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At least 19 recordsLinked to original sources
PubMed1979

Pharmacokinetics of hydralazine, apparent hydralazine and hydralazine pyruvic acid hydrazone in humans.

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.

Acetylation↗
PubMed1977

Comparative evaluation of the in vitro effects of hydralazine and hydralazine acetonide on arterial smooth muscle.

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.

Animals↗
PubMed1978

Interference in assays for hydralazine in humans by a major plasma metabolite, hydralazine pyruvic acid hydrazone.

The present study showed that published spectrophotometric and GLC methods for hydralazine in plasma do not distinguish between the drug and a major plasma metabolite, hydralazine pyruvic acid hydrazone. These methods involve the acid treatment of the sample, which hydrolyzes that hydrazone back to hydralazine. A specific GLC assay for the hydrazone was developed and involves its selective extraction from plasma and transformation to 3-trifluoromethyl-s-triazolo[3,4-a]phthalazine. This derivative could be sensitively measured by GLC using an electron-capture detector. With this procedure, it was shown that most "apparent hydralazine" in plasma is the hydrazone, which forms rapidly from hydralazine and endogenous pyruvic acid. Previous work indicated that the hydrazone was inactive when administered intravenously to rabbits.

Chromatography, Gas↗
PubMed1979

Pharmacokinetics and cardiovascular effects in rabbits of a major hydralazine metabolite, the hydralazine pyruvic-acid hydrazone.

The hydrazone of hydralazine and pyruvic acid (HPH) has been recognized as a quantitatively important metabolite of hydralazine in human plasma. We evaluated the disposition of [14C] HPH after its i.v. administration to normal, anephric and probenecid-pretreated rabbits. Renal clearance of HPH in normal rabbits exceeded the glomerular filtration rate by a factor of 3 to 4 and accounted for 80 to 90% of the total body clearance. Active tubular secretion was established by the effect of probenecid pretreatment to reduce the renal clearance of HPH by 80%. Total body clearance of HPH in anephric rabbits was 10% of that of normal animals, emphasizing the minor importance of metabolic conversion for the overall disposition of HPH. HPH in a maximum dose of 50 mumol/kg i.v. had no hypotensive effect in renal hypertensive rabbits and did not interfere with the subsequent hypotensive response to hydralazine. This HPH dose produced plasma levels at least 50 times in excess of those reported in humans after administration of therapeutic doses of parent hydralazine. HPH is consequently of negligible clinical significance, despite the relatively high plasma concentration of this metabolite which occurs after administration of parent hydralazine.

Animals↗
PubMed1979

High-pressure liquid chromatographic assay for hydralazine in human plasma.

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.

Adult↗
PubMed1978

Interaction of hydralazine with tension development and mechanisms of calcium accumulation in K+-stimulated rabbit aortic strips.

A study was made of the effects of hydralazine on K+ contractures in rabbit aortic strips. Measurements were made of effects on tension generation, Ca++ accumulation measured using 45Ca++ (lanthanum method) and 45Ca++ efflux. Hydralazine relaxed established K+ contractures and inhibited tension development when tissue exposure to hydralazine preceded K+ depolarization. Both the threshold and the maximum tension responses of strips to Ca++ (K+-depolarized tissues) were altered by hydralazine in a dose-dependent manner. The Ca++ uptake associated with K+ depolarization was inhibited by relaxant doses of hydralazine; however, hydralazine did not significantly affect the rate of 45Ca++ efflux. Hydralazine also raised the threshold to the inhibitory (relaxant) effects of higher (greater than 2.5 mM) bath concentrations of Ca++. It is suggested that hydralazine inhibits K+ contractures in aortic strips by interference with the entry of Ca++ into the cell, reflecting an effect of hydralazine at the cell surface membrane.

Aorta, Thoracic↗
PubMed1979

Influence of short-term oral hydralazine therapy on exercise hemodynamics in patients with severe chronic heart failure.

