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To assess the clinical efficacy of chronic vasodilator therapy for refractory congestive heart failure, the long-term follow-up (mean 13 months, range 3-30 months) was evaluated in 56 patients treated with hydralazine, usually in combination with nitrates. In the first 6 months, 73% improved subjectively and 59% improved by one or two New York Heart Association classifications; early improvement was usually sustained. Mortality was high, 22% at 6 months and 37% at 12 months, but was significantly lower in patients who had a clinical response to vasodilators (21% in responders vs 55% in nonresponders at 1 year). The only clinical indicator that differentiated responders from nonresponders was the presence or absence of symptomatic progression before initiation of vasodilator therapy. Pulmonary artery pressure, pulmonary capillary wedge (PCW) pressure and stroke work index (SWI) before and during vasodilator therapy correlated with clinical response and survival. Fifteen of 20 patients with PCW < 20 mm Hg and SWI greater than or equal to 30 g-m/m2 improved and survived, compared with two of 19 with PCS greater than or equal to 20 mm Hg and SWI < 30 g-m/m2. Patients who did not have acute hemodynamic improvement generally did not improve clinically, but neither the percentage change nor the absolute change in any hemodynamic variable predicted outcome in the remaining patients. The findings of this study indicate that vasodilators produce clinical improvement in many patients with refractory heart failure and that hemodynamic measurements are helpful in predicting the outcome of therapy.

Otolaryngologic involvement is rarely a manifestation of drug-induced systemic lupus erythematosus (SLE). Hoarseness developed in a 60-year-old man that was secondary to ulcerated lesions, which involved the epiglottis and aryteno-epiglottic folds, with serologic evidence of SLE after he had been treated with hydralazine for six months. Histopathologic study of an epiglottic "pseudotumor" disclosed necrotizing vasculitis. To our knowledge, this is the first reported case of laryngeal involvement as a complication of hydralazine-induced SLE.

The role of acetylator phenotype in determining the response to hydralazine when it was added to diuretic and beta-blocker at doses not exceeding 200 mg daily was examined in 57 hypertensive patients. 81% of rapid acetylators needed 200 mg hydralazine daily compared to 38% of slow acetylators (p less than 0.01). Despite higher doses of hydralazine the blood pressure was controlled in only 27% of rapid acetylators compared to 65% of slow acetylators (p less than 0.02). The relation of acetylator phenotype to blood pressure response was statistically independent of initial blood pressure, age, sex, body weight and serum creatinine (p less than 0.005). Current recommendations on hydralazine dosage are unsatisfactory for the 40% of hypertensive patients who are rapid acetylators. We suggest measurement of the acetylator phenotype in patients who respond incompletely to 200 mg hydralazine daily. About 70% of these patients will be rapid acetylators in whom the dose of hydralazine can be increased safely.

The contribution of genetic factors in the reduction in erythrocyte CR1 levels observed in hydralazine (Hz) induced systemic lupus erythematosus (SLE) was investigated by determining the frequency of a HindIII restriction fragment length polymorphism (RFLP) in the CR1 gene. This RFLP is associated with quantitative erythrocyte CR1 expression. Individuals who have developed SLE as a reaction to Hz therapy, consanguinous relatives of the Hz-SLE patients, controls who had been treated with Hz without any adverse reaction, and the consanguinous relatives of these controls were included in this study. No difference was found in the frequency of occurrence of the alleles associated with CR1 expression between the Hz-SLE patients and the control groups (P greater than 0.2). Individuals from the Hz-SLE group who were homozygous for the 7.4 kb 'high expressor' allele had lower mean levels of erythrocytes CR1 (564 +/- 65) than the corresponding homozygous subgroups within the Hz-SLE relative group (774 +/- 46), the Hz control group (756 +/- 80) and the Hz control relatives group (825 +/- 66). In addition, 50% of the Hz-SLE patients in the 'high expressor' subgroup who had less than 500 CR1 per erythrocyte had elevated levels of circulating immune complexes. This study suggests that individuals who are genetically low expressors of erythrocyte CR1 are not predisposed to developing SLE in response to Hz therapy, and that in a subgroup of genetically 'high expressors', low CR1 levels are associated with elevated levels of circulatory immune complexes.

