Sex hormone regulation of systemic endothelial and renal microvascular reactivity in type-2 diabetes

Studies in gonadectomized and sham-operated Zucker diabetic rats

A. A. Ajayi, G. O. Ogungbade, Anthony Okorodudu

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background: Male Zucker diabetic rats exhibit a more severe endotheliopathy in comparison with their female diabetic litter mates. The plasma concentrations of both thromboxanes and endothelins are elevated in diabetes, and the receptor cross-talk between TXA2 and ET-1 receptors may be enhanced in type-2 diabetic Zucker rats. Aims: To determine the role of the endogenous sex steroid hormones, testosterone and estradiol on the systemic and renal microvascular reactivity to ET-1, thromboxane-mimetic U46619, ET-TXA 2 receptor interaction, and the nitric oxide vasodilator system in Zucker hypertensive-diabetic rats. Methods: Male and female Zucker rats aged 8-10 weeks were each divided into two groups. The male rats were castrated or underwent a sham operation. The female rats were spayed (bilateral ovariectomy and hysterectomy) or had a sham operation. All rats were studied 4-6 weeks after the gonadectomy or sham operations. Blood glucose and insulin as well as plasma concentrations of testosterone and estradiol were determined. Haemodynamic studies were undertaken with determination of the dose-response curve for mean arterial pressure (MAP), renal cortical flow (RCF) and renal medullary blood flow (MBF) in response to ET-1 and U46619, and the effect of interdiction of the ET-TXA2 interaction with ET-antagonists BQ610 and BQ788. The role of endogenous NO was assessed by its response to graded acetylcholine doses and to a L-NG-nitro-arginine methyl ester (L-NAME) infusion. Results: Castrated male rats had a significantly lower blood glucose concentration (295 ± 33 mg dL-1) compared with their sham-controls (481 ± 40 mg dL -1), P = 0.008. Mean arterial pressure tended to be lower in the castrated rats. Gonadectomy reduced the plasma testosterone and estradiol concentrations. Castration abolished the hypotensive action of U46619 compared with sham-operated male rats (P < 0.0001, ANOVA). Conversely, the presser action of U46619 seen in the sham-operated female rats was reversed to a profound hypotensive action in the spayed rats (P < 0.001, ANOVA).The change in MAP after U46619 was inversely correlated to the plasma testosterone concentration (r = -0.73, P = 0.027). The paradoxical hypotensive response elicited by ET-1 in the Zucker diabetic rats of both sexes was abolished by castration only (P < 0.005, ANOVA). Castration caused a significant (P = 0.011) augmentation of the vasodilator response to acetylcholine, while spaying caused a slight attenuation. Castration, but not spaying, resulted in significant increases in MBF after U46619 (P = 0.003, ANOVA), ET-1 (P = 0.005, ANOVA) and acetylcholine (P = 0.053, ANOVA). The ET-B antagonist BQ788 augmented the U46619-induced rise in MAP in castrated male rats, and also abolished the U46619-induced increase in MBF (P < 0.01 ANOVA). L-NAME (25 mg kg -1) increased MAP and decreased MBF in the gonadectomized and sham-operated rats, except for the castrated male Zucker rats, where it significantly increased MBF (+90 ± 31 PU) (P = 0.0004, ANOVA) despite the increase in MAP. Conclusions: Testosterone and estradiol regulate systemic and microvascular reactivity to TXA2 receptor stimulation in type-2 diabetic Zucker rats. The impact of testosterone on blood glucose concentration, blood pressure, and the systemic and renal microcirculatory response to ET-1 and NO, as well as the endothelin-thromboxane receptor cross talk, is greater, and opposite to that of estradiol. The effects of testosterone withdrawal may at least in part be mediated by the ET-B receptor subtype and NO generation. Androgen blockade should be investigated further for the reversal or delay of hypertensive-diabetic endotheliopathy.

