CO₂ and Nitric Oxide: Their Role in Blood Flow and Sexual Dysfunction
How Carbon Dioxide Affects Nitric Oxide Production
When the levels of carbon dioxide (CO₂) in the body are low, nitric oxide (NO) levels also decrease. In a 2011 study by Ali R. Fathi et al. (ref1), researchers examined the effects of CO₂ on NO production in small blood vessels (microvascular endothelial cells) in the brain.
- High CO₂ levels (hypercapnia) increased NO by 36% in 8 hours, stabilizing at 25% above normal.
- Low CO₂ levels (hypocapnia) reduced NO by 30% within 8 hours, and this remained stable.
This suggests that CO₂ influences blood vessel function by controlling NO levels, which is essential for blood flow, oxygen delivery, and vascular health.
Nitric Oxide: The Discovery Behind Viagra
Nitric oxide (NO) was first identified by Joseph Priestley in the late 18th century, but its biological role wasn't discovered until the 1980s. Researchers Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad found that NO acts as a vasodilator, helping blood vessels relax and improve circulation. This breakthrough earned them the 1998 Nobel Prize in Physiology or Medicine. (ref2)
Their discovery led to the development of Viagra, the well-known treatment for erectile dysfunction (ED). (ref3)
- ED occurs when smooth muscle in blood vessels does not relax properly, reducing blood flow to the penis.
- Viagra works by enhancing NO signaling, which improves blood vessel relaxation and increases blood flow.
Originally, Viagra was tested as a treatment for angina (chest pain) and high blood pressure. However, researchers noticed that it caused unexpected erections, leading to its repurposing as a sexual enhancement drug.
Nitric Oxide: Essential for Blood Vessel Health
In a paper by Richard C. Jin and Joseph Loscalzo, they discuss how NO helps blood vessels by relaxing smooth muscle, preventing blood clots, and reducing inflammation. These functions are critical for maintaining healthy circulation and blood pressure regulation. (ref4)
Smooth muscle is found throughout the body, including in the walls of hollow organs such as the intestines, uterus, and stomach. It is also present in the walls of passageways, including arteries and veins of the cardiovascular system. This type of involuntary muscle, meaning it operates without conscious control, is also present in the urinary, respiratory, and reproductive tracts.
Smooth muscle critical for the body's most basic operations
In the stomach and intestines, smooth muscle aids digestion and nutrient absorption. In the urinary system, it helps eliminate toxins and balance electrolytes. In the cardiovascular system, it regulates blood pressure and ensures tissues receive enough oxygen. These functions are vital for many of the body's essential processes.
Many medical treatments depend on altering smooth muscle function. For example, bronchodilators relax the smooth muscle in the airways to treat asthma. Drugs like metoclopramide enhance gastric emptying by increasing smooth muscle activity. Nitrates are widely used to treat ischemic heart disease by relaxing blood vessels and improving blood flow.
Smooth muscle, which is involuntary (meaning it works without conscious control), is found in:
- Blood vessels (to regulate circulation)
- The stomach and intestines (to move food)
- The urinary system (to remove waste)
- The respiratory tract (to control airway size)
- The reproductive system (to aid childbirth and sperm movement)
Final Thoughts
Carbon dioxide and nitric oxide work together to maintain healthy blood flow, regulate circulation, and support smooth muscle function. CO₂ therapy could lead to new treatments for cardiovascular diseases, erectile dysfunction, and respiratory conditions.
References
Title: Carbon dioxide influence on nitric oxide production in endothelial cells and astrocytes: Cellular mechanisms
Authors: Ali R. Fathi et al.
