Treatment of acute-onset hypertension in pregnancy: A network meta-analysis of randomized controlled trials comparing anti-hypertensives and route of administration.

BACKGROUND: Consensus on the relative efficacy of available antihypertensive agents used in pregnancy is lacking. OBJECTIVE: To compare treatment success with antihypertensives and categorize by route of administration. SEARCH STRATEGY: MEDLINE, Embase, PubMed, Web of Science, Scopus, CINAHL, and clinicaltrials.gov were searched without date restriction. DATA COLLECTION: Peer-reviewed randomized controlled trials (RCTs) comparing pharmacologic agents used to treat hypertension in parturients were included. Evaluated treatment groups included IV-labetalol (BBIV), IV-hydralazine (DIV), oral-nifedipine (CCBPO), sublingual nifedipine (CCBSL), IV-calcium channel blocker (nonspecific)(CCBIV), IV-nitroglycerine (NTG), epoprostenol infusion (PRO), IV-ketanserin (5HT2B), IV-diazoxide (BZO), oral-nifedipine + methyldopa (CCBAG), oral-methyl-dopa (AAG), and oral prazosin (ABPO). ANALYSIS: Seventy-four studies (8324 patients) were eligible post PRISMA guidelines screening. Results were pooled using a Bayesian-approach for success of treatment (study defined target blood pressure), time to achieve target pressure, and neonatal intensive-care admissions. RESULTS: Treatment success (primary outcome, 55 trials with 5518 patients) was analyzed. Surface under the cumulative ranking curve (SUCRA) was categorized for 13 drugs, CCBPO (0.84) followed by CCBSL (0.78) were most likely to be effective in achieving target blood pressure. After sub-grouping by presence/absence of preeclampsia, CCB-PO ranked highest for both [(0.82) vs. (0.77), respectively]. Serotonin antagonists (0.99) and nitroglycerin (0.88) ranked highest for time to target pressure. NICU admissions were lowest for alpha-2 agonists (0.89), followed by BB PO (0.82) and hydralazine IV (0.49). CONCLUSION: Oral calcium-channel blockers ranked highest for treatment success. Ketanserin achieved target blood pressure fastest, warranting additional research. The results should be interpreted with caution as SUCRA values may not indicate whether the differences between interventions have clinically meaningful effect sizes.

Comparative efficacy and safety of oral antihypertensive agents in pregnant women with chronic hypertension: a network metaanalysis.

OBJECTIVE DATA: Chronic hypertension is associated with adverse perinatal outcomes, although the optimal treatment is unclear. The aim of this network metaanalysis was to simultaneously compare the efficacy and safety of antihypertensive agents in pregnant women with chronic hypertension. STUDY: Medline, Scopus, CENTRAL, Web of Science, Clinicaltrials.gov, and Google Scholar databases were searched systematically from inception to December 15, 2019. Both randomized controlled trials and cohort studies were held eligible if they reported the effects of antihypertensive agents on perinatal outcomes among women with chronic hypertension. STUDY APPRAISAL AND SYNTHESIS METHODS: The primary outcomes were preeclampsia and small-for-gestational-age risk. A frequentist network metaanalytic random-effects model was fitted. The main analysis was based on randomized controlled trials. The credibility of evidence was assessed by taking into account within-study bias, across-studies bias, indirectness, imprecision, heterogeneity, and incoherence. RESULTS: Twenty-two studies (14 randomized controlled trials and 8 cohorts) were included, comprising 4464 women. Pooling of randomized controlled trials indicated that no agent significantly affected the incidence of preeclampsia. Atenolol was associated with significantly higher risk of small-for-gestational age compared with placebo (odds ratio, 26.00; 95% confidence interval, 2.61-259.29) and is ranked as the worst treatment (P-score=.98). The incidence of severe hypertension was significantly lower when nifedipine (odds ratio, 0.27; 95% confidence interval, 0.14-0.55), methyldopa (odds ratio, 0.31; 95% confidence interval, 0.17-0.56), ketanserin (odds ratio, 0.29; 95% confidence interval, 0.09-0.90), and pindolol (odds ratio, 0.17; 95% confidence interval, 0.05-0.55) were administered compared with no drug intake. The highest probability scores were calculated for furosemide (P-score=.86), amlodipine (P-score=.82), and placebo (P-score=.82). The use of nifedipine and methyldopa were associated with significantly lower placental abruption rates (odds ratio, 0.29 [95% confidence interval, 0.15-0.58] and 0.23 [95% confidence interval, 0.11-0.46], respectively). No significant differences were estimated for cesarean delivery, perinatal death, preterm birth, and gestational age at delivery. CONCLUSION: Atenolol was associated with a significantly increased risk for small-for-gestational-age infants. The incidence of severe hypertension was significantly lower when nifedipine and methyldopa were administered, although preeclampsia risk was similar among antihypertensive agents. Future large-scale trials should provide guidance about the choice of antihypertensive treatment and the goal blood pressure during pregnancy.