Original languageEnglish (US)
Pages (from-to)349-357
Number of pages9
JournalEuropean Journal of Clinical Investigation
Volume34
Issue number5
DOIs
StatePublished - May 2004

Fingerprint

Zucker Rats
Gonadal Steroid Hormones
Medical problems
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Type 2 Diabetes Mellitus
Rats
Kidney
Analysis of Variance
Testosterone
Analysis of variance (ANOVA)
Arterial Pressure
Castration
Estradiol
Receptor Cross-Talk
Acetylcholine
Blood Glucose
Blood
Thromboxanes
NG-Nitroarginine Methyl Ester
Vasodilator Agents

Keywords

  • Endotheliopathy
  • Gonadectomy
  • Renal circulation
  • Testosterone
  • Type-2 diabetes mellitus
  • Vascular reactivity
  • Zucker rats

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{940aec5da07d4998b8fc51e54eeea327,
title = "Sex hormone regulation of systemic endothelial and renal microvascular reactivity in type-2 diabetes: Studies in gonadectomized and sham-operated Zucker diabetic rats",
abstract = "Background: Male Zucker diabetic rats exhibit a more severe endotheliopathy in comparison with their female diabetic litter mates. The plasma concentrations of both thromboxanes and endothelins are elevated in diabetes, and the receptor cross-talk between TXA2 and ET-1 receptors may be enhanced in type-2 diabetic Zucker rats. Aims: To determine the role of the endogenous sex steroid hormones, testosterone and estradiol on the systemic and renal microvascular reactivity to ET-1, thromboxane-mimetic U46619, ET-TXA 2 receptor interaction, and the nitric oxide vasodilator system in Zucker hypertensive-diabetic rats. Methods: Male and female Zucker rats aged 8-10 weeks were each divided into two groups. The male rats were castrated or underwent a sham operation. The female rats were spayed (bilateral ovariectomy and hysterectomy) or had a sham operation. All rats were studied 4-6 weeks after the gonadectomy or sham operations. Blood glucose and insulin as well as plasma concentrations of testosterone and estradiol were determined. Haemodynamic studies were undertaken with determination of the dose-response curve for mean arterial pressure (MAP), renal cortical flow (RCF) and renal medullary blood flow (MBF) in response to ET-1 and U46619, and the effect of interdiction of the ET-TXA2 interaction with ET-antagonists BQ610 and BQ788. The role of endogenous NO was assessed by its response to graded acetylcholine doses and to a L-NG-nitro-arginine methyl ester (L-NAME) infusion. Results: Castrated male rats had a significantly lower blood glucose concentration (295 ± 33 mg dL-1) compared with their sham-controls (481 ± 40 mg dL -1), P = 0.008. Mean arterial pressure tended to be lower in the castrated rats. Gonadectomy reduced the plasma testosterone and estradiol concentrations. Castration abolished the hypotensive action of U46619 compared with sham-operated male rats (P < 0.0001, ANOVA). Conversely, the presser action of U46619 seen in the sham-operated female rats was reversed to a profound hypotensive action in the spayed rats (P < 0.001, ANOVA).The change in MAP after U46619 was inversely correlated to the plasma testosterone concentration (r = -0.73, P = 0.027). The paradoxical hypotensive response elicited by ET-1 in the Zucker diabetic rats of both sexes was abolished by castration only (P < 0.005, ANOVA). Castration caused a significant (P = 0.011) augmentation of the vasodilator response to acetylcholine, while spaying caused a slight attenuation. Castration, but not spaying, resulted in significant increases in MBF after U46619 (P = 0.003, ANOVA), ET-1 (P = 0.005, ANOVA) and acetylcholine (P = 0.053, ANOVA). The ET-B antagonist BQ788 augmented the U46619-induced rise in MAP in castrated male rats, and also abolished the U46619-induced increase in MBF (P < 0.01 ANOVA). L-NAME (25 mg kg -1) increased MAP and decreased MBF in the gonadectomized and sham-operated rats, except for the castrated male Zucker rats, where it significantly increased MBF (+90 ± 31 PU) (P = 0.0004, ANOVA) despite the increase in MAP. Conclusions: Testosterone and estradiol regulate systemic and microvascular reactivity to TXA2 receptor stimulation in type-2 diabetic Zucker rats. The impact of testosterone on blood glucose concentration, blood pressure, and the systemic and renal microcirculatory response to ET-1 and NO, as well as the endothelin-thromboxane receptor cross talk, is greater, and opposite to that of estradiol. The effects of testosterone withdrawal may at least in part be mediated by the ET-B receptor subtype and NO generation. Androgen blockade should be investigated further for the reversal or delay of hypertensive-diabetic endotheliopathy.",
keywords = "Endotheliopathy, Gonadectomy, Renal circulation, Testosterone, Type-2 diabetes mellitus, Vascular reactivity, Zucker rats",
author = "Ajayi, {A. A.} and Ogungbade, {G. O.} and Anthony Okorodudu",
year = "2004",
month = "5",
doi = "10.1111/j.1365-2362.2004.01339.x",
language = "English (US)",
volume = "34",
pages = "349--357",
journal = "European Journal of Clinical Investigation",
issn = "0014-2972",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Sex hormone regulation of systemic endothelial and renal microvascular reactivity in type-2 diabetes

