A Potential Link between the C5a Receptor 1 and the β1-Adrenoreceptor in the Mouse Heart

Abstract

PurposeInflammation may contribute to the pathogenesis of specific cardiovascular diseases, but it is uncertain if mediators released during the inflammatory process will affect the continued efficacy of drugs used to treat clinical signs of the cardiac disease. We investigated the role of the complement 5a receptor 1 (C5aR1/CD88) in the cardiac response to inflammation or atenolol, and the effect of C5aR1 deletion in control of baseline heart rate in an anesthetized mouse model.MethodsAn initial study showed that PMX53, an antagonist of C5aR1 in normal C57BL6/J (wild type, WT) mice reduced heart rate (HR) and appeared to have a protective effect on the heart following induced sepsis. C5aR1 knockout (CD88-/-) mice had a lower HR than wild type mice, even during sham surgery. A model to assess heart rate variability (HRV) in anesthetized mice was developed to assess the effects of inhibiting the β1-adrenoreceptor (β1-AR) in a randomized crossover study design.ResultsHR and LF Norm were constitutively lower and SDNN and HF Norm constitutively higher in the CD88-/- compared with WT mice (P< 0.001 for all outcomes). Administration of atenolol (2.5 mg/kg) reduced the HR and increased HRV (P< 0.05, respectively) in the wild type but not in the CD88-/- mice. There was no shift of the sympathovagal balance post-atenolol in either strains of mice (P> 0.05), except for the reduced LF/HF (Lower frequency/High frequency) ratio (P< 0.05) at 60 min post-atenolol, suggesting increased parasympathetic tone of the heart due to the effect of atenolol administration. The HR of the WT mice were lower post atenolol compared to the CD88-/- mice (P = 0.001) but the HRV of CD88-/- mice were significantly increased (P< 0.05), compared with WT mice.ConclusionKnockout of the C5aR1 attenuated the effect of β1-AR in the heart, suggesting an association between the β1-AR and C5aR1, although further investigation is required to determine if this is a direct or causal association.

Preclinical Pharmacokinetics of Complement C5a Receptor Antagonists PMX53 and PMX205 in Mice

“…The cyclic peptide complement C5aR1 antagonists, PMX53 and PMX205, have been used extensively by various research groups in various species including mice, rats, cats, dogs, and humans . Out of all the species, studies have been performed most extensively in mice, with >100 publications to date using these compounds for a number of diseases using a variety of administration routes in mice (e.g., i.v., s.c., i.p., p.o., drinking water, and others). − ,− Despite this plethora of mouse studies using these compounds, only a few studies have performed pharmacokinetics, which are generally limited in scope and only examining one route of administration. ,,− Furthermore, pharmacodynamics and therapeutic effects of drugs are difficult to correlate in the absence of pharmacokinetic data from various administration routes within the same species.…”

Sleep fragmentation exacerbates myocardial ischemia‒reperfusion injury by promoting copper overload in cardiomyocytes

“…Spectrum was integrated in low-frequency (LF, 0.20–0.75 Hz) and high-frequency (HF, 0.75–2.5 Hz) bands. The HF was to evaluate cardiac sympathovagal balance as previously reported 80 , 81 .…”

Complement as driver of systemic inflammation and organ failure in trauma, burn, and sepsis

“…However, further clinically meaningful functional hemodynamic data need to be established. In addition, the interplay between adrenoreceptors as drivers of the heart performance and complement receptors, such as the C1 receptor and C5aR1, needs further mechanistic elucidation [ 154 ].…”