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We investigated the roles of the renin-angiotensin system and the significance of interactions between angiotensin II and nitric oxide, in responses of regional kidney perfusion to electrical renal nerve stimulation (RNS) in pentobarbital sodium-anesthetized rabbits. Under control conditions, RNS (0.5-8 Hz) reduced total renal blood flow (RBF; -89 [+ or -] 3% at 8 Hz) and cortical perfusion (CBF; -90 [+ or -] 2% at 8 Hz) more than medullary perfusion (MBF; -55 [+ or -] 5% at 8 Hz). Angiotensin II type 1 (A[T.sub.1])-receptor antagonism (candesartan) blunted RNS-induced reductions in RBF (P = 0.03), CBF (P = 0.007), and MBF (P = 0.04), particularly at 4 and 8 Hz. Nitric oxide synthase inhibition with [N.sup.G]-nitro-L-arginine (L-NNA) enhanced RBF (P = 0.003), CBF (P = 0.001), and MBF (P = 0.03) responses to RNS, particularly at frequencies of 2 Hz and less. After candesartan pretreatment, L-NNA significantly enhanced RNS-induced reductions in RBF (P = 0.04) and CBF (P = 0.007) but not MBF (P = 0.66). Renal arterial infusion of angiotensin II (5 ng x [kg.sup.-1] x [min.sup.-1]) selectively enhanced responses of MBF to RNS in L-NNA-pretreated but not in vehicle-pretreated rabbits. In contrast, greater doses of angiotensin II (5-15 ng x [kg.sup.-1] x [min.sup.-1]) blunted responses of MBF to RNS in rabbits with intact nitric oxide synthase. These results suggest that endogenous angiotensin II enhances, whereas nitric oxide blunts, neurally mediated vasoconstriction in the renal cortical and medullary circulations. In the renal medulla, but not the cortex, angiotensin II also appears to be able to blunt neurally mediated vasoconstriction. renal medullary blood flow; renal cortical blood flow; sympathetic nervous system

The Y chromosome accounts for 15-20mmHg difference in arterial pressure; the gene(s) and mechanism(s) underlying this effect remain unknown. One candidate gene, the Sry3 gene, expressed exclusively on the hypertensive SHR Y chromosome has been shown in vitro to interact with the renin angiotensin system (RAS). Using a reciprocal Y consomic rat approach, we investigated the functional consequences of this interaction in vivo; examining the interaction of the Y chromosome with the renal vasculature. 16 week old normotensive rats (WKY), hypertensive rats (SHRSP) and two reciprocal Y consomic rat strains; one comprising the WKY autosomes and X chromosome with the hypertensive Y chromosome (WKY.SPGlaY) and vice versa (SP.WKYGlaY) were examined. We confirmed via radiotelemetry that systolic blood pressure (SBP) was Y chromosome dependent; SP.WKYGlaY had lower SBP than SHRSP (195±5mmHg vs 227±8mmHg, P<0.03) and was higher in WKY.SPGlaY compared to WKY (157±3mmHg vs 148±3mmHg, P<0.05). Compared to WKY rats, the vasodilator arm of the RAS was enhanced in SHRSP as evidenced by a higher plasma Ang(1-7):Ang II ratio (WKY:0.13±0.01 vs SHRSP:1.33±0.4, P<0.005) and a blunted renal blood flow (RBF) response to graded intrarenal Ang I and Ang(1-7) infusions. In response to 10ng/kg we observed a reduction in RBF of WKY:58±6% and 16±6% vs SHRSP: 17±6%, P<0.01 and 1±4%, P<0.05 respectively. Introgression of the normotensive Y chromosome into the SHRSP background (SP.WKYGlaY) resulted in a reduction in plasma Ang(1-7):AngII ratio (SP.WKYGlaY: 0.24±0.02, P<0.01) and an increased vasoconstrictor response to intrarenal Ang I and Ang(1-7) infusion. In response to 10ng/kg bolus RBF in SP.WKYGlaY reduced by 45±14%, P<0.01 and 41±18%, P<0.005, respectively compared to SHRSP, demonstrating the blunted responsiveness in the SHRSP is Y chromosome dependent. Investigation of the interlobular arteries via wire myography revealed increased sensitivity to Ang II in SHRSP compared to WKY which was reduced following introgression of the WKY Y chromosome (SP.WKYGlaY) confirming that the Y chromosome influences the RAS in the renal vasculature. This study provides novel evidence that the Y chromosome influences the vasodilatory arm of the RAS and intrarenal vascular function. [ABSTRACT FROM AUTHOR]

Vascular inflammation, involving the recruitment, adhesion and infiltration of monocytes to the sub-endothelial space, is a critical early event in the development of atherosclerosis. The renin angiotensin system plays an important role in inflammation via activation of the angiotensin type I receptor (AT1R), which induces pro-inflammatory effects. The angiotensin II type 2 receptor (AT2R) counter-regulates the effects of the AT1R, including AT1R-mediated pro-inflammatory cytokine expression. We investigated the anti-inflammatory effects of AT2R stimulation in vascular inflammation by examining leukocyte to endothelial adhesion. We quantified the effect of AT2R stimulation (Compound 21: C21, 100μM) on TNFα (10ng/mL)-induced monocyte adhesion to cultured human umbilical vascular endothelial cells in vitro. AT2R stimulation attenuated TNFα-induced monocyte adhesion (unstimulated: 8±4% of TNFα: 100%, C21+TNFα: 59±12% of TNFα-induced adhesion). Adhesion of monocytes to the endothelial monolayer following incubation with TNFα+C21+AT2R antagonism (PD 123319, 10μM) was not different to TNFα-induced monocyte adhesion (93±5% of TNFα); demonstrating that the anti-inflammatory effects of C21 are mediated by the AT2R. Furthermore, C21 treatment attenuated TNFα-induced upregulation of adhesion molecules ICAM-1 and E-selectin and abolished TNFα-induced ROS production (unstimulated: 2±2, TNFα: 55±16, TNFα+C21: -3±5 dihydroethidium fluorescence intensity units). We quantified TNFα-induced leukocyte adhesion in intact mouse thoracic aorta ex vivo in real time in the presence and absence of AT2R activation. Consistent with our in vitro findings, we observed that direct AT2R activation (C21, 10μM) abolished TNFα-induced leukocyte adhesion (TNFα: 30±4, vs TNFα+C21: 11±4 adhered leukocytes/field of view (FOV), P<0.01) an effect which was abolished by co-incubation with PD 123319 (10μM: 31±5 adhered leukocytes/FOV). This study provides the first functional evidence that direct AT2R stimulation prevents TNFα-induced leukocyte adhesion, ICAM-1 and E-selectin expression and ROS production revealing the anti-inflammatory and therapeutic potential of the AT2R in the treatment of inflammation-induced cardiovascular disease. [ABSTRACT FROM AUTHOR]