The 5-HT2 antagonist ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channels.

BACKGROUND AND PURPOSE: Ketanserin, a selective 5-HT receptor antagonist, prolongs the QT interval of ECG in patients. The purpose of the present study was to determine whether ketanserin would block human cardiac ether-à-go-go-related gene (hERG) potassium channels. EXPERIMENTAL APPROACH: Whole-cell patch voltage-clamp technique was used to record membrane currents in HEK 293 cells expressing wild type or mutant hERG channel genes. KEY RESULTS: Ketanserin blocked hERG current (I(hERG)) in a concentration-dependent manner (IC50=0.11 microM). The drug showed an open channel blocking property, the block increasing significantly at depolarizing voltages between +10 to +60 mV. Voltage-dependence for inactivation of hERG channels was negatively shifted by 0.3 microM ketanserin. A 2.8 fold attenuation of inhibition by elevation of external K+ concentration (from 5.0 to 20 mM) was observed, whereas the inactivation-deficient mutants S620T and S631A had the IC50s of 0.84 +/- 0.2 and 1.7 +/-0.4 microM (7.6 and 15.4 fold attenuation of block). In addition, the hERG mutants in pore helix and S6 also significantly reduced the channel block (2-59 fold) by ketanserin. CONCLUSIONS AND IMPLICATIONS: These results suggest that ketanserin binds to and blocks the open hERG channels in the pore helix and the S6 domain; channel inactivation is also involved in the blockade of hERG channels. Blockade of hERG channels most likely contributes to the prolongation of QT intervals in ECG observed clinically at therapeutic concentrations of ketanserin.

Ketanserin versus dihydralazine for the treatment of severe hypertension in early-onset preeclampsia: a double blind randomized controlled trial.

OBJECTIVE: Determine the definitive position of ketanserin and dihydralazine for treatment of severe hypertension in pregnancy. STUDY DESIGN: A single centre double blind randomized controlled trial was performed at the obstetrical tertiary high care unit of the University Medical Centre in Rotterdam, the Netherlands. Women with severe hypertension in pregnancy (diastolic blood pressure (DBP)≥110mmHg), and significant proteinuria (≥300mg/24h), and gestational age≤32 weeks were eligible for the study. All patients (n=30) received two infusions (double dummy technique): one contained the active ingredient (ketanserin or dihydralazine), the other was used for placebo. Nicardipine was used as rescue medication. The main outcome measures were persistent severe hypertension (DBP>100mmHg>120min) despite maximum dosage of study medication and prolongation of pregnancy. RESULTS: Dihydralazine was significantly more effective in lowering blood pressure than ketanserin. No significant difference in prolongation of pregnancy was seen between the two groups. After 30 inclusions, the study was stopped because of the high rate of persistent hypertension using ketanserin and the high rate of maternal side effects using dihydralazine and the apparent succesful use of the rescue drug nicardipine. CONCLUSIONS: Our results do not support the use of either dihydralazine or ketanserin for the treatment of severe hypertension in pregnancy. Future research is needed to compare nicardipine with other antihypertensive drugs currently in use for treatment of severe hypertension in pregnancy.

Alpha-adrenergic blockade makes minimal contribution to ketanserin's hypotensive effect.

