Direct vasodilatory effects of sodium glucose co-
transporter 2 inhibitors (SGLT2is) and the underlying
molecular mechanisms in resistance mesenteric arteries
Ahasanul Hasan

• CVDs include hypertension, coronary artery disease, diabetes, stroke etc.
• CVDs ranked No. 1 cause of death globally
• In the USA
• 1 person dies every 37 seconds
• 1 person has a heart attack every 40 seconds
• 1 in every 4 deaths is due to CVD
• Hypertension is the primary contributor to all CVDs
• Approximately 20% of patients with hypertension also have T2DM and 50% of
T2DM patients have hypertension
Cardiovascular diseases (CVDs) facts
Center for Disease Control and Prevention, 2019; Tatsumi et al., 2017; World Health Organization, 2017

• New class of orally active anti-diabetic drugs used in T2DM.
• They are derivatives of glucoside phlorizin (a type of flavonoid)
• Inhibits sodium glucose co-transporter2 (SGLT2) in proximal tubule
• Canagliflozin (2013)
• Empagliflozin (2014)
• Dapagliflozin (2014)
• Ertugliflozin (2017)
• Bexagliflozin (2023)
Fediuk et al., 2020; Giugliano et al., 2019; Haider et al., 2019
Sodium glucose co-transporter 2 inhibitors
(SGLT2is)

Giugliano et al., 2019; van Bommel et al., 2017
Mechanism of action of SGLT2is

SGLT2 Inhibitors (SGLT2is)
Systemic Effects
↑ Glycosuria ↑ Natriuresis
Direct Effects
↓ Inflammation ↓ Oxidative Stress ↓ Apoptosis
↓ Autophagy ↓ Mitochondrial
Dysfunction
↓ Ionic
Dyshomeostasis
↓Gluocotoxicity
↑Insulin sensitivity
↑Glucagon
↑Fuel shift to lipid
↑Ketone bodies
↓Body weight
↓Fat mass
↓ Plasma volume
↓ Blood pressure
↓ Arterial stiffness
↓ Albuminuria
↓ Glomerular
hyperfiltration
↓ NLRP3
inflammasome
↓ IL-1β, IL-18
+M2 macrophage
↓ Macrophage
infiltration
↓ Fibrosis
+STAT3 activation
↓ Superoxide
↓ Nitrotyrosine
↓ Malondialdehyde
↓ Inflammation
↓ Apoptosis
↓ ERS
↓ Bax/Bcl-2 ratio
↓ Caspase activity
↓ Apoptosis
↓ Anomalies
↓ Swelling
↑ PGC1-α, CPT1
↓ Fission, Fusion
↑ Energy
Production
↓ ROS
+NHE inhibition
↓[Na+]c, [Ca2+]c
↑[Ca2+]m
↑ Ca2+ handling
↑ SERCA activity
↑ Rhythm
↑ Contraction
+NHE inhibition
While these effects can occur upon long-term use of SGLT2is, it is not known if acute
SGLT2is application has any effects on the regulation of systemic blood pressure.
Pleiotropic effects of SGLT2is
Lahnwong et al., 2018

• Several cardiovascular outcome trials (CVOTs) namely EMPA-REG, CANVAS and
DECLARE-TIMI have shown that SGLT-2is reduce heart failure, hospitalization and
related death (Zinman et al., 2015; Neal et al., 2017; Wiviott et al., 2019)
• Hypertension has been linked in numerous studies to the development and progression of
cardiovascular disease in diabetics (Long & Dagogo-Jack, 2011; Yamazaki, Hitomi, &
Nishiyama, 2018)
Therefore, it is important to understand whether SGLT-2is have a blood pressure
lowering action in diabetic patients to explain for the favorable outcomes in CVOTs
Cardio-protective effects of SGLT2is

Several pre-clinical studies have suggested that SGLT2is have anti-hypertensive action.
Proposed mechanisms that have been linked to the antihypertensive action involve:
• Diuresis (Briasoulis, Al Dhaybi, & Bakris, 2018)
• Modulation of sympathetic nervous system (Wan, Rahman, Hitomi, & Nishiyama,
2018)
• Increased nitric oxide (NO) production (Han et al., 2015)
• Reversal of renal dysfunction (Kelly, Lewis, Huntsberry, Dea, & Portillo, 2019)
• Inhibition of oxidative stress (Yaribeygi, Panahi, Javadi, & Sahebkar, 2018), etc.
Our study examined the direct effects of three SGLT-2is on the contractility of
resistance mesenteric arteries that regulate vascular resistance and systemic blood
pressure
Antihypertensive effects of SGLT-2is

