Abstract-In the present study we tested the hypothesis whether an anglotensm AT, receptor-mediated stlmulatlon of the bradykmm (BK)/mtnc oxide (NO) system can account for the effects of AT1 receptor antagonism on aortlc cGMP described previously m SHRSP Adult SHRSP were treated for 4 hours with anglotensm II (ANG II) (30 rig/kg per mm IV) or vehicle (0 9% NaCl IV) Animals were pretreated with vehicle, losartan (100 mg/kg PO), PD 123319 (30 mg/kg IV), losartan plus PD 123319, lcatlbant (500 @g/kg IV), NG-mtro-L-argmme methyl ester (L-NAME, 1 mg/kg IV), or mmoxldll (3 mg/kg IV) Mean arterial blood pressure (MAP) was contmuouqly monitored over the 4-hour experlmental period, and plasma ANG II and aortlc cGMP were measured by RIA at the end of the study ANG II infusion over 4 hours raised MAP by about 20 mm Hg. Losartan alone or losartan plus ANG II '1s well as mmoxldll plus ANG II markedly reduced blood pressure when compared to vehicle-treated or ANG II-treated ammals, respectively Plasma levels of ANG II were increased 2-fold by ANG II mfuslon alone or by ANG II m combmallon with lcatlbant, L-NAME, or mmoxldll The increase m plasma ANG II levels was even more pronounced after losartan treatment Aortlc cGMP content was slgmficantly increased by ANG II, losartan, losartan plus ANG II, and mmoxldll plus ANG II by 60%, 45%, 68%, and 52%, respectively (P< 05) The effects of ANG II and of losartan plus ANG II on aortlc cGMP content were both blocked by cotreatment with the AT2 receptor antagonist PD 123319 Icatlbant and L-NAME abohshed the effects of ANG II on aortlc cGMP Our results demonstrate the followmg (1) ANG II increases aortlc cGMP by an AT, receptor-medlated action because the effect could be prevented by an AT1 receptor antagonist, (2) the effect of ANG II was not secondary to blood pressure increase because it remained under reduction of MAP with mmoxldll, (3) losartan increased aortlc cGMP most likely by increasing plasma ANG II levels with a subsequent stlmulatlon of AT, receptors, and (4) the effects of AT1 receptor stlmulatlon are mediated by BK and, subsequently, NO because they were abolished by B, receptor blockade as well as by NO synthase mhlbltlon of ANG II generation, but, m addition, also potentlate the effects of bradykmm (BK) by mhlbltlon of BK degradation ' Two major tools have been introduced m recent years to study the contnbutlon of BK to the cardiovascular actlons of ACE inhibitors first, the combined treatment with an ACE mhlbltor and with a specific BK B2 receptor antagonist such as lcatlbant, and second, the comparison of the effects of an ACE inhibitor with those of an AT, receptor antagonist which block the RAS without an interaction with kmm metabolism. With these approaches, several mvestlgators have demonstrated that a number of actions of ACE mhlbltors IS related to cardiovascular control can be blocked by B2 receptor antagonism and thus be related to kuuns ' For example, m a series of expenrnents our laboratory demonstrated that longterm treatment with ACE inhibitors improved ca...

Angiotensin II (ANG II), generated by activation of local renin-angiotensin systems, is believed to play an important role in tissue repair and remodeling, in part via transforming growth factor-beta (TGF-beta). Angiotensin-converting enzyme (ACE) inhibitors have been shown to abrogate experimental lung injury via a number of potential mechanisms; however, the potentially fibroproliferative role for ANG II in the lung has not been characterized. We hypothesized that, after lung injury, ANG II would stimulate fibroblast procollagen synthesis and promote lung collagen deposition in rats. In vitro, ANG II was a potent inducer of procollagen production in human lung fibroblasts via activation of the type 1 receptor and, at least in part, via the autocrine action of TGF-beta. After bleomycin-induced lung injury, an increase in lung ANG II concentration was observed by day 3 that preceded increases in lung collagen and was maintained until death at day 21. Administration of an ACE inhibitor (ramipril) reduced ACE activity, ANG II concentration, TGF-beta expression, and collagen deposition. Losartan (an ANG II type 1 receptor antagonist) also attenuated the increase in TGF-beta expression and lung collagen deposition. These observations suggest that ANG II, possibly generated locally within the lung, may play an important role in the fibrotic response to acute lung injury, at least in part via the action of TGF-beta. ACE inhibitors and receptor antagonists, already widely used clinically, should be assessed as potential new therapies for fibrotic lung disease.

Up-regulation of cyclooxygenase (COX)-2 exacerbates neuronal injury after cerebral ischemia and contributes to neuronal cell death. The present study clarifies the function of cerebral peroxisome-proliferator-activated receptor(s) gamma (PPARgamma) in the expression of COX-2 in neurons of the rat brain after middle cerebral artery occlusion (MCAO) with reperfusion by immunohistochemistry, Western blot, and immunofluorescence staining. In peri-infarct cortical areas the PPARgamma was located in both microglia and neurons, whereas COX-2 was almost exclusively expressed in neurons. PPARgamma immunolabeling reached the peak 12 h after MCAO, whereas the number of COX-2 immunostained cells gradually rose and reached its peak at 48 h. Intracerebroventricular infusion of pioglitazone, an agonist of the PPARgamma, over a 5-day period before and 2 days after MCAO, reduced the infarct size, the expression of tumor necrosis factor alpha (TNF-alpha), COX-2, and the number of cells positively stained for COX-1 and COX-2 in the peri-infarct cortical regions. COX-2 induction was also attenuated in the ipsilateral but not in the contralateral hippocampus. In primary cortical neurons expressing the PPARgamma, pioglitazone suppressed COX-2 expression in response to oxidative stress. This protective effect was reversed after cotreatment with GW 9662, a selective antagonist of the PPARgamma, clearly demonstrating a PPARgamma-dependent mechanism. Our data provide evidence that activation of neuronal PPARgamma considerably contributes to neuroprotection by prevention of COX-2 up-regulation in vitro and in peri-infarct brain areas.

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Background and Purpose-In vitro and in vivo studies have demonstrated neuroprotective actions of lithium. The present study investigated the effect of a low dose of lithium on infarct volume and neurological outcome as well as on apoptotic and inflammatory processes in rats exposed to focal ischemia. Methods-Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 minutes followed by reperfusion. Lithium (1 mmol/kg) was given subcutaneously daily for 14 days before the onset of MCAO and 2 days thereafter. Blood parameters and cerebral blood flow were assessed before, during, and after MCAO. Rats were examined for neurological deficits 24 and 48 hours after MCAO. Two days after MCAO, the brains were removed for immunohistochemical evaluation of caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), activated microglia, and the expression of AP-1 proteins (c-Fos and c-Jun). Infarct volume was assessed by cresyl violet staining. Results-Pretreatment with lithium did not alter cerebral blood flow or blood parameters. Neurological deficits were significantly decreased in rats treated with lithium at 24 and 48 hours after ischemia. Infarct volume was reduced in rats treated with lithium at 48 hours after ischemia. Lithium significantly decreased the ischemia-induced caspase-3 immunoreactivity and TUNEL staining as well as the AP-1 protein expression in the penumbra of the ischemic cortex.No changes in activated microglia were observed. Conclusions-The