ARTICLE

TOP ARTICLE REFERENCES

SCHNERMANN MAKES several strong points in his article "Adenosine mediates tubuloglomerular feedback responses" (19). We completely agree that the data provided by two independent laboratories demonstrating that tubuloglomerular feedback (TGF) responses to increases in distal perfusion rate are not observed in adenosine A₁-receptor-deficient mice are consistent with the hypothesis that the adenosine A₁ receptor plays a critical role in maintaining the integrity of the TGF mechanism (2, 21). However, we wish to emphasize that there are other observations that are not consistent with the hypothesis that adenosine is released from the macula densa cells into the interstitium in response to increases in distal flow and signals the glomerular microvasculature to cause selective afferent arteriolar vasoconstriction.

As indicated by Schnermann, the TGF mediator must exert selective actions on preglomerular arterioles (11, 12, 16). However, several studies demonstrated that adenosine or adenosine agonists evoke both afferent and efferent arteriolar constriction (3, 4, 7, 13). The response is complex because adenosine also causes afferent and efferent vasodilation via A₂ receptors. As the concentration of adenosine increases, the vasodilatory stimulus becomes predominant (7, 13). It is also recognized that TGF-mediated changes in afferent arteriolar resistance are sustained for long periods (12, 16, 23, 24). In contrast, adenosine elicits transient vasoconstriction in the kidney that spontaneously abates within a few minutes (1, 9, 12, 17, 22). Thus adenosine as the predominant TGF mediator would be in a precarious role, because its effects would wane as the TGF signal intensity increased. Also, the in situ hybridization studies cited, although demonstrating a significant expression of adenosine A₁ receptor in the vicinity of the juxtaglomerular apparatus (25), do not appear to clearly demonstrate that the receptors are selectively expressed in the preglomerular renal vasculature.

Schnermann points out that adenosine receptor antagonists interfere or block TGF responses (5, 8, 10, 20). However, these studies have shown that extremely high concentrations of adenosine A₁-receptor antagonists were required to inhibit the TGF response (5, 8, 10, 20). In some studies, systemic administrations of adenosine A₁-receptor antagonists fail to inhibit the TGF response (5, 8, 10).

Another critical issue involves the role of adenosine in mediating renal autoregulatory responses. Because the TGF mechanism participates in the autoregulatory responses of the arteriolar vasculature to changes in perfusion pressure, it follows that the mediator of the TGF mechanism must also contribute to the changes in renal vascular resistance (RVR) associated with autoregulatory responses (12, 16). However, the data have failed to show that adenosine A₁-receptor antagonists impair renal autoregulatory responses. Ibarrola et al. (6) and others (12, 18) demonstrated that adenosine receptor antagonists do not elicit any perceptible effects on renal blood flow and glomerular filtration rate autoregulatory responses to changes in renal arterial pressure. More recently, we performed experiments using the juxtamedullary nephron preparation to determine if afferent arteriolar responses to increasing renal perfusion pressure are impaired by selective blockade of adenosine A₁ receptors (Nishiyama et al., unpublished data). We used a highly selective adenosine A₁-receptor antagonist, 8-noradamantan-3-yl-1,3-dipropylxanthine (KW-3902, 10 µmol/l), which prevents afferent arteriolar vasoconstriction induced by exogenously administered adenosine (13). Basal afferent arteriolar diameter at 100 mmHg averaged 16.0 ± 1.1 µm (n = 5), and the vasoconstrictor responses to increasing perfusion pressure to 135 and 170 mmHg averaged 8.3 ± 1.1 and 17 ± 2.2%, respectively. Neither basal diameters nor vasoconstrictor responses to the increase in perfusion pressure were altered after treatment with KW-3902 (135 mmHg: 8.2 ± 1.4% and 170 mmHg: 19.5 ± 2.8%). The absence of any effect of adenosine receptor blockade on autoregulatory responses suggests that either the TGF mechanism is not involved in mediating autoregulatory responses or that adenosine is not the TGF mediator.

As previously described (16), the single most important criterion distinguishing between the mediator and modulators is that there should be a direct relationship between the change in the macula densa stimulus and the change in the release or concentration of the TGF mediator associated with the change in RVR. In our recent studies evaluating the renal interstitial concentrations of adenosine and ATP, we demonstrated that renal interstitial adenosine concentrations remain stable within the autoregulatory range and do not show any significant relationship with either the autoregulatory or TGF-related changes in RVR (14, 15). In contrast, ATP clearly demonstrated such a relationship as discussed in the initial essay (16).

In summary, the collective data obtained in different laboratories using various approaches support the concept that adenosine serves as an important modulator rather than mediator of the TGF mechanism. We emphasize, however, that we clearly recognize the importance of the recent elegant work reported by Schnermann in demonstrating that the adenosine A₁ receptors are an essential component needed for the manifestation of TGF responses.