Ang17 receptor mechanisms

Ang-(1-7) is a poor competitor at pharmacologically defined AT1 or AT2 receptors (104-107). Santos et al. (62) designed a selective antagonist for the Ang-(1-7) receptor by replacing the a-proline at position 7 of Ang-(1-7) with D-alamine [D-Ala7]-Ang-(1-7). In initial studies, [D-Ala7]-Ang-(1-7) blocked hemodynamic and renal effects of

Ang-(1-7), did not compete for binding at rat adrenal ATj or AT2 receptors, and did not attenuate pressor or contractile responses to Ang II, demonstrating selectivity for Ang-(1-7). We identified Ang-(1-7) binding sites on bovine aortic endothelial cells (BAEC), canine coronary artery rings, and rat blood vessels that are sensitive to [D-Ala7]-Ang-(1-7) (108-110). In addition, a multitude of physiological responses to Ang-(1-7) are selectively blocked by [D-Ala7]-Ang-(1-7) or the sarcosine analogs of Ang II, but not by ATj or AT2 receptor antagonists, including the depressor response to Ang-(1-7) in the pithed rat and the lowering of blood pressure in hypertensive rats (33,40,111). Collectively, these results demonstrate that the hypotensive response to Ang-(1-7) is mediated by a non-ATp non-AT2, [D-Ala7]-Ang-(1-7)-sensitive receptor. We refer to this receptor as the AT^g receptor, as defined by its sensitivity to Ang-(1-7), its antagonism by [Sar1-Thr8]-Ang II and [D-Ala7]-Ang-(1-7), and its lack of response to ATj or AT2 receptor antagonists, either functionally or in competition for binding.

Identification of an AT^^receptor is confounded by reports of responses to Ang-(1-7) that are sensitive to AT1 or AT2 receptor antagonists or both. Some of the renal and central effects of Ang-(1-7) are mediated by a losartan-sensitive receptor (64,91,112). Arachidonic acid release from rabbit VSMCs and hypothalamic norepinephrine release were blocked by both [D-Ala7]-Ang-(1-7) and the AT2 antagonist PD123319 (113,114). Additional responses to Ang-(1-7) in brain and heart are blocked by both ATj and AT2 receptor antagonists (74,115). These results provide evidence for additional subtypes of the AT^^ receptor that are sensitive to losartan and/or PD123319 or suggest an interaction with the ATj and/or the AT2 receptor.

Many of the physiological and cellular responses that are mediated by the AT^^ receptor are linked to the production of prostaglandins. Ang-(1-7) stimulates prosta-glandin production in endothelial cells, VSMCs, astrocytes, and renal tubular epithelial cells (74,94,104-107,115). In addition, physiological responses to Ang-(1-7) are dependent on prostanoid production, based on the studies using the cyclooxygenase inhibitor indomethacin (Fig. 4).

Recently, Santos et al. (65) reported that the orphan G protein-coupled receptor mas is an Ang-(1-7) receptor. Ang-(1-7) bound with high affinity to cells transfected with the mas receptor, which was blocked by [D-Ala7]-Ang-(1-7), and renal or depressor responses to Ang-(1-7) were lost in mas-depleted mice. We recently showed that antisense oligonucleotides or siRNAs to mas prevent the Ang-(1-7)-mediated inhibition of growth in VSMCs, which is also blocked by [D-Ala7]-Ang-(1-7) (116). These results suggest that the mas receptor serves as a selective Ang-(1-7) binding site. Fig. 4 shows the signal transduction pathway by which Ang-(1-7) activates the G protein-coupled mas receptor to increase the production of NO and prostacyclin (PGI2) via increases in cGMP and cAMP, respectively. Ang-(1-7) also reduces the mitogen-activated protein kinases (MAPKs) by either increasing MAPK phosphatases or reducing the MAPK kinase MEK. The increase in cAMP and cGMP and the decrease in MAPK activity cause vasodilation and inhibit cell growth. The mas receptor is predominantly expressed in the testis and the hippocampus and amygdala of the mammalian forebrain with minimal levels in the rodent heart and kidney. This tissue distribution differs from previous reports of Ang-(1-7) binding and functional responses, suggesting the existence of other AT^t) receptors.

Mas Receptor

Fig. 4. The major signal transduction pathways for Ang-(1-7). Ang-(1-7) activates the G proteincoupled mas receptor to increase the production of nitric oxide (NO) and prostacyclin (PGI2) to increase cGMP and cAMP, respectively. Ang-(1-7) also reduces the mitogen-activated protein kinases (MAPKs) by either increasing MAPK phosphatases or reducing the MAPK kinase MEK. The increase in cAMP and cGMP and the decrease in MAPK activity cause vasodilation and inhibit cell growth. (See color version of this figure on color plates.)

Fig. 4. The major signal transduction pathways for Ang-(1-7). Ang-(1-7) activates the G proteincoupled mas receptor to increase the production of nitric oxide (NO) and prostacyclin (PGI2) to increase cGMP and cAMP, respectively. Ang-(1-7) also reduces the mitogen-activated protein kinases (MAPKs) by either increasing MAPK phosphatases or reducing the MAPK kinase MEK. The increase in cAMP and cGMP and the decrease in MAPK activity cause vasodilation and inhibit cell growth. (See color version of this figure on color plates.)

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Blood Pressure Health

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