Ketanserin is a selective (S2) serotonin receptor antagonist currently under investigation as an antihypertensive. It has been suggested that the antihypertensive action of ketanserin might be principally due to alpha-adrenergic receptor antagonism rather than its effect on serotonin receptors. We therefore determined the contribution of alpha-adrenergic blockade to the hypotensive effects of ketanserin in six patients with hypertension and compared that with the alpha-adrenergic blockade produced by prazosin, a known alpha 1-adrenergic antagonist. Each patient received placebo, ketanserin (40 mg every 8 hours), and prazosin (5 mg every 8 hours). Each agent was administered for 4 weeks in random order. Both ketanserin and prazosin lowered blood pressure significantly and to a similar extent. The extent of alpha-adrenergic blockade was determined from the ability to inhibit the hypertensive effect of phenylephrine infusions. The dose of phenylephrine required to raise the blood pressure by 20 mm Hg was significantly higher during both ketanserin (1.41 +/- 0.27 micrograms/kg/min; p less than 0.05) and prazosin (4.99 +/- 0.77 micrograms/kg/min; p less than 0.01) administration compared with placebo (0.85 +/- 0.15 micrograms/kg/min). However, the dose ratio was more than fourfold higher during prazosin treatment (7.38 +/- 1.99; p less than 0.05) than during ketanserin (1.69 +/- 0.21). Thus at equipotent hypotensive doses the extent of alpha-blockade produced by ketanserin was more than fourfold lower than that of prazosin, implying that mechanisms other than alpha-blockade must contribute to the antihypertensive actions of ketanserin.

Ketanserin in reflex sympathetic dystrophy. A double-blind placebo controlled cross-over trial.

Ketanserin, a selective S2 serotonergic antagonist, was assessed against placebo in a double-blind cross-over study of 16 patients with chronic peripheral burning pain. Nine of these had signs of reflex sympathetic dystrophy (RSD). All patients underwent 4 intravenous regional treatments, 2 with ketanserin (10 mg for upper limb pain, 20 mg for lower limb pain) and 2 with placebo. In those patients with RSD ketanserin and not placebo provided significant (P less than 0.05) sustained pain relief as assessed by linear analogue scales. In patients who did not fulfil the criteria for RSD no significant relief was seen with placebo or ketanserin. Following tourniquet release, drowsiness, shakiness and faintness were reported at a higher (P less than 0.05) frequency after ketanserin than after placebo. All side effects were mild and transient, and no changes occurred in heart rate or blood pressure following ketanserin that were significantly different from those seen following placebo. A role for serotonin in the pathogenesis of RSD is proposed.

Incidence and clinical relevance of QT prolongation caused by the new selective serotonin antagonist ketanserin.

Efficacy and safety of ketanserin were studied prospectively in a randomized, double-blind trial involving 221 patients treated for hypertension or coronary artery disease, or both. Since ketanserin has been suggested to cause QTc prolongation, the incidence and severity of this effect were investigated, as was the incidence of malignant ventricular arrhythmias during Holter monitoring. After a 1-week run-in period, all patients were examined: blood pressure was measured and electrocardiograms and 24-hour Holter electrocardiograms were obtained. Two thirds of the patients (n = 147) were then randomized to receive ketanserin for 1 week (20 mg twice daily) followed by 3 weeks of 40 mg twice daily; one third of the patients (n = 74) received placebo (twice daily) for 4 weeks. After 4 weeks of treatment, blood pressure, electrocardiograms and 24-hour Holter electrocardiograms were repeated. In hypertensive patients, ketanserin significantly reduced systolic (mean reduction 17 +/- 2 mm Hg, p less than 0.0001) and diastolic blood pressure (12 +/- 1 mm Hg, p less than 0.0001) compared to baseline, and to the placebo group (p less than 0.005 for systolic and diastolic blood pressure). The QTc interval was prolonged with ketanserin (mean 400 to 418 ms, p less than 0.01) but not with placebo (399 vs 402 ms). In the ketanserin group 30% of patients and in the placebo group 8% of patients had QTc prolongation greater than 30 ms (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative double-blind study of ketanserin versus propranolol in the treatment of essential hypertension.

To clarify the antihypertensive effect, safety and clinical usefulness of ketanserin, a comparative double-blind study was carried out in 277 patients with essential hypertension using propranolol as a control drug. Ketanserin 10 to 30 mg twice daily and propranolol 20 to 40 mg 3 times daily were administered for 12 weeks. The results showed no difference in antihypertensive effect and clinical usefulness between the drugs. In the ketanserine group, plasma concentration of total cholesterol was decreased significantly, and the reduction in heart rate was less than in the propranolol group. These findings suggest that ketanserin may satisfactorily control blood pressure.

