The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to CYP2C19*2 genotype: first experience in patients.

UNLABELLED: To study the effect of a new direct acting reversible P2Y(12) inhibitor, elinogrel (PRT060128), and the relation to cytochrome P450 (CYP) polymorphisms in patients with high platelet reactivity (HPR) on standard dual antiplatelet therapy. METHODS AND RESULTS: We studied the pharmacodynamic and pharmacokinetic effects of a single 60-mg oral dose of elinogrel in 20 of 45 previously stented stable patients with HPR. We also genotyped for CYP2C19*2,3,5,17 and CYP3A5*3. Platelet reactivity fell within 4 h of dosing, the earliest time point evaluated as measured by the following assays: maximum 5 and 10 microM ADP LTA (P < 0.001 for both vs. predosing); maximum 20 microM ADP LTA (P < 0.05); VerifyNow (P < 0.001); thrombelastography (P < 0.05); VASP phosphorylation (P < 0.01); and perfusion chamber assay (P < 0.05); this was reversible within 24 h in these same assays (P = ns vs. predosing for all assays). CYP2C19*2 was present in 44% of all patients but was more frequent in HPR patients (77% vs. 16%, P = 0.0004). CONCLUSIONS: HPR is reversibly overcome by a single 60-mg oral dose of elinogrel, a drug now being investigated in a phase 2 trial. CYP2C19*2 was associated with HPR during conventional dual antiplatelet therapy.

Noninvasive method for determination of arterial compliance using Doppler echocardiography and subclavian pulse tracings. Validation and clinical application of a physiological model of the circulation.

BACKGROUND: The Poiseuillian model of the arterial system currently applied in clinical physiology does not explain how arterial pressure is maintained during diastole after cessation of pulsatile aortic inflow. Arterial pressure-flow relations can be more accurately described by models that incorporate arterial viscoelastic properties such as arterial compliance. Continuous pressure and flow measurements are needed to evaluate these properties. Since the techniques used to date to acquire such data have been invasive, physiological models of the circulation that incorporate these properties have not been widely applied in the clinical setting. The purpose of this study was (1) to validate noninvasive methods for continuous measurement of central arterial pressure and flow and (2) to determine normal reference values for arterial compliance using physiological models of the circulation applied to the noninvasively acquired pressure and flow data. METHODS AND RESULTS: Simultaneously acquired invasive and noninvasive aortic pressures (30 patients), flows (8 patients), and arterial mechanical properties (8 patients) were compared. Pressure was measured by high-fidelity catheter aortic micromanometer (invasive) and calibrated subclavian pulse tracing (noninvasive). Aortic inflow was determined from thermodilution-calibrated electromagnetic flow velocity data (invasive) and echo-Doppler data (noninvasive). Arterial compliance was determined for two- and three-element windkessel models of the circulation using the area method and an iterative procedure, respectively. Once validated, the noninvasive methodology was used to determine normal compliance values for a reference population of 70 subjects (age range, 20 to 81 years) with normal 24-hour ambulatory blood pressures and without Doppler-echocardiographic evidence for structural heart disease. The limits of agreement between invasive and noninvasive pressure data, compared at 10% intervals during ejection and nonejection, were narrow over a wide range of pressures, with no significant differences between methods. Invasive and noninvasive instantaneous aortic inflow values differed slightly but significantly at the start of ejection (P < .05), but during the latter 90% of ejection, values for the two methods were similar, with narrow limits of agreement. Total vascular resistance and arterial compliance values derived from invasive and noninvasive data were similar. Arterial compliance values for the normal population using the two-element model (C2E) ranged from 0.74 to 2.44 cm3/mm Hg (mean, 1.57 +/- 0.38 cm3/mm Hg), with a beat-to-beat variability of 5.2 +/- 3.9%. C2E decreased with increasing age (r = -.73, P < .001) and tended to be higher in men (1.67 +/- 0.41 cm3/mm Hg) than in women (1.51 +/- 0.35 cm3/mm Hg, P = .07). Compliance values for the three-element model (C3E) were predictably smaller than for the two-element model (mean, 1.23 +/- 0.30; range, 0.59 to 2.16 cm3/mm Hg, P < .001 versus C2E) but correlated with C2E values (r = .81, P < .001) and were also inversely related to age (r = -.56, P < .001). Ridge regression and principal component analyses both showed the compliance value to be a composite function whose variation could be best predicted by consideration of simultaneous values for five major hemodynamic determinants: heart rate, mean flow, mean aortic pressure, minimal diastolic pressure, and end-systolic pressure. Multivariate analysis revealed age and sex to be independent predictors of compliance (P < .01 for both). There were no differences in compliance between black and white subjects. CONCLUSIONS: Noninvasive methods can be used to acquire the hemodynamic data necessary for clinical application of physiological models of the circulation that incorporate arterial viscoelastic properties such as arterial compliance. The strong inverse linear relation between model-based compliance estimates and age mandates incorporation of this demographic parameter in

