Abstract 5431: Pravastatin Reduces Peripheral Cardiac Noradrenergic Hyperactivity in Spontaneously Hypertensive Rats via Angiotensin II Pathway
Hypertension is associated with noradrenergic hyperactivity. Statins, which are 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been found to reduce central sympathetic activity, possibly via increased nitric oxide (NO) synthesis and reduced angiotensin II (ATII) type 1 receptor (AT1R) expression. To investigate the effect of a statin on peripheral cardiac noradrenergic neurotransmission in spontaneously hypertensive rats (SHR), male SHR and Wistar Kyoto rats (WKY) (16–18 weeks old) were given pravastatin in drinking water (100mg/L) for 2 weeks. Separate control (water) groups received no treatment. Electrically evoked [3H]norepinephrine (NE) release from isolated right atria (spontaneously beating) of the SHR control (n=12) was higher than the WKY control (n=12) (320±12% vs 232±14%, p<0.01), but was reduced to 224±14% with statin (n=22, p<0.01 vs SHR control, p=NS vs WKY control). Statin did not reduce evoked NE release in the WKY. Western blotting revealed that the statin did not alter myocardial neuronal NOS, endothelial NOS, soluble guanylyl cyclase or AT1R protein levels in the SHR. Addition of a NO synthase (NOS) inhibitor (Nω-Nitro-L-arginine methyl ester, 1mM) to the organ bath suffusate increased evoked NE release in treated (from 233±38 to 263±39%) and untreated SHR (from 334±17 to 367±14%) in similar proportion such that they remained significantly different (n=6, p<0.05), suggesting that this pathway had not been substantially augmented by the statin. Incubation with an AT1R antagonist (losartan, 5 μM) abolished the difference in evoked NE release between treated (220±35%) and untreated SHR (206±13%). Application of 20 nM ATII increased evoked NE release more in the treated (from 225±19 to 412±37%, n=8) than the untreated SHR (from 330±15 to 447±30%, n=6), suggesting that the statin had possibly reduced the local or circulating ATII. In conclusion, 2 weeks treatment with pravastatin can significantly reduce local cardiac noradrenergic hyperactivity in the SHR, most likely via the ATII pathway rather than NO-cGMP pathway.