Placental transfer of a substituted pteridine from fetus to mother.

In sito near-term sheep placentas transferred triamterene (2,4,7-triamino-6-phenyl-pteridine) from the fetus much more rapidly than to the fetus. This differential transfer effect may significantly influence the distribution of exogenous and endogenous compounds between the maternal and fetal compartments.

Control plasma renin activity and changes in sympathetic tone as determinants of minoxidil-induced increase in plasma renin activity.

A study was made of the possible mechanism(s) underlying minoxidil-induced increase in plasma renin activity (PRA). 10 patients with essential hypertension were treated with minoxidil and subsequently with a combination of minoxidil plus propranolol. Minoxidil lowered mean arterial pressure 31.6 plus or minus 3.3 mm Hg, mean plus or minus SEM. There was an associated increase in both PRA, 6.26 plus or minus 2.43 NG/ML/H, and heart rate, 21.4 plus or minus 2.7 beats/min. The changes in PRA and heart rate were positively correlated, r, 0.79. Addition of propranolol reduced mean arterial pressure by a further 10.1 plus or minus 1.5 mm Hg and returned heart rate to control levels. Propranolol reduced PRA significantly but not to control levels. Control PRA positively correlated with PRA on minoxidil, r, 0.97, and with PRA on minoxidil plus propranolol, r, 0.98. We conclude that control PRA is a major determinant of change in PRA with minoxidil. Minoxidil increased PRA by at least two mechanisms: (a) an adrenergic mechanism closely related to change in heart rate and blocked by propranolol, and (b) a mechanism(s) not sensitive to propranolol and possibly related to decrease in renal perfusion pressure.

The effects of moxonidine, a novel imidazoline, on plasma norepinephrine in patients with congestive heart failure. Moxonidine Investigators.

OBJECTIVE: To evaluate the dose response relationship of moxonidine on plasma concentration of norepinephrine during acute and chronic administration in patients with congestive heart failure (CHF). BACKGROUND: Sympathetic activation is increased in heart failure. Moxonidine is an imidazoline ligand acting on the central nervous system (CNS) receptors to decrease sympathetic activation. METHODS: Ninety-seven patients with heart failure and New York Heart Association class II-III symptoms and ejection fraction <40% were randomized to placebo or one of three target doses of moxonidine, 0.1, 0.2 or 0.3 mg administered twice daily. An initial dose of moxonidine 0.1 mg twice a day (b.i.d.) was followed by weekly increments of 0.1 mg b.i.d. until target dose. The second and third study days occurred after four weeks (at target dose) and after 12 weeks, respectively. At each study day, repeated blood samples were drawn. RESULTS: There was a significant dose-related decrease of systolic blood pressure across all three study days. Heart rate decreased significantly on study day 3 in a dose-related manner. The acute 2 h decrease in plasma norepinephrine in response to all three doses of moxonidine was significantly different compared with placebo after four and 12 weeks. There was a significant linear relation between dose and plasma norepinephrine after four and 12 weeks in both 2 h peak and the time averaged effect (>8 h). The number of adverse events was similar in the moxonidine and placebo groups. CONCLUSIONS: The increased sympathetic activation in CHF can be reduced by moxonidine through CNS inhibition.

Efficacy of captopril in relieving congestive heart failure developing during management of hypertension. Case report.

A 20-year-old woman presented with malignant hypertension, pulmonary edema, anemia, and azotemia. Blood pressure was adequately controlled only after progressively more intensive drug regimens, finally including minoxidil, nadolol, and furosemide. On these drugs, the patient developed progressive left and right heart failure, anasarca, and malnutrition. The control of hypertension, heart failure, and fluid retention, was accomplished by administration of captopril and furosemide. Captopril is a logical alternative to vasodilators in refractory hypertension complicated by congestive heart failure.

Plasma concentration and acetylator phenotype determine response to oral hydralazine.

