Formation and actions of cyclic ADP-ribose in renal microvessels

Recent studies indicated that cyclic ADP-ribose (cADPR) serves as a second messenger for intracellular Ca2+ mobilization in a variety of mammalian cel ls. However, the metabolism and actions of cADPR in the renal vasculature a rt poorly understood. In the present study, we characterized the enzymatic pathway of the production and metabolism of cADPR along the renal vascular tree and determined the role of cADPR in the control of intracellular [Ca2] and vascular tone. The high performance liquid chromatographic analyses s howed that cADPR was produced and hydrolyzed along the renal vasculature. T he maximal conversion rare of nicotinamide guanine dinucleotide (NGD) into cyclic GDP-ribose (that represents ADP-ribosyl cyclase activity for cADPR f ormation) was 8.69 +/- 2.39 nmol/min/mg protein in bulk-dissected intrarena l preglomerular vessels (n = 7) and 4.35 +/- 0.13, 2.23 +/- 0.27, 2.40 +/- 0.19, and 0.31 +/- 0.02 nmol/min/mg protein, respectively, in microdissecte d arcuate arteries (n = 6), interlobular arteries (n = 6), afferent arterio les (n = 7), and vasa recta (n = 10). The activity of cADPR hydrolase was a lso detected in the renal vasculature. Using the fluorescence microscopic s pectrometry, cADPR was found to produce a large rapid Ca2+ release from bet a-escin-permeabilized renal arterial smooth muscle cells (SMCs). In isolate d, perfused, and pressurized small renal arteries, cADPR produced a concent ration-dependent vasoconstriction when added into the bath solution. The va soconstrictor effect of cADPR was completely blocked by tetracaine, a Ca2+- induced Ca2+ release (CICR) inhibitor. These results suggest thar: an enzym atic pathway for cADPR production and metabolism is present along the renal vasculature and that cADPR may importantly contribute to the control of re nal vascular tone through CICR. (C) 2000 Academic Press.