CLINICAL PJ:IAR/vlAGOLOGY & THEIL~PEUTICS P 9 8 American Society for Clinical Pharmacology and Therapeutics FEBRUARY 200S

PDII-C-6 CONTRIBUTION OF GS-ALPHA AND BETA2-

ADRENERGIC RECEPTOR POLYMORPHISMS AND ANTIHY- PERTENSIVE RESPONSE TO BETA-BLOCKERS. A. L. Bei- telshees, PharmD, I. Zineh, PharmD, H. N. Yarandi, PhD, B. J. Puckett, PharmD, D. F. Pauly, MD, PhD, J. A. Johnson, PharmD, University of Florida College of Pharmacy, University of Florida College of Nursing, University of Florida College of Medicine, Gainesville, FL.

We have recently shown [3j-adrenergic receptor ([3 IAR) codon 49 and 389 genotypes (gts) to be associated with antihypertensive re- sponse to metoprolol. We sought to determine whether Gso~ or [32AR gts made additional contributions to variability in response. Forty untreated hypertensives were studied with 24h ambulatory BP mon- itoring at baseline and after titration of metoprolol. All gts were determined by PCR and RFLP. Step-type multiple regression mod- eling with minimum R 2 improvement analysis was conducted, with a p-value <0.10 required for entry into the model. Variables included in the model were baseline daytime DBP (I)BP]~), age, sex, smoking status, body mass index (BMI), exercise, race, S-metoprolol AUC, codon 49, 389 and Gsc~ gts, and [B2AR codon 16 and 27 gts. Parameter estimates were derived (Table). A six-variable model was most predictive of treatment DBE r response to metoprolol according to the equation:

DBP T = 11.18 + 0.68(DBPB)- 7.95(if Arg389Arg) - 5.84(if Ser49Ser) + 0.46(BMI) +0.004(AUC) + 4.25(if Glyl6Gly) (r2=0.66, p<0.0001).

Parameter Variable Estimate P value Partial R2%

DBP B 0.68 <0.0001 22.2 R389R gt -7.95 0.0016 13.0 $49S gt -5.84 0.021 6.4 AUC 0.004 0.028 5.8 BMI 0.46 0.045 4.7 G16G gt 4.25 0.097 3.2

Our results suggest that [31AR 49 and 389 gts, [B2AR 16 gt, DBP~, BMI, and AUC, but not [B2AR 27 or Gse~ gts, are important deter- minants of variable [B-blocker response. These data suggest that consideration of multiple genes may increase the ability to individ- ualize antihypertensive treatment.

PDII-C-7 EVALUATION OF SINGLE NUCLEOTIDE POLYMOR-

PHISMS IN GENES RELATED TO THE VANILLOID RECEP- TOR AND CYCLOOXYGENASE-2 IN HUMAN PAIN SENSITIV- ITY. H. Kim, DI)S, Phi), J. K. Neubert, DDS, Phi), M. J. Iadarola, PhD, D. Goldman, MD, R. A. Dionne, DDA, Phi), NIDCR/NIH, NIAAA/NIH, Bethesda, MD.

While a variety of factors such as cultural or psychological factors may account for interindividual variation, studies in rodent pain models using hot plate and nerve injury demonstrate differences in pain sensitivity due to genetic factors. We investigated the contribu- tion of transient receptor potential subtype l, also known as vanilloid receptor-1 gene (TRPVI), prostaglandin synthase G/H subtype 2, also known as cyclooxygenase-2 gene (PTGS2) and prostaglandin receptor genes (PTGRs). These genes encode proteins related to thermal sensation or the inflammatory process.

Subjects (N=560) rated sensory intensity and unpleasantness for heat stimuli and 3 rain cold pressor test. From the total sample, 121 patients underwent standardized oraI surgery and clinical pain sensi- tivity including NSAID analgesia was evaluated. For genotyping of genomic DNA, Assays-on-Demand SNP Genotyping Products (Ap- plied Biosystem, Foster City, California, USA) was used.

TRPV1, PTGS2 and PTGRs loci showed significant variation in allele frequency between ethnic groups. In the present human cohort, TRPV1 G945C, which predicts amino acid change from methionine to isoleucine, was associated with a significant increase in heat sensitivity in females, but not in males. We could not find significant relationship of SNPs from PTGS2 and PTGRs with experimental or clinical pain sensitivity.

These data provide evidence in humans for a genetic contribution of TRPVI to heat pain sensitivity.

PDII-C-8 ENDOTHELIAL NITRIC OXIDE SYNTHASE GLU298ASP

POLYMORPHISM AND BLOOD PRESSURE RESPONSES TO SALT. G. Sofowora, MD, M. Muszkat, MI), V. Dishy, MD, H-G. Xie, MD PhD, H. C. Prasad, MD PhD, A. J. J. Wood, MD, C. M. Stein, MD, Div. of Clin. Pharm., Vanderbilt University, Nashville TN.

The genetic basis for salt-sensitive hypertension is not known. L-NAME, an endothelial nitric oxide synthase (eNOS) inhibitor induces salt-sensitivity in animals, suggesting that eNOS activity may be an important regulator of blood pressure responses to salt. A common eNOS potymorphism, Glu298Asp, is associated with altered production of nitric oxide but its effect on salt sensitivity is not known. Healthy subjects (n=27 : 7 Glu/Glu, 10 Asp/Asp and 10 Asp/Glu) received a high (400meq/day) and a low salt diet (10meq/ day) for 5 days in random order. Automated blood pressure moni- toring was performed on the last day of each diet. The change in blood pressure between low and high salt days was calculated and compared among genotypes. There was no significant genotypic difference in salt-induced changes in systolic (Glu/Glu 3 -+- 3A mmHg, Asp/Asp 2.3 -+ 2.5 mmHg and Glu/Asp 2.9 + 2.2 mmHg: P = 0.98) or diastolic (Glu/Glu -0.14 +_ 2.2 mmHg, Asp/Asp -2.1 -+ t.4 mmHg and Glu/Asp -0.7 -+ 1.0 mmHg, P = 0.63) blood pressure. These findings suggest that the Gtu298Asp polymorphism is not a significant determinant of blood pressure responses to salt.