E. R. Ramey

Effect of testosterone, sex and age on experimentally induced arterial thrombosis

THE widespread use of large doses of oestrogenic steroids as contraceptive agents or for maintenance therapy in post-menopausal women has led to damaging effects on the cardiovascular system. Most of the reports relate to the increased thromboembolic phenomena which have been observed in both women and men treated with female hormones1,2. In sharp contrast there are no data on the effect of androgenic steroids on the development of arterial thrombosis, in spite of the fact that the incidence of ischaemic heart disease in human males is much greater than in the pre-menopausal females3.

Arachidonate-induced thrombosis in mice: effects of gender or testosterone and estradiol administration

Sodium arachidonate (i.v.) has previously been shown to induce pulmonary emboli formation and a dose dependent cyanosis and respiratory depression in mice. Subsequently, we found that male mice are significantly more sensitive to arachidonate than females. Aspirin given orally 2 hours prior to arachidonate administration inhibits the responses of both males and females. Pretreatment with depo-testosterone markedly increases the effect of arachidonate in both males and females and depo-estradiol pretreatment reduces the responses in all mice. This exacerbation by testosterone of the arachidonate response and the attenuating effects of estradiol is consistent with data reported using other thrombogenic techniques.

Glucocorticoid protection against PAF-acether toxicity in mice

1 Intravenous platelet activating factor (PAF‐acether, 10 to 25 μg/kg body weight) produced dose‐dependent mortality in both male and female mice. 2 Pretreatment with indomethacin (50 mg/kg), verapamil (40 mg/kg) or nifedipine (4 mg/kg) failed to inhibit the lethal effect of 20 μg/kg PAF‐acether. This suggests that neither arachidonate cyclo‐oxygenase products nor availability of extracellular Ca2+ mediate the toxic action. 3 In contrast, pretreatment with 100 mg/kg cortisone acetate (s.c.) daily for four days exerted a highly protective effect, i.e. 100% and 93% survival in males and females, compared to 13% and 7% respectively, in untreated animals. 4 PAF‐acether‐induced death may be a useful model for the in vivo evaluation of pharmacological agents in anaphylactic shock.

Sex and hormonal modification of 6-keto-PGF1α release by rat aorta

Abstract The stable breakdown product of prostacyclin, 6-keto-PGF1α, was estimated in plasma samples after incubation with rat aortic rings. The 6-keto-PGF1α concentration obtained with the male aortae was two-fold higher than that of the female. Ovariectomy markedly increased 6-keto-PGF1α six-fold, but castration had no effect. Estradiol and progesterone treatment of the ovariectomized female suppressed (by 50%) and enhanced (two-fold) 6-keto-PGF1α. Testosterone was without effect in gonadectomized males and females. Castrate males did not respond to gonadal steroid treatment.

GENDER DIFFERENCES IN PROSTAGLANDIN RECEPTORS OF RAT AORTA

The maximal contractile response to the prostaglandin endoperoxide H2 analogue U46619, prostaglandins E2, D2 and F2α and the sensitivity of the superfused aorta preparation to these drugs (except PGF2α) is greater in the male than the female rat. In contrast, gender differences were not observed in the response to noradrenaline or 5‐hydroxytryptamine. In previous studies, testosterone unlike oestrogen or progesterone, increased the response of both rabbit and rat aorta to U46619. We conclude that prostaglandin receptors in rat thoracic aorta may be hormonally regulated.

Prostaglandin synthetase activity in vascular tissue of male and female rats

1. Isolated perfused lungs from mature male rats show greater conversion of 14C Arachidonic Acid to cyclo-oxygenase products than females. 2. Following unlabelled arachidonate infusion, the male lungs release more 6-K-PGF1 alpha and TxB2 than females. 3. Aortic rings from male rats release more PGI2-like material and 6-K-PGF1 alpha than the females. 4. These data indicate an elevated PG synthetase activity in male rats as compared with females.

Sex differences in arachidonate cyclo-oxygenase products in elicited rat peritoneal macrophages

Peritoneal macrophages were elicited by Freunds incomplete adjuvant from adult male and female Fisher 344 rats. The release of prostaglandin E2 and thromboxane B2 from these macrophages was determined by radioimmunoassay. The basal release of these products was the same for males and females. The macrophages of the female rats released, in a dose-dependent manner, significantly more prostaglandin E2 and thromboxane B2 than macrophages from the male, following challenge with either a particulate stimulus, zymosan (25-150 micrograms/ml) or a soluble stimulus, calcium ionophore A23187 (1 X 10(-7) -1 X 10(-6) M). These results may relate to gender differences in immune responses.

The role of gonadal steroids in arachidonate-induced mortality in mice.

Abstract Female mice are significantly more resistant than male mice to intravenous arachidonate. Estradiol treatment of castrated males, but not females or intact males, provides protection. Testosterone treatment, on the other hand, increased the mortality rate of the intact or castrated males but had no significant effect on the responsiveness to arachidonate in female mice. Progesterone pretreatment did not modify the mortality rate in any of the groups studied. Another steroid, cortisone, is much more protective than the ovarian steroids. In both males and females, intact or castrated, exogenous cortisone greatly increased the ability to withstand an arachidonate injection. These data suggest that gonadal and cortical steroids act at a critical step in the tissue response to arachidonate and alter its ultimate effect on morbidity and mortality.

EFFECT OF GENDER ON DEVELOPMENT AND DIURNAL RHYTHM OF PROSTAGLANDIN RECEPTORS IN RAT AORTA

1 The prostaglandin endoperoxide H2 analogue, U‐46619 (15‐hydroxyll, 9‐epoxymethano‐prosta‐5Z, 13E‐enoic acid), was used to determine the effect of gender on the isotonic contractile response of the superfused rat aorta preparation over a 24 h period and at 10 and 16 weeks of age. 2 The maximal responses of the male aortae were 20 ± 3% and 36 ± 4% (P< 0.001) greater than the female at 10 and 16 weeks, respectively. Similarly, sensitivity of the male aorta to the PGH2 analogue increased with age. 3 The male but not the female exhibited a diurnal rhythm in which both the maximum contractile response and sensitivity were significantly decreased at night. 4 We conclude that these gender differences may be related to the secretion of androgen, since reported peak serum testosterone over a 24 h period and testosterone changes with maturation are coincident with the maximum response of male aortae to the PGH2 analogue.

Connective Tissue IV. Effect of Age upon Dermal Chemical Response to Adrenal Hormones.

Summary Both Cortisol and Doca similarly affect the chemistry of the connective tissue in that they result in a decrease in total and insoluble collagen concentration of rat skin. The effects of these hormones upon rat skin are profoundly altered by the age of the animal. The aged rat demonstrates a considerably different dermal chemical response to Cortisol and particularly Doca than does either the young or the mature animal.