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Effect of uncomplicated hypertension on coronary vasoreactivity among similar African and white American subjects.
56A
ASH XIV ABSTRACTS
AJH-APRIL
1999-VOL.
12, N O .
D029
D030
SIMVASTAT1N COUNTERACTS EARLY ENDOTHELIAL ACTIVATION IN HYPERCHOLESTEROLEMICHYPERTENSIVES AND NORMOTENSIVES. A FUNDAMENTAL TOOL FOR CARDIOVASCULARPREVENTION? C. Fen'i, G. Desided, R. Baldoncini, C. Bellinif, A. Santaecif*. 1 Clinica Medica - Cesalpino Foundation, University "La Sapienza", Rome, Departmentof Internal Medicine*, University of I'Aquila, Italy. Up-regulation of vascular adhesion molecule(VCAM)-I represents the critical earliest event in the formation of cholesterol-induead athemma. Simvastatin reduces cardiovascular events also independently on cholesterol reduction, suggesting it might protect the vascular endothelimn by interfering with atherogenic processes. To address this topic, circulating VCAM-1 levels were assessed in 38 non-diabetic, nonobese hypertensives with (Group I, IIM, 7F) and without (Group II, 12M, 8F) lfigh LDL-cholesterol levels and in 36 normotenaives with (Group III, 10M, 6F) and without high LDL levels (Group IV, 11M, 9F), before and after simvastatin (10 mg/day increased of 10 mg per week to the final dose of 40 mg/day) or bezafibrate (200 rag/day increased of 200 per week to the final dose of 800 rag/day) treatments, in a randomized, cross-over fashion. Normocholesterolemic patients (Group III and IV) received simvastatin 10 rag/day or placebo. All treatments lasted 4 months. VCAM-1 levels (gg/l) were higher in Group I (571.45+82.9) than Group II (509.385:43.5, p<0.004) and IV (451.23±65.07, p<0.0001), but not titan Group III (549,34±76.5) and directly correlated with LDLcholesterol concentrations (r=0.497, 13=0.03). Cumulative data from Groups I and III showed tlmt simvastatint significantly reduced LDL and VCAM-I levels (Figure). Bezafibrate'reduced LDL-cholesteml level but not VCAM-I concentrations (Figure). In nonnocholesterolemi~ patients simvastatin (10 mg/day) was followed by non-significant changes in VCAM-1 concentrations, in spite of a significant LDL i tdt ( ~ ) decrement. In conclusion, hypercholesterolemic subjects showed increased VCAM-1 levels. Simvastatin reduced LDL and VCAM-I levels in these patients, suggesting it might protect against cholesterol-induced 0 4 8 12 16 weeks ~pedolllgliglactivation. y words:
L-ARGININEAT A DOSE ABOVE 100 MG/KG IS NOT SUITABLE TO EXAMINE ENDOTHELIAL FUNCTION OF RENAL VASCULATURE. C Delles, J Jacobi, MP Schlaich, S John, and RE Schmieder'. Dept. of Medicine~ephrology, Universityof Erlangen-N0mberg, Germany. L-Arginine (L-Arg) is the substrate of nitric oxide (NO) synthase. It has been used intravenouslyto stimulate NO production and, thus, to determine endothelial function. We have previously found that L-Arc exerts a specific effect as compared with D-arginine at a dose of 100 mg/kg intravenously, wheras unspecific effects were seen at a dose of 500 mg/kg. In this double-blind placebo controlled study, we examined the effect of the inhibitor of NO synthase, N°-monomethyl-L-arginine (L-NMMA), on L-Arg stimulated endothelial function. In 17 healthy subjects (age, 27 + 2 years), L-Arg 100 mg/kg, L-Arc 250 mg/kg, and L-Arg 250 mg/kg combined either with L-NMMA (3 mg/kg as bolus followed by 3 mg/kg over 30 min, N=9) or placebo (NaCl, N=g) were given over 30 minutes, respectively. GIomemlar filtration rate (GFR) and renal plasma flow (RPF) were measured at rest and at the end of each infusion step (constant input clearance technique with inulin and para-aminohippurate, respectively).L-Arg dose dependently increased RPF and GFR (RPF: 589±80 vs. 630±73 vs. 690+98 mL/min, p<0.01; GFR: lll+13 vs. ll5+ll vs. 121_+ll mL/min, p<0.01). However, these changes could not be antagonized by addition of L-NMMA to L-Arg 250 mg/kg. RPF and GFR remained elevated in both the placebo group (RPF, 712+102 vs. 699+77 mL/min, GFR, 124_+10 vs. 1265:13 mL/min; n.s.) and the L-NMMA group (RPF, 669±95 vs. 6655:93 ntL/min; GFR, 1185:11 vs. 1205:14 mL/min; n.s.). Mean arterial blood pressure (MAP) was not affected by L-Arg 100 mg/kg (87.7+86 vs. 89.45:7.6 mmHg at baseline, n.s.), but was changed by L-Arg 250 mg/kg (86.4+8.3 annHg vs. 89.45:7.6 mmHg at baseline, p<0.05). Again, this effect was not affected by L-NMMA. We conclude that L-Arg at a dose of 250 mg/kg exerts no NO synthase mediated effect on endothelial function, since the effect cannot be blocked with L-NMMA. Having our previously performed experiments in mind, we strongly dissuade from using L-Arg at doses above 100 mg/kg to examine endothelial function of fermivasculature. Key Words:
