Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.

Heart failure alters the strength and mechanisms of the muscle metaboreflex. Am. J. Physiol. Heart Circ. Physiol. 278: H818-H828, 2000.-We hypothesized that excessive sympathoactivation observed during strenuous exercise in subjects with heart failure (HF) may result from tonic activation of the muscle metaboreflex (MMR) via hypoperfusion of active skeletal muscle. We studied MMR responses in dogs during treadmill exercise by graded reduction of terminal aortic blood flow (TAQ) before and after induction of HF by rapid ventricular pacing. At a low workload, in both control and HF experiments, large decreases in TAQ were required to elicit the MMR pressor response. During control experiments, this pressor response resulted from increased cardiac output (CO), whereas in HF CO did not increase; thus the pressor response was solely due to peripheral vasoconstriction. In HF, MMR activation also induced higher plasma levels of vasopressin, norepinephrine (NE), and renin. At a higher workload, in control experiments any reduction of TAQ elicited MMR pressor responses. In HF, before any vascular occlusion, TAQ was already below MMR control threshold levels and reductions in TAQ again did not result in higher CO; thus SAP increased via peripheral vasoconstriction. NE rose markedly, indicating intense sympathetic activation. We conclude that in HF, the MMR is likely tonically active at moderate workloads and contributes to the tonic sympathoactivation. dynamic exercise; hormones; dogs; Frank-Starling; rapid ventricular pacing WHEN OXYGEN DELIVERY to active skeletal muscle is insufficient for the ongoing metabolic demands, metabolites accumulate and stimulate afferents within the active skeletal muscle that elicit a powerful pressor response known as the muscle metaboreflex. Activation of the muscle metaboreflex during exercise elicits increases in heart rate, cardiac output, systemic arterial pressure, ventricular performance, central blood volume mobilization, and vasoconstriction in the renal and nonischemic active skeletal muscle vasculatures (9,11,12,14,16,17,22,23,25,33). In addition, metaboreflex activation can also increase the circulating levels of vasoactive hormones (13,18). These marked cardiovascular responses are buffered by arterial (23) and cardiopulmonary (4) baroreflexes. Studies from our laboratory and from others (11, 12, 16-18, 22, 23, 33) have shown that in dogs during mild exercise a clear threshold exists for metaboreflex activation, i.e., initial reductions in blood flow to active skeletal muscle (i.e., hindlimbs) do not elicit any metaboreflex responses. Only when oxygen delivery is reduced below a threshold level do substantial metaboreflex pressor responses occur (25). In contrast, during moderate workloads no clear threshold exists, indicating that the metaboreflex may be tonically active or that the prevailing level of blood flow approximates the threshold for the reflex, and any reduction in perfusion to the active skeletal muscle will engage the muscle metaboreflex (20,22,33).The cardiovas...

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Previous studies have shown that in dogs performing mild to moderate treadmill exercise, partial graded reductions in hindlimb blood flow cause active skeletal muscle to become ischemic and metabolites to accumulate thus evoking the muscle metaboreflex. This leads to a substantial reflex increase in mean arterial pressure (MAP) mediated almost solely via a rise in cardiac output (CO). However, during severe exercise CO is likely near maximal and thus metaboreflex-mediated increases in MAP may be attenuated. We therefore evoked the metaboreflex via partial graded reductions in hindlimb blood flow in seven dogs during mild, moderate, and severe treadmill exercise. During mild and moderate exercise there was a large rise in CO (1.5 +/- 0.2 and 2.2 +/- 0.3 l/min, respectively), whereas during severe exercise no significant increase in CO occurred. The rise in CO caused a marked pressor response that was significantly attenuated during severe exercise (26.3 +/- 7.0, 33.2 +/- 5.6, and 12.2 +/- 4.8 mmHg, respectively). We conclude that during severe exercise the metaboreflex pressor response mechanisms are altered such that the ability of this reflex to increase CO is abolished, and reduced pressor response occurs only via peripheral vasoconstriction. This shift in mechanisms likely limits the effectiveness of the metaboreflex to increase blood flow to ischemic active skeletal muscle. Furthermore, because the metaboreflex is a flow-raising reflex and not a pressure-raising reflex, it may be most appropriate to describe the metaboreflex magnitude based on its ability to evoke a rise in CO and not a rise in MAP.