Effects of adenosine receptor antagonists on the responses to contrast media in the isolated rat kidney

Abstract

Contrast media can induce both a decrease in renal blood flow and a reduction in glomerular filtration rate (GFR) when administered to both experimental animals and humans. In the present study we have examined the role of adenosine in mediating these effects using the isolated perfused rat kidney. Kidneys were perfused with a 6. 7%-(w/v)-albumin-based perfusate supplemented with glucose and amino acids (n=6 per group). They were exposed to diatrizoate [20 mg of iodine (mgI)/ml; osmolality 1650 mOsm/kg of water] or iotrolan (20 mgI/ml; osmolality 320 mOsm/kg of water) in the presence or absence of theophylline (10.8 microg/ml), or to diatrizoate in the presence or absence of a specific adenosine A(1) receptor antagonist (KW-3902; 2 microg/ml) or a specific A(2) receptor antagonist (KF17837; 6 microg/ml). Diatrizoate (n=6) produced a fall in GFR from 0.65+/-0.04 to 0.42+/-0.03 ml.min(-1).g(-1) (P<0.05); renal perfusate flow (RPF) also declined, from 36.5+/-3.8 to 22.0+/-3.2 ml. min(-1).g(-1) (P<0.05). Iotrolan (n=6) produced a fall in GFR from 0. 64+/-0.02 to 0.48+/-0.04 ml.min(-1).g(-1) (P<0.05) and in RPF from 33.3+/-3.8 to 24.0+/-3.0 ml.min(-1).g(-1) (P<0.05). Theophylline (10.8 microg/ml) prevented the fall in GFR caused by either diatrizoate (baseline, 0.63+/-0.05 ml.min(-1).g(-1); diatrizoate+theophylline, 0. 60+/-0.04 ml.min(-1).g(-1)) or iotrolan (baseline, 0.64+/-0.04 ml. min(-1).g(-1); iotrolan+theophylline, 0.67+/-0.05 ml.min(-1).g(-1)), but did not affect the decreases in RPF caused by either agent. KW-3902 (2 microg/ml) also prevented the fall in GFR produced by diatrizoate (baseline, 0.66+/-0.05 ml.min(-1).g(-1); diatrizoate+KW-3902, 0.61+/-0.05 ml.min(-1).g(-1)), while the fall in RPF remained unaffected. KF17837 (6 microg/ml) had no effect on the decreases in either GFR or RPF induced by diatrizoate (n=6 per group). The results suggest a role for adenosine acting at the A(1) receptor in mediating the decrease in GFR induced by contrast media. This effect is independent of a change in renal vascular resistance, and possibly secondary to mesangial cell contraction causing a decrease in the ultrafiltration coefficient.

Adenosine A1 receptors in contrast media-induced renal dysfunction in the normal rat

“…In pilot experiments (unpublished observations), we have used a combination of a selective adenosine A 1 -receptor antagonist (DPCPX) and a selective endothelin ET-A receptor antagonist (BQ123) prior to CM injection, but this did not either prevent the CM-induced hypoperfusion. The results are in line with those of Oldroyd et al [13] showing that CM-induced depression in renal plasma flow is not attributable to adenosine. The CM-induced reduction in GFR was in that study shown to be mediated by adenosine independent of a change in vascular resistance and possibly secondary to mesangial cell contraction.…”

“…The CM may directly stimulate renal vasoconstrictor receptors, release renal vasoconstrictors, inhibit renal vasodilators, induce formation of oxygen-derived free radicals or change physical factors. Some of the factors potentially involved are: the renin-angiotensin system [17]; prostaglandins [18]; calcium [19]; nitric oxide [20]; and adenosine [13,14,16,21]. Furthermore, the high osmolarity [22] and the viscosity [23] of the CM have an effect on renal haemodynamics which may include changes in renal interstitial pressure.…”

“…Recently, Oldroyd et al [13] showed, in an isolated perfused kidney model, that the selective adenosine A 1 -receptor antagonist KW-3902 prevented the decrease in GFR induced by the high osmolar CM diatrizoate but did not prevent the decrease in total renal blood flow. Arakawa et al [14] confirmed these results in an in vivo model where the decrease in GFR and total renal blood flow could be ameliorated with the non-selective adenosine receptor antagonist theophylline or the selective A 1 -receptor antagonist .…”

Contrast Medium-Induced Nephropathy

“…Adenosine is an important intrarenal mediator, which can induce a decrease in the glomerular filtration rate through vasoconstriction of the afferent arterioles and contraction of the mesangial cells of the glomeruli (Oldroyd et al 2000). Adenosine also induces vasoconstriction in the renal cortex and vasodilatation in the renal medulla, increases the generation of oxygen-free radical cells, and is a mediator of the tubuloglomerular feedback (TGF) response.…”

Potential mechanisms behind contrast medium-induced nephropathy

“…Moreover, the general reduction in renal plasma flow and GFR caused by CM is not attributable to enhanced adenosine action. 60 CM can also have direct cytotoxic effects on renal tubular cells. A perturbation of mitochondrial enzyme activity and mitochondrial membrane potential is found under ex vivo conditions in a proximal tubule cell line.…”