Smooth muscle calcium and endothelium-derived relaxing factor in the abnormal vascular responses of acute renal failure.

Abstract

Abnormal renovascular reactivity, characterized by paradoxical vasoconstriction to a reduction in renal perfusion pressure (RPP) in the autoregulatory range, increased sensitivity to renal nerve stimulation (RNS), and loss of vasodilatation to acetylcholine have all been demonstrated in ischemic acute renal failure (ARF). To determine if ischemic injury alters vascular contractility by increasing smooth muscle cell calcium or calcium influx, the renal blood flow (RBF) response to reductions in RPP within the autoregulatory range and to RNS were tested before and after a 90-min intrarenal infusion of verapamil or diltiazem in 7-d ischemic ARF rats. Both calcium entry blockers, verapamil and diltiazem, blocked the aberrant vasoconstrictor response to a reduction in RPP and RNS (both P < 0.001).In a second series of experiments the potential role of an ischemia-induced endothelial injury and of the absence of endothelium-derived relaxing factor (EDRF) production were examined to explain the lack of vasodilatation to acetylcholine. Acetylcholine, bradykinin (a second EDRF-dependent vasodilator), or prostacyclin, an EDRF-independent vasodilator, was infused intrarenally for 90 min, and RBF responses to a reduction in RPP and RNS were tested in 7-d ischemic ARF rats. Neither acetylcholine nor bradykinin caused vasodilatation or altered the slope of the relationship between RBF and RPP. By contrast, prostacyclin increased RBF (P < 0.001), but did not change the vascular response to changes in RPP.It was concluded that the abnormal pressor sensitivity to a reduction in RPP and RNS was due to changes in renovascular smooth muscle cell calcium activity that could be blocked by calcium entry blockers. A lack of response to EDRF-dependent vasodilators, as a result of ischemic endothelial injury, may contribute to the increased pressor sensitivity of the renal vessels.

Predictors of Recurrent AKI

“…The biologic basis for susceptibility may be rooted in experimental and early clinical data indicating that AKI leads to impairments in vascular autoregulation. [32][33][34] Nevertheless, these findings underscore that similar to the prognostic significance of a transient ischemic attack or angina, 35 even mild episodes of AKI may be a harbinger (i.e., or failed stress test) for future, more devastating AKI.…”

Evidence for role of cytosolic free calcium in hypoxia-induced proximal tubule injury.

“…This proposal is based partly on the protective effects in dog (23,24), rat (25,26), and human kidneys (27, 28) of intrarenal or systemic infusions of various, chemically dissimilar Ca2+ channel blockers (CCB). It has been suggested, however, that much ofthe functional renal protection could be explained by renal vascular effects of CCB with the cytoprotective effects on tubular function occurring secondary to improved perfusion.…”

“…3). for example, correct the impaired autoregulation ofrenal blood flow and reduce the hypersensitivity to renal nerve stimulation observed in ischemic rat kidneys (26). These vascular effects in intact kidneys make it virtually impossible to attribute unambiguously a direct protective effect of CCB on renal tubules.…”

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

“…Many vasoconstrictive agents have been suggested to accompany the postischemic increase in vascular tone, including endothelin, angiotensin II (76), thromboxane A 2 (77), leukotriene C 4 (78), adenosine (14), endothelium-derived prostaglandin H2, and sympathetic nerve stimulation (13,18). These abnormalities in vascular reactivity have been associated with increases in cytosolic Ca 2+ (79); such increases in intracellular Ca 2+ may also cause cell death by inducing the activation of proteases, phospholipases, and pro-apoptotic pathways (80). Of all the vasoconstrictive agents, endothelin seems to be particularly important, because endothelin-1 levels have been found to increase after ischemia, and blockage of the endothelin pathway by endothelin A receptor antagonists (70,76) has been shown to protect against I/R injury.…”