Christopher T. Minson - US grants

This study is designed to test the general hypothesis that muscle sympathetic nerve activity (MSNA) and vasoconstrictor responses to sympathoexcitatory maneuvers differs during the follicular versus the luteal phase of the menstrual cycle in healthy young women. Baroreceptor sensitivity is determined by the relationship between the change in diastolic blood pressure (DBP) and MSNA during sequential infusions of nitroprusside (a vasodilator) and phenylephrine (an alpha-agonist vasoconstrictor). Vascular transduction is assessed by the MSNA-calf vascular resistance (CVR) relationship during ischemic handgrip exercise and post-exercise ischemia. Preliminary data suggests that baroreceptor sensitivity is greater during the luteal phase of the menstrual cycle in normally cycling women. This suggests that a decline in DBP during the luteal phase results in a greater increase in sympathetic outflow compared to the follicular phase. Moreover, estrogen concentration appears to be the primary factor that augments baroreceptor sensitivity, and it appears that progesterone antagonizes this effect. Furthermore, vascular transduction may also be augmented during the luteal phase. This would suggest that the vasoconstrictor response to an increase in sympathetic outflow is greater during the luteal phase.

Little information is available regarding the impact of cyclic hormonal changes during the menstrual cycle on cardiovascular control by the sympathetic nervous system in women. In animals, estrogen and progesterone are known to alter circulatory control by affecting cardiovascular reflex function, endothelial function, vasomotor responses, and plasma volume. In this context, there have been limited studies that directly investigate the impact that hormonal changes during the menstrual cycle have on the sympathetic nervous system and cardiovascular function in humans. Additionally, the impact of oral contraceptives on these relationships have not been examined. Lastly, there is limited information regarding how the menstrual cycle or use of oral contraceptives alters the overall autonomic and cardiovascular responses to an integrative challenge such as orthostatic stress. In this proposal we will test the general hypothesis that during the luteal phase of the menstrual cycle(or the high-hormone phase of oral contraceptive use) the muscle sympathetic nerve activity and vasoconstrictor responses to sympathoexcitatory maneuvers (i.e., baroreceptor unloading, handgrip exercise, or orthostatic challenge) will be augmented. The strength of this proposed experimental paradigm is that studies are designed to investigate sequentially baroreceptor sensitivity, record the resulting change in sympathetic activity, and measure the vascular resonses to changes in sympathetic traffic during the follicular and luteal phases of the menstrual cycle. The functional impact of these changes on orthostatic tolerance will also be examined. The role of long-term exogenous estrogen and progesterone administration (oral contraceptives) on autonomic-circulatory control will be evaluated.

[unreadable] DESCRIPTION (provided by applicant): The rise in skin blood flow where humans are exposed to whole body heating is mediated by an active vasodilator reflex that is unique in humans. Although a number of vasoactive substances have been identified that may be involved in active cutaneous vasodilation, the identity of the putative vasodilator is not known. Of these potential vasodilator substances, a role for vasoactive intestinal peptide (VIP) and adenosine in active cutaneous vasodilation appears likely and are specifically targeted in the proposed studies. A portion of the active vasodilator reflex is dependent on NO, but the exact role of NO in this response is unclear. Animal research suggests that NO may act synergistically with the unknown vasodilator to elicit full expression of the active vasodilator response, but that NO is not directly involved. These mechanisms of active cutaneous vasodilation have not been investigated in humans. Thus, the overall goal of this application is to systematically investigate the mechanisms that underlie active cutaneous vasodilation in the skin of humans during whole body heating. This overall goal will be met by addressing the following specific questions: 1) What are the roles of cAMP- and cGMP-dependent pathways in active cutaneous vasodilation? 2) Does cGMP augment cAMP-mediated active vasodilation in the skin of humans during whole body heating? 3) Is the cGMP-mediated portion of active cutaneous vasodilation the same or different as the NO-mediated portion of active cutaneous vasodilation? 4) Does NO act synergistically with the unknown vasodilator substance to allow full expression of active cutaneous vasodilation during whole body heat stress in humans? 5) What is the role of VIP in active cutaneous vasodilation in humans? 6) What is the role of adenosine in active cutaneous vasodilation in humans? These questions will be investigated in humans using state-of-the-art techniques. The findings from these studies will significantly advance our understanding of the control of skin blood flow in humans, and will lead to future studies directed at investigating the diminished thermoregulatory capacity in the elderly and patient populations.

