Hypertension augments cardiac Toll-like receptor 4 expression and activity.

Hypertension causes cardiac hypertrophy characterized by low-grade inflammation. Toll-like receptors (TLRs), members of the innate immune system, contribute to cardiac failure. We hypothesized that hypertension is accompanied by enhanced TLR4 expression and activity. Cardiac TLR4 expression was determined in untreated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY; 4, 8, 16 weeks). Besides, hearts of 8-week-old rats were stimulated with the endogenous TLR4 ligand heparansulfate (HS); the proinflammatory mRNA pattern was assessed (tumor necrosis factor-α (TNF-α), interleukin (IL)-6, monocyte chemotactic protein (MCP)-1). Additionally, we induced hypertension in WKY by L-NAME (N(ω)-nitro-L-arginine-methylester hydrochloride). In both hypertension models the effect of ramipril on TLR4 density was assessed. Cardiac TLR4 distribution was investigated by fluorescence-activated cell sorting analysis. Blood pressure (BP) and heart weight/body weight ratio (HW/BW) were elevated in SHR. Constitutive TLR4 expression was augmented in adolescent and adult, but not young SHR compared with WKY. TLR4 staining was pronounced in cardiomyocytes. HS entailed an aggravated TNF-α and IL-6 mRNA response in cardiac tissue, which was significantly pronounced in SHR. Ramipril (10 mg kg(-1) per day) reduced BP, HW/BW and TLR4 expression in SHR. L-NAME also augmented TLR4 expression in WKY. Ramipril (1 mg kg(-1) per day) lowered BP but TLR4 expression remained unaffected. High-dose ramipril (10 mg kg(-1) per day) however decreased TLR4 expression. Starting from adolescence SHR demonstrated enhanced cardiac TLR4 expression. TLR4 was also upregulated in L-NAME induced hypertension. Thus, enhanced TLR4 expression might be linked to the development and maintenance of hypertension. Finally, the antihypertensive, anti-inflammatory action of angiotensin-converting-enzyme inhibition had no effect on TLR4 expression in therapeutic doses but in a high-dose model.

Effect of inhibition of neuronal nitric oxide synthase and L-arginine supplementation on renal ischaemia-reperfusion injury and the renal nitric oxide system.

The role of nitric oxide synthases (NOS) and the nitric oxide (NO) substrate l-arginine in renal ischaemia-reperfusion (I/R) has been studied extensively. However, the results reported are often controversial. In the present study, we examined the effects of the neuronal (n) NOS inhibitor 7-nitroindazole (7-NI) and L-arginine administration on renal I/R injury and the renal NO system in rats. Following 7 days pretreatment with 7-NI (50 mg/kg per day), L-arginine (2 g/kg per day) or vehicle (dimethylsulphoxide : sesame oil, 1 : 9), the left renal vascular pedicles were clamped for 50 min in male Sprague-Dawley rats and kidneys were removed 24 h after reperfusion (n = 7/group). Neither 7-NI nor L-arginine had any effect on parameters of renal function, the grade of tissue injury or the number of terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL)-positive tubular cells compared with vehicle-treated rats. 7-Nitroindazole decreased nNOS mRNA expression and inducible (i) NOS protein levels, but had no effect on endothelial NOS expression. L-arginine supplementation increased mRNA expression of all NOS isoforms, but only increased protein expression of iNOS. The results of the present study demonstrate that selective inhibition of nNOS has no effect on renal injury, indicating that nNOS does not play a central role in the pathophysiology of renal I/R. In addition, although L-arginine has no effect on renal I/R injury in the model used in the present study, its administration increases the mRNA expression of NOS isoforms.