Regional vascular responses to ATP and ATP analogues in the rabbit kidney in vivo: roles for adenosine receptors and prostanoids

Abstract

Background and purpose: Our knowledge of the effects of P2-receptor activation on renal vascular tone comes mostly from in vitro models. We aimed to characterise the pharmacology of ATP in the renal circulation in vivo.

Experimental approach: In pentobarbitone anaesthetized rabbits, we examined total renal and medullary vascular responses to ATP (0.2 and 0.8 mg kg(-1)), beta, gamma-methylene ATP (beta, gamma-mATP, 7 and 170 microg kg(-1)), alpha, beta-mATP (0.2 and 2 microg kg(-1)) and adenosine (2 and 6 microg kg(-1)) using transit-time ultrasound and laser Doppler flowmetry, respectively. We also determined whether adenosine receptors, NO or prostanoids contribute to the actions of the purinoceptor agonists.

Key results: Renal arterial boluses of ATP, beta,gamma-mATP, and adenosine produced biphasic changes; ischaemia followed by hyperaemia, in total renal and medullary blood flow. alpha,beta-mATP induced only ischaemia. The adenosine receptor antagonist 8-(p-sulphophenyl)theophylline reduced the responses to adenosine and the hyperaemic responses to ATP and beta,gamma-mATP only. NO synthase inhibition (Nomega-nitro-L-arginine) did not significantly alter responses to the P2 receptor agonists. Subsequent cyclooxygenase inhibition (ibuprofen) reduced the ATP- and beta, gamma-mATP-induced increases in renal blood flow. All other responses remained unchanged.

Conclusions and implications: In the rabbit kidney in vivo, alpha, beta-mATP sensitive receptors mediate vasoconstriction. beta,gamma-mATP and ATP induce vasodilation at least partly through adenosine receptors. ATP induced renal vasodilatation is independent of NO and partly dependent on prostanoids in the bulk of the kidney, but not in the vasculature controlling medullary blood flow.

Figure 1

Schematic diagram of our current understanding of the receptors activated within the renal vasculature following intraluminal administration of ATP, α,β-methyleneATP (α,β-mATP), β,γ-methyleneATP (β,γ-mATP) or adenosine. SM, smooth muscle; E, endothelium; L, lumen; 8-SPT, 8-(p-sulphophenyl)theophylline. Solid arrows indicate possible receptor activation. Dotted arrows indicate receptor antagonism. The unfilled arrow represents metabolism of ATP to adenosine. β,γ-mATP, but not α,β-mATP, can also directly activate adenosine A₂ receptors (not shown).

Figure 2

Typical arterial pressure and renal haemodynamic responses to an intrarenal bolus of ATP (0.8 mg kg⁻¹). Dotted line indicates time of injection.

Figure 3

Renal haemodynamic responses to intrarenal bolus administration of ATP before and during administration of 8-SPT (n=4). The symbols and error bars represent the mean ±s.e. of peak increases (above the zero line) and peak decreases (below the zero line) of each variable. P_treatment values represent the outcomes of analysis of variance, testing for effects of 8-SPT treatment on the responses to ATP.

Figure 4

Typical renal haemodynamic responses to an intrarenal arterial bolus of saline (154 mM NaCl, 0.03 ml kg⁻¹). Dotted lines indicate time of bolus administration.

Figure 5

Typical renal haemodynamic responses to intrarenal boluses of (a) β,γ-mATP (170 μg kg⁻¹) and (b) α,β-mATP (2 μg kg⁻¹). Dotted lines indicate time of injection.

Figure 6

Renal haemodynamic responses to intrarenal bolus administration of β,γ-mATP before and during administration of 8-SPT (n=4). The symbols, error bars and P-values are as for Figure 3.

Figure 7

Typical renal haemodynamic responses to an intrarenal bolus of adenosine (6 μg kg⁻¹). Dotted line indicates time of injection.

Figure 8

Renal haemodynamic responses to intrarenal boluses administration of adenosine before and during administration of 8-SPT (n=4). The symbols, error bars and P-values are as for Figure 3.

Figure 9

Renal haemodynamic responses to intrarenal bolus administration of ATP before and during administration of L-NNA, L-NNA plus ibuprofen (ibu) or vehicle treatment (n=5 per group). The columns and error bars represent the mean ±s.e. of peak increases (above the zero line) and peak decreases (below the zero line) of each variable. The asterisk denotes a significant (P<0.05) interaction between group and treatment as determined by analysis of variance. This interaction term tested whether the effects of ibuprofen infusion on responses to ATP differed from those of the corresponding vehicle.