Effects of ketanserin tartrate on serum lipids in patients with essential hypertension.

Several antihypertensive agents such as thiazide diuretics and some beta-blockers have recently been shown to adversely affect lipid metabolism. Moreover, there is a growing suspicion that the adverse effect on plasma lipids might outweigh the favourable effect of lowering blood pressure. The effect of ketanserin tartrate (20 to 60 mg daily), a new antihypertensive drug, on blood lipids was evaluated in a 12-week non-comparative clinical trial in 34 patients with mild or moderate hypertension. Ketanserin reduced systolic and diastolic blood pressure by 12.2 and 9.8%, respectively, without altering heart rates. Total cholesterol and low density lipoprotein (LDL)-cholesterol levels in the fasting plasma were observed to decrease significantly by 6.3 and 8.8% respectively, whereas mean triglyceride and high density lipoprotein (HDL)-cholesterol remained almost unchanged. These changes were consistent irrespective of their initial values. Significant decrease in apolipoprotein B and E was also observed. Apolipoprotein A-I, A-II, C-II and C-III were not altered significantly. It is speculated that ketanserin affects mainly LDL-cholesterol. Based on these findings, ketanserin is considered to have a potentially beneficial effect on coronary risk profile and should be given full consideration when drug therapy is selected for patients with mild to moderate hypertension.

Metabolic and hemodynamic effects of antihypertensive treatment with ketanserin.

Ketanserin, a serotonin-2-receptor antagonist, was administered to 12 subjects with mild to moderate hypertension in a randomized, double-blind, placebo-controlled crossover trial. After 6 weeks of ketanserin (40 mg every 12 hours), blood pressures measured 12 hours after dosing were not significantly different from those obtained after placebo. However, 2 hours after ketanserin administration, supine systolic and diastolic blood pressures declined 11 +/- 10 mm Hg (P less than 0.01) and 6 +/- 5 mm Hg (P less than 0.005) from predose values, whereas placebo caused no change in either systolic or diastolic blood pressure. Except for a slight decline in serum prolactin levels 12 hours after dosing with ketanserin, no changes were observed in pituitary hormone levels, serum testosterone, plasma catecholamines, plasma renin activity, aldosterone, or lipoproteins. Stroke volume, measured 2 hours after dosing, increased with ketanserin therapy, but cardiac output, systemic resistance, and heart rate were unchanged. Ketanserin has a moderate antihypertensive effect and neutral metabolic-hormonal profile when used as monotherapy for the treatment of hypertension. However, further studies are needed to define the frequency of dosing that will provide 24 hours of antihypertensive activity.

Effects of a new serotonin antagonist, ketanserin, in experimental and clinical hypertension.

Ketanserin is an agent whose main pharmacologic action is antagonism of serotonin (5-hydroxytryptamine, 5HT) receptors of the 5HT2 subtype. It also has weak alpha 1-adrenergic blocking properties, which may contribute to the acute blood pressure lowering effects seen in animal models of hypertension. During chronic treatment of hypertension in animals, the 5HT2 antagonistic properties, or a combination of 5HT2 and alpha 1-antagonistic effects, seems to be responsible for ketanserin's hypotensive action. Studies of patients with hypertension have demonstrated the therapeutic effects of ketanserin in monotherapy and combination therapy. In humans, the drug has a terminal half-life of 12-25 hours, and a twice daily dosage will lower blood pressure over the day. Ketanserin is a vasodilator that acts on both resistance and capacitance vessels. Chronic treatment with the drug causes minimal reflex changes in cardiovascular function, as well as sustained blood pressure reduction comparable with the effects of beta-adrenergic blockers or diuretics. In elderly patients, the therapeutic effects of ketanserin appear to be greater, and side effects are less frequent compared with beta-blockers and diuretics. In addition to its antihypertensive action, ketanserin also produces other effects that may be important in reducing cardiovascular morbidity and mortality in patients with hypertension. Some studies have shown a reduction in total and low-density lipoprotein (LDL) cholesterol, and a rise in high-density lipoprotein (HDL) cholesterol. Ketanserin also reduces ex vivo platelet aggregation and inhibits the serotonin-induced platelet release reaction. Worldwide experience with ketanserin in the treatment of hypertension indicates that it is a safe and effective agent for long-term therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Ketanserin in mild to moderate hypertension in the elderly: a double-blind study versus methyldopa.