Endothelium - Nitric oxide - L-Arginine - L-NMMA
VCAM-I, cholesterol, simvastalin
D031
D032
SYNERGISTIC BRADYCARDIA RELATED TO SIMULTANEOUS INFUSION OF L-ARGININE AND ACETYLCHOLINE. JL Houghton', RC Chander, PA Kuhner, SA Fein, AA Cart. Albany Medical College, Albany, NY. Intracoronary (IC) acetylcholine (ACh) is considered the gold standard for the evaluation of coronary endothelial dysfunction. This agent has been proven to be safe, though significant vasospasm and/or bradycardia may occur rarely. Infusion of L-arginine (L-Arg) has been demonstrated to improve endothelial function after ACh in some pts. We investigated the synergism between ACh and L-Arg, which results in bradycardic arrhythmias. After graded infusion of IC ACt ( 10"s, 10"?, 10.6 M) L-Arg (3200 mcmoles) was infused over 5 to l0 minutes followed by repeat infusion of A C t (10 "6 M). CBF was calculated using Doppler wire measurement of velocity and QCA at baseline and after drug infusions. Of 104 pts undergoing study, 8 (8%) demonstrated significant bradycardic arrhythmias. These included marked sinus slowing, sinus pauses and AV conduction delay. Bradycardia or heart block after L-Arg were predicted by baseline heart rate _<75 bpm and recent use of beta or calcium antagonist drugs (p-~).04) but not by gender, race, CBF response to L-Arg, coronary dominance, location of the sinus node artery or presence of HTN. Bradycardic arrhythmias occurred in 8% of the 104 pts undergoing simultaneous IC infusion of ACh and L-Arg. These were predicted by baseline heart rate >_75bpm and recent use of beta or calcium antagonist drugs suggesting that the mechanism is complexly related to vagal tone and/or residual effects of medication induced conduction slowing. Thus, L-Arg appears to significantly enhance the negative chronotropie action of ACh in some pts with baseline increased vagal tone and/or depressed conduction secondary to commonly used cardiac medications.
EFFECT OF UNCOMPLICATED HYPERTENSION ON CORONARY VASOREACTIVITY AMONG SIMILAR AFRICAN AND W H I T E AMERICAN SUBJECTS. JL Houghton', SA Fein, VE Smith. Albany Medical College, Albany, NY. HTN is a clinically heterogeneous disorder. The purpose of our study was to investigate the effect of uncomplicated HTN on coronary vasoreactivity among African American (AA) and white (W) patients with normal coronary arteries. Uncomplicated HTN was defined as BP > 140/90 mm Hg in the absence of stroke, renal insufficiency, or LVH by echo mass criteria. Using the intraenronary Doppler wire, QCA, and infusions of acetylcholine (ACh) and adenosine, percent increase in coronary blood flow (CBF) and epicardial diameter (D) were measured. Patients studied included 17 AA and 32 W with uncomplicated HTN and, for comparison purposes, 19 AA and 28 W with normal pressure (NTS). Both HTS AA and W groups demonstrated borderline significant depression in endothelial responses to ACh when compared with their NTS counterparts. HTS AA had depressed responses at all doses of ACh (11 + 3, 27 +7, 108_+22, 130+ 2 6 v s 2 8 + 6 , 6 0 - + 11,156+23, 189+ 12, % increase CBF, p = 0.1). HTS W subjects showed depressed responses only at the maximal infusion rate (25 + 7, 68 _+ 13, 169 + 25, 182 + 25 vs 29 + 6, 55 + 7, 183 + 22, 217 + 25, % increase CBF, p = 0.3). Significantly depressed adenosine responses were found in HTS APt but not HTS W (190 + 17 vs 244 + 16, p = 0.02, and 213 + 16 vs 212 + 2, p = NS). Our study shows that AA with uncomplicated HTN may have greater endothelial dysfunction and worse endothelium independent reactivity when compared with similar NTS subjects and a cohort of W subjects studied in a parallel fashion.