Ethnic differences in circadian hemodynamic profile.

Since the introduction of 24-h ambulatory blood pressure monitoring (ABPM), some studies, although not all, have suggested the presence of a blunted nocturnal blood pressure decline in black versus white subjects, a difference that may help explain the higher incidence of target organ damage in blacks. To better define ethnic differences in diurnal hemodynamic profiles, we studied ABPM recordings from 275 black (55.6% women) and 246 white (43.1% women) previously untreated subjects, with a similar age distribution (from 20 to 79 years) and a wide range of systolic (100-230 mm Hg) and diastolic (50-130 mm Hg) blood pressures. Average clinic systolic (diastolic) blood pressures were higher in black v white men by 10.2 (7.3) mm Hg; P = .04 (P = .004), with a similar trend in women (P = NS). On ABPM, blacks had higher average values, a difference that was greater during sleep (9.4 mm Hg for systolic blood pressure) than while awake (4.7 mm Hg; P = .003). Average diurnal change in systolic blood pressure (awake minus sleep values) was 13.1 +/- 0.7 v 18.0 +/- 0.6 mm Hg for blacks v whites (P < .001). There was a strong negative correlation between baseline (ie, sleep) blood pressure and the diurnal change (r = -0.58; P < .001), but at each given level, blacks had a lower daytime increment/nocturnal fall (P = .02). Results for diastolic blood pressure and heart rate were similar. The data suggest that the smaller diurnal change in blacks may be related in part to their higher blood pressure levels, but that there is an additional, independent effect of race. This results in a greater 24-h blood pressure load in blacks than whites for each given clinic (daytime) value, and may help explain differences in target organ damage. Future studies investigating the effects of blood pressure on target organs in different populations should consider diurnal profiles in addition to clinic blood pressure.

Low predictive value of positive Osler manoeuvre for diagnosing pseudohypertension.

Pseudohypertension is a condition where indirectly determined BP (e.g. via sphygmomanometry) significantly overestimates actual intraarterial pressure. A patient who has a palpable, although pulseless, radial artery while the blood pressure cuff is inflated above systolic pressure, has a positive 'Osler sign'. This 'Osler manoeuvre' has been reported to predict the presence of pseudohypertension. To evaluate its importance in diagnosing pseudohypertension, 19 hypertensive patients deemed Osler-positive by at least two observers were studied. BP was determined indirectly using a stethoscope and mercury sphygmomanometer. Intraarterial pressure was determined by a brachial artery catheter-transducer-monitoring system. For both pressure-measurement techniques and each patient, six readings were averaged to give a single systolic and diastolic value. Mean arterial pressure was calculated as diastolic pressure plus one-third the pulse pressure. Pseudohypertension was defined as a sphygmomanometric mean pressure that exceeded intraarterial mean pressure by > or = 10 mmHg. In this group of 19 Osler-positive patients, stethoscope-sphygmomanometry underestimated systolic and overestimated diastolic intraarterial pressure. For mean pressure, sphygmomanometry was > or = 10 mmHg higher than intraarterial in two patients and > or = 10 mmHg lower than intraarterial in three patients. Thus, while two patients had pseudohypertension, three could be considered to have pseudohypotension, defined as a condition where indirect blood pressure significantly underestimates intraarterial pressure. Accordingly, a positive Osler manoeuvre did not reliably predict the presence of pseudohypertension in this population.

