Reduced vascular responses to soluble guanylyl cyclase but increased sensitivity to sildenafil in female rats with type 2 diabetes

Styliani Goulopoulou, Johanna L. Hannan, Takayuki Matsumoto, Safia Ogbi, Adviye Ergul, R. Clinton Webb

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Abstract

Impaired nitric oxide (NO), soluble guanylyl cyclase (sGC), and cyclic guanosine monophosphate (cGMP) signaling (NO-sGC-cGMP) has been implicated in the pathogenesis of diabetic vascular dysfunction. Efforts to directly target this signaling have led to the development of sGC agonists that activate the heme group of sGC (stimulators) or preferentially activate sGC when the heme is oxidized (activators). In this study, we hypothesized that resistance arteries from female rats with spontaneous type 2 diabetes (Goto-Kakizaki rats, GK) would have reduced vasodilatory responses to heme-dependent sGC activation and increased responses to heme-independent sGC activation compared with control rats (Wistar). Endothelium-dependent and -independent relaxation was assessed in isolated segments from mesenteric resistance arteries (MA) mounted in a wire myograph. GK MA had reduced responses to acetylcholine (pEC50: 7.96 ± 0.06 vs. 7.66 ± 0.05, P< 0.05) and sodium nitroprusside (pEC50: 8.34 ± 0.05 vs. 7.77 ± 0.04, P < 0.05). There were no group differences in 8-bromoguanosine cGMP-induced relaxation and protein kinase G1 expression (P > 0.05). GK MA had attenuated responses to BAY 41–2272 (heme-dependent sGC stimulator; pEC50: 7.56 ± 0.05 vs. 6.93± 0.06, P < 0.05) and BAY 58–2667 (hemeindependent sGC activator; pEC50: 10.82 ± 0.07 vs. 10.27 ± 0.08, P < 0.05) and increased sensitivity to sildenafil [phosphodiesterase 5 (PDE5) inhibitor; pEC50: 7.89 ± 0.14 vs. 8.25 ± 0.13, P < 0.05]. Isolated resistance arteries from female rats of reproductive age that spontaneously develop type 2 diabetes have increased sensitivity to PDE5 inhibition and reduced responsiveness to sGC activators and stimulators.

Original languageEnglish
Pages (from-to)H297-H304
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume309
Issue number2
DOIs
StatePublished - 1 Jan 2015

Fingerprint

Type 2 Diabetes Mellitus
Blood Vessels
Heme
Mesenteric Arteries
Cyclic GMP
Nitric Oxide
Arteries
Sildenafil Citrate
Soluble Guanylyl Cyclase
Type 5 Cyclic Nucleotide Phosphodiesterases
Phosphodiesterase 5 Inhibitors
Acetylcholine
Endothelium
Wistar Rats

Keywords

  • Sildenafil
  • Soluble guanylyl cycle agonists
  • Type 2 diabetes
  • Vascular smooth muscle
  • Vasorelaxation

Cite this

@article{64e08a2c8f2a438dbeeca58d98f48ac4,
title = "Reduced vascular responses to soluble guanylyl cyclase but increased sensitivity to sildenafil in female rats with type 2 diabetes",
abstract = "Impaired nitric oxide (NO), soluble guanylyl cyclase (sGC), and cyclic guanosine monophosphate (cGMP) signaling (NO-sGC-cGMP) has been implicated in the pathogenesis of diabetic vascular dysfunction. Efforts to directly target this signaling have led to the development of sGC agonists that activate the heme group of sGC (stimulators) or preferentially activate sGC when the heme is oxidized (activators). In this study, we hypothesized that resistance arteries from female rats with spontaneous type 2 diabetes (Goto-Kakizaki rats, GK) would have reduced vasodilatory responses to heme-dependent sGC activation and increased responses to heme-independent sGC activation compared with control rats (Wistar). Endothelium-dependent and -independent relaxation was assessed in isolated segments from mesenteric resistance arteries (MA) mounted in a wire myograph. GK MA had reduced responses to acetylcholine (pEC50: 7.96 ± 0.06 vs. 7.66 ± 0.05, P< 0.05) and sodium nitroprusside (pEC50: 8.34 ± 0.05 vs. 7.77 ± 0.04, P < 0.05). There were no group differences in 8-bromoguanosine cGMP-induced relaxation and protein kinase G1 expression (P > 0.05). GK MA had attenuated responses to BAY 41–2272 (heme-dependent sGC stimulator; pEC50: 7.56 ± 0.05 vs. 6.93± 0.06, P < 0.05) and BAY 58–2667 (hemeindependent sGC activator; pEC50: 10.82 ± 0.07 vs. 10.27 ± 0.08, P < 0.05) and increased sensitivity to sildenafil [phosphodiesterase 5 (PDE5) inhibitor; pEC50: 7.89 ± 0.14 vs. 8.25 ± 0.13, P < 0.05]. Isolated resistance arteries from female rats of reproductive age that spontaneously develop type 2 diabetes have increased sensitivity to PDE5 inhibition and reduced responsiveness to sGC activators and stimulators.",
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Reduced vascular responses to soluble guanylyl cyclase but increased sensitivity to sildenafil in female rats with type 2 diabetes. / Goulopoulou, Styliani; Hannan, Johanna L.; Matsumoto, Takayuki; Ogbi, Safia; Ergul, Adviye; Webb, R. Clinton.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 309, No. 2, 01.01.2015, p. H297-H304.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Reduced vascular responses to soluble guanylyl cyclase but increased sensitivity to sildenafil in female rats with type 2 diabetes

AU - Goulopoulou, Styliani

AU - Hannan, Johanna L.