The vasodepressor response to single and multiple oral doses of hydralazine, 1 mg/kg, was studied in hypertensive patients. The concentration of hydralazine in plasma was measured both by a newly developed specific and a nonspecific assay similar to those used in previous studies. Acetylator phenotype was determined following oral sulfamethazine. Plasma hydralazine concentration peaked at 1 hour after administration and was undetectable 2 hours later. Apparent hydralazine was present in plasma in higher concentration and for a longer duration than hydralazine. The peak decreases in blood pressure (BP) were proportional to plasma hydralazine concentration following administration of both single and multiple doses and were substantially maintained for 8 hours. In contrast there was no significant correlation between decreases in BP and apparent hydralazine concentrations. The plasma concentration of hydralazine after a standard oral dose varied by as much as 15-fold among individuals and was lower in rapid than slow acetylator phenotype patients. The BP responses were positively correlated with plasma hydralazine concentrations and inversely correlated with acetylator indices. Low plasma concentrations may account for poor responses of some patients to conventional oral doses of hydralazine. The applicability of acetylator phenotyping for individualization of hydralazine dosage regimens merits further evaluation.

Captopril modifies the hemodynamic and neuroendocrine responses to sodium nitroprusside in hypertensive patients.

To determine if clinically effective doses of the antihypertensive agent captopril affected the neuronal release of norepinephrine or baroreflex sensitivity, changes in plasma norepinephrine concentration and heart rate were related to the changes in mean arterial pressure seen during the intravenous infusion of stepwise incremental doses of sodium nitroprusside before and during captopril treatment in eight hypertensive men with normal or low plasma renin activity. At all times, significant linear correlations were found between the decrease in mean arterial pressure and the dose of sodium nitroprusside, the increase in heart rate and the decrease in mean arterial pressure, and the increase in plasma norepinephrine concentration and the decrease in mean arterial pressure. When the subjects were treated with captopril (25 mg t.i.d.) for 2 to 4 weeks, supine mean arterial pressure decreased from 130 to 114 mm Hg (-12%; p less than 0.05), heart rate did not change, supine and upright plasma renin activity increased, while supine plasma norepinephrine and epinephrine concentration decreased slightly. Therapy with captopril (25 mg t.i.d.) increased baroreflex sensitivity, as assessed by the slope of the regression line relating the increase in heart rate to the decrease in mean arterial pressure, and increased the responsiveness of the sympathetic nervous system, as assessed by the slope of the regression line relating the increase in plasma norepinephrine concentration to the decrease in mean arterial pressure. These increases were accompanied by a decrease in the slope of the regression line relating the decrease in mean arterial pressure to the dose of sodium nitroprusside and thus were associated with a decreased sensitivity to the vasodepressor effects of sodium nitroprusside.(ABSTRACT TRUNCATED AT 250 WORDS)

Baroreflex sensitivity modulates vasodepressor response to nitroprusside.

Baroreflex activity is a determinant of the homeostatic response to alteration in blood pressure. We examined the factors that determine the magnitude of the vasodepressor response to sequential incremental intravenous infusions of sodium nitroprusside (NP), 0.05 to 6.4 micrograms/kg/min, in eight male patients with essential hypertension. Each infusion level was of 10 minutes' duration. Change from control values of mean arterial pressure (delta MAP), heart rate (delta HR) and plasma norepinephrine (delta NE) were obtained at the end of each infusion level. Significant correlations were found between delta MAP vs log dose NP, delta HR vs delta MAP and delta NE vs delta MAP for each patient (p less than 0.05). However, the slopes of these relationships varied widely between subjects and were significantly correlated with the control blood pressure of each patient. In addition, the sympathetic responsiveness, as measured by delta NE vs delta MAP, was inversely correlated with the degree of vasodepressor response seen. Thus, the magnitude of the vasodepressor response was determined by two major factors: 1) the predrug blood pressure, possibly reflecting altered vascular geometry with hypertension; 2) the degree of sympathetic response, which probably acts by mediating the degree of reflex alpha-adrenergic-mediated arteriolar vasoconstriction.

