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This dissertation investigated the role of two therapeutic interventions (exercise training and hormone replacement therapy) on two different states of endothelial dysfunction, chronic coronary occlusion and aging. Despite remarkable evidence for the therapeutic benefits of physical activity, the mechanisms by which regular exercise improves vascular function in the setting of coronary artery disease are not fully understood. Similarly, the effects of aging and hormone replacement therapy on vascular function are often paradoxical and poorly understood. Thus, the first project utilized a model of chronic coronary artery occlusion to evaluate the effects of exercise training on cellular and molecular adaptations of collateral-dependent coronary vasculature compared to the nonoccluded control. This study provided new evidence that exercise training concomitantly enhanced the contributions of multiple vasodilator mechanisms, including nitric oxide, prostacyclin and BKCa channels to vascular function in the ischemic heart. Increased contribution of multiple vasodilator signaling pathways after exercise training appears to promote compensation or redundancy to ensure adequate vasodilation and coronary vascular blood flow. The second project utilized a model of aging to evaluate the interactive effects of age and hormone replacement therapy on the cellular and molecular mechanisms underlying the regulation of cerebrovascular function. Although the mechanisms underlying the beneficial effects of estrogen on cerebrovascular function have been studied at length, the mechanisms responsible for age-dependent deleterious effects of estrogen are largely unknown. The results of this study revealed that estrogen exerts divergent effects on the cerebrovasculature with advancing age. In younger females, estrogen replacement treatment is beneficial, attenuating vasoconstriction primarily by the COX-1 dependent prostanoid pathway and increased PGI2 production. In contrast, in older reproductively senescent females, estrogen augmented vasoconstriction via the COX-2 dependent prostanoid pathway and increased TXA2 production. A better understanding the mechanisms by which estrogen exerts beneficial versus detrimental effects on the cerebrovasculature may lead to new gender-specific therapeutic agents designed specifically to target the cerebrovascular system and other estrogen-responsive tissues.

Background: During the past 5 decades, hormone replacement therapy (HRT) has been used, and appreciated for its beneficial effects, by millions of women in their menopause. As treatment for climacteric symptoms, estrogen is outstanding, and effects on hot flushes, vaginal dryness, and insomnia have been widely documented. The increased risks of venous thrombosis and breast cancer, however, restrict the use of estrogen. Estrogen treatment in women with a remaining uterus includes a progestin, added to protect the endometrium from hyperplasia and malignancies. The long-standing clinical impression, that progestin addition negatively influences mood, has been discussed in previous studies. Mood deterioration is, however, not mortal, although mood is important to the wellbeing and daily functioning of women treated with hormones. Studies of the mental side effects of HRT add to our understanding of steroid effects in the brain. Aims and methods: In our studies, we aimed to establish to what extent negative side effects cause women to discontinue HRT, and find out which drug compounds lead to mood deterioration. The questions asked were whether the type and dose of progestin and the estrogen dose during the progestin addition influence the mood and physical symptoms during sequential HRT. Compliance with HRT and reasons for discontinuing the therapy were evaluated in a retrospective longitudinal follow-up study. Treatment effects were studied in three randomized, double-blind, cross-over trials. During continuous estrogen treatment, effects of sequential addition of a progestin were studied by comparing two different progestins, medroxyprogesterone acetate (MPA) andnorethisterone acetate (NETA), comparing different doses of the same progestin, MPA, and comparing two doses of estrogen during addition of the same dose of MPA. The main outcome measure was the daily rating on mood and physical symptoms kept by the participants throughout the studies. The clinical trials were carried out at three gynecological centers in northern Sweden. Results and conclusions: Besides fear of cancer and a wish to determine whether climacteric symptoms had meanwhile disappeared, negative side effects was the most common reason or discontinuing HRT. Tension in the breasts, weight gain, a depressed mood, abdominal bloating, and irritability were the most important side effects seen both in women who continued HRT and in women who had discontinued the therapy. In our clinical trials, we showed that addition of a progestin to estrogen treatment induces cyclic mood swings characterized by tension, irritability, and depression, as well as increased breast tension, bloatedness, and hot flushes. Women with a history of premenstrual syndrome (PMS) appeared to be more sensitive to the progestin addition and responded with lower mood scores compared with women without previous PMS. In our studies, MPA provoked depressed mood to a lesser extent than did NETA. Surprisingly, the higher dose of MPA (20 mg) enhanced the mood, compared with 10 mg, when added to estrogen treatment. In women continuously treated with 3 mg estradiol, mood and physical symptoms worsened during the progestin addition, as compared with treatment with 2 mg estradiol. The negative side effects seen during sequential HRT have much in common with symptoms seen in the premenstrual dysphoric disorder (PMDD), which is a psychoneuroendocrine disorder with psychiatric expression. Explanations for treatment effects on mood are likely to be found in drug interactions with neurotransmitter systems of the brain. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 2003</p> / digitalisering@umu

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.