The importance of Nitric Oxide and how non-thermal Low Intensity Pulsed Ultrasound can help increase NO production

Low Intensity Ultrasound and Nitric Oxide Production

Over the course of 33 years in practice (the last 28 spent working with elite, world-class professional and Olympic athletes as well as non-athletes), I’ve had the opportunity to work with a host of modalities, all designed to help the injured patient. But one constant in my bag of tricks – one that has consistently helped me get my athletes back in the game quicker – has been low intensity pulsed or continuous ultrasound.

While many are familiar with the importance of Nitric Oxide in the human body – ranging from strengthening one’s immune system to improving its anti-inflammatory response – not many are familiar with the increase of Nitric Oxide and eNO’s (endothelial Nitric Oxide Synthase) production associated with low intensity ultrasound, either pulsed or continuous, depending on the acuteness of the injury.

While most use therapeutic ultrasound for its thermal effects of heating, attributing vasodilation to the heat, not many are aware of the non-thermal effects associated with ultrasound in the form of acoustic streaming and cavitation: This is the process when the sound wave passes through the cellular cytoplasm and creates a fluid wave. As the fluid wave moves through the cell, the free-floating structures such as the mitochondria, Golgi bodies, vacuoles, lysosomes catch a ride on this fluid wave. As they move through the cytoplasm, they create a wake in which there are gas bubbles consisting of Nitric Oxide. (1)

As stated, most attribute vasodilation to the thermal effect of ultrasound, but it has been proven that NO is key in promoting vasodilation as well.

In the human body there are three pathways in which Nitric Oxide is created, each pathway demonstrating a different purpose for the same by-product, NO. The first pathway is nNOS (or NOS 1), which stands for neuronal Nitric Oxide Synthase. Its primary purpose is synaptic plasticity. iNOS (or NOS2) is known as inducing Nitric Oxide Synthase and its primary purpose is immune, parasitic, anti-tumoral, and anti-inflammatory. eNOS (or NOS3) is known as endothelial Nitric Oxide Synthase and its primary function is cardiovascular and anti-inflammatory. (2)

While the primary focus of therapeutic ultrasound has been on the known thermal effects, there are numerous studies that demonstrate the increase of NO through the eNOS pathway when using LIPUS (low intensity pulsed ultrasound) as well as LICUS (low intensity continuous ultrasound). One such study states:

“Nitric oxide release, intracellular calcium concentration, and endothelial nitric oxide synthase (eNOS) gene and protein expressions after ultrasound exposure were analyzed. It was found that ultrasound exposure did not change the cell proliferation, but it enhanced the release of nitric oxide and Ca2+ ions, and increased the eNOS activity.

The induced phosphorylation of eNOS (Ser1177) by the ultrasound exposure was inhibited by the addition of N- [2-(p-bromocinnamylamino) ethyl]-5-isoquinoline sulfonamide (H89, a protein kinase A inhibitor), but not 2-(4-morpholino)-8-phenyl-4H-1-benzopyran-4-one hydrochloride (LY294002, a phosphoatidylinositol 3-kinase inhibitor). The induced phosphorylation of Akt (protein kinase B, Ser473) by the ultrasound exposure was inhibited by the addition of LY294002, but not by the presence of H89. The results also applied to bovine carotid artery endothelial cells (BAECs) exposed to ultrasound at a larger intensity (68 mW/cm2). The above experiments suggested that low-intensity ultrasound might promote eNOS activity of endothelial cells via the phosphatidylinositol 3-kinase/Akt/protein kinase A signaling pathway. This may have implications on the therapeutic effect of ultrasound in tissue repair.” (3)

As a Health Care Provider, I’ve used ultrasound and pulsed ultrasound (along with soft-tissue mobilization, movement therapy and adjustments/mobilization) as a big part of my regimen in working with and helping athletes and non-athletes perform to their optimum potential.

If you have any questions on how to use the Pulsed setting on your US unit, be on the lookout for next month’s article where I’ll walk you through the process.

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  • Journal of Athletic Training 2002;37(3):293–299q by the National Athletic Trainers’ Association, “Nonthermal Effects of Therapeutic Ultrasound: The Frequency Resonance Hypothesis” Lennart D. Johns
  • Indian J Pediatr.1998 May-Jun;65(3):333-45. Nitric oxide: biological role and clinical uses. Kannan MS1Guiang SJohnson DE.
  • Shan-hui Hsu, Tsung-Bin Huang, and Kuan-Pu Wang,  Eng. Appl. Basis Commun.22, 367 (2010) low-intensity ultrasound increases the endothelial nitric oxide synthase (enos) expression of endothelial cells possibly via the phosphatidylinositol 3-kinase/akt/protein kinase a signaling pathway


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