Changes in left ventricular performance were evaluated in 14 patients with functional New York Heart Association class III or IV chronic heart failure before and after the addition of oral hydralazine to conventional therapy. With conventional therapy, cardiac output increased from 3.4 +/- 0.8 (mean +/- 1 standard deviation) at rest to 4.7 +/- 1.4 liters/min during exercise. This increase in cardiac output on exercise during conventional therapy was mainly due to an increase in heart rate. After the addition of hydralazine, cardiac output at rest increased to 5.0 +/- 1.4 liters/min. The increase in cardiac output was essentially due to an increase in stroke volume. This enhanced stroke volume after hydralazine therapy was maintained during exercise. Hydralazine therapy did not change either the left ventricular filling pressure at rest or the magnitude of increase in left ventricular filling pressure during exercise. Nevertheless, increased cardiac output and stroke volume with similar changes in left ventricular filling pressure during exercise indicated improved left ventricular performance after hydralazine therapy. After short-term hydralazine therapy, symptom-limited peak exercise work load, duration of exercise and maximal oxygen consumption during exercise did not increase. Clinical follow-up at 2 months after long-term therapy revealed subjective improvement in exercise tolerance in 13 of the 14 patients.

Administration, Oral↗
PubMed1979

High-performance liquid chromatographic studies of reaction of hydralazine with biogenic aldehydes and ketones.

To understand hydrazone formation in hydralazine metabolism, the reaction of hydralazine with various biogenic aldehydes and ketones (acetone, pyruvic acid, acetoacetic acid, formaldehyde, and acetaldehyde) in pH 7.4 buffer was studied for potential alterations in hydralazine pharmacokinetics secondary to alcoholism and diabetes. The corresponding hydrazones were isolated, and their structures were characterized. High-performance liquid chromatography was used to monitor the reactions. An aqueous solvent reversed-phase liquid chromatographic system was used to separate hydralazine and its derivatives. Reaction of hydralazine with formaldehyde or acetaldehyde produced the corresponding hydrazones. Formation of an s-triazolo ring system yielded the known s-triazolo[3,4-alpha]phthalazine and 3-methyl-s-triazolo[3,4-alpha]phthalazine metabolites, which also were isolated and characterized and suggested nonenzymatic metabolism.

Aldehydes↗
PubMed1978

Electrophysiologic effects of hydralazine on sinoatrial function in patients with sick sinus node syndrome.

The electrophysiologic effects of hydralazine were evaluated in nine hypertensive patients with sinoatrial dysfunction. Intravenous hydralazine, 0.15 mg/kg, caused no significant reduction in arterial blood pressure. Yet this dose of hydralazine increased heart rate from 61.9 +/- 4.1 beats/min (mean +/- standard error of the mean) to 68.6 +/- 4.9 (P less than 0.001). Sinus nodal recovery time upon termination of atrial pacing shortened from 3,207 +/- 1,098 to 2,064 +/- 573 msec (P less than 0.05) and second escape cycles shortened as well (P less than 0.025). Acceleration of heart rate and abbreviation of recovery time did not closely correlate with change in blood pressure (r = 0.41 and 0.18, respectively). Junctional escape beats became more frequent and junctional escape time shortened from 2,525 +/- 692 to 1,705 +/- 382 msec (P less than 0.05). Sinoatrial conduction time tended to shorten, but a significant change was not observed. Atrial tachyarrhythmias did not occur and atrial refractoriness was unchanged. Thus, a minimal blood pressure response to hydralazine was associated with enhanced automaticity. Hydralazine merits clinical trial for treatment of sick sinus syndrome with concomitant hypertension.

Aged↗
PubMed1978

Effects of hydralazine on canine muscarinic ganglion stimulation.

