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Pharmacogenomic strain differences in cardiovascular sensitivity to propofol.

Thomas A Stekiel¹, Stephen J Contney, Richard J Roman

¹Anesthesia Research, The Medical College of Wisconsin and The Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53226, USA. tstekiel@mcw.edu

|October 25, 2011

Summary

Enhanced cardiovascular sensitivity to propofol in Dahl Salt Sensitive (SS) rats is linked to an altered renin gene. This genetic difference impacts vascular smooth muscle function, increasing propofol

Related Experiment Videos

Area of Science:

Pharmacogenomics
Cardiovascular Pharmacology
Renal Physiology

Background:

Investigated genetic basis for heightened cardiovascular response to propofol in Dahl Salt Sensitive (SS) rats compared to Brown Norway (BN) rats.
Utilized a pharmacogenomic approach to pinpoint the specific genetic region responsible for this sensitivity.

Purpose of the Study:

To precisely localize the genetic locus contributing to propofol-induced cardiovascular sensitivity in SS rats.
To elucidate the role of the renin gene in mediating vascular smooth muscle responses to propofol.

Main Methods:

Measured propofol infusion rates causing 50% blood pressure reduction in congenic rat strains (BN.13(SS) and SS.13(BN)).
Assessed vascular smooth muscle transmembrane potential changes in response to propofol and protein kinase inhibitors (PKA,PKG).
Utilized subcongenic strains to narrow down the genetic region and investigated the renin gene's involvement.

Main Results:

SS rats exhibited significantly greater propofol-induced vascular smooth muscle hyperpolarization, mediated by protein kinase A.
The enhanced sensitivity and hyperpolarization were localized to an eight-gene region containing the renin gene.
Losartan blockade of angiotensin receptors amplified propofol-induced hyperpolarization in subcongenic rats.

Conclusions:

An altered renin gene in SS rats is the primary cause of enhanced propofol cardiovascular sensitivity.
This genetic variation modifies second messenger pathways, affecting vascular smooth muscle contractility and exacerbating propofol's hypotensive effects.