Effects of ketanserin of left ventricular hypertrophy in hypertensive patients

Cobo, Carlos; Alcocer, Luis; Chávez, Antonio González

doi:10.1007/bf00053431

Cited by 10 publications

(5 citation statements)

References 12 publications

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“…Ketanserin, through blockade of serotonin-induced platelet aggregation and vasoconstriction, both of which increase with age, is targeted for elderly hypertensive patients [26]. Ketanserin was recently reported to achieve regression of LV hypertrophy in older hypertensive patients without concomitant deleterious effects on LV function [27,28]. These findings in nine and 13 patients followed for 12 months corroborate earlier data and are similar to those of the present study [10,29].…”

Section: Discussionsupporting

confidence: 82%

Comparison of ketanserin and celiprolol on regression of left ventricular hypertrophy in older hypertensive patients

Vyssoulis

Karpanou

Pitsavos

et al. 1992

Cardiovasc Drug Ther

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The effects of ketanserin, a specific serotonin2-receptor agonist, and celiprolol, a new, highly cardioselective beta 1 blocker with partial beta 2 agonist activity and peripheral vasodilating properties, on left ventricular (LV) structure and function were assessed in 60 older hypertensive patients (greater than 55 years) with clinical LV hypertrophy (LV mass index greater than 130 g/m2). The patients were studied using echocardiography after 1 month of placebo treatment, and 6 and 18 months of monotherapy with active drug. Ketanserin and celiprolol lowered blood pressure to normal levels. Heart rate did not change with ketanserin and fell moderately (-5%) with celiprolol (p less than .001). Regression of LV hypertrophy was achieved with the use of either medication (p less than .0001), although the magnitude of reduction in LV mass was greater with celiprolol at both 6 months (-10% vs -5%, p = .001) and 18 months (-13% vs -7%, p = .002). While LV volume did not change with either drug, celiprolol tended to decrease it, resulting in a 5% reduction in cardiac index (p = .01), which was associated with mild bradycardia. Ketanserin did not change LV ejection fraction, whereas celiprolol caused a slight (1.5%) long-term improvement (p = .003). Systolic wall stress and total peripheral resistance decreased with both agents (p less than .01), with no between-group differences. In conclusion, anti-hypertensive treatment of older persons with ketanserin or celiprolol achieves regression of LV hypertrophy without associated deleterious effects on LV function.

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Section: Discussionsupporting

confidence: 82%

Comparison of ketanserin and celiprolol on regression of left ventricular hypertrophy in older hypertensive patients

Vyssoulis

Karpanou

Pitsavos

et al. 1992

Cardiovasc Drug Ther

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“…In this regard, it is interesting to note that ketanserin has been shown to reduce left ventricular hypertrophy while preserving cardiac function in hypertensive patients (26), and the 5-HT antagonist sarpogrelate attenuates the ability of the hypertrophic agonists angiotensin II and endothelin-1 to stimulate protein synthesis in cardiomyocytes (27).…”

Section: Discussionmentioning

confidence: 99%

A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway

Bush

Fielitz²,

Melvin

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The calcium, calmodulin-dependent phosphatase calcineurin, regulates growth and gene expression of striated muscles. The activity of calcineurin is modulated by a family of cofactors, referred to as modulatory calcineurin-interacting proteins (MCIPs). In the heart, the MCIP1 gene is activated by calcineurin and has been proposed to fulfill a negative feedback loop that restrains potentially pathological calcineurin signaling, which would otherwise lead to abnormal cardiac growth. In a high-throughput screen for small molecules capable of regulating MCIP1 expression in muscle cells, we identified a unique 4-aminopyridine derivative exhibiting an embedded partial structural motif of serotonin (5-hydroxytryptamine, 5-HT). This molecule, referred to as pyridine activator of myocyte hypertrophy, acts as a selective agonist for 5-HT2A/2B receptors and induces hypertrophy of cardiac muscle cells through a signaling pathway involving calcineurin and a kinase-dependent mechanism that inactivates class II histone deacetylases, which act as repressors of cardiac growth. 2). Activation of the calcium, calmodulin-dependent phosphatase calcineurin, is sufficient and, in many cases, necessary for pathological cardiac hypertrophy (3), a major predictor of human morbidity and mortality (4). Thus, there has been intense interest in identifying novel small molecules capable of therapeutically modulating cardiac calcineurin signaling.Many calcineurin-sensitive genes are controlled by members of the nuclear factor of activated T-cell (NFAT) family of transcription factors, which translocate to the nucleus when dephosphorylated by calcineurin (reviewed in ref. 5). The calcineurin pathway also stimulates the myocyte enhancer factor-2 (MEF2) transcription factor by multiple mechanisms (6). We have shown that calcineurin activates a kinase that phosphorylates class II histone deacetylases (HDACs), which act as MEF2 corepressors (7). Signal-dependent phosphorylation of class II HDACs triggers their export from the nucleus and activation of MEF2 target genes (8, 9). HDAC mutants lacking the signalresponsive phosphorylation sites are refractory to calcium signaling and prevent cardiomyocyte hypertrophy. Conversely, mice lacking class II HDACs are hypersensitive to the growthpromoting activity of calcineurin (7).The activity of calcineurin is influenced by cofactors known as modulatory calcineurin-interacting proteins (MCIPs) or calcipressins (reviewed in ref. 10). Recent studies in yeast (11) and mammalian cells (12-14) have revealed both positive and negative roles for these proteins in the control of calcineurin activity. Overexpression of MCIP1 (also called Down syndrome critical region 1), for example, suppresses calcineurin signaling (12). In contrast, MCIP1 also seems to potentiate calcineurin signaling, as demonstrated by the diminution of calcineurin activity in the hearts of MCIP1 knockout mice (13). Intriguingly, the MCIP1 gene is a target of NFAT and is up-regulated in response to calcineurin signaling (15), which has been propo...

