Gtp

c-GMP

Kinases

Other proteins o

Kinases

Other proteins

Inhibition

Figure 15. Schcmatic of nitric oxide mediated signaling. Protein kinase G (PKG) responds to c-GMP, much as PKA responds to c-AMP. An interaction between c-GMP and c-AMP signaling also occurs. See text for a more detailed explanation.

"PDE"= Phosphodiesterase, "MLC"= Myocin light chain

Figure 15. Dose dependently c-GMP inhibits PDE or activates PKG, thereby mediating its effects on the vasculature, platelets and myocytes. The cardiac interstitial NO concentration during early ischemia and early reperfusion is increased. The increase in NO concentration is derived from activated NO synthase (NOS) isoforms (species specific) and from NOS independent pathways. Cardiac c-GMP concentration during ischemia is somewhat increased while upon reperfusion is decreased. NO seems to mediate protective as well as deleterious effects which are critically dependent on the specific experimental conditions. NO at lower concentrations preserves blood flow and attenuates platelet aggregation and neutrophil-endothelium interaction following ischemia and reperfusion. In small amounts might also be beneficial by nitration of the cardioprotective PKCe. Furthermore, NO increases cardiomyocyte function. Figure 16. At higher concentrations, NO depresses cardiomyocyte function, mediates inflammatory processes following ischemia and reperfusion, impairs mitochondrial respiration

Contractile function and relaxation

K(ATP) channel opening

Vasodilation A

eNOS, nNOS

(<100 nM NO) Endothelium, Platelets,

VSMC, Nerves, Myocytes, Leukocytes

Mitochondrial calcium uptake

Oxygen consumption

Platelet Aggregation

Cytokine expression

Adhesion molecules

{ยก-adrenergic responsiveness iNOS

(>1 |jM NO) Leukocytes, VSMC, Myocytes, Lymphocytes, Fibroblasts

Contractile function (in the presence of free radicals)

Apoptosls

Necrosis

Inhibition

Figure 16. Schematic representation of NO mediated cellular effects. NO mediated beneficial or detrimental effects are dependent on NO concentration (modified by Schulz121).

and even induces cardiomyocyte death. Formation of the toxic free radical peroxynitrite contributes to cardiac damage, reviewed by Schulz.121 Figure 16.

The importance of endogenous NO on the postischemic recovery of function after ischemia and reperfusion appears to be species-specific. In guinea pigs and mice, endogenous NO mediates beneficial effects. Blockade of endogenous NO improves and exogenous NO worsens the postischemic function in rabbits and dogs. In rats, a dose dependent effect of NOS inhibitors is observed with low or high concentrations being ineffective or even aggravating myocardial stunning while intermediate concentration of NOS inhibitors are beneficial.121

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