Long-term pretreatment with statins reduces myocardial injury after acute ischemia and reperfusion by increasing the expression of endothelial nitric oxide synthase (eNOS). We hypothesized that statins may act rapidly enough to protect the myocardium from ischemia/reperfusion injury when given right at the beginning of the reperfusion period and tried to delineate the role of PI 3-kinase/Akt pathway in early eNOS activation. Activated simvastatin was given intravenously 3 minutes before starting the reperfusion after temporary coronary artery occlusion (CAO) in anaesthetized rats. Simvastatin significantly increased myocardial PI 3-kinase activity, AktSer473, and eNOSSer1177 phosphorylation and reduced infarct size by 42%. Infarct size reduction as well as activation of PI 3-kinase/Akt/eNOS pathway were not observed in rats co-treated with the PI 3-kinase inhibitor wortmannin. Contribution of eNOS was further delineated using the NOS inhibitor L-NAME, which could completely block cardioprotection by the statin. In summary, simvastatin acutely reduces the extent of myocardial necrosis in normocholesterolemic rats in an NO- dependent manner by activating the PI 3-kinase/Akt pathway. This is the first study demonstrating short-term cardioprotective effects of simvastatin in an in vivo model of ischemia/reperfusion.

Abstract-Angiotensin II (ANG) is known to facilitate catecholamine release from peripheral sympathetic neurons by enhancing depolarization-dependent exocytosis. In addition, a direct excitation by ANG of peripheral sympathetic nerve activity has recently been described. This study determined the significance of the latter mechanism for angiotensininduced catecholamine release in the pithed rat. Rats were anesthetized and instrumented for measuring either hemodynamics and renal sympathetic nerve activity or plasma catecholamine concentrations in response to successively increasing doses of angiotensin infusions. Even during ganglionic blockade by hexamethonium (20 mg/kg), angiotensin dose-dependently elevated sympathetic nerve activity, whereas blood pressure-equivalent doses of phenylephrine were ineffective. Independently of central nervous sympathetic activity and ganglionic transmission, angiotensin (0.1 to 1 g/kg) also induced an up-to 27-fold increase in plasma norepinephrine levels, reaching 2.65 ng/mL. Preganglionic electrical stimulation (0.5 Hz) raised basal norepinephrine levels 11-fold and further enhanced the angiotensin-induced increase in norepinephrine (4.04 ng/mL at 1 g/kg ANG). Stimulation of sympathetic nerve activity and norepinephrine release were suppressed by candesartan (1 mg/kg) or tetrodotoxin (100 g/kg), respectively. Angiotensin enhanced plasma norepinephrine, heart rate, and sympathetic nerve activity at similar threshold doses (0.3 to 1 g/kg), but raised blood pressure at a significantly lower dose (0.01 g/kg). It is concluded that direct stimulation of ganglionic angiotensin type 1 (AT 1 ) receptors arouses electrical activity in sympathetic neurons, leading to exocytotic junctional catecholamine release. In both the absence and presence of preganglionic sympathetic activity, this mechanism contributes significantly to ANG-induced enhancement of catecholamine release. Key Words: angiotensin II Ⅲ angiotensin antagonist Ⅲ catecholamines Ⅲ sympathetic nervous system Ⅲ electric stimulation Ⅲ rats A ngiotensin II (ANG) potently enhances catecholamine release from the peripheral sympathetic system, an action that implies important pathophysiological consequences. Catecholamines released by this mechanism contribute to the vasoconstricting and sodium-retaining properties of ANG. 1 In particular, the chronic effects of ANG at moderately elevated levels are promoted by adrenergic pathways that are significantly involved in the development of hypertension 2,3 and in the concomitant myocardial damage that has elsewhere been attributed to a stimulation of cardiac ␤-adrenoceptors. 4 ANG activates the sympathetic system via several mechanisms. Central nervous sympathetic tone is increased by circulating or locally produced ANG in nuclei responsible for autonomic control. 5 In the peripheral sympathetic system, the termini of adrenergic neurons are equipped with prejunctional angiotensin type 1 (AT 1 ) receptors whose activation enhances the efficacy of catecholamine discharge induced by each acti...

All investigated MAPK pathways appear to be involved in RPC-induced cardioprotection; however, they do not contribute to the alterations that define the preconditioned state of the myocardium prior to the infarction.

Angiotensin II is able to modulate both the presynaptic sympathetic system and the adrenal medulla resulting in an enhanced release of noradrenaline and adrenaline. Consequently, the inhibition of the converting enzyme by ACE inhibitors resulting in a lower concentration of angiotensin II or blockade of the specific AT1 receptors by AT1 receptor blocking agents should lead to a decrease in both noradrenaline and adrenaline release. It has been demonstrated that ACE inhibition did not influence the net catecholamine overflow during stimulation of the sympathetic nerves in contrast to AT1 antagonists which can specifically and dose dependently diminish noradrenaline and adrenaline release, an effect that could be explained by a compensating mechanism of bradykinin. Bradykinin may accumulate during ACE inhibition and is able to stimulate catecholamine release via B2 receptors. To verify the class effect of AT1 antagonists on presynaptic AT1 receptors, the AT1 antagonist candesartan was investigated regarding its presynaptic effect in pithed spontaneously hypertensive rats. As could be demonstrated with losartan and HR 720, candesartan lowered AT1 receptor mediated angiotensin II-induced noradrenaline release in a dose-dependent manner. It is concluded that AT1 antagonists inhibit angiotensin II mediated catecholamine release on presynaptic sympathetic nerves and the adrenal medulla at the specific AT1 receptor site. The effect can be described as a class effect of these imidazole derivatives.

The AT1 antagonists tested do not discriminate between presynaptic neuronal and postsynaptic vascular angiotensin II receptors - a fact that refutes the existence of tissue-specific AT1 receptor subtypes. A marked reduction in vascular sensitivity to NA may contribute to the antihypertensive and cardioprotective mechanisms of AT1 antagonists.

AT1 antagonists at doses that effectively reduce blood pressure in chronic therapy do not generally suppress peripheral sympathetic function. A potential interaction consists in a reduction of vascular noradrenaline sensitivity, which can be considered as a class effect of AT1 antagonists at high dosage.

No abstract

No abstract