Hydroxypropyl-β-cyclodextrin impacts renal and systemic hemodynamics in the anesthetized dog

Area of Science:

• Pharmacology
• Cardiovascular Physiology
• Drug Development

Background:

• Hydroxypropyl-β-cyclodextrin (HPβCD) is a widely used solubilizing agent.
• While HPβCD toxicity is known, its cardiovascular effects require further investigation.
• Understanding HPβCD's hemodynamic impact is crucial for drug formulation and safety studies.

Purpose of the Study:

• To investigate the cardiovascular and hemodynamic effects of intravenous Hydroxypropyl-β-cyclodextrin (HPβCD) administration in anesthetized dogs.
• To determine dose-dependent effects and potential sex differences in HPβCD's cardiovascular impact.
• To elucidate the role of the autonomous nervous system in HPβCD-induced hemodynamic changes.

Main Methods:

• Intravenous infusion of HPβCD (200-800 mg/kg) in anesthetized dogs.
• Measurement of renal and systemic hemodynamic parameters (arteriolar resistance, blood flow, peripheral resistance, heart rate).
• Comparison between non-denervated and denervated animals to assess nervous system involvement.

Main Results:

• HPβCD administration led to immediate increases in renal arteriolar resistance and decreased renal blood flow, more pronounced in females.
• A moderate increase in total peripheral resistance was observed in females, linked to sympathetic tone.
• Heart rate decreased in normally innervated animals due to blood pressure elevation, an effect absent in denervated animals, indicating functional autonomic feedback loops.

Conclusions:

• HPβCD induces significant, dose-dependent systemic and renal hemodynamic changes.
• Renal effects are selective and pronounced, particularly in female subjects.
• At high doses (800 mg/kg), HPβCD can significantly alter hemodynamics, potentially confounding safety assessments in nonclinical studies; lower doses (200-400 mg/kg) may also represent background effects.