In a double-blind study of 30 elderly patients with mild to moderate essential hypertension, the antihypertensive effects of ketanserin and methyldopa were compared. The patients were randomly assigned to receive 20 mg of ketanserin or 250 mg of methyldopa twice daily for two weeks; the dose was then doubled for the rest of the three-month period. Two of the ketanserin group dropped out of treatment, one because of psychic depression, the other because of epigastric pain. After three months of therapy with ketanserin, systolic blood pressure decreased in a dose-dependent manner from 190 +/- 20 to 175 +/- 20 mmHg (P less than 0.05) and diastolic blood pressure from 106 +/- 8 to 91 +/- 9 mmHg (P less than 0.001). Blood pressure was reduced to 160/90 mmHg or less in eight of the 13 ketanserin patients and in five of the 15 methyldopa patients. In both groups heart rate and body weight remained constant. No orthostatic hypotension or hypertensive rebound after ketanserin withdrawal was recorded. It is concluded that 40 mg of ketanserin twice daily can control hypertension in the elderly.

Serotonin antagonism in the treatment of systemic hypertension: the role of ketanserin.

Serotonin has various hemodynamic effects, and may play a role in systemic hypertension. Ketanserin is a specific S2 serotonergic receptor blocker with possible adrenergic blocking activities that has clinical utility in the treatment of hypertension. The drug may have particular advantages for various patient populations.

Evaluation of ketanserin as a tocolytic agent in third trimester pregnant rats.

Ketanserin, as a 5HT2 selective antagonist, was evaluated for its tocolytic effects in pregnant Charles River (CR) rats, at total doses of 1.5 and 3.5 mg/kg IU from day 22 to day 25 of pregnancy. After 18 hours of ethenyl estradiol induction, tocolytic evaluation was carried out by recording uterine activity. When compared to the control group, the administration of Ketanserin resulted in an apparent, nondose dependent suppression of uterine contractility.

Serotonin antagonism and serotonin antagonists in pregnancy: role of ketanserin.

UNLABELLED: Most agree that antihypertensive medication should be used to treat severe hypertension during pregnancy, but its role in patients with mild to moderate disease is debated. None of the regularly used drugs is completely safe for mother and fetus. Ketanserin decreases systolic and diastolic blood pressure in nonpregnant patients with acute and chronic hypertension. Its selective serotonin S2-receptor antagonist activity encouraged investigations into a possible role in pregnant women. These reports can be divided into four groups. Several studies confirmed that intravenous ketanserin decreases blood pressure significantly in patients with severe preeclampsia. There are indications that it may be at least as effective as dihydralazine, possibly with fewer side effects. Its role in chronic hypertension has not been studied adequately, but one randomized, controlled trial indicated efficacy comparable with that of alpha-methyldopa. Thirdly, it was concluded in a single descriptive study that the administration of ketanserin to patients with HELLP syndrome allowed delivery to be postponed for 5.3 days. Lastly, in a randomized, placebo-controlled trial, the addition of ketanserin to aspirin in patients with mild to moderate midtrimester hypertension was associated with a significant decrease in the number of cases of preeclampsia and severe hypertension, as well as a trend to less perinatal mortality, lower rates of abruptio placentae, and early-onset preeclampsia. Additional studies are needed to adequately assess a possible role for ketanserin with acute hypertension or moderate chronic hypertension. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader will be able to list the various drugs and their associated side effects that are used to treat hypertensive disorders during pregnancy; to describe the various effects of serotonin on the cardiovascular system; to summarize the literature concerning the use of ketanserin during pregnancy; and to list the potential uses of ketanserin in this setting.

