Aldosterone Antagonism and Epidermal Growth Factor in Cerebral Ischemia.
Two factors that may contribute to the vascular remodeling involved in the pathogenesis of ischemic cerebrovascular disease are aldosterone (aldo) and epidermal growth factor (EGF). Spironolactone (spir) is known to reduce the frequency of hemorrhagic infarcts, its effects on ischemic infarcts are unknown. We have previously shown that the mRNA for EGF and its receptor (EGFR) are increased in the cerebral blood vessels from stroke-prone spontaneously hypertensive rats (SHRSP) compared to Wistar Kyoto (WKY) rats. We hypothesized that this, along with an altered response to aldo would contribute to a larger experimentally induced ischemic cerebral infarct. Six week old male SHRSP and WKY rats were treated with spir (200mg) or placebo for six weeks. Cerebral ischemia was induced by middle cerebral artery occulsion, infarct size was quantified and expressed as percentage of the hemisphere infarcted. RNA was extracted from aorta and RT-PCR was performed for EGF and EGFR. mRNA was quantified by phosphorimage analysis and corrected for GAPDH. Treatment did not affect blood pressure in either group. Aldo antagonism reduced the size of experimentally induced cerebral infarct in SHRSP (51.7±3.6 vs. 22±6.7 % SHRSP vs. SHRSP + spir p<0.05) and WKY rats (14.2±2.1 vs. 3.2±1.5 % WKY vs. WKY + spir p<0.01). Expression of mRNA for EGFR was higher in the aorta of SHRSP compared to WKY (1.09±0.25 vs. 0.17±0.03 p<0.05 SHRSP vs WKY). The same was true for EGF mRNA expression (13.61 ± 3.73 vs 3.80 ± 1.30 p<0.05 SHRSP vs. WKY). Spir treatment reduced the expression of EGFR mRNA in the aorta of SHRSP (1.09±0.25 vs. 0.56±0.11 SHRSP vs. SHRSP + spir p<0.05) but not WKY rats. Spir treatment had no effect on the EGF mRNA expression in either group. Plasma aldo levels were similar for SHRSP and WKY. The reduction in ischemic infarct size is a novel observation. The mechanism by which spir reduces infarcts in SHRSP may be by its reduction in the expression of the EGFR mRNA leading to reduced vascular remodeling. It is possible that locally produced aldo is responsible for the inceased EGFR mRNA as aldo levels were the same for SHRSP and WKY. Interestingly, the mechanism for the reduction in infarct size appears to be different in the WKY rat.