Cardiac chymase converts rat proAngiotensin-12 (PA12) to angiotensin II: effects of PA12 upon cardiac haemodynamics

Prosser, Hamish; Forster, Malcolm E.; Richards, A. Mark; Pemberton, Chris J.

doi:10.1093/cvr/cvp003

Cited by 61 publications

(63 citation statements)

References 26 publications

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“…ACE has been reported to be involved in the conversion of ANG-(1-12) to ANG II in some regions of the brain (e.g., the NTS) (1). Chymase has been reported to be one of the alternate pathways by which ANG II is formed in various tissues (37). In the central nervous system, this pathway is involved in ANG II formation in the pituitary stalk and pineal gland (2).…”

Section: Discussionmentioning

confidence: 99%

The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1–12) and angiotensin II

Arakawa

Chitravanshi

Sapru

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Arakawa H, Chitravanshi VC, Sapru HN. The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1-12) and angiotensin II. Am J Physiol Heart Circ Physiol 300: H951-H960, 2011. First published December 24, 2010 doi:10.1152/ajpheart.01144.2010.-The hypothalamic arcuate nucleus (ARCN) has been reported to play a significant role in cardiovascular regulation. It has been hypothesized that the ARCN may be one of the sites of cardiovascular actions of angiotensins (ANGs). Experiments were carried out in urethaneanesthetized, artificially ventilated, adult male Wistar rats. The ARCN was identified by microinjections of N-methyl-D-aspartic acid (NMDA; 10 mM). Microinjections (50 nl) of ANG-(1-12) (1 mM) into the ARCN elicited increases in mean arterial pressure (MAP), heart rate (HR), and greater splanchnic nerve activity (GSNA). The tachycardic responses to ANG-(1-12) were attenuated by bilateral vagotomy. The cardiovascular responses elicited by ANG-(1-12) were attenuated by microinjections of ANG II type 1 receptor (AT1R) antagonists but not ANG type 2 receptor (AT2R) antagonist. Combined inhibition of ANG-converting enzyme (ACE) and chymase in the ARCN abolished ANG-(1-12)-induced responses. Microinjections of ANG II (1 mM) into the ARCN also increased MAP and HR. Inhibition of ARCN by microinjections of muscimol (1 mM) attenuated the pressor and tachycardic responses to intravenously administered ANG-(1-12) and ANG II (300 pmol/kg each). These results indicated that 1) microinjections of ANG-(1-12) into the ARCN elicited increases in MAP, HR, and GSNA; 2) HR responses were mediated via both sympathetic and vagus nerves; 3) AT1Rs, but not AT2Rs, in the ARCN mediated ANG-(1-12)-induced responses; 4) both ACE and chymase were needed to convert ANG-(1-12) to ANG II in the ARCN; and 5) ARCN plays a role in mediating the cardiovascular responses to circulating ANGs. blood pressure; heart rate; microinjection; N-methyl-D-aspartic acid; sympathetic nerve activity THE HYPOTHALAMIC ARCUATE NUCLEUS (ARCN) may play a significant role in cardiovascular regulation (10, 38). Consistent with this notion, we (31) have recently reported that chemical stimulation of the ARCN elicited increases in mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). These reports have provided a basis for investigations on different neurotransmitters and neuromodulators in the ARCN that may play a role in the regulation of cardiovascular function in normal and pathological states.A new endogenous angiotensin (ANG), ANG-(1-12), has recently been identified (30,44). Intravenous administration of this peptide has been reported to elicit an immediate pressor response in the rat, and this effect was blocked by prior administration of an ANG-converting enzyme (ACE) inhibitor or an ANG II type 1 receptor (AT 1 R) antagonist (30). These data indicated that in the periphery, ANG-(1-12) exerts its actions via a rapid conversion to ANG II (30). High concentrations of ANG-(1-12) have been reported in th...

