Putative contribution of prostaglandin and bradykinin to muscle reflex hyperactivity in patients on Ace-inhibitor therapy for chronic heart failure.

Aims: In patients with chronic heart failure (CHF), an overactive muscle ergoreceptor reflex (chemo-afferents sensitive to the products of muscle work) is thought to play an important role in the origin of dyspnoea. We sought to investigate whether raised intra-muscular prostaglandins (PG) and bradykinin, as estimated by levels within the venous effluent from exercising skeletal muscle may be involved in symptom generation through the stimulation of the ergoreflex.
Methods and Results: In 19 stable CHF patients and 12 normal controls, cardiopulmonary exercise capacity (peak O2 consumption [peak VO2]) and the ergoreflex contribution to ventilation (post-handgrip regional circulatory occlusion method) were measured. Venous resting and exercise plasma PGE2, PGF1alpha and bradykinin concentrations were assessed. Eleven patients on angiotensin converting enzyme inhibitors and 10 controls were challenged with ketoprofen infusion (to inhibit PG synthesis and bradykinin activity). Patients vs. controls presented lower exercise tolerance (peak VO2 15.9+/-0.7 vs. 33.0+/-1.3 mL/kg/min), an increased ventilatory response to exercise (VE/VCO2 slope 43+/-2 vs. 27+/-0.9) (p<0.0001 for all comparisons). The overactive ergoreflex of CHF (5.1+/-1.3 vs. 0.1+/-0.3 L/min) was significantly related to the increase in PGF1alpha (adjusted R2=0.34, p<0.005) but not PGE2 (adjusted R2=0.16, p>0.05). The increased PG and bradykinin productions both at rest and during exercise in CHF were attenuated after ketoprofen infusion, associated with ergoreflex reduction (-5.1+/-2.2 L/min, p<0.05 vs. saline).
Conclusion: In CHF, overactive muscle ergoreflex is associated with elevated blood concentration of PG and bradykinin. Modulation of these metabolite concentrations acutely reduces the muscle ergoreflex activity, which suggests a causative role in triggering and/or mediating the ergoreflex response.