055P University of Cambridge
Summer Meeting July 2005

 

Mesenteric vasodilatory action of testosterone: influence of the classic androgen receptor, aromatase activity, nitric oxide and dilator prostaglandins

Hall J1, Jones RD1, S Clarke1, Shorthouse AJ2, Adam IJ2, Brown S2, Jones TH1 and Channer KS2,3. 1Academic Unit of Endocrinology, Division of Genomic Medicine, The University of Sheffield. 2Sheffield Teaching Hospitals NHS Foundation Trust, UK. 3Faculty of Health & Well-being, Sheffield Hallam University.

 

Testosterone acts as a coronary vasodilator and reduces myocardial ischemia in men with coronary heart disease (English et al., 2000). The aim of the current study was to study the vasodilatory mechanism of action of testosterone in the human mesenteric circulation. We therefore examined the influence of the classical androgen receptor, the enzyme aromatase, nitric oxide and dilator prostaglandins in the dilatory response to testosterone.

The study was approved by the relevant local Ethics Committee, and full written informed consent was given by all patients. Mesenteric tissue was obtained at surgery from male (n = 14, age = 59 ± 3yrs) and female (n = 10, age = 69 ± 4yrs) patients undergoing resections for bowel carcinoma and was macroscopically normal. Mesenteric arteries (n = 60, mean internal diameter = 538 µm) were carefully dissected and loaded in a wire myograph and maintained at a tension equivalent to the in vivo pressure (100mmHg) in oxygenated krebs at 37 ° C. Vessels were then left to equilibrate in fresh krebs plus one of the following pharmacological agents for 30 min. 7 µl ethanol vehicle (n=12); 10 µM of the cyclooxygenase inhibitor indomethacin (n=12); 100 µM of the nitric-oxide synthase inhibitor L-NAME (n=12); 10 µM of the classic androgen receptor antagonist flutamide (n=12) and 10 µM of the aromatase inhibitor aminoglutethimide (n=12). A cumulative concentration response curve to U46619 (1-1000nM) was obtained and testosterone (10nM-100 µM) or equivalent concentrations of ethanol vehicle were then added cumulatively and changes in tension recorded.

Table 1. Illustrating the vasodilatatory response to testosterone. All p>0.05 compared to control, analysed via Mann Whitney U Test.

 

Testosterone
(µ M)

0.01

0.1

1

10

100

Control

2.1 ± 4.2

-1.3 ± 4.2

-4.5 ± 4.5

-13.2 ± 5.8

-75.0 ± 4.2

10 µM
Indomethacin

0.7 ± 2.4

-1.9 ± 3.4

-1.4 ± 3.8

-13. 9 ± 5.2

-79.5 ± 5.9

100 µM
L-NAME

1.1 ± 2. 1

3.0 ± 2.7

2.3 ± 3.5

-2.4 ± 5.2

-62.1 ± 5.1

10 µM
Flutamide

3.0 ± 2.7

-5.1 ± 3.6

-1.6 ± 2.6

-15.3 ± 3.8

-79.6 ± 6.6

10 µM
Aminoglutethimide

0.2 ± 2.7

-0.6 ± 2.5

-6.2 ± 6.0

-16.2 ± 8.1

-79.0 ± 6.9

 

Dilatation to testosterone was similar in vessels treated with each of the pharmacological agents (Table 1). Results are expressed as % dilatation from baseline, corrected for the negligible vasopressor ethanol response, as mean ± SEM.

This study demonstrates that testosterone induces mesenteric dilatation via a mechanism that is independent of the classical androgen receptor, aromatase-mediated conversion to 17β oestradiol and also of the involvement of nitric oxide or dilator prostaglandins.

 

English K. M et al. (2000) Circulation 102 (16) 1906-1911.