Increased plasma norepinephrine accompanies persistent tachycardia after hydralazine.

To determine the role of the peripheral sympathetic nervous system in the persistent tachycardia caused by the antihypertensive drug hydralazine, we examined the temporal relationships between the changes in heart rate and plasma norepinephrine concentration and the reduction in blood pressure produced by a range of doses of hydralazine administered intravenously to five hypertensive patients. Significant linear correlations were found between the increases in heart rate and plasma norepinephrine concentration and the reduction in blood pressure at 15 and 30 minutes after injection. However, at 240 minutes after injection, changes in heart rate and plasma norepinephrine were not correlated with changes in blood pressure and were disproportionately elevated relative to the reduction in blood pressure. A significant linear correlation between changes in heart rate and plasma norepinephrine concentration was noted at 15, 30, and 240 minutes after injection. The temporal discordance of the changes of both heart rate and plasma norepinephrine relative to the reduction in blood pressure and the significant linear correlation between the increases in heart rate and plasma norepinephrine concentration suggest that continued activation of the peripheral sympathetic nervous system contributes to the persistent tachycardia seen after the administration of hydralazine.

A method for achieving blood pressure control expeditiously with oral minoxidil.

Twelve patients with essential hypertension were treated aggressively with oral minoxidil in order to achieve blood pressure control as expeditiously as possible. Pretreatment blood pressure ranged from 159/109 to 238/161 mm Hg. Following an initial dose of 5 mg, subsequent dosage increments were administered every 6 hr until a fall in blood pressure was observed. The size of additional doses was determined by the magnitude of, and response to, the lowest effective dose and the therapeutic objective. Over a time interval of 24 to 42 hr, the blood pressure was reduced to normal or near normal in each case. Untoward hypotension was uniformly avoided. Analysis of the relationship between blood pressure response and cumulative dose indicates that at suboptimal blood pressure responses, it is safe and efficacious to give half the antecedent cumulative dose as a single dose in arriving at the therapeutic objective. The use of such a regimen should be considered as an alternative to parenteral drug administration in severe hypertension when immediate control of blood pressure is not required.

Determinants of response to intravenous hydralazine in hypertension.

There is marked interindividual variation in hypotensive response to intravenous hydralazine (H). We examined the determinants of response in patients with hypertension. After a single intravenous dose of 0.3 mg/kg H, response was correlated independently (r = 0.8364) with both predrug blood pressure and acetylator index (AI). Intravenous dose ranging studies showed that response also depended on the amount of H in the systemic circulation. Although plasma H levels depend on AI after oral doses, this is not so after intravenous administration. AI must therefore affect response to H by an alternative, presumably nonmetabolic mechanism which, not related to AI, perhaps indicating specificity of this effect for H. These data reinforce the potential usefulness of determining AI before giving H to a patient.

Pharmacodynamics of minoxidil as a guide for individualizing dosage regimens in hypertension.

The antihypertensive effect of minoxidil was studied in 6 patients with varying degrees of hypertension. Their baseline mean arterial pressure (MAP bi) ranged from 122 to 197 mm Hg. Single oral doses between 2.5 and 25 mg were administered in sequence and the time-course of hypotensive action was followed. We have reported previously that when the peak lowering of MAP is linearly regressed against log dose, both the dose-response slope (M) and threshold dose (Dt) are positively correlated with the MAP bi of individual patients. This investigation focuses on the temporal pattern of effect. It was found that the hypotensive effect of minoxidil declined linearly with time at a rate consistent with an average effective biologic half-life of about one day. The rate of decline of effect was apparently independent of dose but was dependent on MAP bi. Since both response to and duration of effect of minoxidil are functions of MAP bi, there is an abvious need to individualize dosage regimens based on the severity of disease. Using pharmacodynamic parameters, guidelines for loading dose, maintenance dose, and dosing frequency as a function of the degree of hypertension are suggested. Loading dose requirements were found to increase with MAP bi while maintenance doses were largely independent of the severity of the disease. Frequently of dosing was found to range from 3 times a day in very severe hypertension to once a day in moderate hypertension.