Ketanserin, a serotonin 2A receptor antagonist, alleviates ischemia-related biliary fibrosis following donation after cardiac death liver transplantation in rats.

Biliary fibrosis is a major complication after donation after cardiac death (DCD) liver transplantation. In this process, the roles of serotonin [5-hydroxytryptamine (5-HT)] and the 5-HT2A receptor subtype are still unknown. In this study, we analyzed markers of portal fibroblast (PF)/myofibroblast (MF) transdifferentiation such as transforming growth factor ß1 (TGF-ß1), phosphorylated smad2/3, α-smooth muscle actin (α-SMA), collagen I, and collagen III in a primary culture system of PFs after the administration of 5-HT or 5-HT plus ketanserin (a selective 5-HT2A receptor antagonist). A rat DCD transplant model was established with 30 minutes of warm ischemia and 4 hours of cold ischemia during organ procurement. Recipients were intraperitoneally injected with ketanserin (1 mg·kg(-1)·day(-1)) or normal saline. Grafts without in situ warm ischemia instead of minimal cold storage (30 minutes) served as controls. The serum biochemistry, the liver contents of 5-HT and hydroxyproline (HYP), and the expression of fibrosis-related genes (including TGF-ß1, matrix metalloproteinase 2, procollagen α1, and α-SMA messenger RNA) were determined. The extent of biliary fibrosis was also assessed histopathologically. The results indicated that ketanserin inhibited 5-HT-activated TGF-ß1-smad2/3 signaling in vitro and thereby depressed the MF conversion of PFs. Rats receiving DCD livers showed increased liver contents of 5-HT and HYP, impaired biliary function, up-regulation of fibrosis-related genes, and aggravated biliary fibrosis. However, these phenomena were alleviated by treatment with ketanserin. We concluded that the profibrotic activity of 5-HT occurred through the activation of TGF-ß1 signaling and the 5-HT2A receptor. Thus, these data suggest that the 5-HT2A receptor may be a potential therapeutic target for ischemia-related biliary fibrosis after DCD liver transplantation.

Spinal segmental and supraspinal mechanisms underlying the pain-relieving effects of spinal cord stimulation: an experimental study in a rat model of neuropathy.

Spinal cord stimulation (SCS) may alleviate certain forms of neuropathic pain; its mechanisms of action are, however, not fully understood. Previous studies have mainly been focused onto segmental spinal mechanisms, though there is evidence indicating a supraspinal involvement. This study aims to evaluate the relative importance of segmental and supraspinal mechanisms related to the activation of the dorsal columns (DCs). Rats were used to induce the spared nerve injury neuropathy and simultaneously subjected to chronic bilateral DC lesions at the C6-C8 level. Two pairs of miniature electrodes were implanted in each animal, with a monopolar system placed in the dorsal epidural space at a low thoracic level (below lesion) and a bipolar system placed onto the dorsal column nuclei (above lesion). Stimulation (50 Hz, 0.2 ms, 2-4V, 5 min) was applied via either type of electrodes, and tests for sensitivity to tactile and thermal stimuli were used to assess its inhibitory effects. Various receptor antagonists {bicuculline (GABA(A)), saclofen (GABA(B)), ketanserine (5HT(2)), methysergide (5HT(1-2)), phentolamine (α-adrenergic), propranolol (ß-adrenergic), sulpiride (D(2)/D(3) dopamine) or saline were injected prior to the SCS. Rostral and caudal stimulations produced a comparable inhibition of neuropathic manifestations, and these effects were attenuated by about 50% after DC lesions. Pretreatment with the various receptor antagonists differentially influenced the effects of rostral and caudal stimulation. Our findings suggest that both supraspinal and segmental mechanisms are activated by SCS, and that in this model with DC lesions, rostral and caudal stimulations may activate different synaptic circuitries and transmitter systems.

