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Key points Central mineralocorticoid receptor (MR) and angiotensin II type 1 receptor (AT1R) activation play a critical role in sympathetic hyperactivity and progressive left ventricle (LV) remodelling and dysfunction after a myocardial infarction (MI)., Intra-paraventricular nucleus (PVN) infusion of adeno-associated virus (AAV) carrying small interfering RNA (siRNA) against MR (AAV-MR-siRNA) markedly decreases both MR and AT1R expression in the PVN post MI, whereas AAV-AT1aR-siRNA only decreases AT1R expression. Both AAVs largely prevent sympathetic hyperactivity and inhibit part of LV remodelling and dysfunction post MI., These findings indicate that enhanced MR-AT1R signalling in the PVN is critical for sympathetic hyperactivity post MI, and contributes to part of LV dysfunction post MI., Abstract Intracerebroventricular infusion of a mineralocorticoid receptor (MR) or angiotensin II type 1 receptor (AT1R) blocker in rats attenuates sympathetic hyperactivity and progressive left ventricular (LV) dysfunction post myocardial infarction (MI). The present study examined whether knockdown of MRs or AT1Rs specifically in the paraventricular nucleus (PVN) contributes to these effects, and compared cardiac effects with those of systemic treatment with the β1-adrenergic receptor blocker metoprolol. The PVN of rats was infused with adeno-associated virus carrying small interfering RNA against either MR (AAV-MR-siRNA) or AT1R (AAV-AT1R-siRNA), or as control scrambled siRNA. At 4 weeks post MI, AT1R but not MR expression was increased in the PVN, excitatory renal sympathetic nerve activity and pressor responses to air stress were enhanced, and arterial baroreflex function was impaired; LV end-diastolic pressure (LVEDP) was increased and LV peak systolic pressure (LVPSP), ejection fraction (EF) and d P/d tmax decreased. AAV-MR-siRNA and AAV-AT1R-siRNA both normalized AT1R expression in the PVN, similarly ameliorated sympathetic and pressor responses to air stress, largely prevented baroreflex desensitization, and improved LVEDP, EF and d P/d tmax as well as cardiac interstitial (but not perivascular) fibrosis. In a second set of rats, metoprolol at 70 or 250 mg kg−1 day−1 in the drinking water for 4 weeks post MI did not improve LV function except for a decrease in LVEDP at the lower dose. These results suggest that in rats MR-dependent upregulation of AT1Rs in the PVN contributes to sympathetic hyperactivity, and LV dysfunction and remodelling post MI. In rats, normalizing MR-AT1R signalling in the PVN is a more effective strategy to improve LV dysfunction post MI than systemic β1 blockade. [ABSTRACT FROM AUTHOR]

Circulating Ang II increases BP through both peripheral and central mechanisms. Activation of both AT1R and MR in the CNS plays a critical role in Ang II-induced hypertension. The subfornical organ (SFO) contains both MR and AT1R and can relay the signals of circulating Ang II to downstream nuclei such as the PVN. In this study, we evaluated the effect of intra-SFO infusion of AAV-MR-siRNA or AAV-AT1aR-siRNA on MR or AT1R mRNA expression in the SFO and PVN and Ang II induced hypertension as assessed by telemetry. Two week sc infusion of Ang II at 500 ng/kg/min in Wistar rats on regular salt diet increased BP by 60~65 mmHg. This pressor effect of Ang II was largely prevented by AAV-MR-siRNA or AAV-AT1R-siRNA in the SFO (Figure). Ang II increased AT1R mRNA expression (1.7± 0.4 vs 0.8 ± 0.04 х10-1, p<0.05) in the SFO. Both MR- and AT1R-siRNA in the SFO prevented this increase (1.1 ± 0.2х10-1 and 1.0± 0.3х10-1). In contrast, Ang II decreased MR mRNA expression (3.2 ± 0.2 vs. 4.1 ± 0.2х10-2, p<0.05) in the SFO. Both MR- and AT1R-siRNA further decreased MR mRNA expression (2.7 ± 0.2 х10-2 and 2.3 ± 0.3 х10-2). In the PVN, Ang II increased AT1R mRNA by ~100% and MR mRNA by ~20%. Only AT1R-siRNA in the SFO prevented these increases in the PVN. AAV mediated eGFP fluorescence expression was observed in the SFO but not the PVN. These results suggest that circulating Ang II differentially regulates MR and AT1R expression in the SFO. Prevention of Ang II induced AT1R up-regulation by knockdown of either AT1R or MR suggests a MR dependent regulation of AT1R in the SFO. MR-AT1R signaling in the SFO appears to play a major role in Ang II-induced hypertension in rats.∗ p<0.05, vs. baseline values; a: p<0.05, vs. AAV-SCM-siRNA [ABSTRACT FROM AUTHOR]