Cardiac
Output
Peripheral
Resistance
Blood
Pressure
X
=
Regulation of blood pressure
Marieb et al., 2019

Arterial diameter regulates peripheral
resistance
Klabunde, 2012

General architecture of the artery
Marieb et al., 2019

Ion Intracellular
Concentration
(mM)
Extracellular
concentration
(mM)
Membrane
Permeability
at rest
K+ 140 4 1
Na+ 15 145 0.05
Cl+ 4 110 0.1
Ca2+ 0.0001 5 0
Resting membrane
potential = -70 mV
Hyperpolarization, < -70 mV
K+ efflux
Depolarization > -70 mV
Ca2+, Na+ influx, Cl- efflux
Contraction
Relaxation
Depolarization
Membrane potential controls the
activity of Ca2+ channels to
regulate SMC contractility
Membrane potential and SMC contractility
Slide courtesy: Dr. Hasan

MLCK: myosin light chain kinase; MLCP: myosin light chain phosphatase; SR: sarcoplasmic reticulum;
eNOS: endothelial nitric oxide synthase; PKG: protein kinase G, GC: guanylate cyclase, LTCC: L-type Ca2+
channel
Ca2+
Ca2+
Ca2+
Ca2+
SR
LTCC
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+ Calmodulin
MLCK
Contraction
Myosin
Myosin-p
Smooth muscle cell Endothelial cell
NO
eNOS
L-arginine
sGC
cGMP
PKG
MLCP
Myosin
Relaxation
Mechanism of SM contraction and relaxation
Slide courtesy: Dr. Hasan

Originality of this research
Recently, pre-clinical studies using rabbit aorta have shown that SGLT-2is relax aorta.
However, aorta is a conduit vessel that does not control systemic blood pressure (Li et al.,
2018; Seo et al., 2020; Seo et al., 2021).
Research using resistance arteries, which play a crucial role in regulating systemic blood
pressure by regulating peripheral resistance, is necessary.
Klabunde, 2012

Specific aims
[1]. We examined whether SGLT2is have direct vasodilatory effects in resistance
mesenteric arteries
[2]. We investigated if SGLT2is stimulate endothelial signaling to induce vasodilation in
mesenteric arteries
[3]. We investigated if SGLT2is act on a smooth muscle target(s) to induce vasodilation in
mesenteric arteries

Experimental tools
• Experimental technique: Pressure Myography
• Animal: Normotensive, Sprague Dawley Rat (SD, 7-10 weeks)
• Tissue: Resistance mesenteric arteries (1-2 mm segment, 150-250 µm in diameter)
• Drugs to be investigated: SGLT2is (Canagliflozin, Empagliflozin, and Dapagliflozin)
• Dose range for concentration curve: 0.001 – 100 µM
• Dose for mechanistic study: 100 µM

Typical pressure myography trace
Time (ms)
Vessel
diameter
(µm)

% 𝑀𝑦𝑜𝑔𝑒𝑛𝑖𝑐 𝑇𝑜𝑛𝑒 = (1 −
𝐷𝑎𝑐𝑡𝑖𝑣𝑒
(80 𝑚𝑚𝐻𝑔)
𝐷𝑝𝑎𝑠𝑠𝑖𝑣𝑒
(80 𝑚𝑚𝐻𝑔)
) 𝑥 100
Dactive = Active diameter at 80 mmHg
Dpassive = Passive diameter at 80 mmHg
Data processing
% 𝐷𝑖𝑙𝑎𝑡𝑖𝑜𝑛 = (
𝐷𝑖𝑎𝑚𝑒𝑡𝑒𝑟 𝑤𝑖𝑡ℎ 𝐷𝑟𝑢𝑔 −𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝐷𝑖𝑎𝑚𝑒𝑡𝑒𝑟 𝑎𝑓𝑡𝑒𝑟 𝑀𝑇
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝐷𝑖𝑎𝑚𝑒𝑡𝑒𝑟 𝑎𝑓𝑡𝑒𝑟 𝑀𝑇
) 𝑥 100
% 𝐷𝑖𝑙𝑎𝑡𝑖𝑜𝑛 = (
𝐷𝑖𝑎𝑚𝑒𝑡𝑒𝑟 𝑤𝑖𝑡ℎ 𝐷𝑟𝑢𝑔 −𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝐷𝑖𝑎𝑚𝑒𝑡𝑒𝑟 𝑤𝑖𝑡ℎ 𝑃𝐸
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝐷𝑖𝑎𝑚𝑒𝑡𝑒𝑟 𝑤𝑖𝑡ℎ 𝑃𝐸
) 𝑥 100