Anti-hyperalgesic effects of anti-serotonergic compounds on serotonin- and capsaicin-evoked thermal hyperalgesia in the rat.

The peripheral serotonergic system has been implicated in the modulation of an array of pain states, from migraine to fibromyalgia; however, the mechanism by which serotonin (5HT) induces pain is unclear. Peripherally released 5HT induces thermal hyperalgesia, possibly via modulation of the transient receptor potential V1 (TRPV1) channel, which is gated by various noxious stimuli, including capsaicin. We previously reported in vitro that 5HT increases calcium accumulation in the capsaicin-sensitive population of sensory neurons with a corresponding increase in proinflammatory neuropeptide release, and both are antagonized by pretreatment with 5HT(2A) and 5HT(3) antagonists, as well as the anti-migraine drug sumatriptan. In the current study, we extended these findings in vivo using the rat hind paw thermal assay to test the hypothesis that peripheral 5HT enhances TRPV1-evoked thermal hyperalgesia that can be attenuated with 5HT(2A) and 5HT(3) receptor antagonists, as well as sumatriptan. Thermal hyperalgesia and edema were established by 5HT injection (0.1-10 nmol/100 µl) into the rat hind paw, and the latency to paw withdrawal (PWL) from noxious heat was determined. Rats were then pretreated with either 5HT before capsaicin (3 nmol/10 µl), the 5HT(2A) receptor antagonist ketanserin or the 5HT(3) receptor antagonist granisetron (0.0001-0.1 nmol/100 µl) before 5HT and/or capsaicin, or the 5HT(1B/1D) receptor agonist sumatriptan (0.01-1 nmol/100 µl) before capsaicin, and PWL was determined. We report that 5HT pretreatment enhances TRPV1-evoked thermal hyperalgesia, which is attenuated with local pretreatment with ketanserin, granisetron, or sumatriptan. We also report that peripheral 5HT induced a similar magnitude of thermal hyperalgesia in male and female rats. Overall, our results provide in vivo evidence supporting an enhancing role of 5HT on TRPV1-evoked thermal hyperalgesia, which can be attenuated by peripheral serotonergic intervention.

Antidepressant-like action of the ethanolic extract from Tabebuia avellanedae in mice: evidence for the involvement of the monoaminergic system.

The antidepressant-like effect of the ethanolic extract obtained from barks of Tabebuia avellanedae, a plant widely employed in folk medicine, was investigated in two predictive models of depression: forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the mechanisms involved in this antidepressant-like action and the effects of the association of the extract with the antidepressants fluoxetine, desipramine and bupropion in the TST were investigated. The extract from T. avellanedae produced an antidepressant-like effect, in the FST (100 mg/kg, p.o.) and in the TST (10-300 mg/kg, p.o.), without accompanying changes in ambulation when assessed in the open-field test. The anti-immobility effect of the extract (30 mg/kg, p.o.) in the TST was prevented by pre-treatment of mice with ketanserin (5 mg/kg, i.p., a preferential 5-HT(2A) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist) and SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist). The combined administration of a subeffective dose of WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) and a subeffective dose of the extract (1 mg/kg, p.o.) produced a significant reduction in the immobility time in the TST. In addition, the combination of fluoxetine (1 mg/kg, p.o.), desipramine (0.1 mg/kg, p.o.), or bupropion (1 mg/kg, p.o.) with a subeffective dose of the extract (1 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing hyperlocomotion in the open-field test. It may be concluded that the extract from T. avellanedae produces an antidepressant-like effect in the FST and in the TST that is dependent on the monoaminergic system. Taken together, our results suggest that T. avellanedae deserves further investigation as a putative alternative therapeutic tool that could help the conventional pharmacotherapy of depression.