Key Words:
Endothelium, L-arginine, Bradycardia
Key Words:
Hypertension, Endotbelium, Vascular Reactivity, Ethnicity,
4, P A R T
2
ASH XIV ABSTRACTS
AJH-APRIL
1999-VOL.
12, N O .
D029
D030
SIMVASTAT1N COUNTERACTS EARLY ENDOTHELIAL ACTIVATION IN HYPERCHOLESTEROLEMICHYPERTENSIVES AND NORMOTENSIVES. A FUNDAMENTAL TOOL FOR CARDIOVASCULARPREVENTION? C. Fen'i, G. Desided, R. Baldoncini, C. Bellinif, A. Santaecif*. 1 Clinica Medica - Cesalpino Foundation, University "La Sapienza", Rome, Departmentof Internal Medicine*, University of I'Aquila, Italy. Up-regulation of vascular adhesion molecule(VCAM)-I represents the critical earliest event in the formation of cholesterol-induead athemma. Simvastatin reduces cardiovascular events also independently on cholesterol reduction, suggesting it might protect the vascular endothelimn by interfering with atherogenic processes. To address this topic, circulating VCAM-1 levels were assessed in 38 non-diabetic, nonobese hypertensives with (Group I, IIM, 7F) and without (Group II, 12M, 8F) lfigh LDL-cholesterol levels and in 36 normotenaives with (Group III, 10M, 6F) and without high LDL levels (Group IV, 11M, 9F), before and after simvastatin (10 mg/day increased of 10 mg per week to the final dose of 40 mg/day) or bezafibrate (200 rag/day increased of 200 per week to the final dose of 800 rag/day) treatments, in a randomized, cross-over fashion. Normocholesterolemic patients (Group III and IV) received simvastatin 10 rag/day or placebo. All treatments lasted 4 months. VCAM-1 levels (gg/l) were higher in Group I (571.45+82.9) than Group II (509.385:43.5, p<0.004) and IV (451.23±65.07, p<0.0001), but not titan Group III (549,34±76.5) and directly correlated with LDLcholesterol concentrations (r=0.497, 13=0.03). Cumulative data from Groups I and III showed tlmt simvastatint significantly reduced LDL and VCAM-I levels (Figure). Bezafibrate'reduced LDL-cholesteml level but not VCAM-I concentrations (Figure). In nonnocholesterolemi~ patients simvastatin (10 mg/day) was followed by non-significant changes in VCAM-1 concentrations, in spite of a significant LDL i tdt ( ~ ) decrement. In conclusion, hypercholesterolemic subjects showed increased VCAM-1 levels. Simvastatin reduced LDL and VCAM-I levels in these patients, suggesting it might protect against cholesterol-induced 0 4 8 12 16 weeks ~pedolllgliglactivation. y words:
L-ARGININEAT A DOSE ABOVE 100 MG/KG IS NOT SUITABLE TO EXAMINE ENDOTHELIAL FUNCTION OF RENAL VASCULATURE. C Delles, J Jacobi, MP Schlaich, S John, and RE Schmieder'. Dept. of Medicine~ephrology, Universityof Erlangen-N0mberg, Germany. L-Arginine (L-Arg) is the substrate of nitric oxide (NO) synthase. It has been used intravenouslyto stimulate NO production and, thus, to determine endothelial function. We have previously found that L-Arc exerts a specific effect as compared with D-arginine at a dose of 100 mg/kg intravenously, wheras unspecific effects were seen at a dose of 500 mg/kg. In this double-blind placebo controlled study, we examined the effect of the inhibitor of NO synthase, N°-monomethyl-L-arginine (L-NMMA), on L-Arg stimulated endothelial function. In 17 healthy subjects (age, 27 + 2 years), L-Arg 100 mg/kg, L-Arc 250 mg/kg, and L-Arg 250 mg/kg combined either with L-NMMA (3 mg/kg as bolus followed by 3 mg/kg over 30 min, N=9) or placebo (NaCl, N=g) were given over 30 minutes, respectively. GIomemlar filtration rate (GFR) and renal plasma flow (RPF) were measured at rest and at the end of each infusion step (constant input clearance technique with inulin and para-aminohippurate, respectively).L-Arg dose dependently increased RPF and GFR (RPF: 589±80 vs. 630±73 vs. 690+98 mL/min, p<0.01; GFR: lll+13 vs. ll5+ll vs. 121_+ll mL/min, p<0.01). However, these changes could not be antagonized by addition of L-NMMA to L-Arg 250 mg/kg. RPF and GFR remained elevated in both the placebo group (RPF, 712+102 vs. 699+77 mL/min, GFR, 124_+10 vs. 1265:13 mL/min; n.s.) and the L-NMMA group (RPF, 669±95 vs. 6655:93 ntL/min; GFR, 1185:11 vs. 1205:14 mL/min; n.s.). Mean arterial blood pressure (MAP) was not affected by L-Arg 100 mg/kg (87.7+86 vs. 89.45:7.6 mmHg at baseline, n.s.), but was changed by L-Arg 250 mg/kg (86.4+8.3 annHg vs. 89.45:7.6 mmHg at baseline, p<0.05). Again, this effect was not affected by L-NMMA. We conclude that L-Arg at a dose of 250 mg/kg exerts no NO synthase mediated effect on endothelial function, since the effect cannot be blocked with L-NMMA. Having our previously performed experiments in mind, we strongly dissuade from using L-Arg at doses above 100 mg/kg to examine endothelial function of fermivasculature. Key Words:
