• The Effect of Mineralocorticoid Receptor Antagonism on Ischemic Infarct Size

      Rigsby, Christiné Spring; Department of Physiology (2006-12)
      Stroke is the third leading cause of death and the leading cause of long-term disability in the United States, where approximately 88% of stroke occurrences are ischemic in origin. Hypertension is a primary risk factor for stroke. Elevated aldosterone levels have also been identified as a risk factor for stroke, as patients with primary aldosteronism incur increased incidences of cardiovascularrelated pathologies than do patients with essential hypertension. Previous studies from our laboratory have shown that mineralocorticoid (aldosterone) receptor (MR) activation can induce deleterious vascular remodeling and, conversely, blockade of the MR with spironolactone reduces cerebral infarct size in male spontaneously hypertensive stroke-prone rats (SHRSP). It is known from studies in SHRSP that cerebral vessel structure is directly related to infarct size. We hypothesized that chronic spironolactone treatment would alter cerebral vessel structure. Six-week-old male SHRSP were treated with spironolactone for six weeks and passive vessel structure was analyzed using a pressurized arteriograph. Spironolactone treatment prevented cerebral vessel remodeling. From a clinical standpoint, many patients present with pre-existing vascular damage; therefore, we hypothesized that chronic MR antagonism would reverse existing vascular damage. Twelve-week-old male SHRSP were treated as described above. Interestingly, spironolactone treatment partially reversed existing cerebral vessel remodeling. Recent analysis of data from the Framingham Heart Study show that females may be more sensitive to the effects of aldosterone, but few studies looking at MR blockade have been performed in females. Similar ischemic stroke and vascular analysis studies were performed in 12-week-old female SHRSP. Contrary to the male studies, MR antagonism, using spironolactone or eplerenone, did not reduce damage from ischemic stroke or improve vessel structure. MR protein expression was evaluated in cerebral arteries collected from 12-week-old male and female SHRSP using Western blot analysis. Surprisingly, female SHRSP had increased MR expression, compared to male SHRSP. These novel studies uncover an apparent sexual dimorphism in the actions of MR antagonists and expression of the MR in SHRSP. The action of the MR antagonists may be influenced by differential MR expression and this could help to explain the sex difference observed.
    • Soluble Epoxide Hydrolase Inhibition Attenuates Vascular Remodeling and Protects Against Cerebral Ischemia

      Simpkins, Alexis Netis; Department of Pharmacology and Toxicology (2008-05)
      Hypertension is linked to the incidence of cardiovascular events such as ischemic stroke due to several mechanisms, including vascular remodeling. The progression of vascular remodeling leads to increased arterial stiffness, plaque formation and rupture, and thrombosis, culminating in blockage of the arterial supply to the brain. A strategy to confer protection from hypertension linked cardiovascular events is inhibition of pathological remodeling. Notably, epoxyeicosatrienoic acids (EETs) modulate vascular smooth muscle cell (VSMC) proliferation and migration and vascular tone. However, their conversion by soluble epoxide hydrolase (SEH) enzyme to less active diols attenuates their protective properties. As a result, an alternative strategy to confer protection from the sequela of hypertension is SEH inhibition. Here we show that SEH inhibition and deletion of the gene responsible for the production of the SEH enzyme protects against pathological vascular remodeling in a model in which the endothelium is preserved via left carotid ligation. Interestingly, this protection was not observed in a model of arterial injury in which the femoral artery is denuded. This demonstrates that SEH antagonism has potential for protecting against pathological remodeling by an endothelium dependent mechanism. In line with this finding, we demonstrated that SEH inhibition restored the plasticity of carotid arteries in hypertensive rats with impaired responses to increases or decreases in flow. Importantly, we demonstrated that these protective properties of SEH inhibition were translatable to vascular protection from cerebral ischemia in an animal model of essential hypertension. Chronic SEH inhibition protected against cerebral ischemia in hypertensive rats by inhibiting vascular remodeling of the middle cerebral artery and increasing microvessel density. Interestingly, we also show that SEH inhibition is able to protect against cerebral ischemia without changing the structure of the vasculature of normotensive animals. In fact, we found that a potential for protection could be afforded by changes in the expression profile of genes involved in apoptosis, neurogenesis, and reactive oxygen species antagonism in models both of hypertension and normotension. The sum of these findings indicates that SEH inhibition has broad pharmacological potential for protecting against the occurrence and severity of ischemic stroke by mechanisms that are attributed to blocking the sequela of hypertension and neuroprotection.