[unreadable] DESCRIPTION (provided by applicant): The long term goal of this project is to better understand the physiologic mechanisms of progesterone and a commonly-prescribed progestin on endothelial function and neural-vascular control in women. We will also explore potential interactions between the progestogens and estrogen on these physiologic mechanisms. Our aim is to investigate NO-dependent vasodilation in conduit and resistance vessels, to examine whether circulating levels of the vascular constrictor endothelin-1 is influenced by progestogens, and to investigate the effects of estrogen and progestogens on sympathetic outflow, baroreflex sensitivity, and vascular transduction. Our general approach is to suppress endogenous production of estrogen and progesterone using a gonadotropin-releasing hormone antagonist to create a hypoestrogen state. We will then administer progesterone or the progestin medroxyprogesterone acetate (MPA) alone or in combination with estrogen. The overall goal will be met by addressing the following specific aims: 1) Determine the acute effects of progesterone and MPA alone and in combination with estrogen on endothelium-dependent and endothelium-independent vasodilation in women. 2) Determine the acute effects of progesterone and MPA on sympathetic outflow, baroreflex sensitivity, and vascular transduction in women. 3) Determine the acute effects of progesterone and MPA on the contribution of nitric oxide and alpha-receptors to vasodilation and vasoconstriction in resistance vessels.PROJECT NARRATIVE Our current understanding of how natural and synthetic forms of progesterone impact the health of blood vessels and control of blood pressure in humans is lacking, despite the overwhelming use of these hormones in young and older women for contraceptive purposes, for hormone replacement therapy, and in the treatment of gynecological disorders. The goal of this project is to better understand how the natural and synthetic forms of progesterone impact blood vessel responsiveness and in the control of blood vessel tone by the sympathetic nervous system in women. We will also examine how these forms of progesterone interact with estrogen, with the goal to improve our understanding of the potential cardiovascular health benefits and risks of hormone therapy in both young and older women. [unreadable] [unreadable] [unreadable]

PROJECT SUMMARY/ABSTRACT In the U.S., hypertension (HTN) accounts for more cardiovascular disease (CVD)-related deaths than any other modifiable CVD risk factor, second only to cigarette smoking as a preventable cause of death for any reason. Based on recently updated clinical classifications, the US prevalence of HTN is 46%. Importantly, non- pharmacological treatment rather than antihypertensive medication is recommended for most adults who have HTN based on the new classifications (i.e., those not previously classified as HTN). Lifestyle interventions such as regular exercise are considered a first-line preventative against the development of HTN and in the treatment of diagnosed HTN. Epidemiological studies have demonstrated an inverse relationship between physical activity and physical fitness and level of blood pressure and HTN. Unfortunately, the vast majority of people are reticent to initiate exercise training and compliance in exercise training regimens that meet the minimum standards are extremely low. Additionally, some patient groups are not able to perform exercise due to a number of limitations or are not able to obtain the full benefits of exercise to reduce CVD risk. Thus, alternative non-pharmacological options to lower blood pressure and improve CVD risk are critically needed. Heat therapy, in the form of hot bath or sauna, is an ancient practice that has recently regained attention in the prevention and treatment of CVD. A recent 20+year prospective cohort study from Finland, where sauna use is extremely common and part of the culture, has demonstrated that regular sauna use was associated with reduced risk of developing HTN, which may explain in part the reduced rates of all-cause cardiovascular deaths with regular sauna use previously reported in the larger cohort. To date, there have been no clinical trials in humans to determine whether heat therapy is an effective treatment to reduce blood pressure in those with HTN. As such, we propose a clinical trial to determine whether heat therapy can effectively reduce blood pressure in HTN. We will compare the blood pressure reductions following heat therapy to standard exercise training. We hypothesize that 30 sessions of passive heat therapy using hot water immersion over 8-10 weeks will improve blood pressure in HTN individuals to a greater extent than exercise. In addition, we will evaluate clinical measures, key vascular and autonomic biomarkers of HTN, and cardiovascular health risk before and following heat therapy and exercise training. We further hypothesize that heat therapy will increase vascular compliance, lower sympathetic outflow, and improve endothelial function in individuals with HTN. Lastly, we will determine whether the acute decreases in blood pressure following a heat therapy session or exercise test will predict the sustained reduction in resting blood pressures following heat therapy treatment or exercise training in HTN subjects. These findings would provide significant predictive information beyond baseline resting blood pressures. Demonstrating that heat therapy can be used as a novel treatment for essential HTN is timely and important as there is a clear need for alternatives to exercise training and pharmacological approaches.