Premise of interesting paper might show promise for those of us with problems in OUR hind limbs?

[Guest guest]

IMO, the issues this addresses are in some ways frequently chronic mold

issues..

I've had some luck recently with arginine. This is slightly different..

___cut here____

Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and

arteriogenesis

http://hwmaint.pnas.org/cgi/content/full/105/21/7540

or for PDF

http://hwmaint.pnas.org/cgi/reprint/105/21/7540

* " Chronic tissue ischemia due to defective vascular perfusion is a hallmark

feature of peripheral artery disease for which minimal therapeutic options

exist. We have reported that sodium nitrite therapy exerts cytoprotective

effects against acute ischemia/reperfusion injury in both heart and liver,

consistent with the model of bioactive NO formation from nitrite during

ischemic stress. Here, we test the hypothesis that chronic sodium nitrite

therapy can selectively augment angiogenic activity and tissue perfusion in

the murine hind-limb ischemia model. Various therapeutic doses (8.25–3,300

µg/kg) of sodium nitrite or PBS were administered. Sodium nitrite

significantly restored ischemic hind-limb blood flow in a time-dependent

manner, with low-dose sodium nitrite being most effective. Nitrite therapy

significantly increased ischemic limb vascular density and stimulated

endothelial cell proliferation. Remarkably, the effects of sodium nitrite

therapy were evident within 3 days of the ischemic insult demonstrating the

potency and efficacy of chronic sodium nitrite therapy. Sodium nitrite

therapy also increased ischemic tissue nitrite and NO metabolites compared

to nonischemic limbs. Use of the NO scavenger carboxy PTIO completely

abolished sodium nitrite-dependent ischemic tissue blood flow and angiogenic

activity consistent with nitrite reduction to NO being the proangiogenic

mechanism. These data demonstrate that chronic sodium nitrite therapy is a

recently discovered therapeutic treatment for peripheral artery disease and

critical limb ischemia.

wound healing | endothelial cell | nitric oxide | peripheral artery disease

| tissue perfusion

Therapeutic angiogenesis remains an attractive treatment modality for

peripheral vascular disease and chronic tissue ischemia. Numerous mediators,

including growth factors, transcription factors, and signaling molecules,

have been reported to augment chronic ischemia-induced angiogenesis in

animal models (1). However, clinical trials of proangiogenic agents have

revealed little to no practical utility in patients suffering from such

disorders (2). Thus, there remains a clear need for better interventions

with which to induce therapeutic angiogenesis.

The signaling molecule nitric oxide (NO) has been shown to be an important

player in stimulating angiogenesis in a variety of settings (3, 4). NO is an

important signaling intermediate governing VEGF-dependent angiogenesis

(5–7). Multiple signaling pathways within endothelial cells may be affected

in response to NO generation, including Erk1/2, PKC, tyrosine kinases, and

transcription factors (4, 8, 9). Moreover, endothelial NO synthase (eNOS)

has been shown to be a critical player in modulating postnatal angiogenesis

activity, because genetic deficiency of this molecule diminishes

ischemia-induced angiogenesis and pericyte recruitment (10, 11). Consistent

with these observations, NO donors have been shown to have cardioprotective

effects including augmentation of angiogenic responses in vitro and in vivo

(9, 12–16). However, a major limitation with the use of NO donors is that

these agents are nonselective and may induce undesired consequences,

including cellular injury to healthy tissue and systemic alterations in

tissue perfusion (17–19). Taken together, these observations indicate that

NO donor therapy would be very beneficial for therapeutic angiogenesis, yet

at present there are no effective means to selectively deliver NO to

ischemic tissues to promote angiogenesis.

Recent discoveries from several laboratories have revealed that nitrite, a

one-electron oxidation product of NO, can act as a selective NO donor

because of reduction back to NO by several mechanisms, including, but not

limited to, deoxyhemoglobin, deoxymyoglobin, xanthine oxidoreductase, acidic

disproportionation, and mitochondrial complex IV (20–26). Common among these

candidate nitrite-reducing transducers is that nitrite reduction will become

more significant as the oxygen tension is lowered, a condition that exists

in peripheral vascular disease (27, 28). Moreover, we and others have

reported that sodium nitrite protects against acute ischemia/reperfusion

injury and other disease states associated with acute tissue ischemia and NO

deficiency (25, 29). These data led us to hypothesize that sodium nitrite

therapy may also be beneficial during settings of chronic ischemia by

augmenting ischemic tissue angiogenesis. We found that prolonged nitrite

therapy robustly augmented ischemic tissue blood flow and angiogenesis,

which did not occur in nonischemic tissues. These data provide compelling

evidence that sodium nitrite therapy serves as a tissue-selective NO donor

that could be of great clinical utility for peripheral vascular disease and

critical tissue ischemic disorders. "

*