Factors influencing isometric exercise training-induced reductions in resting blood pressure.

Hypertension is a major health concern, and current recommendations for blood pressure management (lifestyle modifications and pharmacological intervention) have not been universally successful. For two decades, isometric exercise training (IET) has become established as effective at reducing in resting BP (RBP) in a short period (4-10 weeks). The most common IET modes have comprised isometric handgrip (IHG) or isometric bilateral leg (IBL) training and 4 × 2-min contractions at ∼20-50% maximal voluntary contraction with 1-5-min rest between. Although this type of exercise training could have important implications, for hypertensive patients and in preventing hypertension development, little is known about the mechanisms responsible for IET-induced RBP reductions. This uncertainty derives from a lack of understanding concerning the most effective IET programs for specific populations. Possible influential factors and mechanisms include age, sex, pre-existing disease and medication, and IET-induced adaptations in the exercising muscle and nervous system, which are discussed in this review. Designing effective IET programs may involve manipulation of exercise intensity, frequency, duration and mode, as well as consideration of yet discovered mechanisms for RBP reductions. We call for additional research designed to understand more about the mechanisms involved in IET-induced RBP reductions for maximum effectiveness.

Evidence for prostaglandins and leukotrienes as mediators of phase I of estrogen action in implantation in the mouse.

The inhibition of the cyclooxygenase and/or the lipoxygenase pathways by indomethacin or nordihydroguaiaretic acid during Phase I of estrogen action interfered with estriol-induced initiation of implantation, but not uterine macromolecular uptake and water imbibition. This inhibition of implantation was completely reversed by supplementation with prostaglandin E2 or leukotriene C4. These results suggest that estrogen-induced initiation of implantation in a progesterone-primed uterus is mediated via prostaglandins and leukotrienes as components of Phase I of estrogen action.

A paradoxical effect of an antiestrogen, CI-628, on implantation in the mouse.

Some triphenylethylene compounds (TPE), commonly known as antiestrogens, have been reported to interfere with pregnancy. This effect of these TPE compounds was attributed to their antagonistic effects to estrogen in the uterus and/or the embryo. Paradoxically, recent evidence suggests that several TPE compounds act as estrogen agonists in inducing embryo implantation in the uterus of ovariectomized, progesterone-treated, delayed-implanting mice. The present study was undertaken to determine the effect of CI-628, a TPE compound, on normal pregnancy and its site of action. Mice were given a single injection of CI-628 (1.5, 5, or 15 micrograms/mouse, ip) on Day 3, Day 4, or both days and killed on Day 8 for examination of implantation sites or unimplanted embryos. CI-628 at 5 and 15 micrograms reduced the implantation rate when injected on Day 3 or Days 3 and 4, but not when administered only on Day 4. The lower dose of the compound (1.5 micrograms) was ineffective in altering implantation. The implantation failure was overcome to various degrees by simultaneous injection of progesterone (2 mg/mouse, sc), but not by estradiol-17 beta (20 ng/mouse, sc). These results suggest that Day 3 is critical for CI-628 to exert its inhibitory effect and that this compound appears to affect ovarian progesterone synthesis and/or secretion. This suggestion is consistent with our findings that animals that showed implantation following injection of 5 or 15 micrograms of CI-628 had higher serum progesterone levels than those without implantation. Serum progesterone levels of animals bearing implantation sites following 5 micrograms of CI-628 on Day 3 or Day 4 were comparable to those of vehicle-treated controls, whereas the level of this steroid in animals treated with 15 micrograms of CI-628 and having implantation sites was relatively lower. However, a small number of animals that had implantation following treatment with 5 micrograms of CI-628 on Days 3 and 4 showed lower progesterone levels compared to those of the controls, but not different from those of some of the treated animals without implantation. Treatment with estrogen could not restore progesterone levels or implantation. In summary, the results suggest that CI-628 acts as an estrogen antagonist in interfering with implantation at the ovarian level in intact, pregnant mice.

Release of prostaglandins and leukotrienes from the rat uterus is an early estrogenic response.

The early estrogenic responses are considered to be involved in inducing embryo implantation in a progesterone (P4)-primed uterus. Because of their involvement in the process of implantation and decidualization, prostaglandins (PGs) and leukotrienes (LTs) could be the mediators of early estrogenic responses in a P4-primed uterus. Therefore, temporal effects of estrogen on the production and/or release of PGF2, PGF2 alpha, LTB4 and LTC4 by the P4-primed uterus of hypophysectomized rats were examined. Hypophysectomized mature female rats were injected for 4 days with P4 (2 mg/rat, s.c.) or with P4 plus a single injection of estradiol-17 beta (E2) (100 ng or 200 ng/rat, i.v.) on the last day of P4 treatment. In one set of experiments, animals were killed at 0.5, 2, 4, 8, 12 and 30th after the last steroid treatment. The production of PGs and Lts by uterine homogenates was measured by radioimmunoassays (RIAs). The production of PGE2 and PGF2 alpha in P4-treated animals showed peaks at 2, 6 and 12h. The superimposition of E2 on P4 treatment induced a higher production rate of PGE2 and PGF2 alpha at 0.5h and abolished the peaks induced by P4 at 2h, but not the peaks at 6 or 12h. Irrespective of the kind of steroid hormonal treatments, uterine production of LTs showed a rapid decline between 6 and 8h followed by a sharp rise at 12h. The superimposition of E2 on P4-treatment again increased the production rates of LTB4 and LTC4 at early hours, i.e. at 0.5 and 2h, respectively, as compared to P4 treatment only.

Role of early and late oestrogenic effects on implantation in the mouse.

Oestrogen action in the uterus is expressed in an early phase (Phase I) and a late phase (Phase II). The role of this biphasic oestrogen action in implantation is not clear. To determine the relative importance of Phase I and II responses, triphenylethylene compounds (CI-628, LY-117018, nafoxidine, clomiphene citrate and tamoxifen) and oestrogens (oestriol and oestradiol-17 beta) were used in a physiologically relevant experimental system for studying implantation. All compounds elicited uterine water imbibition to various degrees in ovariectomized-progesterone-treated mice at 6 h (Phase I response) and their effectiveness in inducing implantation in delayed implanting mice correlated with their respective potency to increase uterine wet weight. This suggests that Phase I might be an essential component of oestrogen action in implantation and that the efficiency of a compound to elicit a Phase I response might serve as a predictive indicator of its potential action on implantation.

Metallothionein gene regulation in the preimplantation rabbit blastocyst.

Expression of metallothionein (MT) genes in the preimplantation rabbit blastocyst was analysed by determination of the levels of MT mRNA and relative rates of MT synthesis. MT was found to be constitutively expressed at low levels in the blastocyst. Exposure of the day-6 blastocyst to zinc ions in vitro rapidly increased the level of MT gene expression in a dose-dependent manner, with a ten-fold induction in the relative rate of synthesis at 400 microM-Zn2+. Ion-exchange chromatography of pulse-labelled blastocyst protein showed that the relative rates of synthesis of both MT-I and MT-II were markedly increased following zinc treatment, with MT-I being the predominant isometallothionein. Zinc induction of MT synthesis in the blastocyst was also detected on day 4 of gestation just after the morula-to-blastocyst transition. In contrast to the zinc effects on MT, in vitro exposure to 10 microM-Cd2+ resulted in a large induction of MT mRNA but only a modest increase in the relative rate of MT synthesis. Cadmium was found to be toxic to the day-6 blastocyst, and 10 microM-Cd2+ induced an acute stress response as indicated by a dramatic induction of heat-shock protein (HSP-70) gene expression.