Diurnal blood pressure variability and physical activity measured electronically and by diary.

In order for 24 h ambulatory blood pressure monitoring (ABPM) to be useful in clinical decision making, it is necessary to quantify ambient physical activity and to develop appropriate norms of ambulatory pressure for different levels of activity. The present study has compared the predictive value of physical activity determined by an electronic activity monitor or a written diary, for concomitantly recorded blood pressure during ABPM in healthy normotensive subjects. Each subject wore four activity monitors, on the right and left wrists, on the left ankle and at the waist, respectively. Linear regression analysis was performed for each subject to determine the correlation between ABPM data (systolic and diastolic blood pressure and heart rate) and activity data (obtained from diaries and the four monitors). Significant differences in the degree of correlation were found for both the location of the activity monitor and the time (1/2, 2, 5, 10, 15, and 30 min preceding blood pressure measurement) over which activity was averaged (P < .05 by two-way analysis of variance). The best correlation was obtained with the activity monitor worn on the dominant wrist, and when activity was averaged over 2 to 10 min preceding blood pressure determination, accounting for 18 to 69% (mean 36 +/- 5%) of systolic blood pressure variation. Diaries performed similarly in these well-motivated subjects. It is concluded that because of the significant interaction between activity and blood pressure, ABPM data should be interpreted only in the light of concomitant activity data.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrocardiographic changes during acute treatment of hypertensive emergencies with sodium nitroprusside or fenoldopam.

BACKGROUND: Electrocardiograms are routinely obtained before and during the acute treatment of hypertensive emergencies, usually to rule out "ischemic changes." Despite a few anecdotal reports of electrocardiographic changes, little is known about the incidence and significance of such changes, or their relationship to the treatment used. METHODS: We prospectively analyzed 12-lead electrocardiograms from 21 patients admitted for hypertensive emergencies (average blood pressure, 222 +/- 4/140 +/- 3 mm Hg). Patients were randomly assigned to treatment with sodium nitroprusside (n = 11) or the dopamine receptor agonist fenoldopam mesylate (n = 10). Electrocardiograms were obtained at baseline and within 30 minutes of reaching goal blood pressure (diastolic blood pressure, 100 to 110 mm Hg). RESULTS: There was no significant effect of either drug treatment on PR interval, QRS duration, QT interval, or R-wave amplitude, and no major ST-segment changes were noted. During treatment with either drug, the average T-wave amplitude decreased in all leads except aVR. New T-wave inversions in lead V4 occurred in two and four patients after fenoldopam and nitroprusside treatment, respectively. There were no clinically apparent episodes of myocardial ischemia in any patient. CONCLUSIONS: Even in the absence of obvious myocardial ischemia, a decrease in T-wave amplitude, including T-wave inversion, occurs commonly during acute blood pressure reduction in hypertensive emergencies, an observation that may be explained by the accompanying acute changes in cardiac chamber volumes.

5-Hydroxytryptamine receptor activity of the dopamine receptor agonist fenoldopam in canine tracheal smooth muscle.

Fenoldopam is a new vasodilator undergoing clinical trials for the treatment of hypertensive emergencies. Its pharmacologic effects result from activation of vascular dopamine-1 receptors. In canine tracheal smooth muscle strips, fenoldopam caused a concentration- and calcium-dependent increase in tension, which was not antagonized by atropine, indomethacin or the dopamine-1 receptor antagonist, SCH 23390. The EC50 (1.89 x 10(-6) M) exceeded that of serotonin or acetylcholine (8.38 x 10(-8) and 8.25 x 10(-8) M, respectively). Maximum tension was similar for fenoldopam and serotonin (11.6 +/- 1.5 g, n = 7 and 13.8 +/- 0.8 g, n = 24; P greater than .2) and considerably greater for acetylcholine (20.5 +/- 1.3 g, n = 14; P less than .005). The serotonin antagonists ketanserin and methysergide reversed completely the effect of fenoldopam (5 x 10(-7) M) with IC50 values of 2.5 x 10(-9) and 2.7 x 10(-9) M, respectively. Phentolamine, rauwolscine and chlorpheniramine were also effective, but they were less potent (IC50 values 6.6 x 10(-8), 1.0 x 10(-7) and 1.7 x 10(-7) M, respectively). By contrast, only very high concentrations (IC50, 5.3 x 10(-5) M) of terazosin produced an inhibition of fenoldopam-induced tension increases. The effect of antagonists could be overcome by increasing the fenoldopam concentration. Experiments performed on strips precontracted with serotonin (5 x 10(-8) M) revealed a very similar order of potency for the five antagonists. The addition of serotonin did not increase the tension produced by supramaximal concentrations of fenoldopam (and vice-versa), whereas acetylcholine increased tension further.(ABSTRACT TRUNCATED AT 250 WORDS)

