Determinants of renal microvascular response to ACh: afferent and efferent arteriolar actions of EDHF

Abstract

The renal microvascular actions of ACh were investigated using the in vitro perfused hydronephrotic rat kidney. ACh reversed ANG II-induced vasoconstriction in the afferent and efferent arteriole by 106 ± 2 and 75 ± 5%, respectively. Inhibition of nitric oxide synthase [NOS; 100 μmol/l N G-nitro-l-arginine methyl ester (l-NAME)] and cyclooxygenase (COX; 10 μmol/l ibuprofen) prevented the sustained response of the afferent arteriole but did not reduce the magnitude of the initial dilation (97 ± 7%). However, NOS/COX inhibition abolished the response of the efferent arteriole. The underlying mechanisms mediating this endothelium-derived hyperpolarizing factor (EDHF)-like response were characterized using K channel blockers. Ba (100 μmol/l), tetraethylammonium (1 mmol/l), and ouabain (3 mmol/l) had no effect, arguing against a role of an inward rectifier K channel, large-conductance Ca-activated K channel, or Na,K-ATPase. Charybdotoxin (10 nmol/l) and apamin (1.0 μmol/l) attenuated the response when administered alone (63 ± 7% and 37 ± 5%, respectively) and abolished the response when coadministered (0.1 ± 1.0%). These findings indicate that, as in other vascular beds, the renal EDHF-like response to ACh involves K channels that are sensitive to a combination of apamin and charybdotoxin. Our finding that EDHF modulates preglomerular, but not postglomerular, tone is consistent with the evolving concept that vasomotor mechanisms in cortical efferent arterioles do not involve voltage-gated Ca entry.

Redundant signaling mechanisms contribute to the vasodilatory response of the afferent arteriole to proteinase-activated receptor-2

“…As shown, neither of these treatments was capable of eliminating the response to SLIGRL-NH 2 , although each treatment attenuated the response. In concert with our previous observations (43,44), these findings suggest that the NO-independent response to SLIGRL-NH 2 involves a separate or an additional mechanism that is not seen with either acetylcholine or bradykinin.…”

“…We have previously characterized the nature of the EDHFlike responses of the afferent arteriole to acetylcholine (43) and bradykinin (44), and these findings along with the present results are summarized in Fig. 10.…”

“…We have observed NOindependent afferent arteriolar responses to both acetylcholine and bradykinin that exhibit similar temporal characteristics (43,44). In the case of acetylcholine, this EDHF-like response was fully abolished by combined treatment with charybdotoxin plus apamin (43), whereas with bradykinin, charybdotoxin plus apamin and the addition of either TEA or 17-ODYA was required to fully abolish the response (44). However, as shown in Fig.…”

“…Recent findings from our laboratory indicate that multiple pathways contribute to the afferent arteriolar responses attributed to EDHF, in that we observed distinct EDHF-like responses of this vessel to acetylcholine and bradykinin (43,44). The EDHF-like response to acetylcholine is fully abolished by the combined administration of charybdotoxin plus apamin (43), a treatment that eliminates EDHF responses in a wide variety of vessel types (reviewed in Refs.…”

“…The EDHF-like response to acetylcholine is fully abolished by the combined administration of charybdotoxin plus apamin (43), a treatment that eliminates EDHF responses in a wide variety of vessel types (reviewed in Refs. 11 and 28).…”