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Differences in the frequency of Arg492→Cys polymorphism of the human α1A-adrenergic receptor...
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CLINICAL PHARMACOLOGY & THERAPEUTICS 204 American Society for Clinical Pharmacology and Therapeutics FEBRUARY 1999 OHI-A-1 TRANSGENIC MICE WITH CARDIOMYOPATHY -- AN ATTRACTIVE MODEL FOR DRUG DEVELOPMENT? B.C. Knollmann, MD, K.K. Trivedi,* MD, N.J. Weissman,* MD, M. Morad,* PhD, Divisions of Clin Pharm and Card, Departments of Pharm and Med, Georgetown Univ, Washington, DC. Drug development for heart failure has largely been limited to sur- rogate markers in larger animal models, without assessing survival. Using a mouse model, effects of drug therapy could be assessed inex- pensively in a large number of animals. Therefore, we studied the development of cardiac hypertrophy and failure in transgenic mice overexpressing calsequestrin (a Ca 2§ storage protein) with serial echocardiography over a 6-month period, comparing transgenic vs nontransgenic littermates. At 4 weeks, transgenic mice had already significant left ventricular dilation (end-diastolic diameter EDD: 2.7 vs 1.9mm, p<0.05) with preserved fractional shortening (FS: 0.61 vs 0.69, ns). At 3 months, ventricular function deteriorated, and was severely impaired within 4-6 months (EDD: 5.2 vs 2.5mm, p<0.0I; FS: 0.14 vs 0.69, p<0.01). Two transgenic mice died suddenly at 4 and 5 months. Transgenic mice developed signs of heart failure at 4- 6 months. ECGs showed conduction blocks of varying degrees, bradycardia and QT prolongation. Heart weights were 2x controls (380 vs 175 rag, p<0.01), with atrial dilatation and thrombi. Ventric- ular I~-receptor density was decreased by 65% in transgenic animals (I125-pindolol binding). Conclusion: High mortality and a cardiac phenotype similar to human dilated cardiomyopathy make this mouse model a good can- didate to study drug interventions. OIII-A-2 AN INVERSE ASSOCIATION BETWEEN t~-TOCOPHEROL AND SOLUBLE P-SELECTIN LEVELS IN PATIENTS WITH CORONARY ARTERY DISEASE. C. Parker, III, MD,* J.E. Freedman, MD, Div of Clin Pharm, Georgetown Univ Med Center, Washington, DC. Platelet activation and thrombus formation precipitates most unstable coronary syndromes. Levels of soluble P-selectin, a marker of platelet activation, are elevated in this patient popula- tion. c~-Tocopherol decreases the incidence of acute myocardial infarction in patients with atherosclerosis although the mecha- nism for this effect is unknown. Therefore, we measured plasma levels of soluble P-selectin and tx-tocopherol in patients with ath- erosclerosis undergoing coronary angiography (n=78). Soluble P-selectin levels were significantly elevated in patients with unstable (n=44) vs stable (n=34) atherosclerotic disease (73.0_+2.5 ng/ml vs 52.3_+3.0 ng/ml, respectively, P<0.01). By logistic regression analysis, plasma level of soluble P-selectin was an independent predictor of an unstable coronary syndrome (OR 4.2, CI 1.4-12.9, P<0.01). Importantly, soluble P-selectin was inversely correlated with c~-tocopherol levels (R=-0.443, P<0.001). In summary, plasma soluble P-selectin is significantly increased in patients with unstable coronary syndromes and is associated with decreased levels of t~-tocopherol. Therefore, the beneficial effects of c~-tocopherol in patients with unstable coro- nary disease may be due to inhibition of platelet activation and suppression of subsequent thrombus formation. OIII-A-3 DIFFERENCES IN THE FREQUENCY OF Arg492--->Cys POLYMORPHISM OF THE HUMAN CtlA-ADRENERGIC RECEPTOR (CqA-AR) IN AFRICAN-AMERICANS (AA) AND CAUCASIANS (CA). R.B. Kim, MD, H.G. Xie, MD, PhD, C.M. Stein, MD, J.V. Gainer, MD,* N.J. Brown, MD,* and A.J.J. Wood, MD, Div Clin Pharmacol, Vanderbilt Univ Med Ctr, Nashville, TN 37232-6602. In human vascular smooth muscle, t~IA-AR is the predomi- nant ~IA-AR subtype, tz-AR-mediated vasoconstriction is increased in AA. Variation in the frequency of the 0qA-AR poly- morphism is a potential mechanism for ethnic differences in tZla- AR-mediated vascular response and the pathogenesis of essen- tial hypertension (HT). To determine if the frequency of tXlA- AR's T--->C transition, resulting in Arg492--+Cys, differed between AA and CA, a PCR-based PstI RFLP method was used for the detection of this polymorphism in 179 AA (NT = 106, HT = 73) and 286 CA (NT = 