The effects of hydralazine upon the caudal pressor responses during occlusion of the abdominal aorta and vena cava evoked by: (1) preganglionic electrical stimulation of the lumbar sympathetic chain, (2) neostigmine and (3) McN-A-343 were investigated in the anesthetized dog. Hydralazine (10 microgram/kg, i.v.) produced a small but significant reduction of the pressor response to lumbar electrical stimulation prior and following blockade of nicotinic transmission with chlorisondamine (1.0 mg/kg). However, hydralazine was not effective in blocking the pressor responses elicited by neostigmine and McN-A-343. On the other hand, small doses of atropine (20 microgram/kg) produced a blockade of residual pressor responses evoked by all three stimuli. On the basis of these findings, the site of action of hydralazine appears to be different from that of atropine. It is proposed that hydralazine affects ganglionic transmission by acting at sites other than muscarinic in nature.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1979

Comparison of haemodynamic effects of oral hydralazine and prazosin hydrochloride in patients with chronic congestive heart failure.

The comparative haemodynamic effects of oral prazosin hydrochloride and hydralazine were evaluated in 11 patients with chronic congestive heart failure. The maximum total dose of prazosin received by an individual varied up to 25 mg. Ten patients received a maximum of 75 mg and one received 50 mg of hydralazine at six-hour intervals. There was no significant change in heart rate with either drug. Decrease in mean arterial and left ventricular filling pressures were modest and similar with both agents. With prazosin, the average cardiac index increased 20 per cent and systemic vascular resistance decreased 20 per cent. By contrast, hydralazine increased cardiac index by 58 per cent and decreased systemic vascular resistance by 40 per cent. The increase in stroke work and stroke volume indices was significantly greater with hydralazine than with prazosin. These findings suggest that in some patients with severe chronic congestive heart failure, improvement in left ventricular performance may be greater with hydralazine than with prazosin.

Adult↗
PubMed1979

Comparison of haemodynamic effects of oral prazosin, oral hydralazine, and intravenous nitroprusside in same patients with chronic heart failure.

The haemodynamic effects of oral prazosin and hydralazine were evaluated in patients with refractory heart failure and compared with those of intravenous nitroprusside in the same patients. Both oral agents were well tolerated and appeared to have beneficial haemodynamic effects. Prazosin and hydralazine produced similar increases in cardiac output associated with a similar decrease in systemic vascular resistance. Prazosin and hydralazine produced similar increases in cardiac output associated with a similar decrease in systemic vascular resistance. Prazosin resulted in a more significant decline in left ventricular filling pressure and pulmonary vascular resistance than did hydralazine. Haemodynamic alterations induced by prazosin were similar to those induced by nitroprusside, which suggests a relatively balanced reduction of preload and afterload. With hydralazine, the increase in cardiac output without change in left ventricular filling pressure or pulmonary vascular resistance suggests minimal effect on preload but significant reduction in afterload.

Adult↗
PubMed1975

Hydralazine-induced lupus erythematosus-like syndrome.

A reversible syndrome resembling systemic lupus erythematosus and induced by hydralazine hydrochloride therapy is a well-recognized phenomenon in adults but does not seem to have been reported in children. A 9-year-old girl had fever, arthralgias, modest joint swelling, splenomegaly, antinuclear antibodies (ANAs), anitbodies against native and denatured DNA, and positive LE cell preparations after nine months of hydralazine hydrochloride therapy, 120 mg/day. Clinical findings returned to normal within four weeks of discontinuing the drug therapy, and serological abnormalities disappeared after 11 months. Like previously reported patients, the child is white and has a slow acetylation phenotype. It is not known whether children receiving hydralazine are as susceptible to this complication as adults. Periodic ANA determinations may be advisable for children receiving hydralazine, especially if they are white and have a slow acetylation phenotype.

Acetylation↗
PubMed1975

Combination therapy of essential hypertension with pindolol (Visken) and hydralazine.

Thirty patients suffering from essential hypertension were treated successively with placebo, hydralazine alone, and pindolol (Visken) combined with hydralazine. Hydralazine caused a statistically significant reduction in blood pressure and an increase in pulse rate as compared with the placebo: palpitations were an irritating side-effect. The combination of hydralazine and pindolol resulted in an additional fall in blood pressure (p less than 0.001) and the pulse rate decreased (2 p less than 0.001). The combined treatment also had a favourable effect on palpitations and angina pectoris.

Adult↗
PubMed1976

Effects of hydralazines on canine muscarinic ganglion transmission.