Endothelium - Nitric oxide - L-Arginine - L-NMMA
VCAM-I, cholesterol, simvastalin
D031
D032
SYNERGISTIC BRADYCARDIA RELATED TO SIMULTANEOUS INFUSION OF L-ARGININE AND ACETYLCHOLINE. JL Houghton', RC Chander, PA Kuhner, SA Fein, AA Cart. Albany Medical College, Albany, NY. Intracoronary (IC) acetylcholine (ACh) is considered the gold standard for the evaluation of coronary endothelial dysfunction. This agent has been proven to be safe, though significant vasospasm and/or bradycardia may occur rarely. Infusion of L-arginine (L-Arg) has been demonstrated to improve endothelial function after ACh in some pts. We investigated the synergism between ACh and L-Arg, which results in bradycardic arrhythmias. After graded infusion of IC ACt ( 10"s, 10"?, 10.6 M) L-Arg (3200 mcmoles) was infused over 5 to l0 minutes followed by repeat infusion of A C t (10 "6 M). CBF was calculated using Doppler wire measurement of velocity and QCA at baseline and after drug infusions. Of 104 pts undergoing study, 8 (8%) demonstrated significant bradycardic arrhythmias. These included marked sinus slowing, sinus pauses and AV conduction delay. Bradycardia or heart block after L-Arg were predicted by baseline heart rate _<75 bpm and recent use of beta or calcium antagonist drugs (p-~).04) but not by gender, race, CBF response to L-Arg, coronary dominance, location of the sinus node artery or presence of HTN. Bradycardic arrhythmias occurred in 8% of the 104 pts undergoing simultaneous IC infusion of ACh and L-Arg. These were predicted by baseline heart rate >_75bpm and recent use of beta or calcium antagonist drugs suggesting that the mechanism is complexly related to vagal tone and/or residual effects of medication induced conduction slowing. Thus, L-Arg appears to significantly enhance the negative chronotropie action of ACh in some pts with baseline increased vagal tone and/or depressed conduction secondary to commonly used cardiac medications.
EFFECT OF UNCOMPLICATED HYPERTENSION ON CORONARY VASOREACTIVITY AMONG SIMILAR AFRICAN AND W H I T E AMERICAN SUBJECTS. JL Houghton', SA Fein, VE Smith. Albany Medical College, Albany, NY. HTN is a clinically heterogeneous disorder. The purpose of our study was to investigate the effect of uncomplicated HTN on coronary vasoreactivity among African American (AA) and white (W) patients with normal coronary arteries. Uncomplicated HTN was defined as BP > 140/90 mm Hg in the absence of stroke, renal insufficiency, or LVH by echo mass criteria. Using the intraenronary Doppler wire, QCA, and infusions of acetylcholine (ACh) and adenosine, percent increase in coronary blood flow (CBF) and epicardial diameter (D) were measured. Patients studied included 17 AA and 32 W with uncomplicated HTN and, for comparison purposes, 19 AA and 28 W with normal pressure (NTS). Both HTS AA and W groups demonstrated borderline significant depression in endothelial responses to ACh when compared with their NTS counterparts. HTS AA had depressed responses at all doses of ACh (11 + 3, 27 +7, 108_+22, 130+ 2 6 v s 2 8 + 6 , 6 0 - + 11,156+23, 189+ 12, % increase CBF, p = 0.1). HTS W subjects showed depressed responses only at the maximal infusion rate (25 + 7, 68 _+ 13, 169 + 25, 182 + 25 vs 29 + 6, 55 + 7, 183 + 22, 217 + 25, % increase CBF, p = 0.3). Significantly depressed adenosine responses were found in HTS APt but not HTS W (190 + 17 vs 244 + 16, p = 0.02, and 213 + 16 vs 212 + 2, p = NS). Our study shows that AA with uncomplicated HTN may have greater endothelial dysfunction and worse endothelium independent reactivity when compared with similar NTS subjects and a cohort of W subjects studied in a parallel fashion.
Key Words:
Endothelium, L-arginine, Bradycardia
Key Words:
Hypertension, Endotbelium, Vascular Reactivity, Ethnicity,
4, P A R T
2