Arterial partial pressure alteration of CO2 ( JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM1/v/2017-08-04T230120Z/r/image-tiff ) affects not only the cerebral blood flow velocity but also the systemic arterial blood pressure (BP). At the same time, BP can affect the cerebral blood flow. The objective of the present research is to study the impact of the JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM2/v/2017-08-04T230120Z/r/image-tiff level on cerebrovascular CO2 reactivity ( JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM3/v/2017-08-04T230120Z/r/image-tiff ) and BP as well as the impact of BP upon JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM4/v/2017-08-04T230120Z/r/image-tiff alteration by hypercapnia and hypocapnia. Cerebral blood flow velocity was recorded by means of transcranial Doppler in both middle cerebral arteries (MCAv left and right). The mean arterial pressure (MAP) was studied using the finger photoplethysmography method, arterial blood oxygen saturation was estimated by the pulse oximetry method, and end-tidal JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM5/v/2017-08-04T230120Z/r/image-tiff ( JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM6/v/2017-08-04T230120Z/r/image-tiff ) was measured with an infrared capnograph. After a recording of the reference values of all the parameters, all the volunteers underwent a rebreathing as well as a hyperventilation. At rest, JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM7/v/2017-08-04T230120Z/r/image-tiff was 33.6 (SD 3.1) mmHg. At rebreathing, MCAv increased at 38 mmHg JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM8/v/2017-08-04T230120Z/r/image-tiff , MAP – at 43 mmHg JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM9/v/2017-08-04T230120Z/r/image-tiff . By hyperventilation, MCAv decreased at 28 mmHg JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM10/v/2017-08-04T230120Z/r/image-tiff , MAP – at 26 mmHg JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM11/v/2017-08-04T230120Z/r/image-tiff . When JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM12/v/2017-08-04T230120Z/r/image-tiff reached 43 mmHg, JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM13/v/2017-08-04T230120Z/r/image-tiff increased from 2.3 (SD 1.4) to 3.3 (SD 1.2)%/mmHg (P<0.01). When JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM14/v/2017-08-04T230120Z/r/image-tiff decreased to 26 mmHg, JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM15/v/2017-08-04T230120Z/r/image-tiff increased from −3.6 (SD 2.5) to −5.9 (SD 3.9)%/mmHg (P<0.01). Within the alteration of JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM16/v/2017-08-04T230120Z/r/image-tiff above 43 and under 26 mmHg, BP increased and decreased, respectively, leading to a change in JOURNAL/blpmo/04.02/00126097-201404000-00005/math_5MM17/v/2017-08-04T230120Z/r/image-tiff .

The review introduces the stages of formation and experimental confirmation of the hypothesis regarding the mutual potentiation of neuroprotective effects of hypoxia and hypercapnia during their combined influence (hypercapnic hypoxia). The main focus is on the mechanisms and signaling pathways involved in the formation of ischemic tolerance in the brain during intermittent hypercapnic hypoxia. Importantly, the combined effect of hypoxia and hypercapnia exerts a more pronounced neuroprotective effect compared to their separate application. Some signaling systems are associated with the predominance of the hypoxic stimulus (HIF-1α, A1 receptors), while others (NF-κB, antioxidant activity, inhibition of apoptosis, maintenance of selective blood–brain barrier permeability) are mainly modulated by hypercapnia. Most of the molecular and cellular mechanisms involved in the formation of brain tolerance to ischemia are due to the contribution of both excess carbon dioxide and oxygen deficiency (ATP-dependent potassium channels, chaperones, endoplasmic reticulum stress, mitochondrial metabolism reprogramming). Overall, experimental studies indicate the dominance of hypercapnia in the neuroprotective effect of its combined action with hypoxia. Recent clinical studies have demonstrated the effectiveness of hypercapnic–hypoxic training in the treatment of childhood cerebral palsy and diabetic polyneuropathy in children. Combining hypercapnic hypoxia with pharmacological modulators of neuro/cardio/cytoprotection signaling pathways is likely to be promising for translating experimental research into clinical medicine.