황체호르몬과 그 유도체가 인간 혈관평활근의 긴장도에 미치는 영향 = The effect of progestogens on the tone of human vascular smooth muscles

다국어 초록 (Multilingual Abstract)

The incidence of cardiovascular diseases in women increases dramatically after menopause. The most important benefit of hormone replacement therapy in postmenopausal women is a reduction of the risk of coronary heart disease. Estrogen exerts a favorable influence on cardiovascular system through endothelium-dependent and -independent mechanisms which involve direct action on vascular smooth muscle.
Progesterone/progestogen as an essential component of hormone replacement therapy reduces the risk of endometrial cancer associated with estrogen replacement. Although numerous studies have demonstrated the direct cardiovascular effects of estrogens, there are few reports on the action of progesterone and synthetic progestogens on the vascular system. Furthermore, the cellular mechanism of progestogen-induced changes in the contractility of vascular smooth muscle have not been elucidated.
This study was performed to investigate whether 1) progestogens induce changes of vascular tone in endothelium-denuded smooth muscles of human uterine artery, 2) endothelium-independent vascular reactivity is mediated by intracelluar calcium ion modulation through 2 types of calcium channel, both voltage- and receptor-dependent and 3) 3 kinds of progestogen such as a progesterone, C19 nortestosterone (norethindrone acetate ; NETA) and C21 progestogen (medroxyprogesterone acetate ; MPA), have a different vasoreactivity.
The uterine arteries were obtained at the time of hysterectomy from 24 women who had no cardiovascular disease risk factors and the endothelium was denuded. Vascular reactivity was monitored by using isometric force transducer and recorded by physiograph.
Endothelial integrity was assessed by adding 10μM acetylcholine(endothelium-dependent vasorelaxant) to the specimens, which were pretreated with 1μM norepinephrine(α-adrenergic stimulant). The integrity of smooth muscle was assessed by adding 10μ M sodium nitroprusside(endotelium -independent vasorelaxant) and 10μ M tamsulosin(α-adrenergic blocker) to the specimens, pretreated with 1 μM norepinephrine. The uterine smooth muscles were pretreated with 35mM and 70mM potassium chloride and 10-7M and 10-6M norepinephrine. Three kinds of progestogen - progesterone, NETA and MPA - each at 5 different concentrations(10-9g/ml, 10-8g/ml, 10-7g/ml, 10-6g/ml and 10-5g/ml) were used.
The loss of endothelial function and adequacy of smooth muscle function were confirmed. Three kinds of progestogen had inhibitory effects on high potassium induced vascular smooth muscle contraction. This inhibitory effect was concentration-dependent. In 70mM potassium solution, there were significant differences among the three progestogens-induced inhibitory effects on potassium-induced muscle contraction, while there were no siginificant differences in 35mM concentration of potassium solution. Progesterone showed the most potent inhibitory effect, NETA was intermediate, and MPA had the mildest effect.
All progestogens also demonstrated inhibitory effects on muscular contraction induced by norepinephrine, which was revealed to be concentration-dependent as well. Three progestogens had different inhibitory effects on muscular contraction in 10-7M norepinephrine, but no siginificant differences were noted among the inhibitory effects of three progestogens on 10-6M norepinephrine induced muscular contraction. Progesterone had more potent inhibitory effect on norepinephrine induced contraction than NETA or MPA. The difference between progesterone and NETA/MPA was statistically siginificant, with no statistically significant difference in the inhibitory effect between NETA and MPA, in 10-7M concentration of norepinephrine.
In conclusion, the results of this study revealed that progestogens have a concentration-dependent vaso-relaxant effect on endothelium-denuded vasular smooth muscles via a calcium antagonistic mechanism of direct inhibitory effects on receptor- and voltage-dependent calcium ion channels. This vaso-relaxant effect of progestogens differed among a variety of progestogens.

목차 (Table of Contents)

• I. 서 론 = 1
• II. 연구대상 및 방법 = 6
• III. 결 과 = 11
• IV. 고 찰 = 22
• V. 결 론 = 35
• VI. 참고 문헌 = 37
• 영문 초록 = 47