) and cariporide (30 µM) relaxed mesenteric arteries but had negligible effect on renal or septal arteries. Immunohistochemistry with TRPV1 and CGRP antibodies revealed a dense innervation of sensory nerves in mesenteric arteries that were absent in renal and septal arteries. Consistent with a greater sensory nerve component, the TRPV1 agonist capsaicin relaxed mesenteric arteries more effectively than renal or septal arteries. In mesenteric arteries, relaxations to dapagliflozin, empagliflozin, and cariporide were attenuated by the CGRP receptor antagonist BIBN-4096, depletion of sensory nerves with capsaicin, and blockade of TRPV1 or Kv7 channels. Neither dapagliflozin nor empagliflozin activated heterologously expressed TRPV1 channels or Kv7 channels directly. Sensory nerves also expressed NHE1 but not SGLT2 and cariporide pre-application as well as knockdown of NHE1 by translation stop morpholinos prevented the relaxant response to SGLT2 inhibitors. Conclusion SGLT2 inhibitors relax mesenteric arteries by promoting the release of CGRP from sensory nerves in a NHE1-dependent manner. Graphical Abstract Graphical Abstract Pathway of SGLT2 inhibitor-induced relaxation in mesenteric arteries. SGLT2 inhibitors act on the sodium/hydrogen exchanger (NHE) to induce vasorelaxation. H, hydrogen; Na, sodium; Ca2+, calcium; CGRP, calcitonin gene-related peptide; TRPV1,
doi_str_mv 10.1093/cvr/cvae156
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Various studies have showed that SGLT2 inhibitors relax arteries, but the underlying mechanisms are poorly understood and responses variable across arterial beds. We speculated that SGLT2 inhibitor-mediated arterial relaxation is dependent upon calcitonin gene-related peptide (CGRP) released from sensory nerves independent of glucose transport. Methods and results The functional effects of SGLT1 and 2 inhibitors (mizagliflozin, dapagliflozin, and empagliflozin) and the sodium/hydrogen exchanger 1 (NHE1) blocker cariporide were determined on pre-contracted resistance arteries (mesenteric and cardiac septal arteries) as well as main renal conduit arteries from male Wistar rats using wire myography. SGLT2, CGRP, TRPV1, and NHE1 expression 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. All SGLT inhibitors (1–100 µM) and cariporide (30 µM) relaxed mesenteric arteries but had negligible effect on renal or septal arteries. Immunohistochemistry with TRPV1 and CGRP antibodies revealed a dense innervation of sensory nerves in mesenteric arteries that were absent in renal and septal arteries. Consistent with a greater sensory nerve component, the TRPV1 agonist capsaicin relaxed mesenteric arteries more effectively than renal or septal arteries. In mesenteric arteries, relaxations to dapagliflozin, empagliflozin, and cariporide were attenuated by the CGRP receptor antagonist BIBN-4096, depletion of sensory nerves with capsaicin, and blockade of TRPV1 or Kv7 channels. Neither dapagliflozin nor empagliflozin activated heterologously expressed TRPV1 channels or Kv7 channels directly. Sensory nerves also expressed NHE1 but not SGLT2 and cariporide pre-application as well as knockdown of NHE1 by translation stop morpholinos prevented the relaxant response to SGLT2 inhibitors. Conclusion SGLT2 inhibitors relax mesenteric arteries by promoting the release of CGRP from sensory nerves in a NHE1-dependent manner. Graphical Abstract Graphical Abstract Pathway of SGLT2 inhibitor-induced relaxation in mesenteric arteries. SGLT2 inhibitors act on the sodium/hydrogen exchanger (NHE) to induce vasorelaxation. H, hydrogen; Na, sodium; Ca2+, calcium; CGRP, calcitonin gene-related peptide; TRPV1, transient receptor potential vanilloid 1; CLR, calcitonin receptor-like receptor; RAMP1, receptor activity-modifying protein 1; cGMP, cyclic guanosine monophosphate; PKA, protein kinase A; Kv7, voltage-gated potassium channel.