Junhui Tan

Central Nervous System Blockade by Peripheral Administration of At1 Receptor Blockers

After peripheral administration, AT1 receptor blockers appear to be able to enter the brain and cause AT1 receptor blockade in the central nervous system. In the current study, we investigated the effects of subcutaneous administration of embusartan versus losartan on inhibition of AT1 receptor binding in rat brain by in vitro autoradiography. At 4 hours after single doses of 5, 30, or 100 mg/kg, both losartan and embusartan decreased iodine 125I Ang II binding dose dependently in brain structures that express AT1 receptors both outside (e.g., organum vasculosum laminae terminalis) and within (e.g., paraventricular nucleus) the blood–brain barrier. At low doses, embusartan was twofold more potent than losartan inside but not outside the blood–brain barrier. After chronic treatment (30 mg/kg daily for 6 days), at 4 hours after the last dose, embusartan still caused more inhibition than losartan in the brain structures inside the blood–brain barrier. At 24 hours after the last dose, a modest, better inhibition for embusartan versus losartan remained: from 15% to 33% versus 10% to 24%, respectively. At 36 hours after the last dose, the inhibition for both blockers had almost completely disappeared inside the blood–brain barrier but persisted in, for example, the kidneys. These results demonstrate that—likely because of its high lipophilic character—embusartan appears to penetrate the blood–brain barrier more easily than losartan and therefore causes more effective AT1 receptor blockade in nuclei within the blood–brain barrier.

Regulation of hypothalamic renin-angiotensin system and oxidative stress by aldosterone

In rats with salt‐induced hypertension or postmyocardial infarction, angiotensin II type 1 receptor (AT1R) densities and oxidative stress increase and neuronal NO synthase (nNOS) levels decrease in the paraventricular nucleus (PVN). The present study was designed to determine whether these changes may depend on activation of the aldosterone ‐‘ouabain’ neuromodulatory pathway. After intracerebroventricular (i.c.v.) infusion of aldosterone (20 ng h−1) for 14 days, blood pressure (BP) and heart rate (HR) were recorded in conscious Wistar rats, and mRNA and protein for nNOS, endothelial NO synthase (eNOS), AT1R and NADPH oxidase subunits were assessed in brain tissue. Blood pressure and HR were significantly increased by aldosterone. Aldosterone significantly increased mRNA and protein of AT1R, P22phox, P47phox, P67phox and Nox2, and decreased nNOS but not eNOS mRNA and protein in the PVN, as well as increased the angiotensin‐converting enzyme and AT1R binding densities in the PVN and supraoptic nucleus. The increases in BP and HR, as well as the changes in mRNA, proteins and angiotensin‐converting enzyme and AT1R binding densities were all largely prevented by concomitant i.c.v. infusion of Digibind (to bind ‘ouabain’) or benzamil (to block presumed epithelial sodium channels). These data indicate that aldosterone, via ‘ouabain’, increases in the PVN angiotensin‐converting enzyme, AT1R and oxidative stress, but decreases nNOS, and suggest that endogenous aldosterone may cause the similar pattern of changes observed in salt‐sensitive hypertension and heart failure postmyocardial infarction.

Central infusion of aldosterone synthase inhibitor attenuates left ventricular dysfunction and remodelling in rats after myocardial infarction

AIMS Blockade of mineralocorticoid receptors in the central nervous system (CNS) prevents sympathetic hyperactivity and improves left ventricle (LV) function in rats post-myocardial infarction (MI). We examined whether aldosterone produced locally in the brain may contribute to the activation of mineralocorticoid receptors in the CNS. METHODS AND RESULTS Two days after coronary artery ligation, Wistar rats received an intra-cerebroventricular (icv) infusion via osmotic mini-pumps of the aldosterone synthase inhibitor FAD286 at 100 microg/kg/day or vehicle for 4 weeks. LV function was assessed by echocardiography at 2 and 4 weeks, and by Millar catheter at 4 weeks. At 4 weeks post-MI, aldosterone in the hippocampus was increased by 70% and tended to increase in the hypothalamus by 20%. These increases were prevented by FAD286. Across groups, aldosterone in the hippocampus and hypothalamus showed a high correlation. There were no differences in brain corticosterone levels. Compared to sham rats, at both 2 and 4 weeks post-MI rats treated with vehicle showed increased LV dimensions and decreased LV ejection fraction. Icv infusion of FAD286 attenuated these changes in LV dimensions and ejection fraction by approximately 30%. At 4 weeks post-MI, LV peak systolic pressure (LVPSP) and dP/dt(max/min) were decreased and LV end-diastolic pressure (LVEDP) was increased. In rats treated with icv FAD286, LVPSP and dP/dt(min) remained normal and LVEDP and dP/dt(max) were markedly improved. Post-MI increases in cardiac fibrosis and cardiomyocyte diameter were substantially attenuated by icv FAD286. CONCLUSION These data suggest that aldosterone produced locally in the brain acts as the main agonist of mineralocorticoid receptors in the CNS and contributes substantially to the progressive heart failure post MI.

