Effects of maternal hypoxia on muscle vasodilatation evoked by acute systemic hypoxia in adult rat offspring: changed roles of adenosine and A1 receptors

Abstract

Suboptimal conditions in utero can have long-lasting effects including increased risk of cardiovascular disease in adult life. Such programming effects may be induced by chronic systemic hypoxia in utero (CHU). We have investigated how CHU affects cardiovascular responses evoked by acute systemic hypoxia in adult male offspring, recognising that adenosine contributes to hypoxia-induced muscle vasodilatation and bradycardia by acting on A(1) receptors in normal (N) rats. In the present study, dams were housed in a hypoxic chamber at 12% O(2) for the second half of gestation; offspring were born and reared in air until 9-10 weeks of age. Under anaesthesia, acute systemic hypoxia (breathing 8% O(2) for 5 min) evoked similar biphasic tachycardia/bradycardia, fall in arterial pressure and increase in femoral vascular conductance (FVC) in N and CHU rats (+2.0 vs. +2.7 conductance units respectively). However, in CHU rats, neither the non-selective adenosine receptor antagonist 8-sulphophenyltheopylline (8-SPT), nor the A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) affected the increase in FVC, but DPCPX attenuated the hypoxia-induced bradycardia. Further, in N and CHU rats, 5 min infusion of adenosine induced similar increases in FVC; in CHU rats, DPCPX reduced the adenosine-induced increase in FVC (by >50%) and accentuated the concomitant tachycardia. These results suggest that CHU rats have functional A(1) receptors in heart and vasculature, but the release and/or vasodilator influence of adenosine on the endothelium in acute hypoxia is attenuated and replaced by other dilator factors. Such changes from normal endothelial function may have implications for general cardiovascular regulation.

Figure 1. Effect of chronic hypoxia in utero (12% O₂) on baseline cardiovascular variables and responses evoked by acute systemic hypoxia (8% O₂)

Mean values ±s.e.m. of mean arterial pressure (MAP), heart rate (HR), femoral blood flow (FBF) and integrated femoral vascular conductance (IntFVC) are shown during normoxia (open and filled shading in N and CHU rats respectively) and for the 5 min period of hypoxia (hashed shading). †P < 0.05, †††P < 0.001: difference between normoxia and hypoxia in N or CHU rats; *P < 0.05, ***P < 0.001: difference between N and CHU in normoxia or hypoxia.

Figure 2. Effect of the adenosine receptor antagonist 8-SPT on cardiovascular responses evoked by acute systemic hypoxia in N and CHU rats

Columns show mean change ±s.e.m. from baseline in mean arterial pressure (MAP), heart rate (HR), femoral blood flow (FBF) and integrated femoral vascular conductance (IntFVC) before (N: hatched, CHU: crosshatch) and after 8-SPT (N: hatched, CHU: stippled). †P < 0.05, ††P < 0.01: difference between before and after 8-SPT; *P < 0.05, **P < 0.01: difference between response evoked in N and CHU. There were no significant differences between values recorded before and after 8-SPT in CHU rats.

Figure 3. Cardiovascular responses evoked by infusion of adenosine in N and CHU rats

Mean values ±s.e.m. of mean arterial pressure (MAP), heart rate (HR), femoral blood flow (FBF) and of integrated femoral vascular conductance (IntFVC) are shown before (open and filled shading in N and CHU rats, respectively) and during the 5 min of infusion (hatched shading). ††P < 0.01, †††P < <0.001: difference between values recorded before and during adenosine infusion.

Figure 4. Effect of the A₁ adenosine receptor antagonist DPCPX on changes in cardiovascular variables evoked by infusion of adenosine in CHU rats

Columns show mean change ±s.e.m. from baseline in mean arterial pressure (MAP), heart rate (HR), femoral blood flow (FBF) and integrated femoral vascular conductance (IntFVC) before (crosshatched) and after (stippled) DPCPX administration. ††P < 0.01, †††P < 0.001: difference between values recorded before and during adenosine infusion.

Figure 5. Effect of the A₁ adenosine receptor antagonist DPCPX on changes in cardiovascular variables evoked by acute systemic hypoxia in CHU rats

Columns show mean change ±s.e.m. from baseline in mean arterial pressure (MAP), heart rate (HR), femoral blood flow (FBF) and integrated femoral vascular conductance (IntFVC) before (crosshatched) and after (stippled) DPCPX adminstration. †††P < 0.001: difference between normoxia and hypoxia in N or CHU rats; *P < 0.05: difference between N and CHU in normoxia or hypoxia.