Ming-Guo Feng

Afferent arteriolar vasodilator effect of adenosine predominantly involves adenosine A2B receptor activation.

Adenosine is an important paracrine agent regulating renal vascular tone via adenosine A(1) and A(2) receptors. While A(2B) receptor message and protein have been localized to preglomerular vessels, functional evidence on the role of A(2B) receptors in mediating the vasodilator action of adenosine on afferent arterioles is not available. The present study determined the role of A(2B) receptors in mediating the afferent arteriolar dilation and compared the effects of A(2B) and A(2A) receptor blockade on afferent arterioles. We used the rat in vitro blood-perfused juxtamedullary nephron technique combined with videomicroscopy. Single afferent arterioles of Sprague-Dawley rats were visualized and superfused with solutions containing adenosine or adenosine A(2) receptor agonist (CV-1808) along with adenosine A(2B) and A(2A) receptor blockers. Adenosine (10 micromol/l) caused modest constriction and subsequent superfusion with SCH-58261 (SCH), an A(2A) receptor blocker, at concentrations up 10 micromol/l elicited only slight additional decreases in afferent arteriolar diameter with maximum effect at a concentration of 1 micromol/l (-11.0 +/- 2.5%, n = 6, P < 0.05). However, superfusion of adenosine-treated vessels with MRS-1754 (MRS), an A(2B) receptor blocker, elicited greater decreases in afferent arteriolar diameter (-26.0 +/- 4.7%, n = 5, P < 0.01). SCH did not significantly augment the adenosine-mediated afferent constriction elicited by MRS; however, adding MRS after SCH caused further significant vasoconstriction. Superfusion with CV-1808 dilated afferent arterioles (17.2 +/- 2.4%, n = 6, P < 0.01). This effect was markedly attenuated by MRS (-22.6 +/- 2.0%, n = 5, P < 0.01) but only slightly reduced by SCH (-9.0 +/- 1.1%, n = 5, P < 0.05) and completely prevented by adding MRS after SCH (-24.7 +/- 1.8%, n = 5, P < 0.01). These results indicate that, while both A(2A) and A(2B) receptors are functionally expressed in juxtamedullary afferent arterioles, the powerful vasodilating action of adenosine predominantly involves A(2B) receptor activation, which counteracts A(1) receptor-mediated vasoconstriction.

Angiotensin II-mediated constriction of afferent and efferent arterioles involves T-type Ca2+ channel activation.

Background/Aims: Previous studies have shown that L-type Ca2+ channel (LCC) blockers prevent the afferent arteriolar (AA) vasoconstriction elicited by angiotensin II (Ang II), but do not influence its vasoconstrictor effect on efferent arterioles (EA). The present study tested the hypothesis that Ang II-mediated constriction of AA and EA involves T-type Ca2+ channel (TCC) activation, which may mediate Ca2+ entry responsible for Ang II-induced EA and possibly AA constriction. Methods: Video-microscopic measurements of vascular dimensions were performed on isolated blood-perfused juxtamedullary nephrons from Sprague-Dawley rats. Single AA or EA were visualized and superfused with solutions containing Ang II alone or with a TCC blocker, pimozide, or a LCC blocker, diltiazem. Results: Pimozide at 10 µmol/l significantly dilated EA (19.7 ± 1.4%) as well as AA (24.8 ± 3.6%). In response to superfusion with Ang II at concentrations of 0.1, 1.0 and 10.0 nmol/l, AA diameter decreased significantly by 15.2 ± 1.7, 23.3 ± 3.2 and 36.1 ± 3.4% and EA diameter also decreased significantly by 11.9 ± 1.7, 19.6 ± 2.8 and 31.0 ± 2.6%, respectively. Pimozide (10 µmol/l) markedly blunted AA (4.6 ± 1.2, 7.5 ± 0.6 and 7.9 ± 1.2%) and EA (2.2 ± 0.6, 5.4 ± 1.5 and 7.7 ± 1.3%) diameter responses to Ang II. Diltiazem (10 µmol/l) significantly dilated AA (26.8 ± 2.2%), and prevented Ang II-mediated constriction of AA. In contrast, diltiazem did not dilate EA (3.3 ± 0.6%) and failed to inhibit the Ang II-induced EA vasoconstriction; however, the vasoconstriction was reversed by the subsequent addition of pimozide (5 µmol/l). Conclusion: This study provides further functional evidence for TCC channels in the regulation of AA and EA indicating that Ang II-mediated arteriolar constriction may involve activation of TCC in both AA and EA. TCC may play an important role in mediating Ca2+ entry responsible for Ang-induced EA and AA constriction. The role of TCC in mediating Ang II-constrictor actions on EA may be of particular significance because LCC are not normally functional in these vessels.

Adenosine A2 Receptor Activation Attenuates Afferent Arteriolar Autoregulation During Adenosine Receptor Saturation in Rats

Adenosine is an important paracrine agent regulating renal hemodynamics via adenosine A1 and A2 receptors. To determine the interactions between adenosine A1 and A2 receptors and the possible role of adenosine as a modulator of afferent arteriolar autoregulatory responses, videomicroscopic measurements of afferent arteriolar dimensions were performed at different perfusion pressures (from 100 to 125 and 150 mm Hg) using the isolated-blood–perfused rat juxtamedullary nephron preparation. Single afferent arterioles were visualized and superfused with low or high concentrations of adenosine, either alone or with the adenosine A1 receptor antagonist 8-noradamantan-3-yl-1,3-dipropylxanthine (10 μmol/L) or the adenosine A2 receptor antagonist dimethyl-1-propargylxanthine (10 μmol/L). Adenosine (20 μmol/L) decreased afferent arteriolar diameter by −9.0±0.9%, and this effect was enhanced by dimethyl-1-propargylxanthine (10 μmol/L) to −16.1±1.2%. However, autoregulatory capability was maintained. Adenosine-induced vasoconstriction was prevented by 8-noradamantan-3-yl-1,3-dipropylxanthine (10 μmol/L) with diameter increasing by 9.6±1.2%. Adenosine receptor saturation with a high concentration of adenosine (120 μmol/L) or blocking A1 receptors with 8-noradamantan-3-yl-1,3-dipropylxanthine in the presence of adenosine resulted in marked vasodilation and marked impairment of autoregulatory responses to increases in perfusion pressure (−1.5±1.1% and −3.5±0.9%). However, afferent arteriolar autoregulatory responses to elevations in perfusion pressure were restored after blockade of A2 receptors alone or in combination with A1 receptor blockade. During treatment with dimethyl-1-propargylxanthine in the presence of adenosine receptor saturation (120 μmol/L), afferent arteriolar autoregulatory responses were intact (−16.5±1.6% and −26.4±2.1%). These results indicate that the interactions between adenosine A1 and A2 receptors exert important modulatory influences on afferent arteriolar tone and autoregulatory capability. Activation of A2 receptors abrogates the counteracting influences of A1 receptors leading to marked vasodilation and decreased afferent arteriolar autoregulatory efficiency.