Persistent cognitive alterations in rats after early postnatal exposure to low doses of the organophosphate pesticide, diazinon.

BACKGROUND: Developmental neurotoxicity of organophosphorous insecticides (OPs) involves multiple mechanisms in addition to cholinesterase inhibition. We have found persisting effects of developmental chlorpyrifos (CPF) and diazinon (DZN) on cholinergic and serotonergic neurotransmitter systems and gene expression as well as behavioral function. Both molecular/neurochemical and behavioral effects of developmental OP exposure have been seen at doses below those which cause appreciable cholinesterase inhibition. OBJECTIVES: We sought to determine if developmental DZN exposure at doses which do not produce significant acetylcholinesterase inhibition cause persisting cognitive deficits. METHODS: Rats were exposed to DZN on postnatal days 1-4 at doses (0.5 and 2 mg/kg/d) that span the threshold for cholinesterase inhibition. They were later examined with a cognitive battery tests similar to that used with CPF. RESULTS: In the T-maze DZN caused significant hyperactivity in the initial trials of the session, but not later. In a longer assessment of locomotor activity no DZN-induced changes were seen over a 1-hour session. Prepulse inhibition was reduced by DZN exposure selectively in males vs. females; DZN eliminated the sex difference present in controls. In the radial maze, the lower but not higher DZN dose significantly impaired spatial learning. This type of nonmonotonic dose-effect function has previously been seen with CPF as well. The lower dose DZN group also showed significantly greater sensitivity to the memory-impairing effects of scopolamine a muscarinic acetylcholine antagonist. CONCLUSIONS: Neonatal DZN exposure below the threshold for appreciable cholinesterase inhibition caused persisting neurocognitive deficits in adulthood. The addition of some inhibition of AChE with a higher dose reversed the cognitive impairment. This non-monotonic dose-effect function has also been seen with neurochemical effects. Some of the DZN effects on cognition resemble those seen earlier for CPF, some differ. Our data suggest that DZN and CPF affect transmitter systems supporting memory function, differently, implying participation of mechanisms other than their common inhibition of cholinesterase.

Immediate allergic response in small airways.

The role of small airways in the immediate allergic response is largely unknown. We therefore used the model of precision-cut lung slices (PCLS) in combination with quantitative videomicroscopy to study the early allergic response to allergen in airways ranging from 50 to 900 microm. After PCLS from untreated Wistar rats had been passively sensitized for 16 h with serum from sensitized Brown Norway rats, exposure to 0.1% ovalbumin resulted in an immediate allergic response. Both extent (r = 0.74, p < 0.0001) and velocity (r = 0.49, p < 0.0001) of the allergen-induced bronchoconstriction increased with decreasing airway size. In addition, we observed that smaller airways not only contracted stronger and quicker, but that they also relaxed faster, suggesting that smaller airways are more reactive in principle. The allergen-induced bronchoconstriction in PCLS was prevented by the serotonin receptor antagonist ketanserin (IC(50) 6 nM), but not by antagonists directed against histamine, acetylcholine, PAF, or endothelin receptors, or by cyclooxygenase or lipoxygenase inhibitors. Like allergen, serotonin provoked responses that were stronger in smaller airways. These findings suggest that the immediate allergic response in rat PCLS depends largely on serotonin and that this response can occur in nearly all airway generations, but is most pronounced in the smallest airways, that is, the terminal bronchioles.

Effects of OKY-046 and nifedipine in cyclosporine-induced renal dysfunction in rats.

