The effect of progestogens on the tone of human vascular smooth muscles

Moon, Zong Soo; Park, Hyoung Moo; Hur, Min; Lee, Moo Yeol

Abstract

OBJECTIVE
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.
METHODS
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 10micrometer acetylcholine(endothelium-dependent vasorelaxant) to the specimens, which were pretreated with 1micrometer norepinephrine(alpha-adrenergic stimulant). The integrity of smooth muscle was assessed by adding 10micrometer sodium nitroprusside(endotelium -independent vasorelaxant) and 10micrometer tamsulosin(alpha-adrenergic blocker) to the specimens, pretreated with 1micrometer 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.
RESULTS
The loss of endothelial function and adequacy of smooth muscle function were confirmed. Three kinds of progestogen had concentration-dependent inhibitory effects on vascular smooth muscle contr action induced by high potassium solution and norepinephrine, respcetively. There were no siginificant differences noted among the inhibitory effects of three progestogens in 35mM concentration of potassium solution and 10-6M norepinephrine induced muscular contraction. In 70mM potassium solution, there were significant differences among the three progestogens-induced inhibitory effects. Progesterone showed the most potent inhibitory effect, NETA was intermediate, and MPA had the mildest effect. In 10-7M norepinephrine, progesterone had more potent inhibitory effect than NETA or MPA. The difference between progesterone and NETA/MPA was statistically siginificant, with no significance between NETA and MPA.
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. In conclusion, the progestogens combined with estrogens have not antagonistic effect on vaso-relaxation at least and maybe have synergistic effect with estrogens, in vivo.