</description><identifier>ISSN: 0008-6363</identifier><identifier>ISSN: 1755-3245</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvae156</identifier><identifier>PMID: 39056245</identifier><language>eng</language><publisher>UK: Oxford University Press</publisher><subject>Animals ; Benzhydryl Compounds - pharmacology ; Calcitonin Gene-Related Peptide - metabolism ; Glucosides - pharmacology ; Guanidines - pharmacology ; Male ; Mesenteric Arteries - drug effects ; Mesenteric Arteries - innervation ; Mesenteric Arteries - metabolism ; Original ; Rats, Wistar ; Renal Artery - drug effects ; Renal Artery - innervation ; Renal Artery - metabolism ; Sensory Receptor Cells - drug effects ; Sensory Receptor Cells - metabolism ; Sodium-Glucose Transporter 1 - antagonists &amp; inhibitors ; Sodium-Glucose Transporter 1 - metabolism ; Sodium-Glucose Transporter 2 - metabolism ; Sodium-Glucose Transporter 2 Inhibitors - pharmacology ; Sodium-Hydrogen Exchanger 1 - antagonists &amp; inhibitors ; Sodium-Hydrogen Exchanger 1 - metabolism ; Sulfones - pharmacology ; TRPV Cation Channels - antagonists &amp; inhibitors ; TRPV Cation Channels - metabolism ; Vasodilation - drug effects ; Vasodilator Agents - pharmacology</subject><ispartof>Cardiovascular research, 2024-11, Vol.120 (14), p.1811-1824</ispartof><rights>The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. 2024</rights><rights>The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c301t-45d8a07030dd03065b1c441b1c009dd38bcadb139f419b8616f8389cf716f50c3</cites><orcidid>0000-0002-0603-0492 ; 0000-0001-8721-8843</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39056245$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Forrester, Elizabeth A</creatorcontrib><creatorcontrib>Benítez-Angeles, Miguel</creatorcontrib><creatorcontrib>Redford, Kaitlyn E</creatorcontrib><creatorcontrib>Rosenbaum, Tamara</creatorcontrib><creatorcontrib>Abbott, Geoffrey W</creatorcontrib><creatorcontrib>Barrese, Vincenzo</creatorcontrib><creatorcontrib>Dora, Kim</creatorcontrib><creatorcontrib>Albert, Anthony P</creatorcontrib><creatorcontrib>Dannesboe, Johs</creatorcontrib><creatorcontrib>Salles-Crawley, Isabelle</creatorcontrib><creatorcontrib>Jepps, Thomas A</creatorcontrib><creatorcontrib>Greenwood, Iain A</creatorcontrib><title>Crucial role for sensory nerves and Na/H exchanger inhibition in dapagliflozin- and empagliflozin-induced arterial relaxation</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>Abstract Aims Sodium/glucose transporter 2 (SGLT2 or SLC5A2) inhibitors lower blood glucose and are also approved treatments for heart failure independent of raised glucose. Various studies have showed that SGLT2 inhibitors relax arteries, but the underlying mechanisms are poorly understood and responses variable across arterial beds. We speculated that SGLT2 inhibitor-mediated arterial relaxation is dependent upon calcitonin gene-related peptide (CGRP) released from sensory nerves independent of glucose transport. Methods and results The functional effects of SGLT1 and 2 inhibitors (mizagliflozin, dapagliflozin, and empagliflozin) and the sodium/hydrogen exchanger 1 (NHE1) blocker cariporide were determined on pre-contracted resistance arteries (mesenteric and cardiac septal arteries) as well as main renal