Although hydralazine provokes myocardial ischemic events in hypertensive patients not in heart failure by producing reflex tachycardia, the frequency of and mechanisms underlying ischemic events when this drug is administered as a vasodilator agent to patients with heart failure is unknown. The responses to hydralazine in 52 consecutive patients with severe chronic heart failure secondary to coronary artery disease were reviewed. Twelve patients (23 percent) had 16 ischemic events during the initial administration of hydralazine (angina at rest in 12 and myocardial infarction in 4); these generally occurred in the absence of significant tachycardia and hypotension. Thirty-five of the 52 patients received nitroprusside (8 of whom had ischemic events with hydralazine), but this drug provoked ischemia in only 1 of the 35 although it resulted in greater decreases in systemic arterial pressure than occurred with hydralazine. In patients with ischemic event only with hydralazine, left ventricular filling pressure decreased 14.6 mm Hg with nitroprusside but only 3.9 mm Hg with hydralazine (probability [p] less than 0.01). Provocation of ischemia with hydralazine may therefore be due to the relative preservation of elevated left ventricular preload with this drug, since ischemic events are not in common with nitroprusside despite greater decreases in systemic pressures.

26 patients with systemic lupus erythematosus (SLE) induced by treatment with the antihypertensive drug hydralazine were investigated to determine if predisposition to the toxic effect was associated with an HLA-DR antigen. 25 of the 26 patients were slow acetylators. The group was compared with three others (1) 113 healthy subjects, untested for acetylator phenotype, (2) 16 slow-acetylator hypertensive patients treated with hydralazine for more than a year without developing SLE, and (3) 20 patients with idiopathic SLE. The frequency of HLA-DR4 (73%) was significantly higher in the group with hydralazine-induced SLE than in the other groups (respectively 33%, 25%, and 25%). The ratio of women to men affected was 4:1. If the slow acetylators treated with hydralazine were analysed as one group, it was observed that all women with DR4 developed hydralazine-induced SLE; the only men to do so were those with DR2 who were receiving 200 mg hydralazine per day. These observations have led us to suggest guide lines for hydralazine therapy and point to a striking association between an HLA-DR antigen and an adverse reaction to a therapeutic agent. It was also noted that the distribution of DR antigens in the hydralazine-SLE patients was significantly different from that in the group with idiopathic SLE. This supports the view that the syndromes are separate entities.

Oxdralazine, a pyridazine shown to induce prolonged arteriolar dilation in animals, was given orally in doses of 15 to 30 mg to 7 subjects with hypertension. Arterial pressure fell in 2 hr (average mean of 16 mm Hg), peaking in 3 to 4 hr, and was sustained for more than 6 hr. Cardiac output and heart rate rose in 2 hr (2.1 l/min and 17 bpm) and were elevated at 6 hr (3.1 l/min and 22 bpm). Pulmonary arterial pressure and pulmonary arteriolar resistance did not change. In 6 subjects receiving oxdralazine with hydralazine 50 to 75 mg at 1-wk intervals, hydralazine induced earlier, less sustained decreases in arterial pressure and systemic vascular resistance and less of a rise in heart rate than oxdralazine alone. Circulating norepinephrine levels (radioenzymatic method) 3 hr after oxdralazine rose from a mean of 159 to 294 pg/ml, a greater (p less than 0.05) effect than after hydralazine. At the doses tested, oxdralazine is a potent systemic arteriolar dilator with longer-sustained action and more prominent reflex sympathetic stimulation than hydralazine.

The metabolism of hydralazine in a group of slow acetylator patients with the drug-induced lupus syndrome was compared with the metabolism in asymptomatic control subjects. There were no toxicologically significant difference in metabolite excretion between the groups which reached statistical significance, although there were interesting trends. However, the single lupus patient with the rapid acetylator phenotype excreted considerably greater quantities of phthalazinone than control patients and also increased amounts of hydrazine and hydralazine hydrazones. These results and the trends overall are consistent with the hypothesis that the metabolism of hydralazine may indeed be responsible for the drug induced lupus syndrome.

