Vasodilators Used To Alter Course Of Clinical Acute Renal Failure

Vasodilator

ARF Disorder

Observed Effect

Remarks

Dopamine

Ischemic, toxic

Improved V, Scr if used early

Combined with furosemide

Phenoxybenzamine

Ischemic, toxic

No change in V, RBF

Phentolamine

Ischemic, toxic

No change in V, RBF

Prostaglandin A|

Ischemic

No change in V, Scr

Used with dopamine

Prostaglandin E|

Ischemic

TRBF, no change v, CCr

Used with NE

Dihydralazine

Ischemic, toxic

TRBF, no change V, Scr

Verapamil

Ischemic

TCcr or no effect

Diltiazem

Transplant, toxic

TCcr or no effect

Prophylactic use

Nifedipine

Radiocontrast

No effect

Atrial natriuretic

Ischemic

TCcr

peptide

Ccr—creatinine clearance; NE—norepinephrine; RBF—renal blood flow; Scr—serum creatinine; V—urine flow rate.

Ccr—creatinine clearance; NE—norepinephrine; RBF—renal blood flow; Scr—serum creatinine; V—urine flow rate.

FIGURE 14-15

Vasodilators used in acute renal failure (ARF). A, Vasodilators used in experimental acute ARF. B, Vasodilators used to alter the course of clinical ARF. (From Conger [7]; with permission.)

FIGURE 14-16

Chemical reactions leading to the generation of nitric oxide (NO), A, and enzymes that catalize them, B. (Modified from Gross [8]; with permission.)

Modular structure of nitric oxide synthases

® BH4 ARG CaM FMN FAD NADPH ._.__|_^_□_□_□_■_■_

¡Target domain11 Oxygenase domain || ||_Reductase domain_|

2-3 4-5 6 7-9 10-12 1516-17 21-23 24-29 11-12 16-18

2-3 4-5 6 7-9 10-11 13 14-18 19-21 22-26 2-3 4-8 n 9-12n ,13-16 Mammalian P450 Reductases | | | Ifli^l I

Bacterial Flavodoxins I 1

Plant Ferredoxin NADPH Reductases | |

DHF Reductases | |

B I I Mammalian Syntrophins (GLGF Motif)

L-arginine

L-citrulline

Nitric oxide

: oxide gtP

Smooth muscle N Vasodilatation [

cGMP

Inhibition of Tar et cell

^¡^ Immune cells iron-containing c enzymes

CNS and PNS

z£> Neurotransmission [ Hemoglobin

Urine excretion

Endothelium-dependent vasodilators

Leukocyte (— migration

Platelet

Shear stress

Endothelium-dependent vasodilators

Shear stress

Leukocyte (— migration

Platelet

J DNA damage

Cell death

/ Activation of

Apoptosis

/ apoptotic signal

/Thiols

Induction of stress proteins

y Heme- & iron-

Inactivation of enzymes

containing proteins

>""ROIs

Antioxidant

^^ Guanylate cyclase

cGMP (cellular signal)

Time

Consequences

FIGURE 14-17

Major organ, A, and cellular, B, targets of nitric oxide (NO). A, Synthesis and function of NO. B, Intracellular targets for NO and pathophysiological consequences of its action. C, Endothelium-dependent vasodilators, such as acetylcholine and the calcium ionophore A23187, act by stimulating eNOS activity thereby increasing endothelium-derived nitric oxide (EDNO) production. In contrast, other vasodilators act independently of the endotheli-um. Some endothelium-independent vasodilators such as nitroprus-side and nitroglycerin induce vasodilation by directly releasing nitric oxide in vascular smooth muscle cells. NO released by these agents, like EDNO, induces vasodilation by stimulating the production of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle (VSM) cells. Atrial natriuretic peptide (ANP) is also an endothe-lium-independent vasodilator but acts differently from NO. ANP directly stimulates an isoform of guanylyl cyclase (GC) distinct from soluble GC (called particulate GC) in VSM. CNS—central nervous system; GTP—guanosine triphosphate; NOS—nitric oxide synthase; PGC—particulate guanylyl cyclase; PNS—peripheral nervous system; ROI—reduced oxygen intermediates; SGC—soluble guanylyl cyclase. (A, From Reyes et al. [9], with permission; B, from Kim et al. [10], with permission.)

