The early effects of chronic hypoxia on the cardiovascular system in the rat: role of nitric oxide

Abstract

Experiments were performed under Saffan anaesthesia on normoxic (N) rats and on chronically hypoxic rats exposed to 12% O2 for 1, 3 or 7 days (1, 3 or 7CH rats): N rats routinely breathed 21% O2 and CH rats 12% O2. The 1, 3 and 7CH rats showed resting hyperventilation relative to N rats, but baseline heart rate (HR) was unchanged and arterial blood pressure (ABP) was lowered. Femoral vascular conductance (FVC) was increased in 1 and 3CH rats, but not 7CH rats. When 1-7CH rats were acutely switched to breathing 21% O2 for 5 min, ABP increased and FVC decreased, consistent with removal of a hypoxic dilator stimulus that is waning in 7CH rats. We propose that this is because the increase in haematocrit and vascular remodelling in skeletal muscle help restore the O2 supply. The increases in FVC evoked by acute hypoxia (8% O2 for 5 min) and by infusion for 5 min of alpha-calcitonin gene-related peptide (alpha-CGRP), which are NO-dependent, were particularly accentuated in 1CH, relative to N rats. The NO synthesis inhibitor L-NAME increased ABP, decreased HR and greatly reduced FVC, and attenuated increases in FVC evoked by acute hypoxia and alpha-CGRP, such that baselines and responses were similar in N and 1-7CH rats. We propose that in the first few days of chronic hypoxia there is tonic NO-dependent vasodilatation in skeletal muscle that is associated with accentuated dilator responsiveness to acute hypoxia and dilator substances that are NO -dependent.

Figure 1. Respiratory and cardiovascular responses evoked in normoxic (N rats) by a 5-min period of breathing 12% O₂ and in chronically hypoxic rats exposed to 12% O₂ for 1, 3 or 7 days (1, 3 and 7CH rats) by a 5-min period of breathing 21% O₂

Groups of rats are indicated below the pairs of columns. In each case, left-hand column indicates value recorded under control conditions (breathing 21% O₂ and 12% O₂ for N and CH rats, respectively), while right-hand column shows value recorded in 5th minute of breathing 12% O₂ and 21% O₂ for N and CH rats, respectively. All values are shown as mean ± s.e.m. R_F, V_T, FVC, FBF, HR and MABP indicate respiratory frequency, tidal volume, femoral vascular conductance, femoral blood flow, heart rate and mean arterial blood pressure, respectively. *P < 0.05: baseline in N rats breathing 21% O₂versus CH rats breathing 12% O₂. †P < 0.05: baseline versus 5th minute of breathing 12% O₂ (N rats) or 21% O₂ (CH rats). •P < 0.05: 5th minute of breathing 12% O₂ in N rats versus baseline in CH rats breathing 12% O₂. ▵P < 0.05: 5th minute of breathing 21% O₂ in CH rats versus baseline in N rats breathing 21% O₂

Figure 2. Original recordings of respiratory and cardiovascular responses evoked in 1CH rat by breathing 21% O₂ for 5 min

Arrows below indicate times at which inspirate was changed from 12% O₂ to 21% O₂ and back again. Abbreviations as in Fig. 1.

Figure 3. Respiratory and cardiovascular responses evoked by a 5-min period of acute hypoxia (breathing 8% O₂) in N rats and 1, 3 and 7CH rats before and after l-NAME (left and right panels, respectively)

Groups of rats are indicated below the pairs of columns; abbreviations as in Fig. 1. In each case, left-hand column indicates value recorded under control conditions (breathing 21% O₂ and 12% O₂, N and CH rats, respectively), while right-hand column shows value recorded in the 5th minute of breathing 8% O₂. Values are shown as mean ± s.e.m. ††P < 0.01, †P < 0.05: baseline versus 5th minute of 8% O₂ in N or CH rats. §P < 0.05: 5th minute of breathing 8% O₂ in CH versus N rats. πP < 0.05: baseline before versus after l-NAME in N or CH rats. •P < 0.05: value attained in 5th minute of 8% O₂ before versus after l-NAME in N or CH rats. For simplicity, significance values for baselines in N rats breathing 21% O₂ versus CH rats breathing 12% O₂ are not shown.

Figure 4. Original recordings of respiratory and cardiovascular responses evoked in 1CH rat by breathing 8% O₂ for 5 min before and after l-NAME

Arrows below sets of traces indicate times at which inspirate was switched from 12% O₂ to 8% O₂ and back again. Abbreviations as in Fig. 1.

Figure 5. Respiratory and cardiovascular responses evoked by 5 min infusion of α-CGRP in N rats and 1, 3 and 7CH rats before and after l-NAME

Groups of rats are indicated below pairs of columns; abbreviations as in Fig. 1. In each case, left-hand column indicates value recorded under control conditions (breathing 21% O₂ and 12% O₂ in N and CH rats, respectively), while right-hand column shows value recorded in 5th minute of α-CGRP infusion. Values are shown as mean ± s.e.m. ††P < 0.01, †P < 0.05: baseline value at 5th minute of α-CGRP infusion in N or CH rats. §P < 0.05: 5th minute of α-CGRP in CH versus N rats. ••P < 0.01, •P < 0.05: value attained in the 5th minute of α-CGRP infusion before versus after l-NAME in N or CH rats. For simplicity, effects of l-NAME on baselines are not shown.