Measures of cardiovascular function suggest autonomic nervous system dysregulation in the male lewis rat after surgical induction of joint injury

Abstract

Purpose: A recent review entitled “The brain-joint axis in osteoarthritis: nerves, circadian clocks and beyond” by Prof. Francis Berenbaum provides a framework for the contribution of the autonomic nervous system in osteoarthritis (OA). The autonomic nervous system is comprised of two branches, the parasympathetic (PNS) and sympathetic nervous systems (SNS) with reciprocal effects on involuntary actions throughout the body, such as heart rate and blood pressure. In homeostasis, the PNS and SNS balance these body functions, and serve as important regulators of immune system homeostasis and allostasis. An imbalance between the PNS and SNS functions is known as autonomic dysregulation. Because the two branches have reciprocal effects on heart rate, heart rate parameters may be used as an indicator of autonomic dysregulation. Autonomic balance is dysregulated in chronic inflammatory diseases, such as rheumatoid arthritis, hypertension, and diabetes, among others. To be clear, the etiologies of each of these diseases are different, but the commonality is inflammation that fails to resolve. Similarly, OA presents with chronic inflammation, but OA-related inflammation is low-grade and local, often failing to alter circulating levels of cytokines. Despite the emerging evidence for autonomic nervous system dysregulation in inflammatory joint conditions, changes have not yet been characterized in a rodent model of OA. Methods: Radiotelemetry probes were implanted into the descending aorta to collect blood pressure measurements from which the heart rate was derived from the peaks in pulse pressure. Heart rate was evaluated as an indirect assessment of vagal nerve function, a key part of the autonomic nervous system. Measurements were collected for 5 minutes each hour for 24 hours. Recordings occurred at baseline and every other week for 8 weeks after induction of OA via medial collateral ligament transection plus medial meniscus transection (MCLT+MMT; n=13) or MCLT alone (n=5), with skin incision (n=9) used as a control. Because stress is known to exaggerate autonomic responses, characteristics of heart rate responses to novel environment stress were also assessed (n=4-8/group). A 5-HT3a agonist, 1-phenylbiguanide, with reported vagal activation properties was used to indirectly assess vagal nerve function. Heart rate and blood pressure responses to the 5-HT3a agonist were recorded in anesthetized rats (n=5-8/group). Heart rate responses to mechanical stimuli applied at the knee via a weight and pulley system were used to indirectly assess cardiac vagal responses. Results: Longitudinal heart rate measurements revealed decrease in mean heart rate over time (Fig. 1a; p=0.037, week main effect) in all groups. Additionally, MCLT and MCLT+MMT had a tendency for a more rapid decline in heart rate over the 8 week study period (p=0.082, surgery*week interaction). Introduction to novel environment produced a typical increase in heart rate in all groups, confirming a stressful stimulus. This response was significantly different between groups (Figure 1b; p=0.045, surgery main effect), with a trend of attenuation in MCLT (p=0.067) and MCLT + MMT (p=0.09) groups. Mechanical stimuli at the knee resulted in a sudden drop in heart rate and blood pressure, with no differences seen between groups (Fig. 2a & 2b). However, the 5-HT3a agonist produced a dose-dependent drop in heart rate in all groups (p<0.001; dose main effect) with a larger drop in heart rate in both MCLT (p=0.014) and MCLT+MMT (p=0.010) animals at the highest dose compared to control (Fig. 2c & 2d).Figure 2Heart rate and blood pressure responses to mechanical stimulation at the knee (a,b) and systemic administration of a 5-HT3a agonist (c,d). Sudden drops in heart rate and blood pressure were observed with mechanical stimulation at the knee, with no differences seen between groups. Responses to the 5-HT3a agonist were dose-dependent with MCLT and MCLT+MMT groups having a larger drop in heart rate at the highest dose (bar indicates p<0.05).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusions: Measurement of cardiovascular responses to novelty stress and pharmacological stimulation of 5-HT3a receptors, which are reportedly able to induce acute cardiac vagal responses, demonstrate for the first time a shift in ANS function in rodent knee injury models of OA. Our data suggest a sensitization of cardiac vagal activation to acute stress and 5-HT3a agonist in OA groups, which was also supported by the tendency for a more prominent chronic reduction in heart rate in OA groups. Lastly, acute mechanical stimulation of the knee produced an immediate reduction in heart rate, suggesting a direct neural joint-brain connection that may modulate autonomic responses in OA. Although we did not observe a difference in these responses between control and OA groups, further studies should delineate this using direct measurements of vagal nerve activity in response to mechanical stimulus of the joint in OA.