conduit arteries from male Wistar rats using wire myography. SGLT2, CGRP, TRPV1, and NHE1 expression 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. All SGLT inhibitors (1–100 µM) and cariporide (30 µM) relaxed mesenteric arteries but had negligible effect on renal or septal arteries. Immunohistochemistry with TRPV1 and CGRP antibodies revealed a dense innervation of sensory nerves in mesenteric arteries that were absent in renal and septal arteries. Consistent with a greater sensory nerve component, the TRPV1 agonist capsaicin relaxed mesenteric arteries more effectively than renal or septal arteries. In mesenteric arteries, relaxations to dapagliflozin, empagliflozin, and cariporide were attenuated by the CGRP receptor antagonist BIBN-4096, depletion of sensory nerves with capsaicin, and blockade of TRPV1 or Kv7 channels. Neither dapagliflozin nor empagliflozin activated heterologously expressed TRPV1 channels or Kv7 channels directly. Sensory nerves also expressed NHE1 but not SGLT2 and cariporide pre-application as well as knockdown of NHE1 by translation stop morpholinos prevented the relaxant response to SGLT2 inhibitors. Conclusion SGLT2 inhibitors relax mesenteric arteries by promoting the release of CGRP from sensory nerves in a NHE1-dependent manner. Graphical Abstract Graphical Abstract Pathway of SGLT2 inhibitor-induced relaxation in mesenteric arteries. SGLT2 inhibitors act on the sodium/hydrogen exchanger (NHE) to induce vasorelaxation. H, hydrogen; Na, sodium; Ca2+, calcium; CGRP, calcitonin gene-related peptide; TRPV1, transient receptor potential vanilloid 1; CLR, calcitonin receptor-like receptor; RAMP1, receptor activity-modifying protein 1; cGMP, cyclic guanosine monophosphate; PKA, protein kinase A; Kv7, voltage-gated potassium channel.</description><subject>Animals</subject><subject>Benzhydryl Compounds - pharmacology</subject><subject>Calcitonin Gene-Related Peptide - metabolism</subject><subject>Glucosides - pharmacology</subject><subject>Guanidines - pharmacology</subject><subject>Male</subject><subject>Mesenteric Arteries - drug effects</subject><subject>Mesenteric Arteries - innervation</subject><subject>Mesenteric Arteries - metabolism</subject><subject>Original</subject><subject>Rats, Wistar</subject><subject>Renal Artery - drug effects</subject><subject>Renal Artery - innervation</subject><subject>Renal Artery - metabolism</subject><subject>Sensory Receptor Cells - drug effects</subject><subject>Sensory Receptor Cells - metabolism</subject><subject>Sodium-Glucose Transporter 1 - antagonists &amp; inhibitors</subject><subject>Sodium-Glucose Transporter 1 - metabolism</subject><subject>Sodium-Glucose Transporter 2 - metabolism</subject><subject>Sodium-Glucose Transporter 2 Inhibitors - pharmacology</subject><subject>Sodium-Hydrogen Exchanger 1 - antagonists &amp; inhibitors</subject><subject>Sodium-Hydrogen Exchanger 1 - metabolism</subject><subject>Sulfones - pharmacology</subject><subject>TRPV Cation Channels - antagonists &amp; inhibitors</subject><subject>TRPV Cation Channels - metabolism</subject><subject>Vasodilation - drug effects</subject><subject>Vasodilator Agents - pharmacology</subject><issn>0008-6363</issn><issn>1755-3245</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9kc9PHCEUx4mpqavtqfeGk2liRqEMzMzJNJv6IzHtpT2TN_Bml4aFLcxstIn_u-iuRi898HjAh-97eV9CPnF2ylknzswmlQXIpdojM95IWYmvtXxHZoyxtlJCiQNymPOfcpSyqd-TA9ExqQozI_fzNBkHnqbokQ4x0Ywhx3RHA6YNZgrB0h9wdkXx1iwhLDBRF5aud6OLoaTUwhoW3g0-_nOheuJx9frKBTsZtBTSiOmpFHq4hcf_H8j-AD7jx91-RH5ffP81v6pufl5ez7_dVEYwPla1tC2whglmbQlK9tzUNS-Rsc5a0fYGbM9FN9S861vF1dCKtjNDUzLJjDgi51vd9dSv0BoMYwKv18mtIN3pCE6_fQluqRdxozmXbRmoKgpfdgop_p0wj3rlskHvIWCcshasrZtGKlUX9GSLmhRzTji81OFMPzqmi2N651ihP79u7YV9tqgAx1sgTuv_Kj0AGR6jLA</recordid><startdate>20241125</startdate><enddate>20241125</enddate><creator>Forrester, Elizabeth