Pharmacogenomic strain differences in cardiovascular sensitivity to propofol.
BACKGROUND
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.
Anesthesia Research, The Medical College of Wisconsin and The Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53226, USA. tstekiel@mcw.edu
Thomas A
TA
Stekiel
Stephen J
SJ
Contney
Richard J
RJ
Roman
Craig A
CA
Weber
Anna
A
Stadnicka
Zeljko J
ZJ
Bosnjak
Andrew S
AS
Greene
Carol
C
Moreno
D000704:Analysis of Variance; D000818:Animals; D020296:Animals, Congenic; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002319:Cardiovascular System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D019808:Losartan / Q000008:administration & dosage; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010597:Pharmacogenetics / Q000379:methods*; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D020303:Rats, Inbred Dahl; D012083:Renin / Q000187:drug effects* / Q000235:genetics*
D000959:Antihypertensive Agents; D006993:Hypnotics and Sedatives; D012083:Renin; D019808:Losartan; D015742:Propofol