Drug induced Lupus erythematosus (LE)-like syndromes are generally observed after long-term and/or high-dose therapy with so called "principal inducers" procainamide, hydralazine, isoniazide, chlorpromazine, anticonvulsives and possibly with D-penicillamine, too, and even so in some cases after some additional 26 drugs. The rare pseudo LE syndrome appears after combined drugs which usually contain pyrazolone derivatives used especially against venous diseases. The mechanism of induction of autoimmune reactions in these disorders varies and is after all still unknown. There are individual differences in drug metabolism, genetic disposition for increased autoantibody formation and sometimes humoral and cellular immune reactions against the drug itself. Essentially involved in the indication of autoimmune reactions is often the production of hapten carrier complexes between drugs and body constituents and drug induced changes of autoantigen elimination as well as drug mediated immunologic imbalance.

Nine patients (6 men, 3 women) with rapidly progressive glomerulonephritis developing during hydralazine therapy were seen. Early cessation of hydralazine treatment resulted in improvement in seven patients, while continued hydralazine treatment resulted in permanent renal insufficiency in two. The clinical symptoms of systemic illness associated with the hydralazine syndrome were absent in most patients. Antinuclear antibody test was positive in all, and six investigated patients had antibodies to histones. All patients had anemia, high ESR, and microscopic hematuria. Five of the nine patients were rapid drug acetylators. Renal biopsies from eight patients revealed a uniform histologic picture with segmental necrosis of glomeruli and extracapillary proliferation. Immunofluorescence investigation was positive in all and electron microscopy revealed deposits in the glomerular capillary walls in five of seven specimens. This renal disease may represent a late and monosymptomatic manifestation of the hydralazine syndrome.

The adverse reactions of antihypertensive agents are reviewed, including their clinical implications and suggested methods of preventing, detecting and managing them. The drugs discussed are: (1) diuretics--thiazides, furosemide, ethacrynic acid and spironolactone; (2) sympatholytics--reserpine, methyldopa, guanethidine, propranolol and clonidine; (3) vasodilators--hydralazine, prazosin and minoxidil. It is suggested that cooperative multi-disciplinary efforts should be undertaken to counteract the factors which contribute to improper use of antihypertensive agents.

Fifty patients with arterial hypertension of various causes were treated with a combination consisting of Nepresol, a beta-adrenergic receptor-blocking agent and a diuretic. Duration of treatment ranged between 3 months and 5 years. A significant reduction of blood pressure was attained in all of the cases, with a return of the values to the normal range in a high proportion of the patients. The renal function did not deteriorate during therapy, but owing to potassium loss regular potassium replacement was required in the majority of the cases. Allergic reactions appeared in two cases. Neither SLE nor rheumatoid arthritis was encountered. Positive ANF reaction and a significant elevation of the Rose-Waaler titre were demonstrated in a number of cases. The benefits as well as the hazards of the therapeutic use of hydrazine derivatives are pointed out.

Effective use of modern antihypertensive agents requires an intimate understanding of the various side effects associated with each of the drugs. Some of the undesirable side effects are unavoidable because they are inherent in the action of the drug. For example, hypokalemia and hyperuricemia are inherent side effects of diuretic therapy. Other adverse reactions are idiosyncratic and difficult to predict. With careful monitoring and individual therapeutic planning, these side effects need not inhibit efforts to control hypertension.

Three cases with drug-induced liver diseases (hepatitis caused by hydralasine, steatosis caused by methimazole, choletasis caused by birth control pill) were investigated with respect to their drug metabolising ability. Clinical diagnoses were based on the exclusion of other pathogenetic factors, on histological findings of liver biopsy specimens and on the clinical chemical tests. Investigation of biotransforming ability was carried out using test materials (menthol loading, antipyrine, sulfadimidine, caffeine, indocyanine green kinetics) and measurement of D-glucaric acid excretion. In all cases the results show a defective capacity in some respect of drug metabolism. Possible pathogenetic role of reactive metabolites is discussed in the pathomechanism of genesis of drug-induced liver diseases.

Neutrophilic dermatosis (Sweet's syndrome) is a condition that presents with arthritis and a skin rash. A case report is presented, and an association with hydralazine and lupus is described.

