Effects of Carbon Monoxide Breathing on Blood Vessel Function
Condition: Endothelial Dysfunction
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Carbon Monoxide
Intervention type(s): Drug
Intervention description(s): In healthy young adults 18-39 years of age, The investigator will determine if intermittent inhalation of 0.1% CO, from a 1-Liter bag once every minute for 30-40 min at a level that approaches the CO boost with hookah smoking, augments endothelial function.
Intervention MeSH terms: Carbon Monoxide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other