TRPM8 channel activation triggers relaxation of pudendal artery with increased sensitivity in the hypertensive rats

Darizy Flavia Silva, Camilla Ferreira Wenceslau, Cameron G. Mccarthy, Theodora Szasz, S. Ogbi, R. Clinton Webb

Research output: Contribution to journalArticle

Abstract

Introduction: Erectile dysfunction (ED) is frequently encountered in patients with arterial hypertension and there is a recent functional correlation between the expression of thermoreceptor channels TRPM8 (melastatin 8) and alterations in blood pressure in hypertension. The aim of this study was to investigate the function of cold-sensing TRPM8 channel in internal pudendal artery (IPA) in both normotensive and hypertensive rats. Methods: We performed experiments integrating physiological, pharmacological, biochemical and cellular techniques. Results: TRPM8 channels are expressed in the IPA and in vascular smooth muscle cells from IPA. In addition, TRPM8 activation, by both a cooling compound icilin (82.1 ± 3.0%, n = 6) and cold temperature [thermal stimulus, basal tone (25 °C, 41.2 ± 3.4%, n = 5) or pre-contracted tone induced by phenylephrine (25 °C, 87.0 ± 3.6%, n = 7)], induced relaxation in IPA. Furthermore, the results showed that the concentration-response curve to icilin was significantly shifted to the right in different conditions, such as: the absence of the vascular endothelium, in the presence of L-NAME (10−4 M), or indomethacin (10−5 M) or by a combination of charybdotoxin (10-7 M) and apamin (5 × 10-6 M), and Y27632 (10-6 M). Interestingly, icilin-induced vasodilation was significantly higher in IPA from spontaneously hypertensive (SHR, E10 −4 M = 75.3 ± 1.7%) compared to wistar rats (E10 −4 M = 56.4 ± 2.6%), despite no changes in the TRPM8 expression in IPA between the strains, suggesting that the sensitivity of TRPM8 channels is higher in SHR. Conclusions: These data demonstrate for the first time, the expression and function of TRPM8 channels in the IPA involving, at least in part, endothelium-derived relaxing factors and ROCK inhibition. Overall, this channel could potentially be a new target for the treatment of hypertension associated-ED.

Original languageEnglish (US)
Article number104329
JournalPharmacological Research
Volume147
DOIs
StatePublished - Sep 2019

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Arteries
Erectile Dysfunction
Hypertension
Thermoreceptors
Charybdotoxin
Apamin
Endothelium-Dependent Relaxing Factors
NG-Nitroarginine Methyl Ester
Vascular Endothelium
Phenylephrine
Vascular Smooth Muscle
Vasodilation
Indomethacin
Smooth Muscle Myocytes
Wistar Rats
Hot Temperature
Pharmacology
Blood Pressure
icilin

Keywords

  • Endothelium-derived relaxing factors
  • Internal pudendal artery
  • ROCK
  • Spontaneously hypertensive rats
  • TRPM8 channels
  • Vasodilation

ASJC Scopus subject areas

  • Pharmacology

Cite this

TRPM8 channel activation triggers relaxation of pudendal artery with increased sensitivity in the hypertensive rats. / Silva, Darizy Flavia; Wenceslau, Camilla Ferreira; Mccarthy, Cameron G.; Szasz, Theodora; Ogbi, S.; Webb, R. Clinton.

In: Pharmacological Research, Vol. 147, 104329, 09.2019.

Research output: Contribution to journalArticle

Silva, Darizy Flavia ; Wenceslau, Camilla Ferreira ; Mccarthy, Cameron G. ; Szasz, Theodora ; Ogbi, S. ; Webb, R. Clinton. / TRPM8 channel activation triggers relaxation of pudendal artery with increased sensitivity in the hypertensive rats. In: Pharmacological Research. 2019 ; Vol. 147.
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abstract = "Introduction: Erectile dysfunction (ED) is frequently encountered in patients with arterial hypertension and there is a recent functional correlation between the expression of thermoreceptor channels TRPM8 (melastatin 8) and alterations in blood pressure in hypertension. The aim of this study was to investigate the function of cold-sensing TRPM8 channel in internal pudendal artery (IPA) in both normotensive and hypertensive rats. Methods: We performed experiments integrating physiological, pharmacological, biochemical and cellular techniques. Results: TRPM8 channels are expressed in the IPA and in vascular smooth muscle cells from IPA. In addition, TRPM8 activation, by both a cooling compound icilin (82.1 ± 3.0{\%}, n = 6) and cold temperature [thermal stimulus, basal tone (25 °C, 41.2 ± 3.4{\%}, n = 5) or pre-contracted tone induced by phenylephrine (25 °C, 87.0 ± 3.6{\%}, n = 7)], induced relaxation in IPA. Furthermore, the results showed that the concentration-response curve to icilin was significantly shifted to the right in different conditions, such as: the absence of the vascular endothelium, in the presence of L-NAME (10−4 M), or indomethacin (10−5 M) or by a combination of charybdotoxin (10-7 M) and apamin (5 × 10-6 M), and Y27632 (10-6 M). Interestingly, icilin-induced vasodilation was significantly higher in IPA from spontaneously hypertensive (SHR, E10 −4 M = 75.3 ± 1.7{\%}) compared to wistar rats (E10 −4 M = 56.4 ± 2.6{\%}), despite no changes in the TRPM8 expression in IPA between the strains, suggesting that the sensitivity of TRPM8 channels is higher in SHR. Conclusions: These data demonstrate for the first time, the expression and function of TRPM8 channels in the IPA involving, at least in part, endothelium-derived relaxing factors and ROCK inhibition. Overall, this channel could potentially be a new target for the treatment of hypertension associated-ED.",
keywords = "Endothelium-derived relaxing factors, Internal pudendal artery, ROCK, Spontaneously hypertensive rats, TRPM8 channels, Vasodilation",
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T1 - TRPM8 channel activation triggers relaxation of pudendal artery with increased sensitivity in the hypertensive rats