Decreased plasma protein binding of diazoxide in uremia.

The effect of uremia on the binding of diazoxide to plasma proteins was studied. An equilibrium dialysis technique, using diazoxide-minus14C at approximately 30 and 300 mug/ml in the plasma phase, was used to measure diazoxide binding to plasma. Serum albumin concentration (Alb) and serum creatinine (Cr) or blood urea nitrogen (BUN) were negatively correlated. By single regression analysis, per cent free diazoxide (%FD) correlated negatively with Alb and positively with Cr or BUN. When %FD was regressed simultaneously against Alb and Cr or BUN, Alb emerged as the sole determinant of %FD (p less than 0.001), indicating that creatinine or BUN correlated with %FD by their inverse correlation to Alb rather than by an effect on drug protein binding. At the levels of Alb studied, %FD varied over a 2-fold range. In a retrospective study of the influence of uremia on diazoxide effect in hypertensive patients, a relatively low correlation (r, 0.59) was found between BUN and hypotensive effect. Prospective studies involving correlations of drug effect with renal function and %FD are required to assess the clinical importance of decreased binding of diazoxide to uremic plasma.

Antihypertensive effect of a dopamine beta hydroxylase inhibitor, bupicomide: a comparison with hydralazine.

The cardiovascular effects of a new antihypertensive drug, bupicomide, were compared with those of hydralazine in 6 patients with mild to moderate hypertension. The mean supine arterial pressure of patients was reduced 15.2 mm Hg by bupicomide (900 to 2,000 mg/day) and 15.7 mm Hg by hydralazine (300 to 600 mg/day). Heart rate increased an average of 11.3 bpm during bupicomide and 14.5 bpm by hydralazine. Neither drug was associated with a postural decrease in mean arterial pressure. The heart rate response during maximum tolerated treadmill exercise was not diminished by either drug. Cardiac index was increased during administration of both drugs. Bupicomide and hydralazine reduced forearm vascular resistance, while renal blood flow and renal vascular resistance were not significantly modified. Evidence of equivalent augmentation of sympathetic nervous activity during administration of both drugs consisted of equal and significant increases in heart rate and urinary norepinephrine excretion, and decreases in duration of the pre-ejection period. The absolute values of these parameters were correlated with mean arterial pressure, which may indicate that the increase in sympathetic nervous activity was mediated by baroreceptor reflexes. Although bupicomide inhibits dopamine beta-hydroxylase, our results suggest that it is acting as a direct vasodilator.

Effect of oral dose size on hydralazine kinetics and vasodepressor response.

Levels of hydralazine in blood are log-linearly related to its vasodepressor effect. We examined the effect of oral dose size on the proportion of hydralazine that reaches systemic circulation. Nine subjects with hypertension were given hydralazine in oral doses in the therapeutic range. Blood hydralazine levels, effective liver blood flow, blood pressure, and heart rate were measured. As the hydralazine dose increased, the ratios of the AUC of hydralazine to hydralazine dose and of peak blood hydralazine concentration to hydralazine dose increased, indicating an increase in the proportion of the dose in blood. Liver blood flow tended to increase (maximum 40%) as dose increased above 0.5 mg/kg. Vasodepressor response and degree of tachycardia increased disproportionately with increasing hydralazine dose. There were strong log-linear relationships between peak hydralazine levels and both vasodepressor response and tachycardia that did not change with increasing hydralazine dose. Thus blood hydralazine and vasodepressor response increase disproportionately with increasing hydralazine doses in hypertension.

The response of plasma catecholamines to intravenous labetalol: a comparison with sodium nitroprusside.

