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Angiotensin (1-7) (Ang (1-7)) causes vasodilator effects in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) via angiotensin type 2 receptors (AT2R). However, the role of vascular AT2R in aging is not known. Therefore, we examined the effect of aging on Ang (1-7)-mediated vasodepressor effects and vascular angiotensin receptor localization in aging. Blood pressure was measured in conscious adult (∼17 weeks) and aged (∼19 months) normotensive rats that received drug combinations in a randomised fashion over a 4-day protocol: (i) Ang (1-7) alone, (ii) AT1R antagonist, candesartan, alone, (iii) Ang (1-7) and candesartan, or (iv) Ang-(1-7), candesartan, and the AT2R antagonist, PD123319. In a separate group of animals, the specific MasR antagonist, A779, was administered in place of PD123319. Receptor localisation was also assessed in aortic sections from adult and aged WKY rats by immunofluorescence. Ang (1-7) reduced blood pressure (∼15 mmHg) in adult normotensive rats although this effect was dependant on the background dose of candesartan. This depressor effect was reversed by AT2R blockade. In aged rats, the depressor effect of Ang (1-7) was evident but was now inhibited by either AT2R blockade or MasR blockade.At the same time, AT2R, MasR, and ACE2 immunoreactivity was markedly elevated in aortic sections from aged animals. These results indicate that the Ang (1-7)-mediated depressor effect was preserved in aged animals. Whereas Ang (1-7) effects were mediated exclusively via stimulation of AT2R in adult WKY, with aging the vasodepressor effect of Ang (1-7) involved both AT2R and MasR. [ABSTRACT FROM AUTHOR]

Angiotensin (1-7) (Ang (1-7)) causes vasodilator effects in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) via angiotensin type 2 receptors (AT2R). However, the role of vascular AT2R in aging is not known. Therefore, we examined the effect of aging on Ang (1-7)-mediated vasodepressor effects and vascular angiotensin receptor localization in aging. Blood pressure was measured in conscious adult (∼17 weeks) and aged (∼19 months) normotensive rats that received drug combinations in a randomised fashion over a 4-day protocol: (i) Ang (1-7) alone, (ii) AT1R antagonist, candesartan, alone, (iii) Ang (1-7) and candesartan, or (iv) Ang-(1-7), candesartan, and the AT2R antagonist, PD123319. In a separate group of animals, the specific MasR antagonist, A779, was administered in place of PD123319. Receptor localisation was also assessed in aortic sections from adult and aged WKY rats by immunofluorescence. Ang (1-7) reduced blood pressure (∼15 mmHg) in adult normotensive rats although this effect was dependant on the background dose of candesartan. This depressor effect was reversed by AT2R blockade. In aged rats, the depressor effect of Ang (1-7) was evident but was now inhibited by either AT2R blockade or MasR blockade.At the same time, AT2R, MasR, and ACE2 immunoreactivity was markedly elevated in aortic sections from aged animals. These results indicate that the Ang (1-7)-mediated depressor effect was preserved in aged animals. Whereas Ang (1-7) effects were mediated exclusively via stimulation of AT2R in adult WKY, with aging the vasodepressor effect of Ang (1-7) involved both AT2R and MasR. [ABSTRACT FROM AUTHOR]

Aim: The contribution of adenosine triphosphate (ATP) to the neural control of regional renal perfusion in vivo remains unknown. We therefore examined whether P2X receptors mediate renal vascular responses to electrical stimulation of the renal nerves (RNS) in pentobarbitone anaesthetized rabbits. Methods: Responses to RNS were tested before and during renal arterial infusion of α, β-methylene ATP ( α, β-mATP, 7–56 μg kg−1 min−1) to desensitize P2X1 receptors. RNS consisted of 3 min trains at graded frequencies and short trains of RNS (4–32 pulses). Results: Three-minute trains of RNS reduced renal blood flow (RBF), cortical laser Doppler flux (CLDF), and medullary LDF (MLDF) by −90 ± 3%, −89 ± 3% and −31 ± 11%, respectively, at 4 Hz. MLDF was reduced less than CLDF or RBF. During short train RNS, RBF, CLDF and MLDF were reduced by −22 ± 2%, −15 ± 2% and −12 ± 2%, respectively, for 32 s at 1 Hz. CLDF and MLDF were reduced to a similar extent. Infusion of α, β-mATP induced transient reductions in RBF, CLDF and MLDF, but within 5 min these variables had recovered to control levels. Vascular responses to RNS were not significantly altered by α, β-mATP treatment. Conclusions: In the rabbit kidney in vivo, α, β-mATP-sensitive receptors mediate vasoconstriction and reduce perfusion in both cortical and medullary vascular beds. However, these receptors do not mediate neurally induced reductions in renal perfusion. [ABSTRACT FROM AUTHOR]

Fibrosis refers to the hardening or scarring of tissues that usually results from aberrant wound healing in response to organ injury, and its manifestations in various organs have collectively been estimated to contribute to around 45-50% of deaths in the Western world. Despite this, there is currently no effective cure for the tissue structural and functional damage induced by fibrosis-related disorders. Relaxin meets several criteria of an effective anti-fibrotic based on its specific ability to inhibit pro-fibrotic cytokine and/or growth factor-mediated, but not normal/unstimulated, fibroblast proliferation, differentiation and matrix production. Furthermore, relaxin augments matrix degradation through its ability to up-regulate the release and activation of various matrix-degrading matrix metalloproteinases and/or being able to down-regulate tissue inhibitor of metalloproteinase activity. Relaxin can also indirectly suppress fibrosis through its other well-known (anti-inflammatory, antioxidant, anti-hypertrophic, anti-apoptotic, angiogenic, wound healing and vasodilator) properties. This review will outline the organ-specific and general anti-fibrotic significance of exogenously administered relaxin and its mechanisms of action that have been documented in various non-reproductive organs such as the cardiovascular system, kidney, lung, liver, skin and tendons. In addition, it will outline the influence of sex on relaxin's anti-fibrotic actions, highlighting its potential as an emerging anti-fibrotic therapeutic. Linked Articles This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