185, HT = 101). There were marked racial differences in the allelic and genotypic frequencies of the variant encoding Cys492 between AA and CA (AA vs CA; 32.0% vs 56.0% for the allele; 7.0% vs 30.0% for the homozygous geno- type; all P<0.001), but similar allelic frequencies among NT and HT subjects, both in AA (NT vs HT; 31.6% vs 32.2%) and in CA (56.5% vs 54.5%). These data suggest that racial differences in the distribution of the Arg492--+Cys polymorphism exist, and thus may contribute to ethnic differences in vascular response. OIII-A-4 A KINETIC-DYNAMIC MODEL FOR PERINDOPRILAT EFFECTS IN HEALTHY VOLUNTEERS AND IN CONGESTIVE HEART FAILURE PATIENTS. E. Bellissant, MD, PhD, J.F. Giudicelli,* MD, PhD, Clinical Pharmacology, School of Medicine, 35043 Rennes, France. Objectives: to compare the relationships between the plasma concentrations (C) of perindoprilat (active metabolite of the angiotensin 1-converting enzyme inhibitor perindopril) and the effects (E) induced on plasma converting enzyme activity (PCEA, %) and brachial vascular resistance (BVR, %) in healthy volunteers (HV) and in congestive heart failure (CHF) patients (pts) after single oral doses of perindopril. Methods: Six HV received 3 doses of perindopril (4, 8, 16 mg) in a placebo- controlled, randomized, double-blind and crossover study whereas 9 CHF pts received one dose (4 mg) in an open study. Each parameter was determined before and 7 to 11 times after drug intake. E were individually related to C by the Hill model E = Emax.C~'/(CEs0~'+C~). When data showed a hysteresis loop, an effect compartment was used. In HV, modeling was performed using the data of the 3 doses simultaneously. Results: (mean_+sd) In HV, relationships between C and E were direct whereas in CHF pts, they showed hysteresis loops with optimal keo values of 0.13• and 0.13• h -1 for PCEA and BVR, respectively. For PCEA, with Ema x set to -100%, CEs0 = 1.9• and 1.4• ng/ml (NS) and "r = 0.9• and 1.1• (NS) in HV and CHF pts, respectively. For BVR, Emax = -41• and -60• (p<.01), CEs0 = 4.9+2.6 and 1.4• ng/ml (p<.01), and T = 2.3• and 3.1_+1.4 (NS) in HV and CHF pts, respectively. Conclusion: HV and CHF pts show different hemodynamic responses to perindopril which precludes the use of HV to pre- dict the optimal dosage of the drug in CHF.
Transcript of Differences in the frequency of Arg492→Cys polymorphism of the human α1A-adrenergic receptor...
CLINICAL PHARMACOLOGY & THERAPEUTICS 2 0 4 American Society for Clinical Pharmacology and Therapeutics FEBRUARY 1999
OHI-A-1 TRANSGENIC MICE WITH CARDIOMYOPATHY - - AN
ATTRACTIVE MODEL FOR DRUG DEVELOPMENT? B.C. Knollmann, MD, K.K. Trivedi,* MD, N.J. Weissman,* MD, M. Morad,* PhD, D i v i s i o n s of Clin Pharm and Card, Departments of Pharm and Med, Georgetown Univ, Washington, DC.
Drug development for heart failure has largely been limited to sur- rogate markers in larger animal models, without assessing survival. Using a mouse model, effects of drug therapy could be assessed inex- pensively in a large number of animals. Therefore, we studied the development of cardiac hypertrophy and failure in transgenic mice overexpressing calsequestrin (a Ca 2§ storage protein) with serial echocardiography over a 6-month period, comparing transgenic vs nontransgenic littermates. At 4 weeks, transgenic mice had already significant left ventricular dilation (end-diastolic diameter EDD: 2.7 vs 1.9mm, p<0.05) with preserved fractional shortening (FS: 0.61 vs 0.69, ns). At 3 months, ventricular function deteriorated, and was severely impaired within 4-6 months (EDD: 5.2 vs 2.5mm, p<0.0I; FS: 0.14 vs 0.69, p<0.01). Two transgenic mice died suddenly at 4 and 5 months. Transgenic mice developed signs of heart failure at 4- 6 months. ECGs showed conduction blocks of varying degrees, bradycardia and QT prolongation. Heart weights were 2x controls (380 vs 175 rag, p<0.01), with atrial dilatation and thrombi. Ventric- ular I~-receptor density was decreased by 65% in transgenic animals (I125-pindolol binding).
Conclusion: High mortality and a cardiac phenotype similar to human dilated cardiomyopathy make this mouse model a good can- didate to study drug interventions.
OIII-A-2 AN INVERSE ASSOCIATION BETWEEN t~-TOCOPHEROL
AND SOLUBLE P-SELECTIN LEVELS IN PATIENTS WITH CORONARY ARTERY DISEASE. C. Parker, III, MD,* J.E. Freedman, MD, Div of Clin Pharm, Georgetown Univ Med Center, Washington, DC.
