Subtypes of losartan‐sensitive angiotensin receptor in the rabbit pulmonary artery

Chai, Sie-Yearl

doi:10.1111/j.1476-5381.1996.tb15313.x

Cited by 21 publications

(4 citation statements)

References 6 publications

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“…The effect waned off within a week after cessation of DAA-I treatment. These findings are in agreement with those of earlier studies showing that the actions of DAA-I were losartan- and indomethacin-sensitive [ 7 , 8 , 11 , 13 , 19 , 20 ].…”

Section: Discussionsupporting

confidence: 93%

Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action

2015

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ACE inhibitors and ARBs (angiotensin receptor blockers) have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I), an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy) attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p.) that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia), and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA-I. DAA-I completely attenuated the increase in circulating level of two inflammatory cytokines, TNFα and IL-6, in irradiated mice; and this shows that DAA-I exerted additional anti-inflammatory actions, which could also have contributed to its radioprotection. These findings show that DAA-I acts via a novel mechanism of action on the angiotensin AT1 receptor to specifically release PGE2, which mediates radioprotection in the gamma irradiated mice.

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Section: Discussionsupporting

confidence: 93%

Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action

2015

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“…Earlier studies have shown that the actions of DAA‐I were inhibited by losartan and indomethacin, indicating that the actions were mediated by the angiotensin AT1 receptor that involved prostaglandins as signaling molecules (Sim and Chai, 1996; Sim and Min, 1998; Wen et al ., 2004). In the present study, the protective action of DAA‐I was similarly blocked by losartan.…”

Section: Discussionmentioning

confidence: 99%

Protective actions of des‐aspartate‐angiotensin I in mice model of CEES‐induced lung intoxication

Loke

2010

J of Applied Toxicology

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The present study investigated the protective actions of des-aspartate-angiotensin I (DAA-I) in mice that were intranasally administered 2-chloroethyl ethyl sulfide (CEES), a half sulfur mustard. The protection was dose-dependent, and an oral dose of 75 mg kg⁻¹ per day administered 18 h post exposure and for the following 13 days, offered maximum protection that increased survival by a third. DAA-I attenuated the early processes of inflammation seen in the CEES-inoculated mice. DAA-I attenuated (i) elevated pulmonary ROS, and gp91-phox protein of NADPH oxidase, a non phagocytic enzyme that generates superoxide and subsequent ROS; (ii) intercellular adhesion molecule-1 (ICAM⁻¹) that is involved in the extravasation of circulating leucocytes; and (iii) myeloperoxidase activity, which is a surrogate enzymatic measurement of neutrophil infiltration. These actions led to improved histological lung structures, and survival of type-1 pneumocytes. The action of DAA-I on animal survival was blocked by losartan, a selective angiotensin AT1 receptor blocker, indicting that the AT1 receptor mediates the protection. The presence of elevated PGE2 and PGI2 in lung supernatants of DAA-I treated CEES-inoculated mice indicates that the two prostaglandins are involved in signaling the protective actions of DAA-I. This finding complements earlier studies showing that DAA-I acts on an indomethacin-sensitive angiotensin AT1 receptor. The findings of the present study are the first demonstration of an angiotensin peptide as an effective antidote for CEES intoxication. DAA-I is also an effective therapeutic intervention against CEES that was instituted at 18 h post exposure, and challenges conventional assumptions of limited efficacy with delayed action against alkylating agents.

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“…19.6 mN tension is the standard tension normally used to preload pulmonary arterial segments in mechanical studies (Nedergaard & Schrold, 1977; MacLean et al ., 1993a, b; Sim & Soh, 1995; Sim & Chai, 1996; Tan & Sim, 2000). Intrapulmonary artery rings are much smaller than extrapulmonary segments, therefore the resting tension was varied to determine if this factor could in some way contribute to the generation of the slow contraction.…”

Section: Resultsmentioning

confidence: 99%

“…As the resting membrane potential of smooth muscle cells is determined to a large extent by K + , stretch‐induced depolarization could activate mechano‐sensitive ion channels promoting Na + /Ca 2+ influx, Cl − efflux, or/or inhibiting K + efflux. Although a standard tension of 19.6 mN was applied in previous studies of extrapulmonary arteries (Nedergaard & Schrold, 1977; MacLean et al ., 1993a, b; Sim & Soh, 1995; Sim & Chai, 1996; Tan & Sim, 2000), it is possible that in intrapulmonary arteries, which are much narrower in diameter than extrapulmonary arteries, this degree of resting tone is too high and may activate stretch‐sensitive receptors. This possibility was addressed in two ways.…”

Section: Discussionmentioning

confidence: 99%

Regional variation in electrically‐evoked contractions of rabbit isolated pulmonary artery

Jackson

Trout

Cunnane

2002

British J Pharmacology

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1 Electrically-evoked contractions in dierent regions of the rabbit isolated pulmonary artery have been investigated using stimulation parameters generally assumed to stimulate nerves selectively. 2 In extrapulmonary artery, trains of stimuli (10 Hz; pulse width 0.1 ms) evoked monophasic contractions. In contrast, a biphasic contraction was evoked in the intrapulmonary artery consisting of an initial fast component followed by a secondary very long-lasting component. 3 The contraction in the extrapulmonary artery was prazosin-sensitive (1 mM) whereas that in the intrapulmonary artery was prazosin-resistant. 4 a,b-Methylene ATP (1 mM), atropine (1 mM), losartan (1 mM), BIBO3304 (1 nM) or nifedipine (1 mM) had no eect on the biphasic contraction of the intrapulmonary artery. Bretylium (2 mM) abolished the contraction of extrapulmonary artery but only partially inhibited the initial component in the intra region with no eect on the second component. 5 Tetrodotoxin (0.3 ± 1 mM), abolished the contraction of extrapulmonary artery but only partially reduced the electrically-evoked contraction of intrapulmonary artery. 6 Removal of the endothelium and application of sulphisoxazole (0.6 ± 22 mM) had no eect. 7 Varying the resting tone on the arteries, or applying gadolinium, had no eect on contractions. 8 Using confocal microscopy and calcium imaging, reproducible whole cell calcium transients were evoked in individual smooth muscle cells in intact preparations but only when direct muscle stimulation was used (pulse width of 5 ± 10 ms). No detectable changes in calcium were elicited when brief pulse widths were used (0.1 ± 2 ms). 9 Together, these data suggest that noradrenaline is the neurotransmitter inducing contraction in extrapulmonary artery. Noradrenaline and sympathetic nerves appear to play a less important role in the intrapulmonary artery. The tetrodoxin-resistant component is not mediated by ATP, NPY, acetylcholine, angiotensins, ET-1, stretch-activation or Ca 2+ in¯ux through L-type Ca 2+ channels. Smooth muscle cells do not appear to be damaged by the stimulation protocol. The mechanism underlying the long lasting contraction of intrapulmonary artery evoked by brief electrical stimuli remains to be elucidated.

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Subtypes of losartan‐sensitive angiotensin receptor in the rabbit pulmonary artery

Cited by 21 publications

References 6 publications

Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action

Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action

Protective actions of des‐aspartate‐angiotensin I in mice model of CEES‐induced lung intoxication

Regional variation in electrically‐evoked contractions of rabbit isolated pulmonary artery

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