Aim The renin-angiotensin system ( RAS) depressor arm, particularly renal angiotensin type 2 receptor ( AT2 R) and Mas receptor (mas R) expression, is enhanced in females, which may contribute to renal and cardiovascular protection. We examined the hypotheses that mas R activation increases renal blood flow ( RBF) at rest and attenuates the reduction in RBF in response to angiotensin II (Ang II) infusion in female rats. Furthermore, we postulated that combined activation of the AT2 R and mas R would produce a greater response than mas R activation alone. Methods In anaesthetized male and female Wistar rats, mean arterial pressure ( MAP) and RBF responses during graded Ang II infusion (30-1000 ng kg−1 min−1 i.v.) were assessed following pre-treatment with vehicle, the mas R antagonist A779, or A779 plus the AT2 R antagonist PD123319. Results Basal MAP was not altered by any pre-treatment. Basal RBF decreased approx. 20% in female ( P < 0.05), but not male rats in response to A779. However, basal RBF was not altered by A779 + PD123319. Ang II infusion reduced RBF in a dose-related fashion ( Pdose < 0.0001) and mas R blockade did not alter the RBF response to Ang II infusion in male or female rats. However, A779 + PD123319 attenuated the reduction in RBF response to Ang II in females ( Pgroup < 0.005), but not males. Conclusion The impact of the mas R on renal haemodynamics appears to be sexually dimorphic, with greater effects in female than male rats. However, the paradoxical effects of dual AT2 R and mas R blockade suggest that a greater understanding of the complex interactions between RAS components is required before the therapeutic opportunities of AT2 R and/or mas R stimulation can be advanced. [ABSTRACT FROM AUTHOR]

Previously, we demonstrated that adult blood pressure was increased in offspring of rabbit mothers with chronic secondary renal hypertension. Our study identified sex-specific differences in the programming of hypertension, with female, not male, offspring, having increased blood pressure at 30 wk of age. The aim of this study was to characterize the maternal hypertension during pregnancy to determine potential programming stimuli. Further, we examined the impact of chronic maternal hypertension on offspring birth weight, nephron number, and renal noradrenaline content (as an index of renal innervation density). Three groups of mothers and their offspring were studied: two-kidney, one-wrap (2K-1w, n = 9 mothers) hypertensive, two-kidney, two-wrap (2K-2W, n = 8) hypertensive, and a sham-operated group (n = 9). Mean arterial blood pressure was increased by ∼20 mmHg throughout pregnancy in both hypertensive groups compared with sham mothers (PG < 0.001). Plasma renin activity (PRA; PG < 0.05) and aldosterone (PG < 0.05) levels were increased during gestation in the 2K-1w, but not the 2K-2W mothers. Birth weight was increased by ∼20% in offspring of both groups of hypertensive mothers (PT < 0.00 1), though this was associated with a reduction in litter size. Renal noradrenaline content was increased (∼40%, P < 0.05) at 5 wk of age in female 2K-1w offspring compared with sham offspring. Glomerular number was not reduced in female offspring of either group of hypertensive mothers; however, glomerular tuft volume was reduced in female 2K-2W offspring (P < 0.05), indicative of a reduction in glomerular filtration surface area. In conclusion, the two models of renal hypertension produced differential effects on the offspring. The impact of a stimulated maternal renin-angiotensin system in the 2K-1w model of hypertension may influence development of the renal sympathetic nerves and contribute to programming of adult hypertension. [ABSTRACT FROM AUTHOR]

Fibrosis refers to the hardening or scarring of tissues that usually results from aberrant wound healing in response to organ injury, and its manifestations in various organs have collectively been estimated to contribute to around 45-50% of deaths in the Western world. Despite this, there is currently no effective cure for the tissue structural and functional damage induced by fibrosis-related disorders. Relaxin meets several criteria of an effective anti-fibrotic based on its specific ability to inhibit pro-fibrotic cytokine and/or growth factor-mediated, but not normal/unstimulated, fibroblast proliferation, differentiation and matrix production. Furthermore, relaxin augments matrix degradation through its ability to up-regulate the release and activation of various matrix-degrading matrix metalloproteinases and/or being able to down-regulate tissue inhibitor of metalloproteinase activity. Relaxin can also indirectly suppress fibrosis through its other well-known (anti-inflammatory, antioxidant, anti-hypertrophic, anti-apoptotic, angiogenic, wound healing and vasodilator) properties. This review will outline the organ-specific and general anti-fibrotic significance of exogenously administered relaxin and its mechanisms of action that have been documented in various non-reproductive organs such as the cardiovascular system, kidney, lung, liver, skin and tendons. In addition, it will outline the influence of sex on relaxin's anti-fibrotic actions, highlighting its potential as an emerging anti-fibrotic therapeutic.Linked Articles: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc. [ABSTRACT FROM AUTHOR]