Angiotensin (Ang) II modulates vascular resistance and sympathetic neurotransmission through Ang II type 1 (AT1) receptors. Recent studies reported an involvement of AT2 receptors. We investigated ...whether AT2 receptors participate in modulation of vascular resistance and sympathetic neurotransmission in spontaneously hypertensive rats (SHR).
Kidneys of 6- and 16-week-old normotensive (WKY) and SHR were isolated and perfused.
Noradrenaline release induced by renal nerve stimulation (RNS) was increased in SHR (WKY: 1,837 +/- 128, SHR: 2,310 +/- 192 pg/g). Ang I- and II-induced pressor responses and enhancement of noradrenaline release were greater in SHR than in WKY. Pressor responses to Ang I and II were greater in adult compared with young SHR. The AT1 receptor antagonist EXP3174 (0.1 microM) blocked Ang I- and II-induced renal vasoconstriction and noradrenaline release to RNS in both strains. In contrast, the selective AT2 receptor antagonist PD 123319 (1 microM) had no influence in young and adult WKY and SHR.
Ang I and II had a greater impact on renal vascular resistance and neurotransmission in SHR, which was more pronounced in adult SHR. All effects are mediated by the AT1 receptor and no modulatory influence of the AT2 receptor could be found.
Mesangial cell proliferation is observed in a number of kidney diseases. The sympathetic cotransmitter ATP is suspected to play a major role in proliferative processes. Therefore, the effects of ...exogenous ATP on human mesangial cells in culture were studied.
Fresh human kidney cortex was processed to obtain mesangial cells in culture. Effects of nucleotides on 3Hthymidine incorporation, the activation of mitogen‐activated protein kinase and the cell number were studied. The involved P2‐receptors were characterized pharmacologically. In addition, we searched for mRNA for P2Y‐ and P2X‐receptors by RT–PCR.
ATP (0.1–300 μM) and related nucleotides induced a significant increase in 3Hthymidine incorporation up to 220% of control. The adenine nucleotides ATP and ADP were about equally effective. Also ATP‐γ‐S, UTP, ADP‐β‐S and 2‐m‐thio‐ADP induced a weaker response. UDP and α‐β‐methylene‐ATP failed to induce an effect on 3Hthymidine uptake.
ATP (100μM) induced a fast activation of the MAPK42/44 pathway. The effects of ATP on MAPK42/44 activation and 3Hthymidine incorporation were reduced by the MAPK inhibitor PD 98059. Platelet‐derived growth factor (PDGF 5 ng ml−1) increased the cell number to more than 122% of control. ATP (10 μM) on top of PDGF amplified PDGF induced cell proliferation to 136% of control.
RT–PCR products for P2Y1,2,4,6,11,12‐ and P2X1,2,4,5,6,7‐receptor subtypes were detected in human mesangial cells.
ATP has mitogenic effects on human mesangial cells. DNA synthesis is increased by the activation of the MAPK42/44 pathway. ATP amplifies PDGF‐induced cell hyperplasia.
British Journal of Pharmacology (2003) 139, 1119–1126. doi:10.1038/sj.bjp.0705358
Arterial hypertension is a major risk factor for cardiovascular mortality and remains insufficiently controlled in Germany. The sham controlled Symplicity HTN-3 trial did meet its primary safety ...endpoint but failed to meet its primary efficacy endpoint. Renal denervation can not replace established, well-proven therapies. It can only be used in selected truly resistant hypertensive patients as an additive approach and should be performed by specialized centers only. Randomized controlled trials are needed to further evaluate renal denervation.
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