A</creator><creator>Benítez-Angeles, Miguel</creator><creator>Redford, Kaitlyn E</creator><creator>Rosenbaum, Tamara</creator><creator>Abbott, Geoffrey W</creator><creator>Barrese, Vincenzo</creator><creator>Dora, Kim</creator><creator>Albert, Anthony P</creator><creator>Dannesboe, Johs</creator><creator>Salles-Crawley, Isabelle</creator><creator>Jepps, Thomas A</creator><creator>Greenwood, Iain A</creator><general>Oxford University Press</general><scope>TOX</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0603-0492</orcidid><orcidid>https://orcid.org/0000-0001-8721-8843</orcidid></search><sort><creationdate>20241125</creationdate><title>Crucial role for sensory nerves and Na/H exchanger inhibition in dapagliflozin- and empagliflozin-induced arterial relaxation</title><author>Forrester, Elizabeth A ; 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inhibitors</topic><topic>Sodium-Glucose Transporter 1 - metabolism</topic><topic>Sodium-Glucose Transporter 2 - metabolism</topic><topic>Sodium-Glucose Transporter 2 Inhibitors - pharmacology</topic><topic>Sodium-Hydrogen Exchanger 1 - antagonists &amp; inhibitors</topic><topic>Sodium-Hydrogen Exchanger 1 - metabolism</topic><topic>Sulfones - pharmacology</topic><topic>TRPV Cation Channels - antagonists &amp; inhibitors</topic><topic>TRPV Cation Channels - metabolism</topic><topic>Vasodilation - drug effects</topic><topic>Vasodilator Agents - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Forrester, Elizabeth A</creatorcontrib><creatorcontrib>Benítez-Angeles, Miguel</creatorcontrib><creatorcontrib>Redford, Kaitlyn E</creatorcontrib><creatorcontrib>Rosenbaum, Tamara</creatorcontrib><creatorcontrib>Abbott, Geoffrey W</creatorcontrib><creatorcontrib>Barrese, Vincenzo</creatorcontrib><creatorcontrib>Dora, Kim</creatorcontrib><creatorcontrib>Albert, Anthony P</creatorcontrib><creatorcontrib>Dannesboe, Johs</creatorcontrib><creatorcontrib>Salles-Crawley, Isabelle</creatorcontrib><creatorcontrib>Jepps, Thomas A</creatorcontrib><creatorcontrib>Greenwood, Iain A</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Forrester, Elizabeth A</au><au>Benítez-Angeles, Miguel</au><au>Redford, Kaitlyn E</au><au>Rosenbaum, Tamara</au><au>Abbott, Geoffrey W</au><au>Barrese, Vincenzo</au><au>Dora, Kim</au><au>Albert, Anthony P</au><au>Dannesboe, Johs</au><au>Salles-Crawley, Isabelle</au><au>Jepps, Thomas A</au><au>Greenwood, Iain A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Crucial role for sensory nerves and Na/H exchanger inhibition in dapagliflozin- and empagliflozin-induced arterial relaxation</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2024-11-25</date><risdate>2024</risdate><volume>120</volume><issue>14</issue><spage>1811</spage><epage>1824</epage><pages>1811-1824</pages><issn>0008-6363</issn><issn>1755-3245</issn><eissn>1755-3245</eissn><abstract>Abstract Aims Sodium/glucose transporter 2 (SGLT2 or SLC5A2) inhibitors lower blood glucose and are also approved treatments for heart failure independent of raised glucose. Various studies have showed that SGLT2 inhibitors relax arteries, but the underlying mechanisms are poorly understood and responses variable across arterial beds. We speculated that SGLT2 inhibitor-mediated arterial relaxation is dependent upon calcitonin gene-related peptide (CGRP) released from sensory nerves