T2 - Studies in gonadectomized and sham-operated Zucker diabetic rats

AU - Ajayi, A. A.

AU - Ogungbade, G. O.

AU - Okorodudu, Anthony

PY - 2004/5

Y1 - 2004/5

N2 - Background: Male Zucker diabetic rats exhibit a more severe endotheliopathy in comparison with their female diabetic litter mates. The plasma concentrations of both thromboxanes and endothelins are elevated in diabetes, and the receptor cross-talk between TXA2 and ET-1 receptors may be enhanced in type-2 diabetic Zucker rats. Aims: To determine the role of the endogenous sex steroid hormones, testosterone and estradiol on the systemic and renal microvascular reactivity to ET-1, thromboxane-mimetic U46619, ET-TXA 2 receptor interaction, and the nitric oxide vasodilator system in Zucker hypertensive-diabetic rats. Methods: Male and female Zucker rats aged 8-10 weeks were each divided into two groups. The male rats were castrated or underwent a sham operation. The female rats were spayed (bilateral ovariectomy and hysterectomy) or had a sham operation. All rats were studied 4-6 weeks after the gonadectomy or sham operations. Blood glucose and insulin as well as plasma concentrations of testosterone and estradiol were determined. Haemodynamic studies were undertaken with determination of the dose-response curve for mean arterial pressure (MAP), renal cortical flow (RCF) and renal medullary blood flow (MBF) in response to ET-1 and U46619, and the effect of interdiction of the ET-TXA2 interaction with ET-antagonists BQ610 and BQ788. The role of endogenous NO was assessed by its response to graded acetylcholine doses and to a L-NG-nitro-arginine methyl ester (L-NAME) infusion. Results: Castrated male rats had a significantly lower blood glucose concentration (295 ± 33 mg dL-1) compared with their sham-controls (481 ± 40 mg dL -1), P = 0.008. Mean arterial pressure tended to be lower in the castrated rats. Gonadectomy reduced the plasma testosterone and estradiol concentrations. Castration abolished the hypotensive action of U46619 compared with sham-operated male rats (P < 0.0001, ANOVA). Conversely, the presser action of U46619 seen in the sham-operated female rats was reversed to a profound hypotensive action in the spayed rats (P < 0.001, ANOVA).The change in MAP after U46619 was inversely correlated to the plasma testosterone concentration (r = -0.73, P = 0.027). The paradoxical hypotensive response elicited by ET-1 in the Zucker diabetic rats of both sexes was abolished by castration only (P < 0.005, ANOVA). Castration caused a significant (P = 0.011) augmentation of the vasodilator response to acetylcholine, while spaying caused a slight attenuation. Castration, but not spaying, resulted in significant increases in MBF after U46619 (P = 0.003, ANOVA), ET-1 (P = 0.005, ANOVA) and acetylcholine (P = 0.053, ANOVA). The ET-B antagonist BQ788 augmented the U46619-induced rise in MAP in castrated male rats, and also abolished the U46619-induced increase in MBF (P < 0.01 ANOVA). L-NAME (25 mg kg -1) increased MAP and decreased MBF in the gonadectomized and sham-operated rats, except for the castrated male Zucker rats, where it significantly increased MBF (+90 ± 31 PU) (P = 0.0004, ANOVA) despite the increase in MAP. Conclusions: Testosterone and estradiol regulate systemic and microvascular reactivity to TXA2 receptor stimulation in type-2 diabetic Zucker rats. The impact of testosterone on blood glucose concentration, blood pressure, and the systemic and renal microcirculatory response to ET-1 and NO, as well as the endothelin-thromboxane receptor cross talk, is greater, and opposite to that of estradiol. The effects of testosterone withdrawal may at least in part be mediated by the ET-B receptor subtype and NO generation. Androgen blockade should be investigated further for the reversal or delay of hypertensive-diabetic endotheliopathy.

