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Hydralazine is an antihypertensive vasodilator agent. Lack of specific assay techniques for its measurement have delayed elucidation of its pharmacokinetic profile. This study compares the plasma profiles of hydralazine, measured both by a specific and by a previously published nonspecific assay and of a major plasma metabolite, hydralazine pyruvic acid hydrazone. After po and iv administration of hydralazine, peak hydralazine levels were lower (7-33%) and plasma half lives were shorter (15-31%) when measured by the specific technique. The mean plasma half life of the pyruvic acid hydrazone was 156 min and mean urinary clearance, 28 ml/min. The plasma profile of hydralazine and of the major metabolite, the pyruvic acid hydrazone, do not appear to correspond to the duration of antihypertensive effect of administered hydralazine.

A study was made of the possible mechanisms underlying bupicomide- and hydralazine-induced increase of plasma renin activity. Six patients with mild to moderate hypertension were treated with both bupicomide and hydralazine on separate occasions in random order. Bupicomide lowered mean arterial pressure from 124.2 +/- 3.7 mm Hg (mean +/- SE) to 107.2 +/- 3.9 mm Hg (P less than 0.001). The associated increase in plasma renin activity was 1.27 ng/ml per hour and the increase in heart rate was 16.5 beats/min. Hydralazine reduced mean arterial pressure from 124.2 +/- 3.7 mm Hg to 107.0 +/- 2.0 mm Hg (P less than 0.01). The associated increase in plasma renin activity was 2.20 ng/ml per hour and the increase in heart rate was 22.4 beats/min. Plasma renin activity during bupicomide and hydralazine administration correlated positively with control plasma renin activity (r = 0.98, P less than 0.001). The log of plasma renin activity correlated positively with heart rate (r = 0.51, P less than 0.02) and negatively with mean arterial pressure (r = -0.62, P less than 0.005). We conclude that control plasma renin activity is a major determinant of change in plasma renin activity during administration of bupicomide or hydralazine. Both an increase in sympathetic activity and a decrease in perfusion pressure may contribute to the bupicomide- and hydralazine-induced increase in plasma renin activity, possibly by a baroreceptor-mediated increase in adrenergic tone.

A specific, high-performance liquid chromatographic technique for the measurement of hydralazine pyruvic acid hydrazone is described. This method utilized reversed-phase chromatography for the separation of this hydrophilic metabolite of hydralazine from other fluid constituents present in serum, plasma, or urine of human volunteers and rabbits receiving hydralazine. Detection of the compound of interest is accomplished spectrophotometrically at 250 nm.

Vasodilator antihypertensive agents are defined and classified according to their mechanism and site of action. The effects of minoxidil, in combination with propranolol and a diuretic, on renal blood flow and renal function were studied following acute and chronic therapy. Although renal blood flow is reduced after two weeks on minoxidil, renal blood flow and renal function are not compromised after one year. The haemodynamic effects and pharmacokinetic profile of acute dosing with tolmesoxide, a new vasodilator antihypertensive agent are described. Results suggest that the long-term efficacy and safety of this drug are worth studying.

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.

We previously have demonstrated that the sympathetic nervous system is activated proportionately to the degree of vasodepression induced in hypertensive patients. In the present study, the role of the renin-angiotensin system in modulating the vasodepressor response to sodium nitroprusside was examined. Nine hospitalized hypertensive patients receiving a diuretic were given serially incremental doses of sodium nitroprusside over a dose range of 0.05-4.8 micrograms/kg/min with each dose being infused for 10 min. Mean arterial pressure (MAP), heart rate (HR), plasma renin activity (PRA), and plasma norepinephrine (NE) concentration were measured prior to and during each dose level of sodium nitroprusside. Stepwise increments in PRA were seen in each patient as the dose of sodium nitroprusside was increased. The increase in PRA was proportional to the increase in plasma NE concentration and to the decrease in MAP in each patient. However, considerable intersubject variation was seen in these relationships. When examined by multiple linear stepwise regression analysis, the degree of vasodepression was found to be dependent on the baseline blood pressure and baroreflex sensitivity (r = 0.97). However, increment in PRA was not an independent determinant of the vasodepressor response. Thus, the renin angiotensin system may not be a significant component of the acute homeostatic response to vasodepression in these patients.

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.

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.

The efficacy and toxicity of hydralazine differ widely among individual patients, possibly because of different sensitivities to drug effect or as a reflection of pharmacokinetic differences. Therefore, the variability in plasma hydralazine concentrations after single intravenous and single and multiple oral doses was studied in 9 male hypertensive patients. After an intravenous dose of 0.3 mg/kg the area under the plasma concentration time curve (AUC) varied over less than a twofold range 17.5-29.5 muM-minute. However, after a single oral dose, 1 mg/kg, and after at least the fifth dose of a regimen consisting of 1 mg/kg given every 12 hours, there were much wider variations in AUC values: 4.0-30.4 and 3.2-38.5 muM-minute, respectively. Similar ranges in peak hydralazine concentration, Cp, were also noted, 0.12-1.31 muM after single oral dose and 0.10-1.39 muM after the multiple dose regimen. A significant portion of the observed interpatient variability could be explained by differences in acetylation ability. The AUC and Cp values for both the single and multiple oral doses were significantly lower (P less than 0.001) in rapid than in slow acetylators. Therefore, determining the acetylation ability of patients requiring hydralazine may help to optimize therapeutic benefit and minimize toxicity.