Chronic central versus systemic blockade of AT1 receptors and cardiac dysfunction in rats post-myocardial infarction

In rats, both central and systemic ANG II type 1 (AT(1)) receptor blockade attenuate sympathetic hyperactivity, but central blockade more effectively attenuates left ventricular (LV) dysfunction post-myocardial infarction (MI). In protocol I, we examined whether functional effects on cardiac load may play a role and different cardiac effects disappear after withdrawal of the blockade. Wistar rats were infused for 4 wk post-MI intracerebroventricularly (1 mg.kg(-1).day(-1)) or injected subcutaneously daily (100 mg x kg(-1) x day(-1)) with losartan. LV dimensions and function were assessed at 4 wk and at 6 wk post-MI, i.e., 2 wk after discontinuing treatments. At 4 and 6 wk post-MI, LV dimensions were increased and ejection fraction was decreased. Intracerebroventricular but not subcutaneous losartan significantly improved these parameters. At 6 wk, LV peak systolic pressure (LVPSP) and maximal or minimal first derivative of change in pressure over time (dP/dt(max/min)) were decreased and LV end-diastolic pressure (LVEDP) was increased. All four indexes were improved by previous intracerebroventricular losartan, whereas subcutaneous losartan improved LVEDP only. In protocol II, we evaluated effects of oral instead of subcutaneous administration of losartan for 4 wk post-MI. Losartan ( approximately 200 mg x kg(-1) x day(-1)) either via drinking water or by gavage similarly decreased AT(1) receptor binding densities in brain nuclei and improved LVEDP but further decreased LVPSP and dP/dt(max). These results indicate that effects on cardiac load by peripheral AT(1) receptor blockade or the pharmacokinetic profile of subcutaneous versus oral dosing do not contribute to the different cardiac effects of central versus systemic AT(1) receptor blockade post-MI.

Angiotensin-converting enzyme inhibitors, inhibition of brain and peripheral angiotensin-converting enzymes, and left ventricular dysfunction in rats after myocardial infarction.

The brain renin-angiotensin system contributes significantly to progressive left ventricular (LV) dysfunction in rats after myocardial infarction (MI). The present study evaluated the effects of central versus peripheral plus central angiotensin-converting enzyme (ACE) blockade on sympathetic activity, and LV anatomy and function after MI. Methods: Wistar rats were treated for 4 weeks after MI with the lipophilic ACE inhibitor trandolapril at 5 mg/kg/day or the hydrophilic blocker lisinopril at 50 mg/kg/day by once daily subcutaneous injection, or with a central infusion of lisinopril at 0.1 mg/kg/day. Results: At 24 hours after the last dose, subcutaneous trandolapril caused 70% to 80% ACE inhibition in both brain and kidneys; lisinopril caused 10% to 20% less. Central infusion of lisinopril caused 70% inhibition of brain ACE and minimal (6%) inhibition in the kidneys. All three treatments similarly improved sympathetic reactivity and arterial baroreflex function. All three treatments lowered cardiac Ang I and II, and similarly attenuated the increases in LV end diastolic pressure, circumference, and fibrosis. Both subcutaneous treatments further decreased LV peak systolic pressure and dP/dtmax, whereas icv lisinopril caused no change. Conclusion: Despite marked differences in the extent of peripheral blockade, all three treatments similarly affected sympathetic activity and decreased cardiac Ang II, preload and remodeling after MI. One may speculate that central and peripheral ACE-mediated mechanisms are sequential and therefore only minor additional effects of peripheral ACE blockade are noted.