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Section: Discussionmentioning

confidence: 99%

The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1–12) and angiotensin II

Arakawa

Chitravanshi

Sapru

2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…The vasoconstrictor and pressor effects of proang-12 are abolished by ACE inhibitors and angiotensin receptor blockers, which suggests ACE is involved in the conversion of proang-12 to Ang II. [8][9][10] However, Prosser et al 11,12 reported that chymase inhibition attenuates proang-12-induced cardiac damage caused by ischemia-reperfusion in rat hearts ex vivo, as well as proang-12-induced constriction of isolated rat arteries. This suggests that chymase is also involved in the conversion of proang-12 to Ang II.…”

Section: Introductionmentioning

confidence: 99%

Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system

et al. 2011

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It has been suggested that proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, may function as a component of the tissue renin-angiotensin system (RAS). To investigate the role of proang-12 in the production of angiotensin II (Ang II), we measured its plasma and tissue concentrations in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, with and without RAS inhibition. The 15-week-old male WKY and SHR rats were left untreated or were treated for 7 days with 30 mg kg À1 per day losartan, an angiotensin receptor blocker, or with 20 mg kg À1 per day imidapril, an angiotensin-converting enzyme (ACE) inhibitor. Both treatments increased renin activity and the concentrations of angiotensin I (Ang I) and Ang II in the plasma of WKY and SHR rats, but neither affected plasma proang-12 levels. In contrast to the comparatively low level of proang-12 seen in plasma, cardiac and renal levels of proang-12 were higher than those of Ang I and Ang II. In addition, despite activation of the RAS in the systemic circulation, tissue concentrations of proang-12 were significantly reduced following treatment with losartan or imidapril. Similar reductions were also observed in the tissue concentrations of Ang II in both strains, without a reduction in Ang I. These results suggest that tissue concentrations of proang-12 and Ang II are regulated independently of the systemic RAS in WKY and SHR rats, which is consistent with the notion that proang-12 is a component of only the tissue RAS.

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“…Ang-(1-12) added to the isolated rat heart resulted in increased Ang II production, coronary vasoconstriction, and impaired recovery from ischemia-reperfusion injury. 112 Although the enzymatic mechanism responsible for cardiac Ang-(1-12) formation from angiotensinogen remains an open question, a recent study suggested a chymase-mediated mechanism in the ischemia-reperfusion rat heart. 112 In keeping with these observations, studies from Ferrario's 113 laboratory showed that although both ACE and chymase form Ang II from Ang-(1-12), the latter assumed an even greater role for Ang II formation in spontaneously hypertensive rats.…”

Section: Ang-(1-7) and Ace2 And Other Angiotensin Peptides In The Heartmentioning

confidence: 99%

“…112 Although the enzymatic mechanism responsible for cardiac Ang-(1-12) formation from angiotensinogen remains an open question, a recent study suggested a chymase-mediated mechanism in the ischemia-reperfusion rat heart. 112 In keeping with these observations, studies from Ferrario's 113 laboratory showed that although both ACE and chymase form Ang II from Ang-(1-12), the latter assumed an even greater role for Ang II formation in spontaneously hypertensive rats. In summary, Ang-(1-12) is clearly present in the heart and represents an alternate substrate contributing to formation of Ang peptides by a nonrenin-dependent mechanism.…”

Section: Ang-(1-7) and Ace2 And Other Angiotensin Peptides In The Heartmentioning

confidence: 99%

“…118 In addition, chymase was shown to activate kallikrein, 119 transforming growth factor-␤, and IL-1␤, 120 and recently was reported to convert Ang-(1-12) to Ang II. 112,113 In addition to other mast cell contents, the multiple actions of chymase on tissue remodeling were reported to be associated with the pathophysiology of plaque rupture and abdominal aortic aneurysm in humans. 121 Based on amino acid sequence homology, chymase is divided into two groups, ␣ and ␤.…”

Section: The Importance Of Chymase In Heart Failurementioning

confidence: 99%

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Translational Success Stories: Angiotensin Receptor 1 Antagonists in Heart Failure

Dell’Italia

2011

Circulation Research

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Cardiac chymase converts rat proAngiotensin-12 (PA12) to angiotensin II: effects of PA12 upon cardiac haemodynamics

Abstract: PA12 may act as a circulating substrate for cardiac chymase-mediated AngII production, in contrast to ACE-mediated AngII production from AngI.

Cited by 61 publications

References 26 publications

The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1–12) and angiotensin II

The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1–12) and angiotensin II

Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system

Translational Success Stories: Angiotensin Receptor 1 Antagonists in Heart Failure

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