Renal haemodynamic responses to exogenous and endogenous adenosine in conscious dogs

Abstract

1. Adenosine has been suggested to be the mediator of a metabolic feedback mechanism which transfers acute changes in the tubular load into opposite changes in renal blood flow (RBF). The goal of the present experiments was to assess the importance of endogenously formed adenosine as a 'homeostatic metabolite' during short-term changes in metabolic demand. 2. In nine chronically instrumented conscious foxhounds, both the direct effects of adenosine injections (10, 30 and 100 nmol) into the renal artery and the temporal changes of RBF after short renal artery occlusions (15, 30 and 60 s duration), the most widely used experimental model to study the metabolic feedback mechanism in vivo, were studied. 3. Intrarenal bolus injections of adenosine (10, 30 and 100 nmol) induced dose-dependent decreases of RBF (RBF: -34 +/- 5, -59 +/- 4 and -74 +/- 4 %, respectively). This vasoconstrictor effect of adenosine was significantly larger (RBF: -51 +/- 4, -68 +/- 4 and -83 +/- 3 %, respectively) when the dogs received a low salt diet. 4. The post-occlusive responses were characterized by a transient hyperaemia with no detectable drop of RBF below the preocclusion level. The post-occlusive responses were affected neither by changes in local angiotensin II levels, nor by intrarenal infusions of hypertonic NaCl or blockade of A1 adenosine receptors. 5. When intrarenal adenosine levels were elevated by infusion of the adenosine uptake inhibitor dipyridamole, a transient, although weak, post-occlusive vasoconstriction was detected. 6. In summary, the present data demonstrate that adenosine acts as a potent renal vasoconstrictor in the conscious dog. The endogenous production of adenosine during short-lasting occlusions of the renal artery, however, appears to be too small to induce a post-occlusive vasoconstrictor response of RBF. These results suggest that a metabolic feedback with adenosine as 'homeostatic metabolite' is of minor importance in the short-term regulation of RBF in the conscious, unstressed animal.

Figure 1. Illustration of the components of the renal adenosine system that were experimentally altered in the present study

Activation of smooth muscle A₁ adenosine receptors (site 1) elicits a vasoconstrictor response of the afferent arteriole which is synergistically modulated by angiotensin II via AT₁ receptors (site 2). Renal interstitial adenosine levels are elevated during an increased ATP/ADP breakdown (sites 3 and 4). A major pathway for the removal of adenosine from the interstitial space occurs via the nucleoside transporter (NT; site 5). A₁ adenosine receptors are blocked by the specific receptor antagonist DPCPX. The nucleoside transporter is inhibited by dipyridamole.

Figure 6. Effects of complete occlusions of the renal artery for 60 s on RBF in a single, salt-depleted dog

Illustrated are the responses during control conditions, during an intrarenal infusion of the A₁ adenosine receptor antagonist DPCPX (10 μg kg⁻¹ bolus plus 10 μg kg⁻¹ min⁻¹), and during an intrarenal infusion of the nucleoside transport inhibitor dipyridamole (0.2 mg kg⁻¹ bolus plus 10 μg kg⁻¹ min⁻¹). The dashed lines indicate pre-occlusion levels of mean RBF.

Figure 2. Effects of intrarenal injections of adenosine on arterial blood pressure (ABP) and renal blood flow (RBF) in a single dog

Adenosine was intrarenally injected at doses of 10, 30 and 100 nmol. In the lower traces, pulsatile and mean RBF (dots) are displayed.

Figure 3. Influence of different salt diets on the vasoconstrictor action of exogenous adenosine

Depicted are the effects of intrarenal bolus injections of adenosine (10, 30 and 100 nmol) on mean RBF in 7 conscious dogs maintained on either a normal (○) or a low (•) sodium diet. * P < 0.05vs. normal sodium diet. Values represent means ± s.e.m.

Figure 4. Blockade of adenosine-induced renal vasoconstriction by DPCPX

Depicted are the effects of intrarenal bolus injections of adenosine (10, 30 and 100 nmol) on mean RBF in 6 sodium-restricted conscious dogs without (•) or with infusion of the A₁ adenosine receptor antagonist DPCPX (10 μg kg⁻¹ bolus plus 10 μg kg⁻¹ min⁻¹; □). * P < 0.05vs. control conditions. Values represent means ± s.e.m.

Figure 5. Effects of angiotensin II on the post-occlusive response of RBF

Different angiotensin II levels were achieved by either maintaining the dogs on a normal (○; n = 8) or a low (•; n = 9) sodium diet, or by an intrarenal infusion of angiotensin II (1 ng kg⁻¹ min⁻¹) in dogs on a normal sodium diet (▵; n = 7). Values represent means ± s.e.m. The dashed line indicates no change from pre-occlusion level of mean RBF.

Figure 7. Effects of alterations of the adenosine system on the post-occlusive responses of RBF

Shown are the responses during control conditions (•; n = 9), during an intrarenal infusion of DPCPX (10 μg kg⁻¹ bolus plus 10 μg kg⁻¹ min⁻¹; □; n = 8), and during an intrarenal infusion of dipyridamole (0.2 mg kg⁻¹ bolus plus 10 μg kg⁻¹ min⁻¹; ⋄; n = 4) in conscious, salt-depleted dogs. * P < 0.05vs. control conditions. Values represent means ± s.e.m. The dashed line indicates no change from pre-occlusion level of mean RBF.

Figure 8. Effects of intrarenal infusions of hypertonic NaCl on the post-occlusive responses of RBF

Illustrated are the responses before (•) and during infusion of 1 M NaCl into the renal artery (▿) in 4 conscious, salt-depleted dogs. Values represent means ± s.e.m. The dashed line indicates no change from pre-occlusion level of mean RBF.