Faculty Collaboration Database

Pharmacogenomic strain differences in cardiovascular sensitivity to propofol. Anesthesiology 2011 Dec;115(6):1192-200

Date

10/25/2011

Pubmed ID

22020141

Pubmed Central ID

PMC3245982

DOI

10.1097/ALN.0b013e318238f445

Scopus ID

2-s2.0-81855221872 (requires institutional sign-in at Scopus site)   4 Citations

Abstract

INTRODUCTION: A pharmacogenomic approach was used to further localize the genetic region responsible for previously observed enhanced cardiovascular sensitivity to propofol in Dahl Salt Sensitive (SS) versus control Brown Norway (BN) rats.

METHODS: Propofol infusion levels that decreased blood pressure by 50% were measured in BN.13(SS) rats (substitution of SS chromosome 13 into BN) and in five congenic (partial substitution) strains of SS.13(BN). The effect of superfused 2,6 diisopropylphenol on small mesenteric arterial vascular smooth muscle transmembrane potential was measured in congenic strains before and during superfusion with Rp-adenosine-3',5'-cyclic monophosphorothioate and 2.5 μM (Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate, inhibitors of protein kinase A and G, respectively. The genetic locus and potential role of the renin gene in mediating vascular smooth muscle sensitivity to propofol were determined in three selected subcongenic SS.BN¹³ strains.

RESULTS: A 30-32% smaller propofol infusion rate reduced blood pressure by 50% in BN.13(SS) compared with BN and the SS.13(BN) congenic containing an 80 BN gene substitution. Compared with the 80 BN gene-containing SS.13(BN) congenic, SS exhibited greater protein kinase A dependent vascular smooth muscle hyperpolarization in response to propofol. Using subcongenics, the increased propofol-induced cardiovascular sensitivity and hyperpolarization was further localized to an eight-gene region (containing the BN renin gene). Blockade of angiotensin receptors with losartan in this subcongenic increased propofol-induced hyperpolarization by threefold to that observed in SS.

CONCLUSIONS: Enhanced cardiovascular sensitivity to propofol in SS (compared with BN) is caused by an altered renin gene. Through modified second messenger function, this differentially regulates vascular smooth muscle contractile state and reduces vascular tone, thereby exacerbating cardiovascular depression by propofol.

Author List

Stekiel TA, Contney SJ, Roman RJ, Weber CA, Stadnicka A, Bosnjak ZJ, Greene AS, Moreno C

MESH terms used to index this publication - Major topics in bold

Analysis of Variance
Animals
Animals, Congenic
Antihypertensive Agents
Blood Pressure
Cardiovascular System
Dose-Response Relationship, Drug
Hypnotics and Sedatives
Losartan
Male
Muscle, Smooth, Vascular
Pharmacogenetics
Propofol
Rats
Rats, Inbred BN
Rats, Inbred Dahl
Renin