A rat model was developed for use in evaluating postural hypotensive activity of a compound. Conscious normotensive rats were restrained on a tilt board with special restrainers to avoid blocking limb circulation. Dose response curves were explored to delineate the potential postural hypotensive activity of a compound. In response to a 2-min 90 degree head-up tilt, only a negligible changes in blood pressure was observed in the control state. The conscious rat was therefore able instantaneously to compensate for postural change. This ability, however, was blocked by guanethidine. The compound induced a dose-related hypotension and a further, dose-dependent drop in blood pressure on tilt. Hydralazine, on the other hand, induced only dose-dependent hypotension, but no change in blood pressure response from control tilts. Since these findings appear to be in accord with human clinical data, this rat model may be suitable for use in evaluating potential postural hypotensive activity of compounds.

Prazosin was compared with hydralazine in 39 patients (mean age 49 years), who were already on beta-blockade for arterial hypertension. They all had a resting DBP greater than 100 mm Hg on propranolol 80 mg b i d. They were randomly allocated to prazosin or hydralazine treatment. Blood pressure was measured after 4, 8 and 12 weeks. We noted a significant fall in blood pressure in both groups, in most cases to normotensive levels. Side-effects and other variables of interest are discussed. Together with beta blockade, i e propranolol, both prazosin and hydralazine give good blood-pressure control and no important differences could be found.

Twenty-seven hypertensive patients (23 blacks, 4 whites) treated with hydralazine had frequent serologic evidence of autoimmunity. However, only 1 patient developed a lupus syndrome. Acetylator phenotype influenced the autoimmune response; slow acetylators had a higher incidence and titers of autoantibodies. The lupus patient not only had high titers of autoantibodies but they were predominantly IgG in contrast to the predominant IgM antibodies found in other slow acetylators. Hydralazine treatment did not alter cell-mediated immune responses and hydralazine antibodies were not detected. However, half the patients tested who received hydralazine had positive lymphoproliferative responses to the drug.

Previous studies have documented potentially adverse effects of diuretics and beta-blocking agents on plasma lipid profiles. This study was designed to establish the effects on lipid profiles of the angiotensin-converting enzyme inhibitors lisinopril and enalapril, alone and in combination with hydrochlorothiazide (HCTZ), the calcium-channel blocker nitrendipine, HCTZ, and hydralazine. After a two-week, single-blind, placebo phase, 77 patients with essential hypertension were given active agent as monotherapy in a double-blind fashion for 8-20 weeks. The dose of each agent was titrated to achieve diastolic blood pressure less than 90 mm Hg. At the end of placebo and treatment phases, plasma was analyzed for triglycerides, total cholesterol, and high-(HDL), and low-density lipoprotein (LDL) cholesterol. Overall, few changes in lipid contents were noted. Total cholesterol decreased during therapy with hydralazine but increased in patients receiving the combination of lisinopril and HCTZ. HDL cholesterol was depressed in those taking HCTZ alone and in combination with lisinopril. LDL cholesterol was lowered during therapy with hydralazine but was otherwise unaffected by all other agents. None of the agents evaluated significantly affected triglyceride concentrations. Thus, monotherapy with lisinopril, enalapril, and nitrendipine do not affect plasma lipid concentrations. Hydralazine lowers total and LDL cholesterol. If these findings are confirmed in trials with larger numbers of patients, these effects on lipid profiles may influence choice of agent in the therapy of essential hypertension.

This report describes a 59-year-old woman, who, after an initial reaction to hydralazine, inadvertently took the drug again. She promptly developed symptoms of acute cholangitis--fever, right upper quadrant tenderness, obtundation, and hypotension. Cholecystectomy was performed and no obstruction or infection of the biliary tract was present. Perioperative studies support a diagnosis of hydralazine-induced acute cholangitis, a side effect of the drug which has not been previously described.

We compared the efficacy and safety of nitrendipine with that of hydralazine in 21 subjects with essential hypertension. Nitrendipine or hydralazine was given in a double-blind manner after a placebo period. Dose was titrated to diastolic blood pressure (BP) less than or equal to 90 mm Hg and the dose established during titration was continued for 5 to 7 wk. Both supine and erect BP were decreased by both drugs, but heart rate was affected only minimally. Myocardial oxygen demand decreased only with nitrendipine (P less than 0.05), although the change may have been the result of somewhat higher systolic BP while on placebo. Hydralazine induced minimal changes in levels of plasma catecholamines, but plasma norepinephrine levels rose in subjects on nitrendipine. Side effects encountered with both drugs were much the same, although nitrendipine was more often associated with mild fatigue. There were mild elevations in liver function parameters in two subjects on nitrendipine. There was little difference between the effects of nitrendipine and hydralazine in hypertension.