Changes in mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of norepinephrine (NE) and epinephrine were measured in eight hypertensive patients in a supine position after stepwise infusion of incremental sodium nitroprusside doses and intravenous injection of cumulative labetalol doses. Both drugs induced rises in plasma NE concentration that were linearly related to reductions in MAP. For any reduction in blood pressure (BP), however, the rise in plasma NE concentration induced by labetalol was approximately four times that induced by sodium nitroprusside. The difference can be explained by two effects of labetalol: impairment of neuronal NE uptake and beta-adrenergic-receptor blockade, which are known to reduce NE clearance from plasma. After both drugs there was a correlation between changes in HR and changes in BP and a correlation between changes in HR and changes in plasma NE concentration. Slopes of the regression lines for both relationships were less after labetalol than after sodium nitroprusside, presumably because of the beta-adrenergic-blocking properties of labetalol. Multiple-regression analysis indicated that the plasma NE rise was an important determinant of the vasodepressor response to each drug. The greater plasma NE elevation after labetalol may limit its antihypertensive effect.

Effects of hydralazine and sodium nitroprusside on plasma catecholamines and heart rate.

Hydralazine and sodium nitroprusside induce different effects on systemic hemodynamics, but their effects on sympathetic neuronal activity have not been compared. Five hypertensive subjects receiving only hydrochlorothiazide were studied during two sessions. During one session, four doses of hydralazine, 0.1 to 0.6 mg/kg, were given intravenously at least 3 days apart, and during the other session, sodium nitroprusside was infused in stepwise doses, 0.05 to 4.8 micrograms/kg/min for 10 min per dose. Mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine (NE) and epinephrine concentrations were determined before and after dosing. The following correlated linearly for hydralazine and sodium nitroprusside: delta HR/delta MAP, delta NE/delta MAP, and delta HR/delta NE. Comparison of these relationships, however, indicated significant differences between the sympathetic neuronal and hemodynamic responses to hydralazine and sodium nitroprusside. Increase in HR relative to decrease in MAP was greater for hydralazine than for sodium nitroprusside. There were greater increases in plasma NE concentration relative to falls in MAP with sodium nitroprusside than with hydralazine, but increases in HR relative to increases in plasma NE concentration were smaller for sodium nitroprusside than for hydralazine. Such responses may reflect differential effects of hydralazine and sodium nitroprusside on the systemic clearance of NE or of the activity of cardiopulmonary baroreceptors.

Hydralazine kinetics in hypertensive patients after intravenous administration.

Previous studies on intravenous hydralazine kinetics have been performed using nonselective analytical techniques that measure not only hydralazine but also certain hydralazine metabolites such as hydralazine pyruvic acid hydrazone (HPH). We studied the time course of hydralazine and HPH in eight hypertensive patients after 0.3 mg/kg intravenous with selective high-pressure liquid chromatographic assays. "Apparent" hydralazine concentrations were also determined using a nonselective gas-liquid chromatographic procedure. Total plasma clearance, CLT[72.9 +/- 4.9 (SEM) ml . min-1 . kg-1], apparent volume of distribution, Vd area (5.83 +/- 0.30 1 . kg-1), steady-state volume of distribution, Vd ss (1.83 +/- 0.17 . kg-1), and terminal half-life, t1/2 (53.7 min, harmonic mean) were independent of acetylator phenotype. The high ClT is compatible with rapid intravascular conversion of hydralazine to HPH and a high hepatic extraction ratio. Peak HPH concentrations occurred 10 to 60 min after dose; mean HPH t1/2 was 239 min. "Apparent" hydralazine concentrations were usually highest in the 2-min plasma sample and declined with a mean t1/2 of 296 min. Reports based on nonselective assay methods have underestimated CLT, Vd ss, and Vd area and have overestimated the t1/2 of hydralazine.

Hydralazine kinetics after single and repeated oral doses.