K+ contractures were induced in paired strips of rabbit aortic smooth muscle. The relationship between relaxant effects and the bath concentration of hydralazine acetone hydrazone (HA), 4-OH-hydralazine (HH) and phthalazine (P) was studied over the concentration range 10(-5)-10(-3)M. All compounds were active, HA = HH greater than P (p less than 0.05; n = 6) at concentrations in the range 10(-4)-10(-3M, HA greater than HH at a concentration of 10(-3M (pgreater than 0.01). The activity of HA did not depend on significant reconversion to hydralazine (H) in the bath ( less than 0.5%). A range of H derivatives may contribute to the hypotensive effects of administered H.

The circulatory response of the kidney to drugs is conditioned by a variety of factors, such as basal vascular tone, dietary sodium and structural changes in the renal vasculature which accompany aging and disease. In addition, any drug which affects systemic arterial pressure will activate renal autoregulatory processes, which are superimposed upon the direct effects of the drug on the renal circulation. Renal autoregulation in addition to passive pressure effects probably accounts for the relative constancy of renal blood flow during the administration of renal vasodilators such as nitroprusside, diazoxide and minoxidil. Renal vasodilators which have minor effects on systemic arterial pressure, such as dopamine and glucagon, increase renal blood flow. These effects have been employed clinically in low cardiac output states. A variety of drugs affect the renal circulation by modifying the effects of endogenous vasoactive substances. The mechanisms of action include: receptor blockade; ex, adrenergic and Ag II-mediated vasoconstriction: enhanced production by the administration of biochemical precursors; ex, arachidonic acid and I-dopa: inhibition of endogenous production; ex, prostaglandin synthetase inhibitors: and inhibition of breakdown of endogenous substances; ex, converting enzyme inhibition. The effect of each of these interventions will depend in part upon the rate of endogenous production of the relevant vasoactive material. The administration of diuretics affects renal blood flow in individually distinctive ways, the mechanisms of which have been only partially elucidated.

1. Dose-response relationships to K+ were determined in isolated strips of rabbit aorta. 2. K+ contractures were induced by 30 mM K+ in paired strips from individual animals. The effects of hydralazine and hydralazine acetone hydrazone (hydralazine acetonide) on these contractures were studied. 3. Hydralazine and hydralazine acetonide both produced dose-dependent decreases of K+-induced tone. Threshold concentrations for hydralazine were 11.89 +/- 4.5 X 10(-5) M (mean +/- s.d.) and for hydralazine actonide 9.7 +/- 4.6 X 10(-5) M (0.5 less than P less than 0.4). 4. The magnitude of the effect of hydralazine acetonide was greater than that of hydralazine at all concentrations above threshold, as reflected in a significant difference (P less than 0.05) in the slopes of dose-response curves to the two treatments. The vasodilator effects of hydralazine and the acetonide were terminated by washout of the bath. 5. The differences in effect were not due to instability of hydralazine under in vitro conditions. 6. It is concluded that hydralazine acetonide has intrinsic activity on vascular smooth muscle which differs significantly from that of the parent compound and that this may contribute to the hypotensive effects which follow administration of the parent compound.

The hydralazine--acetone hydrazone (HAH) has previously been identified as a metabolite of hydralazine (H) in humans. We compared the hypotensive effects of HAH and H in groups of hypertensive rabbits. Both compounds caused a dose-dependent depressor response, with a potency ratio of HAH to H of approximately 0.2. Upon their intravenous administration to anephric rabbits, both H and HAH produced sustained concentrations in plasma of the H-pyruvic acid hydrazone, demonstrating that back-conversion of HAH to H occurred in vivo. We conclude that HAH is hydrolyzed in vivo to yield parent H. The levels of the H-metabolite, the pyruvic acid hydrazone, suggest that the hypotensive effect of HAH could be explained entirely by generation of H in vivo. This combined pharmacokinetic and pharmacodynamic approach can be applied to other H-hydrazones to evaluate their backconversion to H in vivo.

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.

A specific high-performance liquid chromatographic assay for hydralazine in human plasma was developed. Plasma hydralazine is reacted with 10 microliter of p-anisaldehyde for 7 min at room temperature to form hydralazine p-anisaldehyde hydrazone. This derivative is extracted into ethyl acetate, and the solvent is removed by evaporation. The residue is reconstituted in 100 microliter of methanol, and 90 microliter is injected onto a reversed-phase column. The mobile phase is 32% acetonitrile in 0.75 M acetate buffer, pH 3.4, at a flow rate of 2 ml/min. The retention time of hydralazine p-anisaldehyde hydrazone is 6.5 min. The average coefficient of variation over 10-200 ng/ml is 5.5%, and the sensitivity limit is 5 ng/ml. Under the assay conditions, hydralazine pyruvic acid hydrazone, a known plasma metabolite of hydralazine, yields less than 0.1% hydralazine. Detectable plasma hydralazine levels of 5-20 ng/ml were found 10-30 min after a 0.5-mg/kg oral dose of hydralazine hydrochloride was given to a male volunteer.

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.