Diurnal blood pressure variation: differences among disparate ethnic groups.

We examined the possibility that excess cardiovascular morbidity in American blacks compared with whites might be partly the result of differences in diurnal blood pressure variation. Urban American blacks have higher night-time blood pressures and show a smaller increase in blood pressure during the waking day than whites. This difference is associated with a higher cardiac mass in the blacks and occurs despite similar duration and quality of sleep in blacks and whites. Both groups show similar levels of sympatho-adrenal activity at night, but the diurnal increase is smaller in blacks, paralleling the smaller increase in blood pressure. In Africa blacks show a diurnal pressure pattern similar to American whites. Disparities in cation consumption do not explain the differences in blood pressure variation between these groups.

Influence of diuretic therapy on the clonidine suppression test.

Moduretic has been reported to inhibit the suppression of plasma norepinephrine (NE) levels by the alpha 2 adrenoceptor agonist, clonidine. To determine whether plasma volume reduction by hydrochlorothiazide (HCTZ) or antagonism of Na+/H+ exchange by amiloride (the constituents of Moduretic) is responsible, the authors performed a modified clonidine suppression test (CST) in nine normal volunteers (aged 25 +/- 2 years), pretreated for 1 week with HCTZ 50 mg daily, amiloride 10 mg daily, or placebo, in a randomized, double-blind, crossover study. Baseline characteristics were identical on all study days, except serum [K+] and weight, which were lowest on HCTZ (3.6 +/- 0.2 mEq/L and 78.7 +/- 2.5 kg), compared with amiloride (4.2 +/- 0.1 mEq/L and 79.9 +/- 2.4 kg) and placebo (4.0 +/- 0.1 mEq/L and 80.2 +/- 2.7 kg, P less than .05). Oral clonidine (0.3 mg) produced a reduction in mean blood pressure by about 20%. Plasma norepinephrine levels were similar in patients receiving placebo, HCTZ, and amiloride (205 +/- 18, 272 +/- 40 and 277 +/- 44 pg/mL, P greater than .20), and decreased significantly during CST. The maximal reduction for each subject averaged 72.7 +/- 12.4%, 87.9 +/- 3.8%, and 82.9 +/- 5.7% for placebo, HCTZ, and amiloride. Clonidine also produced a four to seven-fold increase in plasma growth hormone levels, reduced salivary flow by about 75%, and increased the level of sedation. There were no differences among the three pretreatment regimens in the effects of clonidine, indicating that diuretic therapy does not need to be systematically discontinued in patients undergoing CST.

Cerebral blood flow during the acute therapy of severe hypertension with oral clonidine.

