N-0861 selectively antagonizes adenosine A1 receptors in vivo

Barrett, Richard J.; Droppleman, David A.; Wright, Kathryn F.

doi:10.1016/0014-2999(92)90202-f

Cited by 10 publications

(7 citation statements)

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“…However, such a slight a decrease in blood pressure would most likely not trigger renin release and sympathetic reflexes to an extent that would have influenced the rates of urine and electrolyte excretion. The higher dose (30 pmol/kg) did not reduce MAP in these experiments, nor has N-0861 reduced blood pressure over a wide dose range in several species [Barrett et al, 1992;Wesley et al, 1993;Pelleg and Hurt, 1992;Sidi et al, 1994;Nagashima et al, 19941. Adenosine is known to constrict afferent arte-rioles and to dilate efferent arterioles via activation of adenosine A, and A, receptors, respectively [Spielman and Arend, 19911. It is possible that antagonizing A, receptors with N-0861 may alter intrarenal hemodynamics and interstitial pressure, and thus may indirectly contribute to the observed diuresis/iiatriuresis.…”

Section: Disc U Ssi 0 Nmentioning

confidence: 60%

“…N6-endonorbornan-2-yl-9-methyladenine) was a specific and > 100-fold selective antagonist at adenosine A, receptors that had only weak phosphodiesterase inhibitory activity [May et al, 19911. N-0861 antagonized the negative dromotropic, chroriotropic, and inotropic effects of A,-receptor stimulation in isolated guinea pig hearts and atria, but failed to effect A,-receptor mediated coronary vasodilation or aortic relaxation [Shryock et al, 1992;Martin et al, 19931. In vivo, N-0861 selectively antagonized adenosine A,receptor mediated events (bradycardia, negative dromotropism, and post-defibrillation cardiovascular depression) without altering A,-receptor mediated vasodilation in rats, dogs, pigs, and humans [Barrett et al, 1992;Wesley et al, 1993;Pelleg and Hurt, 1992;Sidi et al, 1994;Nagashima et al, 19943. The present studies were conducted to determine the renal hemodynamic and excretory responses to N-0861 in rats.…”

Section: Introductionmentioning

confidence: 99%

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Renal hemodynamic and excretory effects of n‐0861, a non‐xanthine adenosine A₁‐receptor antagonist

Barrett¹,

Wright²,

Droppleman³

1994

Drug Development Research

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I Strategy, Management and Health Policy I ABSTRACTThe renal hemodynarnic and excretory effects of intravenous N-0861, a non-xanthine adenosine A,-receptor antagonist, were evaluated in conscious and anesthetized male SpragueDawley rats. In conscious rats, N-0861 (10, 30 pmol/kg, iv) significantly increased the excretion of urine, Na+, and K + ; U, , V was increased only in the rats treated with 10 FmoVkg, N-0861. The relative excretion of K + was similar to that of Na*. Lower doses of N-0861 (1,3 Fmol/kg, iv) had no effect. During clearance studies in anesthetized rats, N-0861 (3, 10, 30 pmollkg, iv) had little effect on systemic or renal hemodynamics, but provoked significant saluresis that was poorly related to dose, and that was characterized by a somewhat greater excretion of Na+ and CI-relative to K + .These results indicate that the selective adenosine A, receptor antagonist N-0861 has little influence on resting renal hernodynamics and suggest that the natriuretic responses are due to inhibition of tubular Na ' reabsorption. o

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Section: Disc U Ssi 0 Nmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Renal hemodynamic and excretory effects of n‐0861, a non‐xanthine adenosine A₁‐receptor antagonist

Barrett¹,

Wright²,

Droppleman³

1994

Drug Development Research

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“…N‐0861 (10 −5 M ), a relatively A 1 selective antagonist (Barrett et al ., 1992) did not produce any significant ( P >0.05) effect on the contractile response to phenylephrine (10 −7 M ) in WKY and SHR tissues and abolished the contractions elicited by ENBA (Figure 2A), R‐PIA and CPA. R‐PIA produced a concentration‐dependent relaxant response in endothelium‐intact aortic rings from SHR (Figure 3A,C).…”

Section: Resultsmentioning

confidence: 99%

“…Concentration‐response curves to ENBA, CAD, R‐PIA, and CGS‐21680 were carried out in endothelium‐intact and‐denuded rings from SHR and WKY aortae. Concentration‐response curves to ENBA, CPA and R‐PIA were also carried out following the treatment of endothelium‐intact tissues with N‐0861, an adenosine A 1 receptor antagonist (Barrett et al ., 1992), indomethacin (cyclo‐oxygenase inhibitor), superoxide dismutase plus catalase and deferoxamine (free radical scavengers) and dilazep (an adenosine uptake inhibitor). Concentration‐response curves to adenosine analogues were also carried out in endothelium‐intact rings from SHR and WKY before and after treating the tissues with DMPX (10 −5 M), an adenosine A 2 receptor antagonist (Vangalen et al ., 1992).…”

Section: Methodsmentioning

confidence: 99%

Evidence for the presence of A₁ adenosine receptors in the aorta of spontaneously hypertensive rats

