Kim, Taek-Soo;Park, Jeong Hoon;Lee, Jun Young;Yang, Seung Dae;Chang, Dong-Jo
Journal of Radiation Industry
/
v.10
no.4
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pp.181-187
/
2016
Selective ${\beta}_1$-agonist and antagonists are used for the treatment of cardiac diseases including congestive heart failure, angina pectoris and arrhythmia. Selective ${\beta}_1$-antagonists including nebivolol have high binding affinity on ${\beta}_1$-adrenergic receptor, not ${\beta}_2$-receptor mainly expressed in smooth muscle. Nebivolol is one of most selective ${\beta}_1$-blockers in clinically used ${\beta}_1$-blockers including atenolol and bisoprolol. We tried to develop clinically useful cardiac PET tracers using a selective ${\beta}_1$-blocker. Nebivolol is $C_2$-symmetric and has two chromane moiety with a secondary amino alcohol and aromatic fluorine. We adopted the general synthetic strategy using epoxide ring opening reaction. Unlike formal synthesis of nebivolol, we prepared two chromane building blocks with fluorine and iodine which was transformed to diaryliodonium salt for labelling of $^{18}F$. Two epoxide building blocks were readily prepared from commercially available chromene carboxylic acids (1, 8). Then, the amino alcohol building block (15) was prepared by ammonolysis of epoxide (14) followed by coupling reaction with the other building block, epoxide (7). Diaryliodonium salt, a precursor for $^{18}F$-aromatic substitution, was synthesized in moderate yield which was readily subjected to $^{18}F$-aromatic substitution to give $^{18}F$-labelled nebivolol.
The pharmacological actions of ambrein were investigated alone or in combination as a pretreatment with agonists (adrenaline, noradrenaline, acetylcholine, histamine, nicotine), antagonists (atropine, atenolol) and calcium channel blocker (verapamil) in vivo in anaesthetized SWR rats using blood pressure, heart rate and myocardial contractility as parameters. Ambrein in the dose range of 50-200 mg/kg to the normotensive anaesthetized rats demonstrated negative chronotropic effect and increased the myocardial contractility significantly. At the mid dose (100 mg/kg) this increase in contractile force was 36% and 44% above the normal at 30 min and 60 min intervals post-treatment, respectively. Both of the lower and high doses (50 mg/kg and 200 mg/kg) had similar effects. Furthermore, this contractile response was dose related. Also, this compound produced a considerable increase in myocardial contractility when used as a pretreatment with some agonists and antagonists. The results on blood pressure did not show a considerable change when ambrein was used alone. However, ambrein pretreatment at the dose of 100 mg/kg did not block the effects of adrenaline, noradrenaline, isoprenaline and acetylcholine on heart rate and blood pressure. On the other hand, this pretreatment attenuated the sympathoadrenal effects of nicotine significantly. Chronotropic and blood pressure changes produced by histamine were also inhibited by ambrein pretreatment. This pretreatment significantly reversed the effects of atenolol but failed to demonstrate any change in the negative chronotropic, inotropic and hypotensive responses induced by verapamil. It is concluded that ambrein induced nonselective dose dependent antagonism of the effects of some agonists and antagonists require contribution of some neuromediators. However, the positive isotropic effects of ambrein possibly involve the enhancement of slow Ca channels and/or activation of ${\beta}-adrenergic$ receptors in the heart. At this moment it is difficult to explain the exact mode of action of ambrein and the studies dealing with Ca channel blocker and adrenergic blocker followed by ambrein may help to define the factors which contribute to its positive inotropic effects.
