Cardiovascular and Renal Effects of Blocking A1 Adenosine Receptors

Kuan, Chia-Jen; Herzer, William A.; Jackson, Edwin K.

doi:10.1097/00005344-199305000-00020

Cited by 43 publications

(31 citation statements)

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“…In the present study, we did not detect an effect of DPSPX on arterial blood pressure, renal perfusion, or glomerular filtration. Because DPSPX is an adenosine receptor blocker (Daley and Jacobson, 1995) and because blockade of A 1 adenosine receptors reproducibly increases urine volume and sodium excretion (Kuan et al, 1993), it is not surprising that in the current study, DPSPX caused a large initial increase in urine volume and sodium excretion. However, as has been noted previously, diuretic breaking occurs quickly following A 1 receptor blockade (Bak and Thomsen, 2004); therefore, with time, we observed a gradual return of urine volume and sodium excretion to basal values.…”

Section: Discussionmentioning

confidence: 55%

The Extracellular cAMP-Adenosine Pathway Significantly Contributes to the in Vivo Production of Adenosine

Jackson

Mi²,

Dubey³

2006

J Pharmacol Exp Ther

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The extracellular cAMP-adenosine pathway is the cellular egress of cAMP followed by extracellular conversion of cAMP to adenosine by the sequential actions of ecto-phosphodiesterase and ecto-5Ј-nucleotidase. Although detailed studies in isolated organs, tissues, and cells provide evidence for an extracellular cAMP-adenosine pathway, whether this mechanism contributes significantly to adenosine production in vivo is unclear. 1,3-Dipropyl-8-p-sulfophenylxanthine is restricted to the extracellular compartment due to a negative charge at physiological pH and, at high concentrations (Ն0.1 mM), blocks ecto-phosphodiesterase. Here, we show that administration of 1,3-dipropyl-8-p-sulfophenylxanthine at a dose that provided concentrations in plasma and urine of approximately 0.3 and 6 mM, respectively, inhibited urinary adenosine excretion. In Sprague-Dawley rats i.v., 1,3-dipropyl-8-p-sulfophenylxanthine (10 mg ϩ 0.15 mg/min) significantly decreased by 48 and 39% the urinary excretion of adenosine (from 3.57 Ϯ 0.38 to 1.87 Ϯ 0.14 nmol/30 min; p ϭ 0.0003) and the ratio of urinary adenosine to cAMP (from 0.93 Ϯ 0.08 to 0.57 Ϯ 0.06; p ϭ 0.0044), respectively, without altering blood pressure, renal blood flow, or glomerular filtration rate. Although 1,3-dipropyl-8-p-sulfophenylxanthine transiently increased urine volume and sodium excretion, these effects subsided, yet adenosine excretion remained reduced. Thus, changes in systemic and renal hemodynamics and excretory function could not account for the effects of 1,3-dipropyl-8-p-sulfophenylxanthine on adenosine excretion. Additional experiments showed that 1,3-dipropyl-8-p-sulfophenylxanthine, as in Sprague-Dawley rats, significantly attenuated adenosine excretion and the ratio of urinary adenosine to cAMP in both Wistar-Kyoto rats and spontaneously hypertensive rats. We conclude that the extracellular cAMPadenosine pathway significantly contributes to the in vivo production of adenosine.

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Section: Discussionmentioning

confidence: 55%

The Extracellular cAMP-Adenosine Pathway Significantly Contributes to the in Vivo Production of Adenosine

Jackson

Mi²,

Dubey³

2006

J Pharmacol Exp Ther

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“…Selective A 1 receptor blockade has also demonstrated a physiological role for adenosine in the control of tubular function. 9 A 1 adenosine receptor blockade seems to directly impact the proximal and distal tubules, increasing Na ϩ excretion. 10 At the distal tubule, this could lead to a potassium-neutral natriuresis, as was demonstrated in this study.…”

Section: Possible Mechanism Of Actionmentioning

confidence: 99%

BG9719 (CVT-124), an A ₁ Adenosine Receptor Antagonist, Protects Against the Decline in Renal Function Observed With Diuretic Therapy

et al. 2002

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Background-Adenosine may adversely affect renal function via its effects on renal arterioles and tubuloglomerular feedback, but effects of adenosine blockade in humans receiving furosemide and ACE inhibitors is unknown. Methods and Results-This was a randomized, double-blind, ascending-dose, crossover study evaluating 3 doses of BG9719 in 63 patients with congestive heart failure. Patients received placebo or 1 of 3 doses of BG9719 on 1 day and the same medication plus furosemide on a separate day. Renal function and electrolyte and water excretion were assessed. BG9719 alone caused an increase in urine output and sodium excretion (PϽ0.05). Although administration of furosemide alone caused a large diuresis, addition of BG9719 to furosemide increased diuresis, which was significant at the 0.75-g/mL concentration. BG9719 alone improved glomerular filtration rate (GFR) at the 2 lower doses. Furosemide alone caused a decline in GFR. When BG9719 was added to furosemide, however, creatinine clearance remained at baseline at the 2 lower doses. Conclusions-In patients with congestive heart failure on standard therapy, including ACE inhibitors, BG9719 increased both urine output and GFR. In these same patients, furosemide increased urine output at the expense of decreased GFR. When BG9719 was given in addition to furosemide, urine volume additionally increased and there was no deterioration in GFR. A 1 adenosine antagonism might preserve renal function while simultaneously promoting natriuresis during treatment for heart failure.