A 48-year-old white woman who for 3 years had been taking hydralazine, 100 mg three times a day, propranolol, 160 mg twice a day, and chlorothiazide, 500 mg/day, for hypertension suddenly developed rapidly expanding ulcers that looked like pyoderma gangrenosum. Arthralgias, fevers, and occasional shortness of breath were also noted. A pericardial effusion was diagnosed by echocardiography. The antinuclear antibody (ANA) titer on routine mouse liver substrate was initially negative, but the ANA titer was positive (1:1,920) on human epithelioid cell substrate. Antibodies to histones and single-stranded DNA were also elevated. After discontinuing hydralazine, all signs and symptoms cleared over a 4-week period. At the time of discharge the ANA titer had decreased to 1:480.

In 36 patients with normal renal function receiving hydrochlorothiazide and propranolol, lying diastolic blood pressure remained above 95 mmHg. In a double-blind trial, Step 3 therapy with 5-40 mg/day of minoxidil reduced blood pressure somewhat more effectively than 25-200 mg/day of hydralazine. The percentage of patients with lying diastolic blood pressure below 90 mmHg was 69 versus 35% at four weeks, and 55 versus 40% at 28 weeks. Transient falls in blood pressure within 4 h of any dose were greater with hydralazine which usually needed to be given in divided daily doses. Minoxidil caused tachycardia, and more adverse effects. Minoxidil is more effective, produces more consistent blood pressure control throughout the day, and may often be administered once daily.

The effects of dipyridamole, a coronary and peripheral vasodilator drug, on cardiac performance were investigated in nine patients with severe chronic heart failure. Dipyridamole (30 to 80 mg IV) increased cardiac index (1.63 to 2.65 l/min/m2) and decreased systemic vascular resistance (2097 to 1124 dyn/sec/cm-5). Left ventricular filling pressure decreased (23.7 to 20.7 mm Hg) without significant changes in mean right atrial pressure or heart rate. These effects were similar to the hemodynamic responses after 100 mg hydralazine in the same patients, but they were of shorter duration (less than 90 min). In contrast, oral dipyridamole induced only modest responses in three of eight patients despite large single doses of the drug (150 to 300 mg). Dipyridamole is a rapid-acting short-lived vasodilator, which exerts predominantly arterial vasodilator actions similar to those of hydralazine. Due to inconsistent response after oral doses, however, the therapeutic application of dipyridamole in long-term management of chronic heart failure appears to be limited.

Beginning in the early 1950s, when a ganglioplegic agent and a vasodilator were used in combination to provide long-term control of severe hypertension, which neither drug alone could control, much has been learned about the management of hypertension from the use of new antihypertensive agents in man and from clinical trials of antihypertensive regimens. Some of this information includes: the unexpected yet very real hazards as well as benefits associated with the long-term use of powerful drugs, in particular the original description of hydralazine-induced lupus, its relation to genetic markers and its association with control of hypertension; the apparently decreasing need for antihypertensive drugs in subjects with well-controlled severe and moderate hypertension; the identification of risk factors for the complications of hypertension and the quantitation of their effects; the decrease in the incidence of hypertensive complications associated with the pharmacologic treatment of severe, moderate and, at least, the upper ranges of mild hypertension; the possibility of designing a chemical to block a specific reaction and the realization that it would have broader than expected effects; and the primary prevention of myocardial infarction in very high risk subjects.

The choice of an effective method to treat priapism is challenging because precise causes in the majority of patients have not been well defined. A review of 48 patients treated during a 22-year period shows evolution of a regimen of management that has yielded a high percentage of success. Idiopathic priapism and sickle cell disease accounted for 81 per cent of the subjects. An evaluation should include a medication history, a search for specific diseases, as well as a thorough physical examination to detect possible etiologic factors. The explanation for the frequent association of fever deserves further investigation. Initial therapy consisting of aspiration and irrigation, and intermittent pneumatic cuff compression should be undertaken for a trial period of 12 to 36 hours, repeating the aspiration 2 or 3 times if necessary. The failure of priapism to resolve after such treatment is an indication for a shunt operation. Patients with known etiology should be treated specifically for the primary disease and usually more conservatively for priapism. Resolution occurred in all patients and approximately 50 per cent regained sexual potency.