Results

Results for Aim 1
Aim 1: To examine whether SGLT2is (Cana, Empa, and Dapa) have direct
vasodilatory effects in resistance mesenteric arteries
Experiment 1A: Determination of direct effect of SGLT2is on the contractility of
resistance mesenteric arteries under myogenic vasoconstriction
Experiment 1B: Determination of direct effect of SGLT2is on the contractility of
phenylephrine (PE) pre-constricted mesenteric arteries
Experiment 1C: To determine whether the vasomodulatory effects of SGLT2is are
mediated by the inhibition of SGLT2

Experiment 1A
Determination of direct effect of SGLT2is (Cana, Empa, and Dapa) on the
contractility of resistance mesenteric arteries under myogenic vasoconstriction
Drugs: Cana, Empa, and Dapa
Dose: 0.001-100 µM
Cumulative drug application

Results 1A
SGLT2is (Cana, Empa, and Dapa) vasodilates pressurized myogenic toned artery
1A 2A 3A
1B 2B 3B

Results 1A (continued)
SGLT2is (Cana, Empa, and Dapa) vasodilates pressurized myogenic toned artery
Cana > Empa > Dapa
at 100 µM: 24.37% > 13.31% > 12.68%
at 100 µM: 85 µm > 60 µm > 43 µm
1A 2A 3A

Experiment 1B
Determination of direct effect of SGLT2is (Cana, Empa, and Dapa) on the
contractility of phenylephrine (PE) pre-constricted mesenteric arteries
0 1000 2000 3000 4000 5000
250
300
350
400
B
A
B
Baseline (40 mmHg)
PE-baseline
Cumulative drug application
Drugs: Cana, Empa, and Dapa
Dose: 0.001-100 µM

Results 1B
SGLT2is (Cana, Empa, and Dapa) vasodilates PE-preconstricted arteries
1A 2A 3A
1B 2B 3B

Results 1B (continued)
SGLT2is (Cana, Empa, and Dapa) vasodilates PE-preconstricted arteries
Cana > Empa > Dapa
at 100 µM: 95.60% > 72.24% > 62.52%
at 100 µM: 120 µm > 102 µm > 93 µm
Cana 10 µM > Empa 1 µM > Dapa 0.5 µM
62 µm > 25 µm > 15 µm
1A 2A 3A

Experiment 1C
To determine whether the vasomodulatory effects of SGLT2is (Cana, Empa, and
Dapa) are mediated by the inhibition of SGLT2
Baseline
(40 mmHg)
PE
SGLT2is +
PE
PE
Phlorizin+
PE
PE
SGLT2is +
Phlorizin +
PE
Group 1: SGLT2is (100 µM; Cana, Empa, and Dapa)
Group 2: Phlorizin (1 µM)
Group 3: SGLT2is + Phlorizin
Baseline
(40 mmHg)
Baseline
(40 mmHg)
Baseline
(40 mmHg)

Results 1C
SGLT2is (Cana, Empa, and Dapa)-induced vasodilation is independent of SGLT-2
inhibition
1A 2A 3A
1B 2B 3B

Conclusion 1
23
• SGLT2is (Cana, Empa, and Dapa) dilate pressurized resistance mesenteric arteries in a
dose-dependent manner.
• SGLT2is (Cana, Empa, and Dapa) dilate PE-preconstricted resistance mesenteric arteries
in a dose-dependent manner.
• SGLT2is (Cana, Empa, and Dapa)-induced vasodilation of resistance mesenteric arteries is
independent of SGLT2 inhibition.
• Cana as a vasodilator is superior to either Empa or Dapa.

Results for Aim 2
Aim 2: To investigate if SGLT2is (Cana, Empa, and Dapa) stimulate endothelial
signaling to induce vasodilation in mesenteric arteries
Experiment 2A: To determine the role of NO-sGC-PKG signaling axis in SGLT2is-mediated
vasodilation in PE pre-constricted mesenteric arteries
Experiment 2B: To determine the role of prostacyclin I2 (PGI2) in SGLT2is-mediated
vasodilation in PE pre-constricted mesenteric arteries
Experiment 2C: To determination the role of endothelium in SGLT-2is-mediated
vasodilation in PE pre-constricted mesenteric arteries
23

Experiment 2A
To determine the role of NO-sGC-PKG signaling axis in SGLT2is (Cana, Empa, and
Dapa)- mediated vasodilation in PE pre-constricted mesenteric arteries
PE
SGLT2is +
PE
PE
Inhibitor +
PE
SGLT2is +
Inhibitor +
PE
Group 1: SGLT2is (100 µM; Cana, Empa, and Dapa)
Group 2: SGLT2is + Inhibitors
eNOS inhibitor: L-NNA (10 µM)
sGC inhibitor: ODQ (10 µM)
PKG inhibitor: KT5823 (1 µM)
Baseline
(40 mmHg)
Baseline
(40 mmHg)
Baseline
(40 mmHg)