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“…Other studies also showed that 5-HT 2A receptors mediated positive inotropic response in ventricular myocytes and were overexpressed in different models of cardiac hypertrophy, along with human heart failure 7, 28. Additionally, 5-HT 2A receptor blockade reverses hypertrophy during pressure overload and reduces left ventricular hypertrophy 8, 29. 5-HT 2B receptors have also been implicated in ventricular hypertrophy.…”

Section: Discussionmentioning

confidence: 96%

A Xanthine-Derivative K⁺-Channel Opener Protects against Serotonin-Induced Cardiomyocyte Hypertrophy via the Modulation of Protein Kinases

Kuo

Lai

et al. 2014

Int. J. Biol. Sci.

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This study investigated whether KMUP-1, a xanthine-derivative K+ channel opener, could prevent serotonin-induced hypertrophy in H9c2 cardiomyocytes via L-type Ca2+ channels (LTCCs). Rat heart-derived H9c2 cells were incubated with serotonin (10 μM) for 4 days. The cell size increased by 155.5%, and this was reversed by KMUP-1 (≥1 μM), and attenuated by the LTCC blocker verapamil (1 μM) and the 5-HT2A antagonist ketanserin (0.1 μM), but unaffected by the 5-HT2B antagonist SB206553. A perforated whole-cell patch-clamp technique was used to investigate Ca2+ currents through LTCCs in serotonin-induced H9c2 hypertrophy, in which cell capacitance and current density were increased. The LTCC current (ICa,L) increased ~2.9-fold in serotonin-elicited H9c2 hypertrophy, which was attenuated by verapamil and ketanserin, but not affected by SB206553 (0.1 μM). Serotonin-increased ICa,L was reduced by KMUP-1, PKA and PKC inhibitors (H-89, 1 μM and chelerythrine, 1 μM) while the current was enhanced by the PKC activator PMA, (1 μM) but not the PKA activator 8-Br-cAMP (100 μM), and was abolished by KMUP-1. In contrast, serotonin-increased ICa,L was blunted by the PKG activator 8-Br-cGMP (100 μM), but unaffected by the PKG inhibitor KT5823 (1 μM). Notably, KMUP-1 blocked serotonin-increased ICa,L but this was partially reversed by KT5823. In conclusion, serotonin-increased ICa,L could be due to activated 5-HT2A receptor-mediated PKA and PKC cascades, and/or indirect interaction with PKG. KMUP-1 prevents serotonin-induced H9c2 cardiomyocyte hypertrophy, which can be attributed to its PKA and PKC inhibition, and/or PKG stimulation.

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Effects of ketanserin of left ventricular hypertrophy in hypertensive patients

Cited by 10 publications

References 12 publications

Comparison of ketanserin and celiprolol on regression of left ventricular hypertrophy in older hypertensive patients

Comparison of ketanserin and celiprolol on regression of left ventricular hypertrophy in older hypertensive patients

A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway

A Xanthine-Derivative K⁺-Channel Opener Protects against Serotonin-Induced Cardiomyocyte Hypertrophy via the Modulation of Protein Kinases

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Effects of ketanserin of left ventricular hypertrophy in hypertensive patients

Cited by 10 publications

References 12 publications

Comparison of ketanserin and celiprolol on regression of left ventricular hypertrophy in older hypertensive patients

Comparison of ketanserin and celiprolol on regression of left ventricular hypertrophy in older hypertensive patients

A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway

A Xanthine-Derivative K+-Channel Opener Protects against Serotonin-Induced Cardiomyocyte Hypertrophy via the Modulation of Protein Kinases

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A Xanthine-Derivative K⁺-Channel Opener Protects against Serotonin-Induced Cardiomyocyte Hypertrophy via the Modulation of Protein Kinases