In reports on hydralazine kinetics plasma hydralazine levels have been measured with nonspecific assay techniques. The techniques used also include acid-labile hydralazine metabolites and therefore markedly overestimate hydralazine levels. We have developed specific, sensitive assay methods for the measurement of hydralazine and its major plasma metabolite, hydralazine pyruvic acid hydrazone (HPH). By these methods, we determined hydralazine and HPH kinetics after single and repeated oral doses of hydralazine in eight hypertensive patients. Hydralazine bioavailability in the fast acetylator group (9.5% single dose, 6.6% repeated doses) and in the slow acetylator group (31.3% single dose, 39.3% repeated doses) was phenotype dependent. Peak plasma levels were lower than those reported with nonspecific assays: 0.32 microM for the single dose and 0.14 microM for repeated doses in the fast acetylator group and 1.03 microM for the single dose and 0.96 microM repeated doses in the slow acetylator group. There was no alteration in kinetics and no cumulation in plasma on repeated administration. HPH plasma levels were proportional to those of hydralazine in both acetylator groups and were 2.5 to 4 times as high as those of hydralazine. Elimination half-lifes were phenotype independent, ranging from 4 to 6 hr. HPH cumulated in the rapid but not in the slow acetylator group after repeated doses of hydralazine.

Population pharmacokinetic-pharmacodynamic modeling of moxonidine using 24-hour ambulatory blood pressure measurements.

OBJECTIVES: To develop a model for 24-hour ambulatory blood pressure measurements (ABPM) that can be applied in a pharmacokinetic-pharmacodynamic model. METHODS: Four different data sets were prepared from 2 studies to accommodate different modeling strategies. In study A, a double-blind placebo-controlled study in 47 patients, 24-hour ABPM profiles (74 to 99 measurements per profile) were obtained during the placebo run-in phase and after 3, 5, and 11 weeks during the treatment. Three to 5 plasma samples were taken. Cosine and polynomial models were evaluated to describe the circadian rhythm in blood pressure based on 3 data sets (1: only run-in data; 2: only placebo data; 3: all data). In study B, a double-blind placebo-controlled study in 94 patients, two 24-hour ABPM profiles per patient (during placebo run-in and after 8 weeks) were recorded and randomly reduced to 15 measurements per profile to evaluate the robustness of the baseline model. RESULTS: The mean moxonidine clearance was 35 L/h, and the volume of distribution was 132 L. The final baseline model consisted of 2 cosine terms with fixed-effect parameters for rhythm-adjusted 24-hour mean blood pressure, amplitude, phase, and period; random-effect parameters for interindividual variability in rhythm-adjusted 24-hour mean, amplitude, and clock time; and interoccasion variability in rhythm-adjusted 24-hour mean and clock time. The final baseline model was combined with an Emax model for the drug effect. An effect compartment was used (kco = 0.198 h-1). The maximum decrease in diastolic blood pressure (Emax) was 16.7%, and EC50 was 0.945 microgram/L. CONCLUSION: The pharmacokinetic-pharmacodynamic model for 24-hour ABPM can be used to estimate the concentration-effect relationship of antihypertensive drugs.

Effect of intravenous dose on hydralazine kinetics after administration.

Six male hypertensive patients, three rapid and three slow acetylators, each received four different intravenous hydralazine doses by constant infusion over 100 sec. Two to four days elapsed between doses. Plasma or whole-blood hydralazine concentrations were measured by HPLC after each dose. There was no influence of acetylator phenotype on hydralazine kinetics after intravenous dosing. There also was no consistent effect of dose size on hydralazine clearance or volume of distribution at doses up to 0.45 mg (2.3 mumol/kg). One subject, who received doses up to 0.6 mg/kg (3.05 mumol), had an apparent decrease in clearance at the higher doses. These findings are consistent with the fact that hydralazine is converted intravascularly to hydralazine pyruvic acid hydrazone and the fact that potentially saturable hepatic metabolic pathways play only a modest role in systemic clearance.