Cyclosporine (CsA) (37.4 mumol/kg per day for 7 days) treated female Wistar rats exhibited significantly decreased creatinine clearance (Ccr) and body weight loss (BWL), but had neither proteinuria (PU) nor alteration in their urine volume (V). Light microscopic (LM) sections of rat kidneys showed that all kidneys were affected by lesions, mainly diffuse vacuolization. These changes were associated with decreased urinary excretion ratios of 6-ketoprostaglandin F1 alpha to thromboxane B2 (6kPGF1 alpha/TXB2) and prostaglandin E2 to TXB2 (PGE2/TXB2). When OKY-046, a TXA2-synthetase inhibitor or nifedipine (NFD), a calcium channel blocker and an antagonist of endotheline (ET), were administered in addition to CsA, they restored Ccr and increased urine V but they did not prevent BWL. LM sections showed that only 5 or 7 out of 9 kidneys of animals were affected, respectively. These changes were associated with prevention of the diminished ratios of urinary PGE2/TXB2 and 6kPGF1 alpha/TXB2 mainly in the OKY-046 treated animals. In conclusion, our results suggest that inhibitors of TXA2 or antagonists and/or inhibitors of endothelin play a protective role in the development of the dysfunction induced by CsA. However, the protection observed using OKY-046 and NFD did not reach that obtained by evening primrose oil (EPO) or Ketanserine (KTS), substances which prevented the fall of Ccr and BWL. Furthermore, with these protective agents only 5 out of 9 kidneys were affected and the lesions were of minor importance.

[The use of capillary videomicroscopy in the therapeutic assessment of acral vasospastic phenomena: microcirculatory effect of ketanserin and nifedipine]. / Der Einsatz der Kapillarvideomikroskopie bei der therapeutischen Beurteilung akraler vasospastischer Phänomene: mikrozirkulatorischer Einfluss von Ketanserin und Nifedipin.

In-vivo videomicroscopy is one of the few noninvasive and clinically useful direct methods for evaluating the effect of a drug on microcirculation of normal and ischemic areas. By using nailfold videomicroscopy in conjunction with local exposure to cold air, the hemodynamic effects of ketanserine and nifedipine are reviewed in patients with primary Raynaud's disease.

Effects of a new calcium antagonist, CD-832, on experimental coronary artery spasm in miniature pigs.

The effects of a new calcium antagonist, CD-832, on experimental coronary artery spasms were studied in Göttingen miniature pigs. Pigs underwent endothelial denudation at the left anterior descending coronary artery using a balloon catheter. Changes in the diameter of the denuded and nondenuded site in response to an intracoronary administration of serotonin (10 micrograms/kg) or histamine (10 micrograms/kg) were assessed quantitatively by selective coronary arteriography 1 week after endothelial denudation. Percent reductions of the coronary artery diameter induced by serotonin or histamine in the denuded site were significantly greater than those in the nondenuded site (p < 0.01). Coronary artery spasm induced by serotonin or histamine in the denuded site was attenuated in a dose-dependent manner by intravenous infusion of CD-832 (10 and 30 micrograms/kg/min) or nifedipine (1 and 3 micrograms/kg/min). The degrees of inhibition of coronary artery spasm by CD-832 were similar to those produced by nifedipine. CD-832 and nifedipine at the high dose caused comparable increases in the basal coronary artery diameter. These results suggest that CD-832 may be a useful drug for the treatment of coronary artery spasm.

[Evaluation of acute and chronic effects of ketanserin in the treatment of hypertension and hypothesis on a new mechanism of action]. / Valutazione degli effetti acuti e cronici della ketanserina nel trattamento dell'ipertensione e ipotesi su un nuovo meccanismo di azione.

Ketanserin is a specific antagonist of the 5-HT2 serotoninergic receptors; it is located on the smooth muscle cells of the vessel wall, and its stimulation causes vasoconstriction. The aim of this study is to evaluate the antihypertensive effect of ketanserin in patients with essential and secondary hypertension. Both systolic and diastolic blood pressure significantly decreased, in 18 patients, after chronic treatment with oral therapy (40-80 mg/day), and in 37 patients, after acute administration of sublingual (20 mg) and intravenous (10 mg) ketanserin. Acute administration of ketanserin was less effective than nifedipine (10 mg) in severe hypertension. Ketanserin, compared to placebo, permitted the normalization of blood pressure in 6/10 patients. Cardiovascular effects of ketanserin were studied with the ECOCG method in 8 patients with hypertension: peripheral resistances decreased, but left ventricular function and structure did not change. The effect of ketanserin on Na transmembrane transport systems in erythrocytes was studied both in vivo and in vitro, in order to evaluate the ketanserin action mechanism. The Na/K pump decreased and Na/Li countertransport increased, while different concentrations of serotonin did not change the transmembrane transport systems. In conclusion, ketanserin has a direct effect on transmembrane transport systems, not mediated by the serotonin receptors. This effect, with an antagonist of 5-HT2 serotoninergic and alpha 1 adrenergic receptor action, can cause a hypotensive effect.

