Impairment of exercise hyperaemia in familial hypercholesterolaemia: Complex interplay of vasodilators vs. vasoconstrictors

The Scottish surgeon John Hunter is credited with positing the fundamental physiological concept that, ‘blood goes where it is needed’ in his famous A treatise on the blood, inflammation and gun-shot wounds, a work published posthumously in 1794. Although studies have specifically examined this phenomenon for well over a century, precisely how blood knows where it needs to go and how specific disease states impact this fundamental phenomenon remains one of the central questions of physiology to this day. Understanding the mechanisms responsible for maintaining the overall balance between tissue oxygen delivery and metabolism is critical as impaired microvascular function is recognized as an early independent predictor of cardiovascular morbidity and mortality (Murthy et al. 2012). Recent evidence indicates that while nitric oxide plays a relatively modest role in skeletal muscle hyperaemia during exercise-induced increases in metabolism (Tschakovsky & Joyner, 2008), endothelial dysfunction in the setting of disease states such as hypercholesterolaemia is potentially quite deleterious as diminished bioavailability of nitric oxide not only decreases a vasodilator influence but could also act to augment vasoconstrictor influences. Thus, attenuation of cardiac output responses to exercise in hypercholesterolaemia (de Beer et al. 2013) may be related as much if not more so to the augmentation of potent vasoconstrictor pathways (e.g. endothelin) as to the moderation of vasodilator pathways. This scenario is supported by prior studies which demonstrated that the inhibition of endothelin type A receptors (ETA) enhanced forearm blood flow responses to handgrip exercise in hypertensive but not normotensive human subjects (McEniery et al. 2002). However, whether this effect is evident in non-hypertensive disease states has not been examined. In the present issue of The Journal of Physiology, Bender et al. (2014) specifically address this intriguing hypothesis by investigating the extent to which enhanced endothelin-mediated vasoconstriction contributes to the impairment of exercise hyperaemia in the setting of severe familial hypercholesterolaemia. This hypothesis was examined in chronically instrumented swine with and without familial hypercholesterolemia. Rapacz familial hypercholesterolaemic swine were fed a high-fat chow for ∼5 months. This dietary regimen significantly increased low-density lipoprotein cholesterol levels >20-fold relative to normal control swine. Importantly, no differences in blood pressure, glucose or triglyceride concentrations were noted between the groups. Consistent with previous results from this investigative team (de Beer et al. 2013), exercise-induced increases in cardiac index (cardiac output normalized to body weight) were diminished by ∼50% in hypercholesterolaemic swine. However, contrary to the stated hypothesis, combined inhibition of ETA and ETB receptors augmented systemic vascular conductance ∼45% at rest and ∼15% at the highest level of exercise in normal control swine but only increased systemic conductance ∼20% at rest, with no effect during exercise, in hypercholesterolaemic swine. Similar diminished effects of endothelin receptor blockade were also observed in the pulmonary circulation of hypercholesterolaemic vs. normal control swine. Thus, findings from this investigation actually support a reduced role for endothelin in regulating systemic and pulmonary vascular tone in the setting of hypercholesterolaemia. The diminished effects of endothelin in hypercholesterolaemic swine were associated with a modest ∼10% reduction in circulating endothelin concentration while vascular smooth muscle expression of ETA and ETB receptor protein was essentially identical between groups. Interestingly, endothelin-mediated vasoconstriction of skeletal muscle arterioles was enhanced in hypercholesterolaemic swine. This effect was abolished by the inhibition of nitric oxide synthesis, indicating that augmented constriction of the skeletal microcirculation is indeed mediated by decreased nitric oxide bioavailability. These data highlight the potential for the heightened vasoconstrictor hypothesis in selective vascular beds, which should be further explored. In particular, it is unclear whether deficits in blood flow to active skeletal or cardiac muscle were present in hypercholesterolaemic swine. Such deficits, along with the potential for limitations in the redistribution of cardiac output with exercise, could contribute to the marked decreases in whole body oxygen consumption and cardiac index observed in hypercholesterolaemic swine. Alternatively, under resting conditions mixed ETA/B receptor blockade with tezosentan significantly decreased mean arterial pressure, but had no effect on pulmonary arterial pressure in normal swine. Interestingly, the pressure effects of tezosentan were opposite in hypercholesterolaemic swine, where endothelin receptor inhibition had a more modest effect on resting systemic pressure but significantly decreased pulmonary artery pressure. Although the overall effect of endothelin receptor blockade on systemic and pulmonary conductance is diminished in hypercholesterolaemic swine, the collective influence on pulmonary vascular resistance and cardiac index (key determinants of pulmonary artery pressure) suggests that endothelin probably contributed to the pulmonary hypertension which was quite pronounced in the hypercholesterolaemic swine at rest. Accordingly, the vascular effects of endothelin appear to be specific to the vascular bed being studied and to the underlying conditions of these beds at the time of study. Further examination of potential differences in the activation of ETA vs. ETB receptors and downstream end-effector mechanisms should also be considered. In conclusion, the study by Bender et al. (2014) reveals novel effects of familial hypercholesterolaemia on vascular function and the complex (and somewhat paradoxical) interplay between endothelial-derived factors in the regulation of systemic and pulmonary resistance. Although the findings do not support a specific role for ETA/B receptor signalling in the impairment of exercise hyperaemia, the possibility that other vasoconstrictor pathways are augmented in the setting of disease states such as familial hypercholesterolaemia (e.g. thromboxane A2, α-adrenoceptors, angiotensin II) warrants further investigation.