AB - Background: Male Zucker diabetic rats exhibit a more severe endotheliopathy in comparison with their female diabetic litter mates. The plasma concentrations of both thromboxanes and endothelins are elevated in diabetes, and the receptor cross-talk between TXA2 and ET-1 receptors may be enhanced in type-2 diabetic Zucker rats. Aims: To determine the role of the endogenous sex steroid hormones, testosterone and estradiol on the systemic and renal microvascular reactivity to ET-1, thromboxane-mimetic U46619, ET-TXA 2 receptor interaction, and the nitric oxide vasodilator system in Zucker hypertensive-diabetic rats. Methods: Male and female Zucker rats aged 8-10 weeks were each divided into two groups. The male rats were castrated or underwent a sham operation. The female rats were spayed (bilateral ovariectomy and hysterectomy) or had a sham operation. All rats were studied 4-6 weeks after the gonadectomy or sham operations. Blood glucose and insulin as well as plasma concentrations of testosterone and estradiol were determined. Haemodynamic studies were undertaken with determination of the dose-response curve for mean arterial pressure (MAP), renal cortical flow (RCF) and renal medullary blood flow (MBF) in response to ET-1 and U46619, and the effect of interdiction of the ET-TXA2 interaction with ET-antagonists BQ610 and BQ788. The role of endogenous NO was assessed by its response to graded acetylcholine doses and to a L-NG-nitro-arginine methyl ester (L-NAME) infusion. Results: Castrated male rats had a significantly lower blood glucose concentration (295 ± 33 mg dL-1) compared with their sham-controls (481 ± 40 mg dL -1), P = 0.008. Mean arterial pressure tended to be lower in the castrated rats. Gonadectomy reduced the plasma testosterone and estradiol concentrations. Castration abolished the hypotensive action of U46619 compared with sham-operated male rats (P < 0.0001, ANOVA). Conversely, the presser action of U46619 seen in the sham-operated female rats was reversed to a profound hypotensive action in the spayed rats (P < 0.001, ANOVA).The change in MAP after U46619 was inversely correlated to the plasma testosterone concentration (r = -0.73, P = 0.027). The paradoxical hypotensive response elicited by ET-1 in the Zucker diabetic rats of both sexes was abolished by castration only (P < 0.005, ANOVA). Castration caused a significant (P = 0.011) augmentation of the vasodilator response to acetylcholine, while spaying caused a slight attenuation. Castration, but not spaying, resulted in significant increases in MBF after U46619 (P = 0.003, ANOVA), ET-1 (P = 0.005, ANOVA) and acetylcholine (P = 0.053, ANOVA). The ET-B antagonist BQ788 augmented the U46619-induced rise in MAP in castrated male rats, and also abolished the U46619-induced increase in MBF (P < 0.01 ANOVA). L-NAME (25 mg kg -1) increased MAP and decreased MBF in the gonadectomized and sham-operated rats, except for the castrated male Zucker rats, where it significantly increased MBF (+90 ± 31 PU) (P = 0.0004, ANOVA) despite the increase in MAP. Conclusions: Testosterone and estradiol regulate systemic and microvascular reactivity to TXA2 receptor stimulation in type-2 diabetic Zucker rats. The impact of testosterone on blood glucose concentration, blood pressure, and the systemic and renal microcirculatory response to ET-1 and NO, as well as the endothelin-thromboxane receptor cross talk, is greater, and opposite to that of estradiol. The effects of testosterone withdrawal may at least in part be mediated by the ET-B receptor subtype and NO generation. Androgen blockade should be investigated further for the reversal or delay of hypertensive-diabetic endotheliopathy.

KW - Endotheliopathy

KW - Gonadectomy

KW - Renal circulation

KW - Testosterone

KW - Type-2 diabetes mellitus

KW - Vascular reactivity

KW - Zucker rats

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U2 - 10.1111/j.1365-2362.2004.01339.x

DO - 10.1111/j.1365-2362.2004.01339.x

M3 - Article

VL - 34

SP - 349

EP - 357

JO - European Journal of Clinical Investigation

JF - European Journal of Clinical Investigation

SN - 0014-2972

IS - 5

ER -