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Cardiovascular Reflexes and Regional Blood Flows Part 3

By Danielle Senador, PhD | 06 May 2021

Heart with PAU probeThis is the third installment in our “Cardiovascular Reflexes and Regional Blood Flows” blog series. In each of the papers examined previously, we discussed the muscle metaboreflex's different effects on distinct regional blood flows. Through strategic instrumentation, the experimental model distinguishes mechanistic variations in the systemic and the ischemic (active muscle/exercise) vasculatures.

In “Cardiovascular Reflexes and Regional Blood Flows Part 1” the authors conclude a net vasodilation prevalence over vasoconstriction on the systemic/peripheral vasculature during metaboreflex activation. In “Cardiovascular Reflexes and Regional Blood Flows Part 2” the experiments uncovered a neurogenic vasoconstriction within the active ischemic muscle.

In this third and last installment of the series, we will review the publication “Muscle metaboreflex activation during dynamic exercise vasoconstricts ischemic active skeletal muscle” (available with open access - we recommend you view it alongside this blog). In this publication, the vasoconstriction/vasodilation balance and its mechanistic processes are evaluated under pathological conditions. Since heart failure (HF) is marked by an increased sympathetic activity, the study evaluates how this pathological sympathetic overactivity interacts with the metaboreflex-induced vasoconstriction previously described.

Background and Rationale

  1. Muscle metaboreflex is activated by increased O2 demand and metabolite accumulation in the exercising ischemic musculature.
  2. Activation of the metaboreflex mechanism increases sympathetic activity, heart rate (HR), cardiac output (CO), ventricular contractility and blood pressure all aimed to restore adequate O2 supply to the active ischemic muscle.
  3. Metaboreflex activation induces epinephrine release, resulting in β2-adrenergic-mediated vasodilation in the systemic and within the active ischemic muscle vasculatures.
  4. Metaboreflex activation also induces sympathetically mediated vasoconstriction within the active ischemic muscle vasculatures.
  5. The active muscle metaboreflex-induced vasoconstriction limits blood flow restoration to the active muscle, therefore continuously activating the reflex via the balance in O2 demand/supply and O2 delivery/ washout.
  6. Since HF is marked by increased sympathetic activity, it is possible that the muscle metaboreflex-induced vasoconstriction of the ischemic active muscle is exacerbated in HF and could be partially responsible for exercise intolerance observed in HF patients.

Methodology

Using a similar design to what we saw in Experimental Puzzles 2, this study describes the instrumentation of mongrel canines used to independently evaluate the vasoactivity of systemic and regional blood flows.

  1. An ultrasound transit-time flow probe placed around the ascending aorta provided CO.
  2. A second ultrasound transit-time flow probe was placed around the abdominal aorta to provide direct information regarding hindlimb blood flow. This blood flow is directly related to the muscle metaboreflex activation via ischemia, which is induced by gradual occlusion of the abdominal aorta by occluders during treadmill exercise.
  3. Arterial pressure was obtained directly from two catheters: The first pressure catheter was positioned in the abdominal aorta cranial to the occluders to provide mean arterial pressure. The second pressure catheter was positioned in the abdominal aorta caudal to the occluders, or in the femoral artery to provide hindlimb blood pressure.
    • Blood pressure and flow data provided vasoactivity index expressed as resistance (calculated as blood pressure divided by blood flow) and conductance (calculated as blood flow divided by blood pressure).
    • Once the muscle metaboreflex was activated by partial inflation of terminal aortic occluders during moderate treadmill exercise, the hindlimb blood flow can be described as the ischemic vasculature. 
    • The assessment of the vasoactivity in the non-ischemic vasculature was expressed as conductance (non-ischemic vasculature conductance NIVC), and was calculated as CO (total blood flow) minus the abdominal aorta blood flow (ischemic vasculature) divided by mean arterial pressure. 
    • The assessment of the vasoactivity in the ischemic vasculature, calculated as hindlimb blood pressure divided by hindlimb blood flow, was expressed as
  4. Experimental procedures: The muscle metaboreflex activation protocol was performed under the following conditions:
    • Control
    • α1-adrenergic receptor blockade: Prazosin was administered on the day of the experiment.
    • HF: Experiments were performed after HF induction (via continuous rapid ventricular pacingfor approximately 4 weeks).
    • α1-adrenergic receptor blockade in HF: Prazosin was administered on the day of the experiment, once HF was established.

Results and Discussion Highlights

  1. As previously and extensively described, the activation of the muscle metaboreflex, achieved by gradual reductions in hindlimb blood flow (abdominal aorta occluders), drives characteristic increases in cardiac output and blood pressure (see publication figure # 1).
  2. Results described in table 1 of the paper show the expected metaboreflex induced increases in MAP, CO, HR, NIVC and ventricular contractility (first data column in table 1). It also includes, as expected, α-blockade reduced MAP and further increased CO, HR, NIVC and ventricular contractility (second data column in table 1).
  3. The same table also shows the HF effect in lowering MAP, CO and ventricular contractility at rest and during reflex activation. Also, in accordance with the sympathetic overflow in HF, there was a significant vasoconstriction in the nonischemic vasculature shown as decreased NIVC (third data column in table 1). Metaboreflex activation under α1-adrenergic blockade increased CO, HR, NIVC and ventricular contractility in HF animals (fourth data column in table 1).
  4. The study focused mainly on the mean arterial pressure and hindlimb resistance calculated as hindlimb blood pressure divided by hindlimb blood flow, which is graphed and analyzed by a dual linear regression model. The model shows three distinct characteristics: initial slope, threshold, and pressor slope. Once the reduction of the hindlimb blood flow reaches the metaboreflex activation threshold, the characteristic reflex increase in pressure is clearly shown. The two slopes and threshold profile are also present in the hindlimb resistance data (see publication figure #2 and 3).
  5. The pressor slope of the hindlimb resistance is analyzed in control and α1-adrenergic blockade experiments before and after induction of HF (see publication figure #4). The accentuated slope (higher gain) after HF induction signifies an amplified vasoconstriction, which in theory, under continuous stimulus (exercise) presence, would sustain a progressively higher vasoconstriction towards a hypothetical total vasoconstriction.
  6. This sympathetic overdrive, also observed in cardiac sympathetic afferent fibers and chemoreflex activation in HF, could contribute to the exercise intolerance observed in this condition.

 

We hope that you have enjoyed this series and the pathophysiological mechanisms behind exercise-mediated vasomotor regulation in the canine model. Dr. Kaur, the author of the papers discussed here, will be presenting a live-webinar where she will give a more in-depth view of the protocol development, data analysis and answer questions. We hope to see you on May 11th!

 

References:

Muscle metaboreflex activation during dynamic exercise evokes epinephrine release resulting in β2-mediated vasodilation. American Journal of Physiology. Heart and Circulatory Physiology, 24 December 2014, 308: H524 - H529. 

Muscle metaboreflex activation during dynamic exercise vasoconstricts ischemic active skeletal muscle. American Journal of Physiology. Heart and Circulatory Physiology, 15 December 2015, 309: H2145 – H2151.

Muscle metaboreflex activation during dynamic exercise vasoconstricts ischemic active skeletal muscle” (American Journal of Physiology. Heart and Circulatory Physiology, 22 September 2017, 314: H11 – H18.

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