Effects of Carbon Monoxide Breathing on Blood Vessel Function
| Status: | Completed |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 39 |
| Updated: | 4/3/2019 |
| Start Date: | June 23, 2017 |
| End Date: | March 1, 2019 |
In healthy young adults 18-39 years of age, the investigators will determine if intermittent
inhalation a 0.1% CO, from a 1-liter bag once every minute for 30-40 minutes, at a level that
approaches the CO boost with hookah smoking, augments endothelial function, thus implicating
CO as the major endothelial vasodilator substance in hookah smoke.
Rationale: Our group has demonstrated (PRO36547) that in contrast to cigarette smoking,
hookah smoking (tobacco heated with charcoal) acutely augments, rather than impairs, brachial
artery FMD. Importantly, our data strongly implicate—but do not prove—that the augmentation
in FMD is caused by CO. Therefore; the investigators would like to extend the scientific
priority of this work by directly investigating cause and effect of CO breathing (similar
levels than ones obtained after hookah smoking) on brachial artery FMD.
inhalation a 0.1% CO, from a 1-liter bag once every minute for 30-40 minutes, at a level that
approaches the CO boost with hookah smoking, augments endothelial function, thus implicating
CO as the major endothelial vasodilator substance in hookah smoke.
Rationale: Our group has demonstrated (PRO36547) that in contrast to cigarette smoking,
hookah smoking (tobacco heated with charcoal) acutely augments, rather than impairs, brachial
artery FMD. Importantly, our data strongly implicate—but do not prove—that the augmentation
in FMD is caused by CO. Therefore; the investigators would like to extend the scientific
priority of this work by directly investigating cause and effect of CO breathing (similar
levels than ones obtained after hookah smoking) on brachial artery FMD.
Carbon monoxide (CO) is an endogenously produced gas that play important physiological roles
in the circulation. Traditionally considered a poisonous gas that causes tissue hypoxia, CO
produced by vascular cells as a byproduct of heme catabolism, also functions to regulate
blood flow by inhibiting vasomotor tone, smooth muscle cells proliferation, and platelet
aggregation. These vascular effects are thought to be mediated by cyclic guanosine
monophosphate (cGMP) because both clinical observations and experimental data provide
precedent that CO, like nitric oxide, constitutes a cGMP-dependent vasodilator. Drugs that
upregulate the endogenous production of CO by heme oxygenase, such as CO releasing molecules
(CORMs), are being developed to treat several vascular diseases.
The toxicity of CO is dependent on the dose and duration of exposure. Studies have shown that
CO inhalation is fatally toxic at concentrations of 800 parts per million (ppm) or 0.08% in
the air. Studies have also demonstrated that CO inhalation at low doses (<250 ppm) offers
protection against inflammation and ischemic injury in the heart, liver, and kidney.
According to a recent study published in Nature, repeated exposures of 250 ppm of CO for 1
hour inhibit experimental atherosclerosis by a cGMP-dependent process in rats. Other studies
have also demonstrated that exogenous CO causes cGMP-dependent vasodilation in isolated
vascular rings, and, in intact animals, can augment nitric oxide-dependent vasodilation.
Initial studies by our group allowed us to discover that, in young healthy hookah smokers,
hookah smoking is a potent acute stimulus to augment—not impair—endothelial function measured
by brachial artery flow mediated dilation (FMD). The data implicate a pivotal mechanistic
role of one or more charcoal combustion products in the augmented endothelial function: when
burning charcoal was replaced with a healthier electronic heat source ("e-coal"), FMD became
acutely impaired just as with cigarettes and almost all other known tobacco products
including electronic-cigarettes. Interestingly, the CO boost after our hookah subjects smoked
charcoal-heated hookah tobacco was ~10-fold higher than after smoking a cigarette (25+11 vs.
3+2 ppm). Tobacco literature provide evidence that the repeated CO exposure from cigarette
smoking is associated with a reduced risk of pre-eclampsia (associated with pathological
vasoconstriction) in pregnant women as compared with both non-smokers or users of smokeless
tobacco (snuff) which does not generate CO.
Recently published studies by our group showed that sustained CO inhaled by healthy smokers,
to achieve mean carboxyhemoglobin 5+1% (which is equivalent to our proposed exhaled CO levels
of 35 ppm), had no significant effect on blood pressure, heart rate, plasma catecholamines,
platelet aggregation or C-reactive protein, a marker of inflammation. The effects of low
levels of CO on human endothelial function has yet to be determined.