[The antioxidant action of dalargin on the liver in experimental acute cholestasis]. / Antioksidantnoe deistvie dalargina na pechen' v usloviiakh ostrogo kholestaza v éksperimente.

Experiments were conducted on 182 rats with acute cholestasis to study the effect of intra-abdominal dalargin injection (10 mcg/kg) with the serotonin antagonist ketanserine (150 mg/kg) on xanthine oxidase (XO) activity and level of lipid peroxidation in the hepatic tissue and on the activity of the hepatospecific enzymes histidase and urokaninase in hepatic tissue and blood serum 1, 3, and 5 hours after the injection. Dalargin reduced XO activity by 32-37% in different periods after the injection, dalargin in combination with ketanserine--by 37-48%. Dalargin reduced the level of lipid peroxidation by 29-35%, and when combined with ketanserine--by 37-49%. The administration of dalargin reveals a distinct tendency towards reduction of the release of the hepatospecific enzymes histidase and urokanase into the blood and increase of their activity in the hepatic tissue. Dalargin with ketanserine produces a similar effect but of a higher degree. These data allow us to speak of the hepatoprotective effect of dalargin, which is potentiated by its injection together with ketanserine. It was found that dalargin (50 mcg/kg, intraperitoneally) increases the leu-enkephalin content in the hepatic tissue more than 3.5 fold one hour after injection.

Sublingual and intravenous ketanserin versus sublingual nifedipine in the treatment of severe hypertension: a randomized study.

Thirty-seven patients with severe hypertension were randomly assigned to receive 20 mg of ketanserin sublingually, 10 mg of ketanserin intravenously, or 20 mg of nifedipine sublingually. Systolic and diastolic blood pressures fell significantly after the three treatments. The maximum effects were reached 25 minutes after sublingual ketanserin (with decreases of 7.7% in systolic and 7.1% in diastolic blood pressure), six minutes after intravenous ketanserin (decreases of 9.4% and 9.6%, respectively), and 25 minutes after sublingual nifedipine (decreases of 16.9% and 15.9%, respectively). Blood pressure returned to pretreatment levels 20 minutes after intravenous ketanserin. Heart rate increased significantly in the group receiving nifedipine. No changes in plasma aldosterone, sodium, or potassium levels or in erythrocyte sodium and potassium levels were found after ketanserin. It is concluded that even intravenous ketanserin is inferior to sublingual nifedipine in the control of blood pressure.

[The effect of pharmacologic blockade of serotonin receptors (S2) on arterial pressure in rats with 2 forms of hereditary arterial hypertension]. / Vliianie farmakologicheskoi blokady serotoninovykh (S2) retseptorov na arterial'noe davlenie u krys s dvumia formami nasledstvennoi arterial'noi gipertenzii.

The influence of blockade of serotonin S2 receptors with ketanserin was studied in two strains of rats with inherited arterial hypertension: spontaneously hypertensive rats (SHR strain) and rats with inherited stress-induced arterial hypertension (ISIAH strain). It was found that peripheral injection of ketanserin produced a greater decrease of arterial blood pressure than i.c.v. administration. ISIAH rats were more sensitive to the hypotensive effect of ketanserin when compared to normotensive Wistar or SHR rats.

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).

Comparison of the hemodynamic responses to ketanserin and prazosin in portal hypertensive rats.

