Alpha-adrenergic inhibition increases collateral circuit conductance in rats following acute occlusion of the femoral artery

Abstract

This study evaluated whether alpha-adrenergic activation contributes to collateral circuit vascular resistance in the hindlimb following acute unilateral occlusion of the femoral artery in rats. Blood pressures (BPs) were measured above (caudal artery) and below (distal femoral artery) the collateral circuit. Arterial BPs were reduced (15-35 mmHg) with individual (prazosin, rauwolscine) or combined (phentolamine) alpha-receptor inhibition. Blood flows (BFs) were measured using microspheres before and after alpha inhibition during the same treadmill speed. alpha(1) inhibition increased blood flow by approximately 40% to active muscles that were not affected by femoral occlusion, whereas collateral-dependent BFs to the calf muscles were reduced by 29 +/- 8.4% (P < 0.05), due to a decrease in muscle conductance with no change in collateral circuit conductance. alpha(2) inhibition decreased both collateral circuit (39 +/- 6.0%; P < 0.05) and calf muscle conductance (36 +/- 7.3%; P < 0.05), probably due to residual alpha(1) activation, since renal BF was markedly reduced with rauwolscine. Most importantly, inhibiting alpha(2) receptors in the presence of alpha(1) inhibition increased (43 +/- 12%; P < 0.05) collateral circuit conductance. Similarly, non-selective alpha inhibition with phentolamine increased collateral conductance (242 +/- 59%; P < 0.05). We interpret these findings to indicate that both alpha(1)- and alpha(2)-receptor activation can influence collateral circuit resistance in vivo during the high flow demands caused by exercise. Furthermore, we observed a reduced maximal conductances of active muscles that were ischaemic. Our findings imply that in the presence of excessive sympathetic activation, which can occur in the condition of intermittent claudication during exertion, an exaggerated vasoconstriction of the existing collateral circuit and active muscle will occur.

Figure 1. Arterial vessels of the hindlimb and diagram illustrating the collateral circuit in the hindlimb

Occlusion of the femoral artery causes the distal limb muscles to become collateral-dependent tissues. Note that blood flow to the distal limb tissues must circumvent the obstruction of the femoral artery through the upper limb vasculature (as defined by the thick lines and resistances). The X in the X-ray shows the site of femoral artery occlusion, whereas the black arrow shows the internal iliac vessel complex (hypogastric trunk; Greene, 1963) from which collateral flow emanates. The white arrow on the X-ray illustrates re-entry vessels which deliver collateral blood flow into the ‘normal’ distal limb arteries (e.g. distal femoral, popliteal, saphenous). The formulas define how collateral circuit and distal limb tissue conductances were calculated. G is vascular conductance; R vascular resistance; Q_t total blood flow; P (pressure) = zero is the pressure of the femoral vein, assumed to be 0 mmHg. Note that R_coll entry (resistance from the origin of the internal iliac to entry of the collateral vessels) can have vascular elements in common that contribute to the total resistance of the thigh muscles.

Figure 2. Blood flows and conductances in the kidney and non-ischaemic, non-hindlimb muscles following prazosin infusion

*Significantly increased with prazosin (P < 0.01).

Figure 3. Blood flows and conductances in the proximal, distal and calf muscle regions of the occluded and non-occluded hindlimbs before and after prazosin infusion

Note the differences in y-axes between the non-occluded and occluded hindlimbs. *Significantly increased or decreased with prazosin (P < 0.05).

Figure 4. Blood flows and conductances in the muscle fibre sections of the occluded and non-occluded hindlimbs before and after prazosin infusion

Soleus: slow-twitch red; Red: fast-twitch red; White (white gastrocnemius): fast-twitch white; and Plantaris: mixed fibre. Note the differences in y-axes between the non-occluded and occluded hindlimbs. *Significantly increased or decreased with prazosin (P < 0.05).

Figure 5. Blood flows and conductances in the kidney and non-ischaemic, non-hindlimb muscles following rauwolscine infusion

*Significantly increased or decreased with rauwolscine (P < 0.025).

Figure 6. Blood flows and conductances in the proximal, distal and calf muscle regions of the occluded and non-occluded hindlimbs before and after rauwolscine infusion

Note the differences in y-axes between the non-occluded and occluded hindlimbs. *Significantly decreased with rauwolscine (P < 0.001).

Figure 7. Blood flows and conductances in the muscle fibre sections of the occluded and non-occluded hindlimbs before and after rauwolscine infusion

Soleus: slow-twitch red; Red: fast-twitch red; White (white gastrocnemius): fast-twitch white; and Plantaris: mixed fibre. Note the differences in y-axes between the non-occluded and occluded hindlimbs. *Significant decrease with rauwolscine (P < 0.05).

Figure 8. Blood flows and conductances in the proximal, distal and calf muscle regions of the occluded and non-occluded hindlimbs with prazosin and after the addition of rauwolscine

Note the differences in y-axes between the non-occluded and occluded hindlimbs. *Significant increase with the addition of rauwolscine (P < 0.01).

Figure 9. Blood flows and conductances in the muscle fibre sections of the occluded and non-occluded hindlimbs with prazosin and the addition of rauwolscine

Soleus: slow-twitch red; Red: fast-twitch red; White (white gastrocnemius): fast-twitch white; and Plantaris: mixed fibre. Note the differences in y-axes between the non-occluded and occluded hindlimbs. *Significantly increased with rauwolscine (P < 0.001).

Figure 10. Blood flows and conductances in the kidney and non-ischaemic, non hindlimb muscles following phentolamine infusion

*Significantly increased or decreased with phentolamine (P < 0.05).

Figure 11. Blood flows and conductances in the proximal, distal and calf muscle regions of the occluded and non-occluded hindlimbs before and after phentolamine infusion

Note the differences in y-axes between the non-occluded and occluded hindlimbs. *Significantly increased with phentolamine (P < 0.005).

Figure 12. Influence of bilateral versus unilateral occlusion of the femoral artery on the conductances in the muscle fibre sections before and after phentolamine infusion

Soleus: slow-twitch red; Red: fast-twitch red; White (white gastrocnemius): fast-twitch white; and Plantaris: mixed fibre. *Significantly greater than occluded (unilateral or bilateral; P < 0.001). †Significantly greater than corresponding group, Pre-Phentolamine (P < 0.001).

Figure 14. Collateral circuit conductance prior to and following pharmacological inhibition of α-receptors

Pre-drug, prazosin, and phentolamine values are the combined responses across treatment groups for each of these respective measurements. *Significant reduction in collateral conductance from pre-drug, observed with α₂-receptor inhibition (rauwolscine); † was removed by the prior inhibition of α₁-receptors with prazosin (different from rauwolscine only; P < 0.05); whereas ‡ combined inhibition of α₁- and α₂-receptors with non-selective phentolamine significantly increased collateral circuit conductance (above pre-drug; P < 0.01).

Figure 13. Influence of luminal pressure on the vasoresponsiveness of isolated collateral vessels, obtained from the distal perforating artery of the rat hindlimb

Acetylcholine-induced dilatation was significantly less (P < 0.05) at the low pressure, typical in the artery following femoral artery occlusion, whereas vasoconstriction to phenylephrine was not different across pressures.