Fahim

Mustafa

2001

British J Pharmacology

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1 Isolated aortic rings (endothelium-intact and -denuded) from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats were used in this study to examine the vasoactive e ects of various adenosine analogues. 2 In phenylephrine contracted aortic rings, concentration-response curves were constructed by cumulative additions (10 711 ± 10 75 M) of (2S)-N 6 -[2-endo-Norbornyl] adenosine (ENBA), N 6 -cyclopentyladenosine (CPA), R-N 6 -(2-phenylisopropyl) adenosine (R-PIA), 2-p-(-2-carboxyethyl) phenethylamino-5'-N-thylcarboxamido adenosine (CGS-21680). 3 A non-speci®c adenosine receptor agonist 2-chloroadenosine (CAD) resulted in biphasic response with a small contraction at lower concentrations (10 79 ± 10 78 M) followed by a signi®cant relaxation at higher concentration in endothelium-intact SHR tissues, suggesting presence of both A 1 and A 2 adenosine receptors in SHR aorta. However, only relaxation was observed in WKY. 4 Contractile response in SHR had the following rank order of potency: ENBA4CPA4R-PIA4CAD. The relaxation response in SHR and WKY had the following rank order of potency: CGS 216804CAD4R-PIA4CPA4ENBA. 5 Removal of endothelium abolished the adenosine analogue induced contractions in SHR aorta and attenuated the vasorelaxation responses in the WKY and SHR. 6 The contractile response in SHR was abolished by A 1 adenosine receptor antagonist N 6 -endonorbornan-2-yl-9-methyladenine (N-0861). A 2 adenosine receptor antagonist, 3,7-dimethyl-1-proparglyxanthine (DMPX) did not a ect the contraction response of adenosine analogues. 7 Endothelium-dependent contractions elicited by A 1 receptor agonists were blocked by indomethacin and by free radical scavengers. 8 These data suggest that the contractile response to adenosine analogues in SHR aorta is probably mediated by free radicals which are generated through the increased cyclo-oxygenase activity occurring in the vascular endothelium of SHR but not the WKY rats.

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“…and catheters were implanted into the jugular vein and carotid artery for the administration of drugs and for measurement of arterial blood pressure, respectively, and exteriorized at the nape of the neck. Rats were tethered to swivels that allowed free movement about their cages while continuously recording blood pressure and heart rate [Barrett et al, 1992]. Bolus doses of MRE-0470 (0.04-117 µg/kg) were administered i.v.…”

Section: Administration Of Bolus Injections Vs Continuous Infusions mentioning

confidence: 99%

Pharmacology and toxicology of the A2A-adenosine receptor agonist 2- [(cyclohexylmethylene)hydrazino]adenosine (MRE-0470) in the rat

et al. 1997

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2‐[(cyclohexylmethylene)hydrazino]adenosine (MRE‐0470) is an A2A‐adenosine receptor agonist that is a potent and selective coronary vasodilator. As part of a preclinical program, the pharmacology and toxicology of MRE‐0470 have been studied in the rat. In isolated vas deferens, MRE‐0470 activated A2A receptors (EC50 = 6.3 nM) and at higher concentrations activated A2B receptors (EC50 = 13 μM). In atrial tissues, MRE‐0470 produced negative inotropic and chronotropic actions through activation of A1 receptors (EC50 ˜ 9 μM). MRE‐0470 produced no positive inotropic or chronotropic actions in atrial or ventricular tissues. In anesthetized, reflex‐blocked rats, MRE‐0470 produced a decrease in hindquarter perfusion pressure (A2: ED50 = 0.31 μg) and a decrease in heart rate (A1: ED50 = 620 μg). In conscious rats, MRE‐0470 (0.04–117 μg/kg bolus or 0.03–150 μg/kg/min infusion) produced dose‐dependent hypotension and reflex tachycardia. MRE‐0470 was rapidly eliminated from rat plasma with an elimination half‐life of 10 min. In toxicology studies, once per day 10‐minute i.v. infusions of 3, 30, or 150 μg/kg/min MRE‐0470 for 14 consecutive days resulted in no deaths and no changes in blood chemistry, but resulted in decreased motor activity and dose‐related cardiomyopathy. Cardiomyopathy did not occur following single doses of MRE‐0470. The incidence of this lesion is related to the duration of the repeated reflex tachycardia. These studies show that MRE‐0470 is a potent and selective A2A receptor agonist in the rat. The observed toxicology of MRE‐0470 is consistent with the exaggerated pharmacology due to high‐dose drug administration. Drug Dev. Res. 42:76–85, 1997. © 1997 Wiley‐Liss, Inc.

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N-0861 selectively antagonizes adenosine A1 receptors in vivo

Cited by 10 publications

References 11 publications

Renal hemodynamic and excretory effects of n‐0861, a non‐xanthine adenosine A₁‐receptor antagonist

Renal hemodynamic and excretory effects of n‐0861, a non‐xanthine adenosine A₁‐receptor antagonist

Evidence for the presence of A₁ adenosine receptors in the aorta of spontaneously hypertensive rats

Pharmacology and toxicology of the A2A-adenosine receptor agonist 2- [(cyclohexylmethylene)hydrazino]adenosine (MRE-0470) in the rat

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N-0861 selectively antagonizes adenosine A1 receptors in vivo

Cited by 10 publications

References 11 publications

Renal hemodynamic and excretory effects of n‐0861, a non‐xanthine adenosine A1‐receptor antagonist

Renal hemodynamic and excretory effects of n‐0861, a non‐xanthine adenosine A1‐receptor antagonist

Evidence for the presence of A1 adenosine receptors in the aorta of spontaneously hypertensive rats

Pharmacology and toxicology of the A2A-adenosine receptor agonist 2- [(cyclohexylmethylene)hydrazino]adenosine (MRE-0470) in the rat

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Resources

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Renal hemodynamic and excretory effects of n‐0861, a non‐xanthine adenosine A₁‐receptor antagonist

Renal hemodynamic and excretory effects of n‐0861, a non‐xanthine adenosine A₁‐receptor antagonist

Evidence for the presence of A₁ adenosine receptors in the aorta of spontaneously hypertensive rats