Journal: Brain Research
Abstract: Cerebral vessels may regulate cerebral blood flow by responding to changes in carbon dioxide (CO2) through nitric oxide (NO) production. To better determine the role of NO production by human adult cerebral microvascular endothelial cells and human fetal astrocytes under different CO2 conditions, we studied endothelial cell and astrocyte production of NO under hypo-, normo-, and hypercapnic conditions. Human cerebral endothelial cell and fetal astrocyte cultures were exposed to hypocapnic (pCO2 21.7±6.7 mmHg), normocapnic (pCO2 40.1±0.9 mmHg) and hypercapnic (pCO2 56.3±8.7 mmHg) conditions. NO production was recorded continuously over 24 hours with stable pH. N-nitro-L-arginine [NLA; a nitric oxide synthase (NOS) inhibitor] and Larginine (substrate for NO production via NOS) were used to further define the role of NOS in chemoregulation. NO levels in endothelial cells increased during hypercapnia by 36% in 8 hours and remained 25% above baseline. NO increase in astrocytes was 30% after 1 hour but returned to baseline at 8 hours. NLA blocked NO increase in endothelial cells under hypercapnia. During hypocapnia, NO levels in the endothelial cells decreased by 30% at 8 hours but were unchanged in astrocytes. L-arginine prevented NO decrease in endothelial cells under hypocapnia. NO changes in the endothelial cells correlated with changes in pCO2 (R=0.99) and were independent of pH. This study suggests that cerebral endothelial cells and astrocytes release NO under normocapnic conditions, and NO production is increased during hypercapnia and decreased during hypocapnia independent of pH. Further, this demonstrates that endothelial cells may play a pivotal role in chemoregulation by modulating NOS activity.
Title: Historical origins of the discovery of mammalian nitric oxide (nitrogen monoxide) production/physiology/pathophysiology
Authors: Jack R Lancaster Jr
Journal: Biochemical Pharmacology
Pubmed: Access here 
Abstract: The award of the 1998 Nobel Prize in Physiology or Medicine to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad "for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system" highlighted the discovery of NO in mammals. This breakthrough also coincided with the discoveries of the role of NO as a cytotoxic effector in the immune system and as an intercellular neurotransmitter in the nervous system. This brief overview describes the chronological development of this trilinear convergence in 1986-1988, including background chemistry and history of human/nitrogen oxide interactions in general.
Title: Erectile Dysfunction: Key Role of Cavernous Smooth Muscle Cells
Authors: Iara Leão Luna de Souza et al.
Journal: Frontiers in Pharmacology
Link to full text : Erectile Dysfunction: Key Role of Cavernous Smooth Muscle Cells (in pdf-format) 
Abstract: Erectile dysfunction is increasingly affecting men, from the elderly to young adults, being a sexual disorder related to the inability to generate or maintain a penile erection. This disorder is related to psychosocial factors such as anxiety, depression, and low self-esteem, to organic factors such as the presence of preexisting conditions like hypertension, diabetes and dyslipidemia. The pathophysiology of the disease is related to changes in the neurotransmission of the autonomic or the non-cholinergic non-adrenergic nervous system, as well as the release of local mediators, such as thromboxane A2 and endothelin, and hormonal action. These changes lead to impaired relaxation of cavernous smooth muscle, which reduces local blood flow and impairs penile erection. Currently, therapy is based on oral vasodilation, such as sildenafil, tadalafil, vardenafil and iodenafil, or by direct administration of these agents into the corpus cavernosum or by intraurethral route, such as alprostadil and papaverine. Despite this, studies that consolidate the understanding of its pathophysiological process contribute to the discovery of new more efficient drugs for the treatment of erectile dysfunction. In this sense, in the present work an extensive survey was carried out of the mechanisms already consolidated and the most recent ones related to the development of erectile dysfunction.
Title: Vascular nitric oxide: formation and function
Authors: Richard C Jin, Joseph Loscalzo
Journal: Journal of Blood Medicine
Link to full text: Vascular nitric oxide: formation and function (in pdf-format)
Abstract: Nitric oxide (NO) is a structurally simple, highly versatile molecule that was originally discovered over 30 years ago as an endothelium-derived relaxing factor. In addition to its vasorelaxant effects, NO is now recognized as a key determinant of vascular health, exerting antiplatelet, antithrombotic, and anti-inflammatory properties within the vasculature. This short-lived molecule exerts its inhibitory effect on vascular smooth muscle cells and platelets largely through cyclic guanosine monophosphate-dependent mechanisms, resulting in a multitude of molecular effects by which platelet activation and aggregation are prevented. The biosynthesis of NO occurs via the catalytic activity of NO synthase, an oxidoreductase found in many cell types. NO insufficiency can be attributed to limited substrate/cofactor availability as well as interactions with reactive oxygen species. Impaired NO bioavailability represents the central feature of endothelial dysfunction, a common abnormality found in many vascular diseases. In this review, we present an overview of NO synthesis and biochemistry, discuss the mechanisms of action of NO in regulating platelet and endothelial function, and review the effects of vascular disease states on NO bioavailability.