Dihydralazine or ketanserin for severe hypertension in pregnancy? Preliminary results.

OBJECTIVE: To compare the efficacy and safety of intravenous dihydralazine with ketanserin in the management of severe hypertension in the third trimester. STUDY DESIGN: A double blind randomised controlled trial, comparing 5 mg dihydralazine with 10 mg ketanserin after an intravenous infusion of 500 ml of a crystalloid solution. Medication was repeated every 20 min till the therapeutic goal of 90 mm Hg was reached, to a maximum of 4 dosages. Main outcome measures were treatment failures and emergency deliveries for fetal distress. RESULTS: The therapeutic goal was met more often in patients receiving dihydralazine (36/38 compared to 27/42; P < 0.01). The need for delivery for fetal distress did not differ (3 after dihydralazine, 1 after ketanserin, P = 0.29) No therapy related perinatal loss occurred, but one mother with an undiagnosed phaechromocytoma died 24 h after receiving dihydralazine. CONCLUSION: Ketanserin in this dosage is less effective to lower diastolic blood pressure. The place of a fluid load prior to dihydralazine needs to be further investigated, as fetal heart rate decelerations were less common than previously reported.

Pharmacological treatment of severe hypertension in pregnancy and the role of serotonin(2)-receptor blockers.

Hypertensive disorders of pregnancy are the leading cause of maternal and perinatal mortality and morbidity in developing and developed countries. The etiology of preeclampsia is still unknown. Delivering the baby is the only definite treatment. The benefits of acute pharmacological control of severe hypertension prior to and/or post-delivery are generally accepted. Most drugs commonly used in the management of severe hypertension in pregnancy have significant maternal and/or neonatal adverse side effects. Furthermore, some are not effective to acutely lower the blood pressure in patients with a hypertensive crisis. Until recently not one of the commonly used antihypertensive drugs has been tailored to the pathophysiology of severe preeclampsia, being a clinical syndrome characterized by endothelial cell dysfunction, vasospasm and platelet aggregation. Ketanserin, a serotonin(2)-receptor blocker, is a drug that appears to be tailored for treating this pregnancy-associated enthothelial cell dysfunction. The results of several prospective trials show that there is a definite place for serotonin(2)-receptor blockers in the treatment of pregnancy-induced hypertensive disorders. This review provides a summary on the more established drugs as well as on some of the newer antihypertensive drugs used in pregnancy with emphasis on the existing experience with ketanserin.

Long-term antihypertensive efficacy of ketanserin plus chlorthalidone.

The long-term antihypertensive efficacy of a combination of ketanserin (20 mg), an S2 antagonist with alpha 1 blocking activity, and chlorthalidone (25 mg), given o.d., was evaluated in fifteen patients with primary hypertension of mild to moderate degree, aged 45-65 years, up to a 12-month observation period. Systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) were measured by an automatic recorder (Sentron Bard Biomedical) twice at rest after 5 min in a supine position and after 2 and 5 min in an upright position, 24 h after the last antihypertensive dose. Thirteen patients completed the study whilst two were lost to the follow-up. A significant reduction was observed in both SBP and DBP at rest. In particular, SBP was reduced from 167 +/- 17 mmHg to 152 +/- 21 mmHg (p less than 0.01) after 1 month of therapy and was kept constant at this level throughout the observation period. DBP was also reduced from the first control [99 +/- 7 vs. 90 +/- 9 mmHg (p less than 0.01)] without any increase during the follow-up. HR was unchanged throughout the study. Four patients had dizziness and orthostatic hypotension after the first dose of the drug combination but were able to continue the study without further adverse reactions. These data support the conclusion that long-term treatment with the combination of a small dose of ketanserin and chlorthalidone is able to reduce systolic and diastolic blood pressure, without remarkable untoward side-effects.