AU - Matsumoto, Takayuki

AU - Ogbi, Safia

AU - Ergul, Adviye

AU - Webb, R. Clinton

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Impaired nitric oxide (NO), soluble guanylyl cyclase (sGC), and cyclic guanosine monophosphate (cGMP) signaling (NO-sGC-cGMP) has been implicated in the pathogenesis of diabetic vascular dysfunction. Efforts to directly target this signaling have led to the development of sGC agonists that activate the heme group of sGC (stimulators) or preferentially activate sGC when the heme is oxidized (activators). In this study, we hypothesized that resistance arteries from female rats with spontaneous type 2 diabetes (Goto-Kakizaki rats, GK) would have reduced vasodilatory responses to heme-dependent sGC activation and increased responses to heme-independent sGC activation compared with control rats (Wistar). Endothelium-dependent and -independent relaxation was assessed in isolated segments from mesenteric resistance arteries (MA) mounted in a wire myograph. GK MA had reduced responses to acetylcholine (pEC50: 7.96 ± 0.06 vs. 7.66 ± 0.05, P< 0.05) and sodium nitroprusside (pEC50: 8.34 ± 0.05 vs. 7.77 ± 0.04, P < 0.05). There were no group differences in 8-bromoguanosine cGMP-induced relaxation and protein kinase G1 expression (P > 0.05). GK MA had attenuated responses to BAY 41–2272 (heme-dependent sGC stimulator; pEC50: 7.56 ± 0.05 vs. 6.93± 0.06, P < 0.05) and BAY 58–2667 (hemeindependent sGC activator; pEC50: 10.82 ± 0.07 vs. 10.27 ± 0.08, P < 0.05) and increased sensitivity to sildenafil [phosphodiesterase 5 (PDE5) inhibitor; pEC50: 7.89 ± 0.14 vs. 8.25 ± 0.13, P < 0.05]. Isolated resistance arteries from female rats of reproductive age that spontaneously develop type 2 diabetes have increased sensitivity to PDE5 inhibition and reduced responsiveness to sGC activators and stimulators.

AB - Impaired nitric oxide (NO), soluble guanylyl cyclase (sGC), and cyclic guanosine monophosphate (cGMP) signaling (NO-sGC-cGMP) has been implicated in the pathogenesis of diabetic vascular dysfunction. Efforts to directly target this signaling have led to the development of sGC agonists that activate the heme group of sGC (stimulators) or preferentially activate sGC when the heme is oxidized (activators). In this study, we hypothesized that resistance arteries from female rats with spontaneous type 2 diabetes (Goto-Kakizaki rats, GK) would have reduced vasodilatory responses to heme-dependent sGC activation and increased responses to heme-independent sGC activation compared with control rats (Wistar). Endothelium-dependent and -independent relaxation was assessed in isolated segments from mesenteric resistance arteries (MA) mounted in a wire myograph. GK MA had reduced responses to acetylcholine (pEC50: 7.96 ± 0.06 vs. 7.66 ± 0.05, P< 0.05) and sodium nitroprusside (pEC50: 8.34 ± 0.05 vs. 7.77 ± 0.04, P < 0.05). There were no group differences in 8-bromoguanosine cGMP-induced relaxation and protein kinase G1 expression (P > 0.05). GK MA had attenuated responses to BAY 41–2272 (heme-dependent sGC stimulator; pEC50: 7.56 ± 0.05 vs. 6.93± 0.06, P < 0.05) and BAY 58–2667 (hemeindependent sGC activator; pEC50: 10.82 ± 0.07 vs. 10.27 ± 0.08, P < 0.05) and increased sensitivity to sildenafil [phosphodiesterase 5 (PDE5) inhibitor; pEC50: 7.89 ± 0.14 vs. 8.25 ± 0.13, P < 0.05]. Isolated resistance arteries from female rats of reproductive age that spontaneously develop type 2 diabetes have increased sensitivity to PDE5 inhibition and reduced responsiveness to sGC activators and stimulators.

KW - Sildenafil

KW - Soluble guanylyl cycle agonists

KW - Type 2 diabetes

KW - Vascular smooth muscle

KW - Vasorelaxation

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U2 - 10.1152/ajpheart.00079.2015

DO - 10.1152/ajpheart.00079.2015

M3 - Article

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SP - H297-H304

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 2

ER -