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“…It seems that in the rat, the renal hemodynamic effect of CAI is mediated independently of either adenosine's actions at the A1AR or angiotensin's actions at the AT1 receptor. (Knight et al, 1993;Kuan et al, 1993). Natriuretic responses to A1AR antagonists were previously shown to be accompanied by increased fractional excretion of lithium (Knight et al, 1993) and decreased fluid reabsorption in the PT (Wilcox et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Adenosine A1 Receptor Antagonist Blunts Urinary Potassium Excretion, but Not Renal Hemodynamic Effects, Induced by Carbonic Anhydrase Inhibitor in Rats

Zhou¹,

Kost²

2005

J Pharmacol Exp Ther

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Acetazolamide (AZ) is a carbonic anhydrase inhibitor with diuretic actions at the proximal tubule. Clinical use of AZ is limited, in part, because of the urinary potassium loss and decrease of renal hemodynamic function that accompanies the drug. There is recent interest in A1 adenosine receptor (A1AR) antagonists, a novel class of diuretic agents that do not cause loss of potassium or tubuloglomerular feedback-(TGF) mediated reductions of renal hemodynamics. We tested whether the A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) could attenuate the adverse effects normally associated with use of AZ. Renal blood flow (RBF) and urine output were measured during two consecutive 40-min periods in anesthetized rats. In the first period, vehicle or DPCPX was infused. DPCPX alone increased urine output and sodium excretion but did not significantly alter potassium output or RBF. In the second period, the initial infusion of vehicle or DPCPX was continued, and either AZ or its vehicle was administered. AZ alone increased urinary excretion of both sodium and potassium and decreased RBF. DPCPX significantly attenuated the AZ-induced increase of potassium excretion by 50% but did not blunt the renal hemodynamic response to AZ. In a separate study, angiotensin II type 1 (AT1) receptor blockade also failed to blunt the renal hemodynamic response to AZ. In summary, A1AR antagonists may be useful diuretic agents alone or in combination with other conventional diuretic agents. The decrease of RBF that occurred in response to carbonic anhydrase inhibition was not attenuated by either A1AR blockade or AT1 receptor blockade and does not seem to be mediated by a TGF-dependent mechanism.Diuretics are recommended as first-line therapy for the treatment of edema and hypertension (Chobanian et al., 2003). However, a recent and controversial epidemiologic report outlined data linking diuretic use to the incidence of end-stage renal disease (Hawkins and Houston, 2005). The effect, if true, may be a consequence of potential detrimental effects of diuretics on GFR and RBF, which could augment the progression of pre-existing renal disease.In addition, diuretic-induced alterations of renal hemodynamics limit the efficacy of these agents. For example, carbonic anhydrase inhibition (CAI) attenuates sodium reabsorption in the proximal tubule (PT), resulting in a diuretic effect; however, the diuretic effect is self-limiting, in part, because of a marked decrease in the GFR and RBF. The CAI-induced decreases of GFR and RBF are believed to be mediated through activation of tubuloglomerular feedback (TGF) (Tucker et al., 1978). An increase of sodium chloride delivery to tubular macula densa cells, as occurs after inhibition of proximal sodium reabsorption, stimulates the release of a putative chemical mediator that induces vasoconstriction of the adjacent afferent arteriole. An increase of resistance in the afferent arteriole reduces GFR and RBF, resulting in decreased filtration of sodium into the tubular lumen of that nephron, ...

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Cardiovascular and Renal Effects of Blocking A1 Adenosine Receptors

Cited by 43 publications

References 0 publications

The Extracellular cAMP-Adenosine Pathway Significantly Contributes to the in Vivo Production of Adenosine

The Extracellular cAMP-Adenosine Pathway Significantly Contributes to the in Vivo Production of Adenosine

BG9719 (CVT-124), an A ₁ Adenosine Receptor Antagonist, Protects Against the Decline in Renal Function Observed With Diuretic Therapy

Adenosine A1 Receptor Antagonist Blunts Urinary Potassium Excretion, but Not Renal Hemodynamic Effects, Induced by Carbonic Anhydrase Inhibitor in Rats

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Cardiovascular and Renal Effects of Blocking A1 Adenosine Receptors

Cited by 43 publications

References 0 publications

The Extracellular cAMP-Adenosine Pathway Significantly Contributes to the in Vivo Production of Adenosine

The Extracellular cAMP-Adenosine Pathway Significantly Contributes to the in Vivo Production of Adenosine

BG9719 (CVT-124), an A 1 Adenosine Receptor Antagonist, Protects Against the Decline in Renal Function Observed With Diuretic Therapy

Adenosine A1 Receptor Antagonist Blunts Urinary Potassium Excretion, but Not Renal Hemodynamic Effects, Induced by Carbonic Anhydrase Inhibitor in Rats

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BG9719 (CVT-124), an A ₁ Adenosine Receptor Antagonist, Protects Against the Decline in Renal Function Observed With Diuretic Therapy