Cyclic Adenosine Diphosphate Ribose cAdpr Sr Ca2 Release and Maintained Hypoxic Pulmonary Vasoconstriction in Isolated Pulmonary Arteries

Given our finding that maintained HPV in arteries without endothelium was abolished by depletion ofryanodine-sensitive intracellular stores, we considered the possibility that an endogenous regulator of RyRs may be involved. This led us to investigate the role of a novel Ca2+ mobilizing pyridine nucleotide, namely cyclic adenosine diphosphate ribose (cADPR) (37). The enzymes that synthesize (ADP-ribosyl cyclase/CD38) and metabolize (cADPR hydrolase) cADPR are present in many cell types including arterial smooth muscle (37, 66), and, significantly, an elevation in cADPR levels has previously been shown to sensitize Ca2+-induced Ca2+ release via RyRs in the SR and to induce SR Ca2+ release by RyR activation (22). Furthermore, we were struck by the fact that cADPR was a P-NAD+ metabolite, since hypoxia had been shown to increase p-NADH levels in all 02-sensing cells studied to date (5, 59, 67). This offered the possibility that cADPR synthesis itself may, in some way, be sensitive to changes in the metabolic state of pulmonary artery smooth muscle.

Figure 3. Synthesis and metabolism of cADPR in pulmonary arteries and the effect of hypoxia. A and B: Synthesis of cADPR from 0-NAD+ (A) and metabolism of cADPR (B) in smooth muscle homogenates from a series of pulmonary (PA) and mesenteric (MA) arteries. C: Relative cADPR levels in 2nd or 3rd order branches of the pulmonary artery in the presence of normoxia and hypoxia, respectively.

Figure 3. Synthesis and metabolism of cADPR in pulmonary arteries and the effect of hypoxia. A and B: Synthesis of cADPR from 0-NAD+ (A) and metabolism of cADPR (B) in smooth muscle homogenates from a series of pulmonary (PA) and mesenteric (MA) arteries. C: Relative cADPR levels in 2nd or 3rd order branches of the pulmonary artery in the presence of normoxia and hypoxia, respectively.

9.1. ADP-ribosyl Cyclase and cADPR Hydrolase Activities are Differentially Distributed in Pulmonary Versus Systemic Artery Smooth Muscle

Given the fact that HPV is the critical and distinguishing characteristic of pulmonary artery smooth muscle, our initial investigations into the role of cADPR in HPV focused on measurements of the enzyme activities for the synthesis and metabolism of cADPR in pulmonary versus systemic artery smooth muscle. Our findings were striking, in that the enzyme activities for the synthesis and metabolism of cADPR were at least an order of magnitude higher in homogenates of pulmonary artery smooth muscle than in those of aortic or mesenteric artery smooth muscle (Fig. 3A and B) (66). Thus, the differential distribution of these enzyme activities offered the pulmonary selectivity required of a mediator of HPV. Of perhaps even greater significance was the finding that the level of these enzyme activities was inversely related to pulmonary artery diameter (Fig. 3A and B) (66), given that the magnitude of constriction by hypoxia has also been shown to be inversely related to pulmonary artery diameter (32, 35).

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