Taken all the current evidence together, the present application aims to investigate the
acute effects of breathing very low doses CO—to replicate levels obtained with hookah
smoking—on peripheral vessel function in humans. the investigators hypothesize that CO is the
key charcoal combustion product in hookah smoke that enhances endothelial function, thus
masking the impairment seen with hookah tobacco toxicants. The benefit of this amendment is
beyond this project, especially if CO inhalation at very low dose, non-toxic levels is shown
to decrease cardiovascular risk and augment endothelial function.
in the circulation. Traditionally considered a poisonous gas that causes tissue hypoxia, CO
produced by vascular cells as a byproduct of heme catabolism, also functions to regulate
blood flow by inhibiting vasomotor tone, smooth muscle cells proliferation, and platelet
aggregation. These vascular effects are thought to be mediated by cyclic guanosine
monophosphate (cGMP) because both clinical observations and experimental data provide
precedent that CO, like nitric oxide, constitutes a cGMP-dependent vasodilator. Drugs that
upregulate the endogenous production of CO by heme oxygenase, such as CO releasing molecules
(CORMs), are being developed to treat several vascular diseases.
The toxicity of CO is dependent on the dose and duration of exposure. Studies have shown that
CO inhalation is fatally toxic at concentrations of 800 parts per million (ppm) or 0.08% in
the air. Studies have also demonstrated that CO inhalation at low doses (<250 ppm) offers
protection against inflammation and ischemic injury in the heart, liver, and kidney.
According to a recent study published in Nature, repeated exposures of 250 ppm of CO for 1
hour inhibit experimental atherosclerosis by a cGMP-dependent process in rats. Other studies
have also demonstrated that exogenous CO causes cGMP-dependent vasodilation in isolated
vascular rings, and, in intact animals, can augment nitric oxide-dependent vasodilation.
Initial studies by our group allowed us to discover that, in young healthy hookah smokers,
hookah smoking is a potent acute stimulus to augment—not impair—endothelial function measured
by brachial artery flow mediated dilation (FMD). The data implicate a pivotal mechanistic
role of one or more charcoal combustion products in the augmented endothelial function: when
burning charcoal was replaced with a healthier electronic heat source ("e-coal"), FMD became
acutely impaired just as with cigarettes and almost all other known tobacco products
including electronic-cigarettes. Interestingly, the CO boost after our hookah subjects smoked
charcoal-heated hookah tobacco was ~10-fold higher than after smoking a cigarette (25+11 vs.
3+2 ppm). Tobacco literature provide evidence that the repeated CO exposure from cigarette
smoking is associated with a reduced risk of pre-eclampsia (associated with pathological
vasoconstriction) in pregnant women as compared with both non-smokers or users of smokeless
tobacco (snuff) which does not generate CO.
Recently published studies by our group showed that sustained CO inhaled by healthy smokers,
to achieve mean carboxyhemoglobin 5+1% (which is equivalent to our proposed exhaled CO levels
of 35 ppm), had no significant effect on blood pressure, heart rate, plasma catecholamines,
platelet aggregation or C-reactive protein, a marker of inflammation. The effects of low
levels of CO on human endothelial function has yet to be determined.
Taken all the current evidence together, the present application aims to investigate the
acute effects of breathing very low doses CO—to replicate levels obtained with hookah
smoking—on peripheral vessel function in humans. the investigators hypothesize that CO is the
key charcoal combustion product in hookah smoke that enhances endothelial function, thus
masking the impairment seen with hookah tobacco toxicants. The benefit of this amendment is
beyond this project, especially if CO inhalation at very low dose, non-toxic levels is shown
to decrease cardiovascular risk and augment endothelial function.
Inclusion Criteria:
- 18-39 years of age
Exclusion Criteria:
- History of cardiopulmonary, diabetes, dyslipidemia or psychiatric disease
- BP > 140/90 mmHg
- BMI <18.5 or > 30 kg·m2
- Resting heart rate > 100 beats/min
- Taking prescription medication
- Hemoglobin levels < 11.6 g/dL
- Total cholesterol > 240 or HDL < 36
- Fasting glucose >100 mg/dL or <60 mg/dL
- Bilirubin >1.2 mg/dL; albumin < 3.5 or > 5.5 g/dL; alkaline phosphatase (alk phos)
>125 IU/L; alanine aminotransferase (ALT) > 45 U/L; aspartate aminotransferase (AST) >
35 U/L
- Positive (+) toxicology screen
- Pregnant
We found this trial at
1
site
8700 Beverly Blvd # 8211
Los Angeles, California 90048
Los Angeles, California 90048
(1-800-233-2771)
Principal Investigator: Ronald G Victor, MD
Phone: 310-248-8080
Cedars Sinai Med Ctr Cedars-Sinai is known for providing the highest quality patient care. Our...
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