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Chronic Ang II stimulation is linked to cardiac remodeling characterized by fibrosis and cardiac hypertrophy. However, the underlying cellular mechanisms involved are not yet fully known. Here, we studied the molecular mechanisms underlying the chronic effect of Ang II on cardiac hypertrophy, fibrosis, and autophagy.The role of class I PI3-kinase in these actions of Ang II was studied using lentiviral vector-mediated expression of a dominant negative form of PI3-kinase subunit p85α (Lv-DNp85) in the heart. Ang II was infused subcutaneously for 4 weeks on rats using osmotic pumps. Cardiac hypertrophy, fibrosis, reactive oxygen species (ROS), and autophagy were examined in four groups of rats (Ang II+Lv-DNp85, Ang II+Lv-GFP, Saline+Lv-DNp85, Saline+Lv-GFP).Chronic infusion of Ang II induced severe cardiac hypertrophy and perivascular fibrosis in the heart. These effects were associated with a significant reduction in LC3 II and elevation in ROS levels, suggesting marked impairment of cardiac autophagy and increased generation of ROS. Cardiac transduction of Lv-DNp85 significantly attenuated Ang II-induced impairment of autophagy and elevation of ROS, as well as Ang II-induced cardiac hypertrophy and perivascular fibrosis. To study the cellular mechanisms underlying those actions of Ang II, phosphorylated Akt and mTOR were measured in hearts from these rats. Ang II increased phosphorylation of Akt and mTOR; and cardiac transduction of Lv-DNp85 significantly abolished Ang II-induced phosphorylation of Akt and mTOR, a signaling pathway inhibiting autophagy.These results demonstrate that class I PI3-kinase, via activation of the Akt-mTOR pathway, is involved in Ang II-induced impairment of autophagy, elevation of ROS, cardiac hypertrophy, and fibrosis, suggesting a novel target for cardiac protection.

The objective of this study is to examine effects of extracts from cooked lentils on angiotensin II (Ang II)-induced hypertension, cardiac hypertrophy and fibrosis in normotensive rats.Animals were divided into four groups (n=5 each group): control group, Ang II group, Ang II plus cooked lentil extract (Ang II+CLE) group, and Ang II plus raw lentil extract (Ang II+RLE) group. The telemetry blood pressure transducers were implanted into all rats. A telemetry BP probe was positioned intra-abdominally and secured to the ventral abdominal muscle with the catheter inserted into the lower abdominal aorta. Heart wall thickness, cross-sectional area of cardiomyocytes, diameter of the arterial cross-sections, and perivascular fibrosis in heart and kidney were measured. The surface area of positive-staining cardiomyocytes was analyzed using image analysis software. Reactive oxygen species (ROS) generation was determined using an oxidant-sensitive fluorogenic probe.Rats that received cooked or raw lentil extracts (oral administration, 8 weeks) show significantly attenuated Ang II-induced elevation in blood pressure, cardiac hypertrophy, perivascular fibrosis. Results demonstrated that pretreatment of cardiomyocytes with cooked or raw lentil extract significantly attenuated the Ang II-induced increase in the size of cells (16.0±1.7% and 21.2±2.9%, respectively, n=5, p0.05), and cooked or raw lentil extracts also attenuated the Ang II-induced increase in the reactive oxygen species levels in cardiomyocytes (19.8±2.2%26.6±3.1%, respectively, n=5, p0.05).This study showed that extracts from cooked lentils could prevent Ang II-induced elevation in blood pressure, cardiac hypertrophy, small arterial remodeling and perivascular fibrosis, and heating process does not have any significant affect on these protective effects.

To identify the calcium channel blockade and anti-free-radical actions of panaxadiol saponins Rb1, Rb2, Rb3, Rc, and Rd.On ventricular myocardiocytes of Wistar rats, single channel activities of L, T, and B type Ca2+ channels were recorded with the cell-attached configuration of patch-clamp technic, and free radical contents were measured with electron spin resenance method.Rb1, Rb2, Rb3, and Rc 200 mumol.L-1 shortened the open times, prolonged the close times, and reduced the openstate probabilities of calcium channels and 30 mumol.L-1 antagonized the increase of free radical content induced by xanthine 0.42 mmol.L-1-xanthine oxidase 5.3 nmol.L-1, but Rd in the same dose behaved none of the effects.Rb1, Rb2, Rb3, and Rc had both the calcium channel blockade and anti-free-radical actions.

Based on the patch clamp technique, the effect of ginsenoside Rb2 on the single channel activity of Ca2+ was observed through the single ventricular myocytes of Wistar rats. Electron spin resonance was used to measure the free radical contents of cultured cardiomyocytes. It is proved that Rb2 can inhibit the activities of single calcium channel and significantly antagonize the increase of free radical contents induced by xanthine-xanthine oxidase.

Eleven ginsenoside monomers were added to cultured myocardiocytes of neonatal Wistar rats in a concentration of 20 micrograms.ml-1. And the action potentials (AP) were led with microelectrodes. Rb1, Rb2, Rb3, Rc, Rg1, Rg2, Re, and Rh1 inhibited AP, decreasing APA by 20%, 13%, 5%, 18%, 30%, 37%, 28%, and 23%, respectively. The potency of the most effective monomer Rg2 20 micrograms.ml-1 was similar to that of the calcium channel blocker nimodipine 1.25 micrograms.ml-1. Rd, Rf, and Ro had no significant influence on AP. The average potency of the panaxatriol saponin (PTS) monomers were greater than that of the panaxadiol saponin (PDS) monomers. The above demonstrate the reason why the calcium channel blockade action of PTS is stronger than that of PDS results from the summation of monomer drug effects.

It has been demonstrated that resting coronary vascular resistance is elevated with chronic hypertension and concomitant cardiac hypertrophy. The present study employed a model of 6-week, one-kidney, one wrapped Page hypertension to determine if the ability of the heart to match an increase in oxygen demand with an increase in oxygen supply (coronary blood flow) is impaired, and to determine if these vasoregulatory abnormalities are attributable to inadequate adenosine release. Studies were performed in a pentobarbital anesthetized, open-chest canine preparation using a pericardial infusate method to determine adenosine release. Results showed that dobutamine (a beta-receptor agonist) induced increases in myocardial oxygen consumption (MVO2) over a physiological range (8-30 ml O2 X min-1 X 100 g-1) that were accompanied by an increase in coronary blood flow (CBF) with no change in oxygen extraction. The relationship between MVO2 and CBF was not different between the normotensive (NTC) and hypertensive (RHT) animals. Pericardial infusate adenosine (PI ADO) concentrations were not different for the same MVO2 and CBF, and the relationships for MVO2 vs PI ADO as well as PI ADO vs CBF were unaltered by hypertension. However, the relationship between PI ADO and coronary vascular resistance (CVR) was altered in the RHT group such that a given PI ADO concentration was associated with a significantly higher CVR. These data suggest that, over the range of MVO2 studied, there are no limitations in metabolic regulation of the coronary circulation of RHT animals, and that the higher CVR encountered in the RHT group is not the result of a reduced release of the endogenous vasodilator, adenosine.