A major risk associated with the acute treatment of severe hypertension is a reduction in cerebral blood flow (CBF) with ischemic injury to the central nervous system. The authors studied CBF before and after the acute treatment of severe hypertension (diastolic blood pressure greater than 115 mm Hg) with clonidine in 13 patients. One patient did not reach goal blood pressure (diastolic blood pressure 105 mm Hg or a decrease by 30 mm Hg) after clonidine alone. In the remaining 12 patients, oral clonidine reduced supine blood pressure from 201.7 +/- 5.0/126.3 +/- 2.1 mm Hg to 149.4 +/- 5.3/96.8 +/- 1.7 mm Hg over an average time period of 85 +/- 7 minutes. Although mean CBF for the group did not change (72.6 +/- 4.2 v 73.7 +/- 3.5 mL/100 mg/min), a significant (greater than 10%) change occurred in 9 of the 12 patients (5 increases and 4 reductions). The magnitude and direction of the change were dependent upon initial CBF (r = -0.65, P less than .05); patients with low pretreatment CBF experienced an increase, whereas those with high initial flow exhibited a decrease. No significant adverse effects were observed. These data confirm previous reports that clonidine is effective in the acute treatment of severe hypertension and demonstrate that its effects on CBF are determined by the pretreatment levels of flow.

Renal and hemodynamic effects of intravenous fenoldopam versus nitroprusside in severe hypertension.

The renal and hemodynamic effects of intravenously administered fenoldopam mesylate, a novel dopamine-1 receptor agonist, were compared with those of sodium nitroprusside in 28 patients (18 male; 26 black, two white; average age, 49 +/- 3 years) with an average blood pressure of 219/137 mm Hg, most of whom presented with acute target organ damage. Fenoldopam and nitroprusside lowered blood pressure safely to an average pressure of 176/105 mm Hg; highly significant dose-response relations were found for the 13 patients receiving fenoldopam and the 15 receiving nitroprusside. Volume and sodium, potassium, and creatinine concentrations were measured in freely voided urine specimens both before and during intravenous therapy. In the fenoldopam-treated patients, there were significant increases in urinary flow (92 +/- 21 to 168 +/- 37 ml/hr, p less than 0.003), sodium excretion (227 +/- 73 to 335 +/- 90 mu eq/min, p less than 0.001), and creatinine clearance (70 +/- 11 to 93 +/- 13 ml/hr, p less than 0.003). In the nitroprusside-treated group, however, all these parameters decreased, but not significantly. For direct comparison of the two agents, the increments in urinary flow rate (+76 +/- 20 vs. -16 +/- 15 ml/hr, fenoldopam vs. nitroprusside), sodium excretion (+109 +/- 28 vs. -39 +/- 28 mu eq/min), and creatinine clearance (+23 +/- 6 vs. -11 +/- 7 ml/min) were significantly greater (p less than 0.001 for each) in the fenoldopam-treated group. Significant differences were also obtained when these parameters were calculated as percentage increase over baseline. Fenoldopam and nitroprusside are effective therapies for severe, accelerated, or malignant hypertension, but fenoldopam had additional salutary renal effects in these patients.

Strophanthidin and potassium on intracellular sodium activity in sheep heart.

Double-barrelled sodium-selective microelectrodes were used to measure intracellular Na+ activity (aiNa) in sheep cardiac Purkinje fibres. A single rubber membrane gap voltage clamp controlled transmembrane potential (Vm) in some experiments. In quiescent preparations, the mean (+/- S.E.M.) aiNa was 8.9 +/- 0.3 mM (n = 46, Vm = -74.7 +/- 0.6 mV) at an extracellular potassium concentration [( K]o) of 5.4 mM and 7.5 +/- 0.4 mM (n = 37, Vm = -63.3 +/- 0.6 mV) at 10.8 mM [K]o. Brief strophanthidin exposures (5 X 10(-6) M for 6 to 10 mins) reversibly increased aiNa by 2 to 18 mM. The magnitude of this increase (delta aiNa) was similar in quiescent and paced (1 Hz) preparations but was inversely related to [K]o in the range studied (2.7, 5.4 and 10.8 mM). Voltage clamp experiments at a constant [K]o (5.4 or 10.8 mM) demonstrated a 27% lower delta aiNa at a Vm of -64 mV compared to -76 mV. In contrast, delta aiNa decreased by 48% when [K]o was increased from 5.4 to 10.8 mM with Vm held constant at either -64 or -76 mV. Hence, the observed antagonism between K+ ions and strophanthidin appeared to be due to a voltage-dependent effect and, to a greater extent, a specific ion-dependent effect. This latter finding is consistent with competitive behaviour between K+ ions and strophanthidin at the Na/K ATPase receptor.