Central blockade of mineralocorticoid receptor (MR) prevents aldosterone (aldo)-salt induced hypertension. We examined the role of the subfornical organ (SFO), aldo synthesized locally in the brain, and MR specifically in the paraventricular nucleus (PVN) in aldo-salt hypertension. Wistar rats with telemetry probes were treated with chronic intra-cerebroventricular infusion of aldo synthase (AS) inhibitor FAD286 (25 μg/day), MR blocker eplerenone (5 μg/day) or vehicle. After 2 days, subcutaneous (sc) aldo infusion (1 μg/h) was started and saline was provided as drinking water. In a second set of rats with telemetry, electrolytic or sham lesions of the SFO, or bilateral intra-PVN infusion of AAV-MR-siRNA or AAV-SCM-siRNA (1 μl of 5x1010 genomic particles/ml) at 100ng/min were performed, and sc aldo infusion started 1 week later. AAV-MR-siRNA decreased MR mRNA and protein expression in the PVN by ~60 and 30%, but had no effects on MR expression in other nuclei such as the SFO and SON. SFO lesion, blockade of brain AS or MR, or knockdown of MR in the PVN attenuated aldo-salt hypertension by ~60%.Data=means± SE (n=5-9/group). ∗p<0.05, vs. others, a:p<0.05, vs. vehicle or sham lesion.These results suggest that an increase in circulating aldosterone may via MR and AT1R in the SFO increase local aldosterone production in hypothalamic nuclei such as the SON and PVN, and via MR in the PVN activate a central aldosterone-MR-AT1R neuro-modulatory pathway, which plays a major role in the progressive hypertension.(Supported by grant # FRN:MOP-74432 from the Canadian Institutes of Health Research) [ABSTRACT FROM AUTHOR]

Circulating Ang II activates an aldosterone-MR-AT1R pathway in the hypothalamus. To obtain insights into the actual aldosterone-MR- AT1R neuronal pathway, the present study examined whether intra-PVN infusion of AAV-AT1aR-siRNA or AAV-MR-siRNA prevents the Ang II induced increases in AT1R and MR expression and BP. Two weeks sc infusion of Ang II at 500ng/kg/min in Wistar rats on regular salt diet increased BP by telemetry by 66 ± 3 mm Hg, and AT1R and MR protein in the SFO, SON and PVN. Intra-PVN AT1aR-siRNA decreased AT1R but not MR expression in the PVN by sc Ang II, and MR-siRNA decreased MR but not AT1R expression in the PVN. AT1R and MR expression in both SFO and SON were not significantly changed by the two AAV-siRNA. Specific knockdown of AT1R or MR in the PVN by AAV-siRNA prevented ~80% of the increase in BP induced by sc Ang II. These results suggest that circulating Ang II up-regulates brain Ang II and aldosterone and increases MR and AT1R in the SFO, SON and PVN. Prevention of Ang II induced increases in MR but not AT1R by knockdown of MR and vice versa suggests an independent regulation of MR and AT1R in the PVN. Both AT1R and MR in the PVN play a critical role in Ang II-induced hypertension in rats.∗ p<0.05 versus AAV-SCM alone. a: p<0.05 versus AAV-SCM + Ang II. [ABSTRACT FROM AUTHOR]

Background and Objectives: Sweet potato [Ipomoea batatas (L.) Lam] is an important locally grown cash crop in China; it was demonstrated to suppress the invasive plant Mikania micrantha (M. micrantha) H.B.K through strong competitiveness, but its allelopathic effects on this weed were unknown. The present study aimed to explore the allelopathic potential of sweet potato on M. micrantha., Materials and Methods: The allelopathic effects of water extracts and soil incorporation from leaves of three sweet potato cultivars (SP1, SP0 and SP9) on the sprout seedling growth of invasive plant M. micrantha in Yunnan Province, China, were studied under laboratory and greenhouse conditions., Results: Stem length, root biomass, aboveground biomass and total biomass of M. micrantha were significantly reduced with increasing concentration in both leaf water extracts and leaf soil incorporation of three sweet potato cultivars. Among these, SP1 had the strongest inhibition and the next highest impact was from SP0 with the lowest effect from SP9. The highest inhibition rates were seen for root biomass, followed by total biomass, whereas the lowest impact was on aboveground biomass. The strong correspondence between results for both leaf water extracts and leaf soil incorporation provided a good demonstration that compounds produced by sweet potato have allelopathic effects on M. micrantha. The general inhibition of M. micrantha by sweet potato followed the order among the three sweet potato cultivars tested as SP1, SP0 and SP9. Moreover, the synthetical allelopathic indices of leaf soil incorporation of three cultivars on M. micrantha were generally higher than these of leaf water extracts., Conclusion: Competition and allelopathy have primarily been seen as separate ecological weed management tools, but as these have demonstrated in the case of sweet potato where both mechanisms inhibit weed growth, there is potential for synergism between competition and allelopathy in the reduction of weed infestations.