Renal Effects of Adenosine A1-Receptor Blockade with 8-Cyclopentyl-1,3-Dipropylxanthine in Hypoxemic Newborn Rabbits

Abstract

The key role of intrarenal adenosine in mediating the hypoxemic acute renal insufficiency in newborn rabbits has been well demonstrated using the nonspecific adenosine antagonist theophylline. The present study was designed to define the role of adenosine A 1 receptors during systemic hypoxemia by using the specific A 1 -receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Renal function parameters were assessed in 31 anesthetized and mechanically ventilated newborn rabbits. In normoxia, DPCPX infusion induced a significant increase in diuresis (ϩ44%) and GFR (ϩ19%), despite a significant decrease in renal blood flow (RBF) (Ϫ22%) and an increase in renal vascular resistance (RVR) (ϩ37%). In hypoxemic conditions, diuresis (Ϫ19%), GFR (Ϫ26%), and RBF (Ϫ35%) were decreased, whereas RVR increased (ϩ33%). DPCPX administration hindered the hypoxemia-induced decrease in GFR and diuresis. However, RBF was still significantly decreased (Ϫ27%), whereas RVR increased (ϩ22%). In all groups, the filtration fraction increased significantly. The overall results support the hypothesis that, in physiologic conditions, intrarenal adenosine plays a key role in regulating glomerular filtration in the neonatal period through preferential A 1 -mediated afferent vasoconstriction. During a hypoxemic stress, the A 1 -specific antagonist DPCPX only partially prevented the hypoxemiainduced changes, as illustrated by the elevated RVR and drop in RBF. These findings imply that the contribution of intrarenal adenosine to the acute adverse effects of hypoxemia might not be solely mediated via the A 1 receptor. Adenosine is ubiquitous in the kidney. Intrarenal adenosine vasoconstricts the preglomerular vessels via the A 1 receptors, while dilating the efferent arterioles via the A 2 receptors. It thus affects GFR as well as RBF and its distribution within the kidney. In addition to its vascular actions, intrarenal adenosine modulates renal mechanisms, including TGF, renin release, and the tubular handling of electrolytes and water. Intrarenal adenosine also appears to be an important hemodynamic mediator in some models of vasomotor nephropathy, such as those induced by intramuscular glycerol injection (1), contrast media (2), cisplatin (3), or hypoxemia (4).In animal models as in humans, hypoxemia can lead to functional renal insufficiency (5-7). In the newborn rabbit, acute normocapnic hypoxemia induces renal hypoperfusion with decreased GFR and RBF (4, 7-9). The underlying mechanism of this hypoxemia-induced vasomotor nephropathy still remains controversial. The chemoreceptor-mediated reflex and/or the activation of vasoactive factors such as angiotensin II (AII) (9), endothelin (10), nitric oxide (8), or bradykinin (11) have been suggested to play a role.We previously demonstrated that the administration of theophylline, a nonspecific antagonist to adenosine receptors, ameliorates the hypoxemia-induced renal hemodynamic changes seen in the newborn rabbit model (4). Moreover, in neonates with respiratory distress syndrome (12)

Beneficial effect of insulin-like growth factor-1 on hypoxemic renal dysfunction in the newborn rabbit

“…As we previously reported, acute normocapnic hypoxemia in newborn rabbits was associated with a significant increase in RVR and a concomitant decline in RBF, GFR, MAP and diuresis [3][4][5][6]25]. We formerly demonstrated that renal hypoperfusion has a vasomotor origin and that the underlying mechanisms involve the complex activation and interaction of vasoconstrictor and vasodilator factors acting on renal arterioles, including angiotensin II [5], adenosine [3,4], or NO [6].…”

“…All the methods have been described previously [3,5]. Briefly, the rabbits were anesthetized by intraperitoneal injection of 25 mg/kg body weight (BW) of sodium pentobarbital and were artificially ventilated via tracheotomy with an oxygen-enriched gas mixture (respiratory rate 40 breaths/min, tidal volume adjusted for age and weight).…”

“…From this point onward, all animals were given a constant infusion of a modified rabbit Ringer solution at a rate of 1 ml/h per 100 g BW [3,5].…”

“…We then induced acute hypoxemia (period Hx) over 30 min by reducing the fractional inspiratory oxygen concentration with a gas mixture of 1% oxygen (O 2 ) and 90% nitrogen (N 2 ), in order to reach a partial pressure of arterial oxygen (PaO 2 ) of approximately 40-50 mmHg [3,5]. Hypoxemia was maintained at the same PaO 2 level until the end of the experiment.…”

“…The pathophysiologic mechanisms of this vasomotor nephropathy involve numerous local and humoral vasoactive agents. Previous studies from our laboratory have demonstrated that hypoxemia induces an alteration in the balance of local vasomediators in the newborn rabbit's kidney, including the vasoconstrictors adenosine and angiotensin II [3][4][5], as well as the vasodilator nitric oxide (NO) [6].…”