21 patients with systemic lupus erythematosus induced by long-term treatment with hydralazine were investigated to see whether susceptibility to this syndrome was associated with deficiency of the classical pathway complement protein, C4. 16 of 21 (76%) patients had one or more C4 null (ie, non-productive) alleles compared with 35 of 82 normal subjects (43%). This difference was significant. The HLA-DR4 antigen, known to be in linkage disequilibrium with the C4B null allele, was also significantly more frequent in the patients (14 of 21 patients compared with 31 of 81 normal subjects). Susceptibility to hydralazine-induced lupus, as in idiopathic systemic lupus erythematosus, may depend partly upon genetically determined C4 levels.

This study was undertaken to see whether the presence of antihistone antibodies, measured by indirect immunofluorescence assay, could distinguish between patients who were symptomatic from a drug-induced lupus-like illness (DILE) and asymptomatic patients who had drug-induced antinuclear antibodies (DANA). In this study, 82% of the patients with DILE had antihistone antibodies detectable in their sera, compared with 32% of the patients in the DANA group (P less than 0.01). When the patients taking procainamide were analyzed separately, it was found that 92% of the patients with DILE had demonstrable antihistone antibodies, contrasted with 33% of the patients in the DANA group (P less than 0.01). In those patients with antihistone antibodies (DILE versus DANA patients), there were no differences in the mean antibody titers. We conclude that the presence of antihistone antibodies is strong, statistically significant evidence that the symptoms of a given patient are due to drug-induced lupus erythematosus.

The immunological side-effects under treatment with antihypertensive drugs are mainly limited to autoimmunity and autoimmune disease caused by alpha-methyldopa and hydralazine. Autoimmune hemolytic anemia is more common during treatment with alpha-methyldopa. Hydralazine may induce antinuclear antibodies. Some patients develop a SLE-like syndrome. Its clinical picture is less severe and its prognosis is more favourable than that of spontaneous SLE. During treatment with low doses the disease develops exclusively in patients who are slow acetylators. It may appear also in rapid acetylators during the high dose treatment. The symptoms are usually reversible after withdrawal of the drug.

Forty-three patients with mild essential hypertension were randomized into two double-blind studies: pinacidil vs. placebo or pinacidil vs. hydralazine. Pinacidil (62 +/- 18 mg/day) decreased office systolic and diastolic blood pressures from 145 to 137 mm Hg and from 98 to 89 mm Hg, respectively, after 6 weeks of therapy. Similarly, hydralazine (128 +/- 28 mg/day) reduced supine systolic blood pressure from 140 to 134 mm Hg and supine diastolic blood pressure from 93 mm Hg to 84 mm Hg. Significant tachycardia was not noted with either drug. Ambulatory blood pressure was monitored for 24 h during the placebo-washout and efficacy phases with both pinacidil and hydralazine. Mean 24-h blood pressure was 128 systolic and 81 diastolic with pinacidil and 121 systolic and 76 diastolic with hydralazine. Reduction in awake hypertensive diastolic blood pressure was significant for both pinacidil and hydralazine. Normal sleep diastolic blood pressure was not reduced by pinacidil but was reduced by hydralazine. Side-effects with both drugs included edema, headache, and palpitations. These data demonstrate that pinacidil is as effective an antihypertensive agent as hydralazine.

Thirty-seven hypertensive patients were treated with cyclopenthiazide, oxprenolol and hydrallazine. Blood pressure was controlled in 31 patients and a subsequent double-blind crossover study in 27 patients comparing hydrallazine with placebo confirmed the efficacy of hydrallazine in combination with diuretic and beta-adrenergic-blocking agent. The combination was effective in patients with renal hypertension and renal impairment. No adverse effects on renal function were observed. Patients who were slow acetylators had significantly better blood pressure control and more side effects. In view of the frequency of hydrallazine related side effects, prior institution of beta-adrenergic blocking drugs is desirable.