AU - Silva, Darizy Flavia

AU - Wenceslau, Camilla Ferreira

AU - Mccarthy, Cameron G.

AU - Szasz, Theodora

AU - Ogbi, S.

AU - Webb, R. Clinton

PY - 2019/9

Y1 - 2019/9

N2 - Introduction: Erectile dysfunction (ED) is frequently encountered in patients with arterial hypertension and there is a recent functional correlation between the expression of thermoreceptor channels TRPM8 (melastatin 8) and alterations in blood pressure in hypertension. The aim of this study was to investigate the function of cold-sensing TRPM8 channel in internal pudendal artery (IPA) in both normotensive and hypertensive rats. Methods: We performed experiments integrating physiological, pharmacological, biochemical and cellular techniques. Results: TRPM8 channels are expressed in the IPA and in vascular smooth muscle cells from IPA. In addition, TRPM8 activation, by both a cooling compound icilin (82.1 ± 3.0%, n = 6) and cold temperature [thermal stimulus, basal tone (25 °C, 41.2 ± 3.4%, n = 5) or pre-contracted tone induced by phenylephrine (25 °C, 87.0 ± 3.6%, n = 7)], induced relaxation in IPA. Furthermore, the results showed that the concentration-response curve to icilin was significantly shifted to the right in different conditions, such as: the absence of the vascular endothelium, in the presence of L-NAME (10−4 M), or indomethacin (10−5 M) or by a combination of charybdotoxin (10-7 M) and apamin (5 × 10-6 M), and Y27632 (10-6 M). Interestingly, icilin-induced vasodilation was significantly higher in IPA from spontaneously hypertensive (SHR, E10 −4 M = 75.3 ± 1.7%) compared to wistar rats (E10 −4 M = 56.4 ± 2.6%), despite no changes in the TRPM8 expression in IPA between the strains, suggesting that the sensitivity of TRPM8 channels is higher in SHR. Conclusions: These data demonstrate for the first time, the expression and function of TRPM8 channels in the IPA involving, at least in part, endothelium-derived relaxing factors and ROCK inhibition. Overall, this channel could potentially be a new target for the treatment of hypertension associated-ED.

AB - Introduction: Erectile dysfunction (ED) is frequently encountered in patients with arterial hypertension and there is a recent functional correlation between the expression of thermoreceptor channels TRPM8 (melastatin 8) and alterations in blood pressure in hypertension. The aim of this study was to investigate the function of cold-sensing TRPM8 channel in internal pudendal artery (IPA) in both normotensive and hypertensive rats. Methods: We performed experiments integrating physiological, pharmacological, biochemical and cellular techniques. Results: TRPM8 channels are expressed in the IPA and in vascular smooth muscle cells from IPA. In addition, TRPM8 activation, by both a cooling compound icilin (82.1 ± 3.0%, n = 6) and cold temperature [thermal stimulus, basal tone (25 °C, 41.2 ± 3.4%, n = 5) or pre-contracted tone induced by phenylephrine (25 °C, 87.0 ± 3.6%, n = 7)], induced relaxation in IPA. Furthermore, the results showed that the concentration-response curve to icilin was significantly shifted to the right in different conditions, such as: the absence of the vascular endothelium, in the presence of L-NAME (10−4 M), or indomethacin (10−5 M) or by a combination of charybdotoxin (10-7 M) and apamin (5 × 10-6 M), and Y27632 (10-6 M). Interestingly, icilin-induced vasodilation was significantly higher in IPA from spontaneously hypertensive (SHR, E10 −4 M = 75.3 ± 1.7%) compared to wistar rats (E10 −4 M = 56.4 ± 2.6%), despite no changes in the TRPM8 expression in IPA between the strains, suggesting that the sensitivity of TRPM8 channels is higher in SHR. Conclusions: These data demonstrate for the first time, the expression and function of TRPM8 channels in the IPA involving, at least in part, endothelium-derived relaxing factors and ROCK inhibition. Overall, this channel could potentially be a new target for the treatment of hypertension associated-ED.

KW - Endothelium-derived relaxing factors

KW - Internal pudendal artery

KW - ROCK

KW - Spontaneously hypertensive rats

KW - TRPM8 channels

KW - Vasodilation

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