Results 2A
SGLT2is (Cana, Empa, and Dapa)-induced vasodilation is independent of NO-sGC-
PKG signaling axis
1A 2A 3A
1B 2B 3B

Experiment 2B
To determine the role of prostacyclin I2 (PGI2) in SGLT2is (Cana, Empa, and Dapa)-
mediated vasodilation in PE pre-constricted mesenteric arteries
PE
SGLT2is +
PE
PE
Inhibitor +
PE
SGLT2is +
Inhibitor +
PE
Group 1: SGLT2is (100 µM; Cana, Empa, and Dapa)
Group 2: SGLT2is + Inhibitor
COX inhibitor: Indomethacin (10 µM)
25
Baseline
(40 mmHg)
Baseline
(40 mmHg)
Baseline
(40 mmHg)

Results 2B
SGLT2is (Cana, Empa, and Dapa)-induced vasodilation is independent of PGI2
signaling axis
1A 2A 3A
1B 2B 3B

Experiment 2C
To determine the role of endothelium in SGLT2is (Cana, Empa, and Dapa)-mediated
vasodilation in PE pre-constricted mesenteric arteries
PE
SGLT2is +
PE
PE
SGLT2is +
PE
Endo-intact artery Endo-denuded artery
Denudation Process: Passage of air bubble through the lumen of artery
SGLT2is: Cana, Empa, and Dapa (100 µM)
Baseline
(40 mmHg)
Baseline
(40 mmHg)
Baseline
(40 mmHg)
Baseline
(40 mmHg)

Results 2C
SGLT2is (Cana, Empa, and Dapa)-induced vasodilation is independent of endothelium
1A 2A 3A
1B 2B 3B

Results 2C (continued)
SGLT2is (Cana, Empa, and Dapa)-induced vasodilation is independent of endothelium
1A 2A 3A
1B 2B 3B

Conclusion 2
23
• SGLT2is (Cana, Empa, and Dapa)-induced vasodilation of resistance mesenteric arteries is
independent of NO-sGC-PKG signaling axis.
• SGLT2is (Cana, Empa, and Dapa)-induced vasodilation of resistance mesenteric arteries is
independent of endothelial PGI2 synthesis.
• SGLT2is (Cana, Empa, and Dapa)-induced vasodilation of resistance mesenteric arteries is
independent of endothelium denudation and thus, cancels out the role of EDHF or
endothelial SKCa and IKCa channels in vasodilation.

Results for Aim 3
Aim 3: To investigate if SGLT2is (Cana, Empa, and Dapa) act on a smooth muscle
target(s) to induce vasodilation in mesenteric arteries
Experiment 3A: To determine the role of smooth muscle cells voltage gated potassium (KV)
channels in SGLT2is-mediated vasodilation in PE pre-constricted mesenteric arteries
Experiment 3B: To determine the role of calcium activated potassium (KCa) channels
(BKCa) and ATP-sensitive K+ (KATP) channels in SGLT2is-mediated vasodilation in PE pre-
constricted mesenteric arteries
Experiment 3C: To determine the role of calcium activated potassium (KCa) channels IKCa
and SKCa channels in SGLT2is-mediated vasodilation in PE pre-constricted mesenteric
arteries
Experiment 3D: To determine the role of Ca2+-ATPase (SERCA) pump in SGLT2is-
mediated vasodilation in PE pre-constricted mesenteric arteries

Experiment 3A
To determine the role of smooth muscle cells voltage gated potassium (KV) channels in
SGLT2is (Cana, Empa, and Dapa)-mediated vasodilation in PE pre-constricted
mesenteric arteries
PE
SGLT2is +
PE
PE
Inhibitor +
PE
SGLT2is +
Inhibitor +
PE
Group 1: SGLT2is (100 µM; Cana, Empa, and Dapa)
Group 2: SGLT2is + Inhibitors
Baseline
(40 mmHg)
Baseline
(40 mmHg)
Baseline
(40 mmHg)
Non-selective Kv channel inhibitor: 4-AP (1 mM)
Kv1.3 channel inhibitor: Psora-4 (100 nM)
Kv1.5 channel inhibitor: DPO-1 (1 µM)
Kv2.1 channel inhibitor: Guangxitoxin (100 nM)
Kv7 channel Inhibitor: Linopirdine (10 µM)

