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Renal medullary interstitial infusion of norepinephrine in anesthetized rabbits: methodological considerations
A G Correia1, G Bergström, A J Lawrence
1Department of Physiology, Monash University, Clayton, Victoria 3168, Australia.
Abstract:
We tested methods for delivery of drugs to the renal medulla of anesthetized rabbits. Outer medullary infusion (OMI) of norepinephrine (300 ng. kg(-1). min(-1)), using acutely or chronically positioned catheters, reduced both cortical (CBF; 15%) and medullary perfusion (MBF; 23-31%). Inner medullary infusion (IMI) did not affect renal hemodynamics, whereas intravenous infusion reduced CBF (15%) without changes in MBF. During OMI of [(3)H]norepinephrine, much of the radiolabel (approximately 40% with chronically positioned catheters) spilled over systemically. Nevertheless, autoradiographic analysis showed the concentration of radiolabel was about fourfold greater in the infused medulla than the cortex. In contrast, during IMI, only approximately 5% of the infused radiolabel spilled over into the systemic circulation and approximately 64% was excreted by the infused kidney. The resultant intrarenal levels of radiolabel were considerably less with IMI compared with OMI. In rabbits, OMI therefore provides a useful method for targeting agents to the renal medulla, but given the considerable systemic spillover with OMI, its utility is probably limited to substances that are rapidly degraded in vivo.
Insights
Outer medullary infusion effectively targets drugs to the renal medulla in rabbits. However, significant systemic drug spillover limits its use to agents rapidly degraded in vivo.
Area of Science:
- Nephrology
- Pharmacology
- Renal Physiology
Background:
- Targeted drug delivery to the renal medulla is challenging.
- Understanding renal hemodynamics is crucial for effective therapeutic strategies.
Purpose of the Study:
- To evaluate outer medullary infusion (OMI) and inner medullary infusion (IMI) for drug delivery to the renal medulla in rabbits.
- To assess the impact of these methods on renal blood flow and systemic drug distribution.
Main Methods:
- Anesthetized rabbits underwent OMI or IMI of norepinephrine using acutely or chronically positioned catheters.
- Renal cortical (CBF) and medullary (MBF) blood flow were measured.
- Systemic and intrarenal distribution of radiolabeled norepinephrine was analyzed using autoradiography.
Main Results:
- OMI reduced both CBF (15%) and MBF (23-31%).
- IMI did not significantly alter renal hemodynamics.
- Autoradiography showed higher radiolabel concentration in the medulla with OMI compared to cortex, despite significant systemic spillover (approx. 40%).
- IMI resulted in less systemic spillover (approx. 5%) but lower intrarenal drug levels.
Conclusions:
- OMI is a viable method for targeting agents to the renal medulla in rabbits.
- The significant systemic spillover associated with OMI suggests its application is best suited for drugs that undergo rapid in vivo degradation.