This is the second installment in our “Cardiovascular Reflexes and Regional Blood Flows” blog series. Here, we target a practical approach to different research models, focusing on complicated mechanisms and their results. As mentioned before, each of these blogs can be read as independent pieces, however, the “series format” will facilitate a progressive understanding of the approaches and methodologies used in the studies subsequently discussed.

In “Cardiovascular Reflexes and Regional Blood Flows Part 1”  we reviewed the publication “Muscle metaboreflex activation during dynamic exercise evokes epinephrine release resulting in β2-mediated vasodilation.”

To summarize, the authors explored how the muscle metaboreflex affects different regional blood flows. Via a combination of carefully chosen instrumentation and pharmacological maneuvers, the experimental model could discriminate mechanistic differences between the systemic and the ischemic (active muscle/exercise) vasculatures’ regulation. This ultimately revealed a net vasodilation prevalence over vasoconstriction on the systemic/peripheral vasculature during metaboreflex activation.

In this installment, we will review the publication “Muscle metaboreflex activation during dynamic exercise vasoconstricts ischemic active skeletal muscle” which is freely available online.

Background and Rationale

1. Muscle metaboreflex is activated by increased O₂ demand and metabolite accumulation in the exercising musculature (active ischemic muscle).
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. The continuous engagement of the reflex is a balance in O₂ demand/supply and O₂ delivery/ washout.
4. Although the muscle metaboreflex aims to restore adequate O₂ supply to the active ischemic muscle, through epinephrine-β2-mediated vasodilation, it can also vasoconstrict the under under-perfused muscle from which it originates via the sympathetic system (α-mediated).
5. This study evaluates the interaction between vasodilation and sympathetic-mediated vasoconstriction in the ischemic skeletal muscle, in which vasoconstriction would be attenuated after α-receptor blockade and potentiated after β-receptor blockade.

Methodology

Using a similar design to what we saw in Experimental Puzzles Part 1 blog, 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. An ultrasound transit-time flow probe was also paced 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, cranially to the occluders, and provided mean arterial pressure. The second pressure catheter was positioned in the abdominal aorta, caudally to the occluders, or in the femoral artery providing hindlimb blood pressure.
   1. 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).
   2. Once the muscle metaboreflex is activated, by partial inflation of terminal aortic occluders during moderate treadmill exercise, the hindlimb blood flow can be described as the ischemic vasculature.
   3. The assessment of the vasoactivity in the non-ischemic vasculature was expressed as conductance and was calculated as CO (total blood flow) minus the abdominal aorta blood flow (ischemic vasculature) divided by mean arterial pressure.
   4. The assessment of the vasoactivity in the ischemic vasculature was expressed as resistance and was calculated as hindlimb blood pressure divided by hindlimb blood flow.
4. Experimental procedures: The muscle metaboreflex activation protocol was performed under the following conditions:
   1. Control
   2. α1-adrenergic receptor blockade (prazosin)
   3. β-adrenergic receptor blockade (propranolol)
   4. α1 + β receptor blockade

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. The study focuses mainly on hindlimb resistance, 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 (via occluders) of the hindlimb blood flow reaches the metaboreflex activation threshold, we can clearly see the characteristic reflex increase in pressure. The dual slopes and threshold profile is also present in the hindlimb resistance data (see publication figure #2).
3. In control experiments, the activation of the muscle metaboreflex (pressor slope) increased hindlimb resistance (see publication figure # 3). The initial hindlimb blood flow reductions resulted in metabolic vasodilation, as shown by a decrease in hindlimb vascular resistance. Once the threshold was reached, this metabolic vasodilation was opposed by vasoconstriction, in further occlusions.
4. The α1-blocklade not only abolished the increase but also decreased hindlimb resistance (see publication figure # 3, 1st graph), indicating α1-mediated sympathetic vasoconstriction in the ischemic skeletal muscle during metaboreflex activation.
5. As expected, since previous work demonstrated a metaboreflex- induced β2-mediated vasodilation in ischemic skeletal muscle, the β-blockade increased hindlimb resistance (see publication figure # 3, 2nd graph).
6. The α1-blocklade + β-blockade showed similar vasoconstriction observed in control experiments (see publication figure # 3, 3rd graph). While control experiments show a predominant neurogenic vasoconstriction, the double blockade results show how other hemodynamic factors contribute to the vasomotor tone of ischemic muscle.

We are two-thirds into the journey of this blog series, and I hope that you have found the topics engaging. For any questions that might arise here, practical or data related, we would like to invite you to attend our upcoming free live webinar on May 11th featuring Dr. Kaur, the author of the papers discussed here. During this webinar, Dr. Kaur will present these topics in greater depth and there will be time reserved to ask questions. To register for this webinar or view our past webinar topics on demand, click here. I look forward to talking with you in the next blog, coming soon.