Platelet activation and thrombus formation precipitates most unstable coronary syndromes. Levels of soluble P-selectin, a marker of platelet activation, are elevated in this patient popula- tion. c~-Tocopherol decreases the incidence of acute myocardial infarction in patients with atherosclerosis although the mecha- nism for this effect is unknown. Therefore, we measured plasma levels of soluble P-selectin and tx-tocopherol in patients with ath- erosclerosis undergoing coronary angiography (n=78). Soluble P-selectin levels were significantly elevated in patients with unstable (n=44) vs stable (n=34) atherosclerotic disease (73.0_+2.5 ng/ml vs 52.3_+3.0 ng/ml, respectively, P<0.01). By logistic regression analysis, plasma level of soluble P-selectin was an independent predictor of an unstable coronary syndrome (OR 4.2, CI 1.4-12.9, P<0.01). Importantly, soluble P-selectin was inversely correlated with c~-tocopherol levels (R=-0.443, P<0.001). In summary, plasma soluble P-selectin is significantly increased in patients with unstable coronary syndromes and is associated with decreased levels of t~-tocopherol. Therefore, the beneficial effects of c~-tocopherol in patients with unstable coro- nary disease may be due to inhibition of platelet activation and suppression of subsequent thrombus formation.
OIII-A-3 DIFFERENCES IN THE FREQUENCY OF Arg492--->Cys
POLYMORPHISM OF THE HUMAN CtlA-ADRENERGIC RECEPTOR (CqA-AR) IN AFRICAN-AMERICANS (AA) AND CAUCASIANS (CA). R.B. Kim, MD, H.G. Xie, MD, PhD, C.M. Stein, MD, J.V. Gainer, MD,* N.J. Brown, MD,* and A.J.J. Wood, MD, Div Clin Pharmacol, Vanderbilt Univ Med Ctr, Nashville, TN 37232-6602.
In human vascular smooth muscle, t~IA-AR is the predomi- nant ~IA-AR subtype, tz-AR-mediated vasoconstriction is increased in AA. Variation in the frequency of the 0qA-AR poly- morphism is a potential mechanism for ethnic differences in tZla- AR-mediated vascular response and the pathogenesis of essen- tial hypertension (HT). To determine if the frequency of tXlA- AR's T--->C transition, resulting in Arg492--+Cys, differed between AA and CA, a PCR-based P s t I RFLP method was used for the detection of this polymorphism in 179 AA (NT = 106, HT = 73) and 286 CA (NT = 185, HT = 101). There were marked racial differences in the allelic and genotypic frequencies of the variant encoding Cys492 between AA and CA (AA vs CA; 32.0% v s 56.0% for the allele; 7.0% vs 30.0% for the homozygous geno- type; all P<0.001), but similar allelic frequencies among NT and HT subjects, both in AA (NT v s HT; 31.6% vs 32.2%) and in CA (56.5% vs 54.5%). These data suggest that racial differences in the distribution of the Arg492--+Cys polymorphism exist, and thus may contribute to ethnic differences in vascular response.
OIII-A-4 A KINETIC-DYNAMIC MODEL FOR PERINDOPRILAT
EFFECTS IN HEALTHY VOLUNTEERS AND IN CONGESTIVE HEART FAILURE PATIENTS. E. Bellissant, MD, PhD, J.F. Giudicelli,* MD, PhD, Clinical Pharmacology, School of Medicine, 35043 Rennes, France.
Objectives: to compare the relationships between the plasma concentrations (C) of perindoprilat (active metabolite of the angiotensin 1-converting enzyme inhibitor perindopril) and the effects (E) induced on plasma converting enzyme activity (PCEA, %) and brachial vascular resistance (BVR, %) in healthy volunteers (HV) and in congestive heart failure (CHF) patients (pts) after single oral doses of perindopril. Methods: Six HV received 3 doses of perindopril (4, 8, 16 mg) in a placebo- controlled, randomized, double-blind and crossover study whereas 9 CHF pts received one dose (4 mg) in an open study. Each parameter was determined before and 7 to 11 times after drug intake. E were individually related to C by the Hill model E = Emax.C~'/(CEs0~'+C~). When data showed a hysteresis loop, an effect compartment was used. In HV, modeling was performed using the data of the 3 doses simultaneously. Results: (mean_+sd) In HV, relationships between C and E were direct whereas in CHF pts, they showed hysteresis loops with optimal keo values of 0.13• and 0.13• h -1 for PCEA and BVR, respectively. For PCEA, with Ema x set to -100%, CEs0 = 1.9• and 1.4• ng/ml (NS) and "r = 0.9• and 1.1• (NS) in HV and CHF pts, respectively. For BVR, Ema x = -41• and -60• (p<.01), CEs0 = 4.9+2.6 and 1.4• ng/ml (p<.01), and T = 2.3• and 3.1_+1.4 (NS) in HV and CHF pts, respectively. Conclusion: HV and CHF pts show different hemodynamic responses to perindopril which precludes the use of HV to pre- dict the optimal dosage of the drug in CHF.