Ischemia (I) alone

I + _ nitroprusside

I + _ Acetylcholine

0 20 40 60 80 Increase in RVR above control, %

Ischemia (I) alone

I + _ nitroprusside

I + _ Acetylcholine

:

i i

0 20 40 60 80 Increase in RVR above control, %

Impaired production of endothelium-dependent nitric oxide (EDNO) contributes to the vasoconstriction associated with established acute renal failure (ARF). Ischemia-reperfu-sion injury in the isolated erythrocyte-perfused kidney induced persistant intarenal vasoconstriction. The endothelium-independent vasodilators (atrial natriuretic peptide [ANP] and nitroprusside) administered during the reflow period caused vasodilation and restored the elevated intrarenal vascular resistance (RVR) to normal. In marked contrast, two endothelium-dependent vasodilators (acetylcholine and A23187) had no effect on renal vascular resistance after ischemia-reflow. These data suggest that EDNO production is impaired following ischemic injury and that this loss of EDNO activity contributes to the vasoconstriction associated with ARF. (Adapted from Lieberthal [11]; with permission.)

6050403020100

^ Hypoxia

20 30 40 50

Time, min

150 10050

Ischemia

Normoxia Hypoxi Wild type mice

Normoxia Hypoxia iNOS knockout mice

FIGURE 14-19

Deleterious effects of nitric oxide (NO) on the viability of renal tubular epithelia. A, Hypoxia and reoxygenation lead to injury of tubular cells (filled circles); inhibition of NO production improves the viability of tubular cells subjected to hypoxia and reoxygena-tion (triangles in upper graph), whereas addition of L-arginine enhances the injury (triangles in lower graph). B, Amelioration of ischemic injury in vivo with antisense oligonucleotides to the iNOS: blood urea nitrogen (BUN), and creatinine (CR) in rats subjected to 45 minutes of renal ischemia after pretreatment with antisense phosphorothioate oligonucleotides (AS) directed to iNOS or with sense (S) and scrambled (SCR) constructs. C, Resistance of proximal tubule cells isolated from iNOS knockout mice to hypox-ia-induced injury. LDH—lactic dehydrogenase. (A, From Yu et al. [12], with permission; B, from Noiri et al. [13], with permission; C, from Ling et al. [14], with permission.)

100500200150 — 10050 0

Iothalamate

Iothalamate

Iothalamate

20 40 Minutes

10050 0

10050 0

Iothalamate h-r

20 40 Minutes h-r

20 40 Minutes

Pretreatment with L-NAME (n = 6)

FIGURE 14-20

Radiocontrast

Normal kidneys

Compensatory increase in PGI2 and EDNO release

Chronic renal insufficiency

Increased endothelin

Mild vasoc

onstriction

\

7

No loss of GFR

Reduced or absent increase in PGI2 or EDNO

Severe vasoconstriction lz

Acute renal failure

Proposed role of nitric oxide (NO) in radiocontrast-induced acute renal failure (ARF). A, Administration of iothalamate, a radiocon-trast dye, to rats increases medullary blood flow. Inhibitors of either prostaglandin production (such as the NSAID, indomethacin) or inhibitors of NO synthesis (such as L-NAME) abolish the compensatory increase in medullary blood flow that occurs in response to radiocontrast administration. Thus, the stimulation of prostaglandin and NO production after radiocontrast administration is important in maintaining medullary perfusion and oxygenation after administration of contrast agents. B, Radiocontrast stimulates the production of vasodilators (such as prostaglandin [PGy and endothelium-dependent nitric oxide [EDNO]) as well as endothelin and other vasoconstrictors within the normal kidney. The vasodilators counteract the effects of the vasoconstrictors so that intrarenal vasoconstriction in response to radiocontrast is usually modest and is associated with little or no loss of renal function. However, in situations when there is preexisting chronic renal insufficiency (CRF) the vasodilator response to radiocontrast is impaired, whereas production of endothelin and other vasoconstrictors is not affected or even increased. As a result, radiocontrast administration causes profound intrarenal vasoconstriction and can cause ARF in patients with CRF. This hypothesis would explain the predisposition of patients with chronic renal dysfunction, and especially diabetic nephropathy, to contrast-induced ARF. (A, Adapted from Agmon and Brezis [15], with permission; B, from Agmon et al. [16], with permission.)