The effects of hydralazine, dihydralazine and 4-propyl-1-hydrazinophthalazine (4-propylhydralazine) were investigated on reflex pressor responses to increased intracranial fluid pressure (IIP) during occlusion of the abdominal aorta and the vena cava (MVO). It has been shown that application of MVO, caudal to the renal arteries, produces two independent vascular zones in the animal (Steinberg and Hilton, 1966a). Increasing intracranial fluid pressure during MVO elicits a reflex pressor response which consists of two components. One component is blocked by the nicotinic ganglionic blocking agent, chlorisondamine, and the other component is blocked by small doses of atropine. It was found that hydralazine and dihydralazine were effective in blocking residual pressor responses following partial blockade of reflex pressor responses to IIP with chlorisondamine. 4-Propylhydralazine, which is chemically similar to hydralazine and dihydralazine, was less active in inhibiting the residual pressor responses. It is suggested that hydralazine may act in part by interfering with muscarinic ganglionic transmission.

Animals↗
PubMed1978

Renal plasma flow and cardiac output during hydralazine and propranolol treatment in essential hypertension.

Eleven patients with essential hypertension were given hydralazine (25 mg b.i.d.) for 2 weeks, hydralazine and propranolol (80 mg b.i.d.) for the next 2 weeks, and propranolol alone for the last 2 weeks. The changes in the renal and systemic circulation elicited by the drugs were studied before start of medication and bi-weekly during the treatment, using non-invasive radioisotope techniques. Hydralazine alone did not alter mean arterial blood pressure (MAP), heart rate (HR), cardiac index (CI), effective renal plasma flow (ERPF), peripheral renin activity (PRA) and plasma aldosterone (Aldo) but when propranolol was added MAP fell 15.2%, HR 22.5% and CI 18.4%, while ERPF was unchanged. When hydralazine was withdrawn and propranolol was given alone, ERPF decreased 13.2%. Plasma aldosterone was unchanged, whereas PRA decreased during propranolol treatment. The reduction in ERPF elicited by propranolol, was highly significant (P less than 0.01). From the test sequence it appears that dihydralazine prevents this effect of propranolol on kidney function. These findings might have a direct bearing on the choice of antihypertensive treatment.

Adult↗
PubMed1978

Changes in plasma volume and extracellular fluid volume and after addition of hydralazine to propranolol treatment in patients with hypertension.

In 16 patients with hypertension, BP could not be controlled satisfactorily by treatment with propranolol alone (mean dosage 325 mg/day). Plasma volume (PV) (T-1824) and extracellular fluid volume (ECV) (82Br-distribution space) were determined in these patients before and after the addition of hydralazine for three months (mean dosage 135 mg/day). After the addition of hydralazine, PV and ECV increased significantly, by 9% and 3%, respectively. Systolic and diastolic BPs decreased, by 15% and 13%. The mechanisms inducing fluid retention during treatment with hydralazine and the clinical significance of the problem are discussed. It is concluded that the addition of a diuretic to propranolol-hydralazine treatment is often well indicated.

Adult↗
PubMed1978

Hemodynamic effects of nitroprusside and hydralazine in experimental cardiac tamponade.

Cardiac tamponade is associated with decreased cardiac output and increased systemic vascular resistance. Thus, vasodilator drugs might lower systemic resistance and increase cardiac output. Three groups of dogs were studied during tamponade. Group I received nitroprusside only; group II received blood transfusion and then nitroprusside; group III received hydralazine. In group I, nitroprusside lowered right artrial pressure and systemic resistance; cardiac output was unchanged. In group II, transfusion raised right atrial pressure but not cardiac output. Then nitroprusside raised cardiac output significantly. Hydralazine decreased right atrial pressure less than nitroprusside but decreased vascular resistance and raised cardiac output. Both nitroprusside and hydralazine decreased systemic vascular resistance during tamponade, but only hydralazine raised cardiac output probably because of its lesser effect upon the capacitance vessels. Nitroprusside maintained cardiac output during tamponade despite lowered right atrial pressure but increased cardiac output only after transfusion.

Animals↗