Ketanserin, hypertension, and chronic alcoholism: double-blind study in forty patients.

In a randomized double-blind trial involving 40 alcoholic hypertensive patients, the antihypertensive activity of ketanserin, a serotonin antagonist with high affinity for S2 serotonergic receptors, was compared with a placebo. Patients in both groups were matched for age, body weight, blood pressure, alcoholic consumption, and length of alcoholism. The administration of ketanserin significantly reduced (p less than 0.001) mean supine blood pressure from 167/106 mmHg (22.3/14.1 kPa) at baseline to 145/87 mmHg (19.3/11.6 kPa) after 90 days of treatment versus a slight non-significant reduction with the placebo. No significant changes in heart rate, body weight, or laboratory parameters occurred. The incidence of side-effects was low in both groups. The results of this study suggest the possible role of serotonin in the pathogenesis of alcohol-related hypertension and the potential treatment of the disease using S2-receptor antagonists such as ketanserin.

Cardiac effects of ketanserin, a serotonin antagonist--electrophysiological examinations as a part of toxicity studies.

Cardiac effects of ketanserin were examined mainly electrophysiologically with using rat and guinea pig heart muscle preparations. 10(-6)M ketanserin slightly antagonized the positive chronotropic but not inotropic action of serotonin in spontaneously beating guinea pig atria. Ketanserin, only at the concentration as high as 10(-4)M, produced slight rightward shift of the positive chronotropic but not inotropic dose-response curves for norepinephrine in guinea pig atria. In both rat and guinea pig atria, ketanserin per se produced negative chronotropic effect and slight prolongation of action potential duration (APD) at high concentrations, 0.1 or 0.3 mg/ml. In guinea pig ventricular preparation, 1 mg/ml of ketanserin did not affect the rate of rise of the action potential (+Vmax), action potential amplitude and APD. In rat ventricular free wall preparations, 1 mg/ml of ketanserin produced slight increase in APD without affecting the other action potential parameters. In rat ventricular papillary muscle and septum preparations, 0.3 mg/ml of ketanserin tended to produce a decrease in +Vmax and an increase in APD. However, since these changes were produced only at extremely high concentrations and slight in degree, it was concluded that ketanserin does not produce electrophysiological side effects of clinical relevance.

Placebo-controlled trial of ketanserin in the treatment of intermittent claudication.

The effect of ketanserin on the symptoms of 21 patients with stable intermittent claudication was examined in a double-blind, placebo-controlled, parallel-group study. Benefit was assessed by repeated treadmill exercise tests, recording claudication and total walking times. After three months' treatment with ketanserin (mean dose 167 mg/day) there was no significant change in claudication time (mean change + 12%, 95% CI -9; + 33%) or total walking time (mean change -14%, 95% CI -47%; + 19%). The confidence intervals show that ketanserin treatment is unlikely to be associated with clinically important improvement.

Controlled comparison of ketanserin and nifedipine in Raynaud's phenomenon.

Twenty-eight patients suffering from either primary or secondary Raynaud's phenomenon were treated with nifedipine and ketanserin. Each patient was treated with one of the two drugs administered after an adequate washout period. Furthermore each patient was submitted before and after treatment with each drug to computerized digital thermometry to evaluate the therapeutic response. The data obtained during the intake of the two drugs at zero, five, and twenty-three minutes were compared with thermometry-relevant baseline data at the same periods. Ketanserin proved to be useful in the treatment of Raynaud's phenomenon and statistically significantly superior (alpha less than 0.05) with respect to nifedipine in the thermometric controls and also in the subjective evaluation of the patients (p less than 0.02). In this study nifedipine did not show particular efficacy. Furthermore only 2 patients had to discontinue treatment with ketanserin, whereas 8 had to discontinue treatment with nifedipine (p less than 0.001).