Results 3A
SGLT2is (Cana, Empa, and Dapa)-induced vasodilation involves SMC Kv channels
1A 2A 3A
1B 2B 3B

Results 3A (continued)
SGLT2is (Cana, Empa, and Dapa)-induced vasodilation involves SMC Kv1.5, Kv2.1,
and Kv7.x channels
1A 2A 3A
1B 2B 3B

Experiment 3B
To determine the role of calcium activated potassium (KCa) channels (BKCa) in SGLT2is
(Cana, Empa, and Dapa)-mediated vasodilation in PE pre-constricted mesenteric
arteries
PE
SGLT2is +
PE
PE
Inhibitor +
PE
SGLT2is +
Inhibitor +
PE
Group 1: SGLT2is (100 µM; Cana, Empa, and Dapa)
Group 2: SGLT2is + Inhibitors
BKCa channel inhibitor: Paxilline (10 µM)
Baseline
(40 mmHg)
Baseline
(40 mmHg)
Baseline
(40 mmHg)

Results 3B
SGLT2is (Cana, Empa, and Dapa)-induced vasodilation is independent of SMC BKCa
and KATP channels
1A 2A 3A
1B 2B 3B

Experiment 3C
To determine the role of calcium activated potassium (KCa) channels (IKCa and SKCa) in
SGLT2is (Cana)-mediated vasodilation in PE pre-constricted mesenteric arteries
PE
SGLT2is +
PE
PE
Inhibitor +
PE
SGLT2is +
Inhibitor +
PE
Group 1: SGLT2is (100 µM; Cana, Empa, and Dapa)
Group 2: SGLT2is + Inhibitors
IKCa channel inhibitor: TRAM-34 (10 µM)
SKCa channel inhibitor: Apamin (1 µM)
Baseline
(40 mmHg)
Baseline
(40 mmHg)
Baseline
(40 mmHg)

Results 3C
SGLT2is (Cana)-induced vasodilation is independent of SMC IKCa and SKCa channels
1A 1B

Experiment 3D
To determine the role of Ca2+-ATPase (SERCA) pump in SGLT2is (Cana)-mediated
vasodilation in PE pre-constricted mesenteric arteries
PE
SGLT2is +
PE
PE
Inhibitor +
PE
SGLT2is +
Inhibitor +
PE
Group 1: SGLT2is (100 µM; Cana, Empa, and Dapa)
Group 2: SGLT2is + Inhibitors
SERCA pump inhibitor: Thapsigargin (0.1 µM)
Baseline
(40 mmHg)
Baseline
(40 mmHg)
Baseline
(40 mmHg)

Results 3D
SGLT2is (Cana)-induced vasodilation is independent of SMC SERCA pumps
1A 1B

Conclusion 3
• SGLT2is (Cana, Empa, and Dapa)-induced vasodilation of resistance mesenteric arteries is
dependent on activation of smooth muscle cells voltage gated potassium (Kv) channels.
• Cana activates Kv1.5, Kv2.1, and Kv7.x; Empa activates Kv1.5, and Kv7.x; Dapa
activates Kv7.x.
• SGLT2is (Cana, Empa, and Dapa)-induced vasodilation of resistance mesenteric arteries is
independent of SMC BKCa and KATP channels.
• SGLT2is (Cana)-induced vasodilation of resistance mesenteric arteries is independent of
SMC SKCa and IKCa channels.
• SGLT2is (Cana)-induced vasodilation of resistance mesenteric arteries is independent of
SMC SERCA pumps.

Summary
• SGLT2is (Cana, Empa, and Dapa) dilate pressurized and Pe-preconstricted resistance
mesenteric arteries in a dose-dependent manner and independent of both SGLT2 inhibition
and endothelial signals.
• SGLT2is (Cana, Empa, and Dapa)-induced vasodilation of resistance mesenteric arteries is
dependent on activation of smooth muscle cells voltage gated potassium (Kv) channels.
However, SGLT2is vary in specificity as Cana activates Kv1.5, Kv2.1, and Kv7.x; Empa
activates Kv1.5, and Kv7.x; Dapa activates Kv7.x.
• SGLT2is (Cana, Empa, and Dapa)-induced vasodilation is a ‘class effect’ and Cana as a
vasodilator is superior to either Empa or Dapa.

Summary

Future directions
• To extend this study using diabetic animal models
• To conduct preliminary pre-clinical studies including blood pressure measurement in
ambulatory animals and in vivo blood flow monitoring
• To conduct preliminary clinical studies using human vasculature and measuring blood flow
and blood pressure in humans
• Finally, to extend our mechanistic experiments using electrophysiology, membrane
potential monitoring, and isoform-specific knockdown of Kv channels.
35

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