independent of glucose transport. Methods and results The functional effects of SGLT1 and 2 inhibitors (mizagliflozin, dapagliflozin, and empagliflozin) and the sodium/hydrogen exchanger 1 (NHE1) blocker cariporide were determined on pre-contracted resistance arteries (mesenteric and cardiac septal arteries) as well as main renal conduit arteries from male Wistar rats using wire myography. SGLT2, CGRP, TRPV1, and NHE1 expression 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. All SGLT inhibitors (1–100 µM) and cariporide (30 µM) relaxed mesenteric arteries but had negligible effect on renal or septal arteries. Immunohistochemistry with TRPV1 and CGRP antibodies revealed a dense innervation of sensory nerves in mesenteric arteries that were absent in renal and septal arteries. Consistent with a greater sensory nerve component, the TRPV1 agonist capsaicin relaxed mesenteric arteries more effectively than renal or septal arteries. In mesenteric arteries, relaxations to dapagliflozin, empagliflozin, and cariporide were attenuated by the CGRP receptor antagonist BIBN-4096, depletion of sensory nerves with capsaicin, and blockade of TRPV1 or Kv7 channels. Neither dapagliflozin nor empagliflozin activated heterologously expressed TRPV1 channels or Kv7 channels directly. Sensory nerves also expressed NHE1 but not SGLT2 and cariporide pre-application as well as knockdown of NHE1 by translation stop morpholinos prevented the relaxant response to SGLT2 inhibitors. Conclusion SGLT2 inhibitors relax mesenteric arteries by promoting the release of CGRP from sensory nerves in a NHE1-dependent manner. Graphical Abstract Graphical Abstract Pathway of SGLT2 inhibitor-induced relaxation in mesenteric arteries. SGLT2 inhibitors act on the sodium/hydrogen exchanger (NHE) to induce vasorelaxation. H, hydrogen; Na, sodium; Ca2+, calcium; CGRP, calcitonin gene-related peptide; TRPV1, transient receptor potential vanilloid 1; CLR, calcitonin receptor-like receptor; RAMP1, receptor activity-modifying protein 1; cGMP, cyclic guanosine monophosphate; PKA, protein kinase A; Kv7, voltage-gated potassium channel.</abstract><cop>UK</cop><pub>Oxford University Press</pub><pmid>39056245</pmid><doi>10.1093/cvr/cvae156</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-0603-0492</orcidid><orcidid>https://orcid.org/0000-0001-8721-8843</orcidid><oa>free_for_read</oa></addata></record>
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source MEDLINE; Oxford University Press Journals All Titles (1996-Current)
subjects Animals
Benzhydryl Compounds - pharmacology
Calcitonin Gene-Related Peptide - metabolism
Glucosides - pharmacology
Guanidines - pharmacology
Male
Mesenteric Arteries - drug effects
Mesenteric Arteries - innervation
Mesenteric Arteries - metabolism
Original
Rats, Wistar
Renal Artery - drug effects
Renal Artery - innervation
Renal Artery - metabolism
Sensory Receptor Cells - drug effects
Sensory Receptor Cells - metabolism
Sodium-Glucose Transporter 1 - antagonists & inhibitors
Sodium-Glucose Transporter 1 - metabolism
Sodium-Glucose Transporter 2 - metabolism
Sodium-Glucose Transporter 2 Inhibitors - pharmacology
Sodium-Hydrogen Exchanger 1 - antagonists & inhibitors
Sodium-Hydrogen Exchanger 1 - metabolism
Sulfones - pharmacology
TRPV Cation Channels - antagonists & inhibitors
TRPV Cation Channels - metabolism
Vasodilation - drug effects
Vasodilator Agents - pharmacology
title Crucial role for sensory nerves and Na/H exchanger inhibition in dapagliflozin- and empagliflozin-induced arterial relaxation
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