FIGURE 14-21

Cellular calcium metabolism and potential targets of the elevated cytosolic calcium. A, Pathways of calcium mobilization. B, Patho-physiologic mechanisms ignited by the elevation of cytosolic calcium concentration. (A, Adapted from Goligorsky [17], with permission; B, from Edelstein and Schrier [18], with permission.)

FIGURE 14-21

Cellular calcium metabolism and potential targets of the elevated cytosolic calcium. A, Pathways of calcium mobilization. B, Patho-physiologic mechanisms ignited by the elevation of cytosolic calcium concentration. (A, Adapted from Goligorsky [17], with permission; B, from Edelstein and Schrier [18], with permission.)

400-

300-

200-

150-

400-

300-

200-

150-

Significant vs. time 0

Significant vs. time 0

604020-

0 60

Pre NE

rNS_i rNSn

Control

Post NE Verapamil before NE

Verapamil after NE

24 h

FIGURE 14-22

Pathophysiologic sequelae of the elevated cytosolic calcium (C2+). A, The increase in cytosolic calcium concentration in hypoxic rat proximal tubules precedes the tubular damage as assessed by propidi-um iodide (PI) staining. B, Administration of calcium channel inhibitor verapamil before injection of norepinephrine (cross-hatched bars) significantly attenuated the drop in inulin clearance induced by norepi-nephrine alone (open bars). (A, Adapted from Kribben et al. [19], with permission; B, adapted from Burke et al. [20], with permission.)

FIGURE 14-23

Dynamics of heat shock proteins (HSP) in stressed cells. Mechanisms of activation and feedback control of the inducible heat shock gene. In the normal unstressed cell, heat shock factor (HSF) is rendered inactive by association with the con-stitutively expressed HSP70. After hypoxia or ATP depletion, partially denatured proteins (DP) become preferentially associated with HSC73, releasing HSF and allowing trimerization and binding to the heat shock element (HSE) to initiate the transcription of the heat shock gene. After translation, excess inducible HSP (HSP72) interacts with the trimer-ized HSF to convert it back to its monomeric state and release it from the HSE, thus turning off the response. (Adapted from Kashgarian [21]; with permission.)

Free Radical Pathways in the Mitochondrion Catalase/GPx complex? Hydrogen V1

membrane

fcAx

Wkmf) V^Tissue EC-SOD

fcAx

Wkmf) V^Tissue EC-SOD

Hydrogen /

peroxide

FIGURE 14-24

Hydrogen /

peroxide

FIGURE 14-24

Cellular sources of reactive oxygen species (ROS) defense systems from free radicals. Superoxide and hydrogen peroxide are produced during normal cellular metabolism. ROS are constantly being produced by the normal cell during a number of physiologic reactions. Mitochondrial respiration is an important source of superoxide production under normal conditions and can be increased during ischemia-reflow or gentamycin-induced renal injury. A number of enzymes generate superoxide and hydrogen peroxide during their catalytic cycling. These include cycloxygenases and lipoxygenes that catalyze prostanoid and leukotriene synthesis. Some cells (such as leukocytes, endothelial cells, and vascular smooth muscle cells) have NADH/ or NADPH oxidase enzymes in the plasma membrane that are capable of generating superoxide. Xanthine oxidase, which converts hypoxathine to xanthine, has been implicated as an important source of ROS after ischemia-reperfu-sion injury. Cytochrome p450, which is bound to the membrane of the endoplasmic reticulum, can be increased by the presence of high concentrations of metabolites that are oxidized by this cytochrome or by injurious events that uncouple the activity of the p450. Finally, the oxidation of small molecules including free heme, thiols, hydroquinines, catecholamines, flavins, and tetrahydropterins, also contribute to intracellular superoxide production. (Adapted from [22]; with permission.)

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