Ketanserin, a serotonin antagonist, is effective in lowering portal pressure in a rat model of portal hypertension. As ketanserin has alpha 1-adrenoceptor-blocking properties in addition to its serotonin-blocking effects, we sought to define further the mechanism of ketanserin's portal pressure-lowering effect. We attempted to determine whether the portal pressure-reducing effect of ketanserin was due to the unspecific effect of arterial blood pressure reduction mediated by alpha 1-adrenoceptor blockade or to serotonin receptor-blocking properties of ketanserin. The hemodynamic action of prazosin and alpha 1-adrenoceptor antagonist and ketanserin were compared in portal hypertensive rats in which the arterial pressure was equally reduced by both agents. The portal pressure was significantly lower in the ketanserin-treated group (11.3 +/- 0.4 mm Hg) when compared to the saline-treated group (13.6 +/- 0.7 mm Hg). The portal pressure was not significantly lower in the prazosin-treated group when compared to the saline-treated group (12.3 +/- 0.5 vs. 13.6 +/- 0.7 mm Hg, respectively). The same relationship held true for portal venous inflow and cardiac output. For each measurement, results in the ketanserin group were significantly lower when compared to the saline-treated group. These data in the prazosin-treated group were similar to data in the saline-treated group. The differences between the effect of ketanserin and prazosin were obtained despite similar blood pressure decreases. Ketanserin produced an 18% decrease and prazosin a 14% decrease in blood pressure when values were compared to their preinjection baselines.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of ketanserin and slow-release nifedipine added to the treatment of hypertensive patients uncontrolled by a thiazide diuretic plus beta-adrenoceptor blocker.

1. Ketanserin or slow-release nifedipine were added to the treatment of 24 patients with hypertension uncontrolled by a thiazide diuretic plus beta-adrenoceptor antagonist in an observer-blind, randomised parallel-group study of 6 months duration. 2. At 6 months the mean falls in supine blood pressure were for ketanserin (mean daily dose 77 mg) 7/5 mm Hg and for nifedipine (mean daily dose 62 mg) 27/10 mm Hg. The difference between the treatments was significant for systolic blood pressure (P less than 0.02) and mean arterial pressure (P less than 0.05). Six nifedipine-treated patients reached target blood pressure, compared with one patient with ketanserin (P less than 0.02). 3. One patient taking nifedipine, and none taking ketanserin withdrew because of side-effects. The tolerability of the two drugs was broadly similar. 4. Ketanserin treatment was associated with significant changes in supine pulse rate (-8 beats min-1, P less than 0.05) and corrected QT interval (+27 ms, P less than 0.05). Nifedipine treatment had no effect on these variables. The change in pulse rate was significantly different between the groups. 5. In patients treated with a diuretic and beta-adrenoceptor blocker who required additional treatment ketanserin was significantly inferior to nifedipine.

Effects of intravenous ketanserin on severely hypertensive patients with double-blind crossover assessment of central side-effects.

Ketanserin, the specific S2 serotonin antagonist, is undergoing evaluation for the therapy of hypertension of all degrees of severity. We studied 20 patients with severe hypertension [diastolic blood pressure (DBP) greater than 120 mm Hg after 40 min of supine rest]. In the first dose-ranging study on eight patients, multiple i.v. injections of 5 mg ketanserin were administered every 4 min (mean 38 mg). Only 4 patients responded adequately (DBP less than 100 mm Hg), 2 responded partially, and 2 did not respond to ketanserin. The major adverse effect of ketanserin, found in all patients, was severe dose-dependent sleepiness. A second double-blind crossover study with ketanserin and placebo (12 patients) assessed neural side effects. The supine DBP dropped from a mean of 134 +/- 4 mm Hg to 112 +/- 4 mm Hg 20 min after ketanserin when the sedation score rose from 0 to 1.2 +/- 0.3 (range 1-3) and the dizziness score from 0.1 +/- 0.1 to 1.4 +/- 0.3 (range 1-3; both p less than 0.01 vs. 1-2 min after ketanserin). Only 7 of 12 patients responded adequately to ketanserin. Twelve of the 20 patients were subsequently given nifedipine 10 mg sublingually; the DBP fell from a mean of 128 +/- 3 mm Hg to 101 +/- 4 mm Hg (p less than 0.001) after 40 min without side effects. Ketanserin does not appear to be a suitable agent for the acute therapy of severe hypertension because of: the imperfect and short-lived blood pressure control; the variability of the hypotensive effect; and sleepiness and dizziness as significant side effects.