In a normal state, sympathetic efferent activity does not elicit discharges of sensory neurons, whereas it becomes associated with and excites sensory neurons in a pathophysiological state such as injury to a peripheral nerve. Although this sympathetic-sensory interaction is reportedly adrenergic, involved subtypes of adrenoreceptors are not yet clearly revealed. The purpose of this study was to determine which adrenorceptor subtypes were involved in sympathetic-sensory interaction that was developed in rats with an experimental peripheral neuropathy. Using rats that received a tight ligation of one or two of L4-L6 spinal nerves 10~15 days previously, a recording was made from afferent fibers in microfilaments teased from the dorsal root that was in continuity with the ligated spinal nerve. Electrical stimulation of sympathetic preganglionic fibers in T13 or L1 ventral root (50 Hz, 2-5 mA. 0.5 ms pulse duration, 10 sec) was made to see if the activity of recorded afferents was modulated. About half of afferents showing spontaneous discharges responded to sympathetic stimulation, and had the conduction velocities in the A-fiber range. Most of the sympathetically induced afferent responses were excitation. This sympathetically induced excitation occurred in the dorsal root ganglion (DRG), and was blocked by yohimbine (${\alpha}_2$ blocker), neither by propranolol ($\beta$ blocker) not by prazosine (${\alpha}_1$ blocker). The results suggest that after spinal nerve ligation, sympathetic efferents interact with sensory neurons having A-fiber axons in DRG where adrenaline released from sympathetic nerve endings excites the activity of sensory neurons by acting on 2-adrenoreceptors. This 2-adrenoreceptor mediated excitation of sensory neurons may account for sympathetic involvement in neuropathic pain.
To elucidate the effects of purinergic nerve on relaxation of pig coronary artery, the effects of ATP, 2-methylthio ATP and electrical perivascular nerve stimulation were investigated from physiograph on the isolated coronary artery of pig. The results btained were as follows; 1. The relaxative responses induced by perivascular nerve stimulation(20V, 0.5msec, 10sec) were the frequency(1~8Hz) dependent manner with phentolamine($10^{-5}M$) and atropine($10^{-6}M$) on isolated coronary artery of pig. 2. The relaxative responses induced. by adenosine($10^{-7}{\sim}5{\times}10^{-3}M$) or ATP($10^{-7}{\sim}5{\times}10^{-5}M$) on precontraction with histamine($10^{-5}M$) were the dose-dependent manner, but the contractile responses were often induced by ATP($10^{-4}M$ and $10^{-3}M$). 3. The relaxative responses induced by 2-methylthio ATP($2.5{\times}10^{-8}{\sim}2.5{\times}10^{-6}M$) on precontraction with histamine($10^{-5}M$) were the dose-dependent manner. 4. The relaxative response induced by 2-methylthio ATP($10^{-7}M$) on precontraction with histamine($10^{-5}M$) was completely blocked by the pretreatment with $P_{2Y}$-purinoceptor blocker, reactive blue 2($10^{-4}M$). 5. The neurogenic relaxative response induced by perivascular nerve stimulation(20V, 8Hz, 0.5msec, 10sec) was weakly inhibited by the pretreatment with ${\beta}$-adrenoceptor blocker, propranolol($10^{-5}M$) and blocked by the addition with $P_{2Y}$-purinoceptor blocker, reactive blue 2($10^{-4}M$). The results suggest that the purinergic nerve is innervated, and its relaxative response was mediated by $P_{2Y}$-purinoceptor on isolated coronary artery in pig.
The present study was performed to elucidate the effects of extracellular $Ca^{2+}$ on contractile responses in isolated porcine coronary artery ring using by perivascular nerve stimulation (PNS). Especially, the study was focused on the source of $Ca^{2+}$ on $P_{2X}$-purinoceptor mediated muscle contraction which one of $P_2$-purinoceptor subtypes. The following results can be drawn from these studies : 1. The phasic contractions induced by PNS were inhibited with muscarinic receptor antagonist, atropine ($10^{-6}M$). 2. The phasic contractions induced by PNS were significantly inhibited by sequential treatment with atropine and adrenergic neural blocker, guanethidine ($10^{-6}M$). 3. The phasic contractions induced by PNS were inhibited with $P_{2X}$-purinoceptor desensitization by repetitive application of $\alpha$,$\beta$-Me ATP ($10^{-4}M$). 4. The phasic contractions induced by PNS were so weakened in calcium-free medium. 5. The phasic contractions induced by PNS were inhibited with calcium channel blocker, verapamil ($10^{-6}{\sim}5{\times}10^{-6}M$). 6. The phasic contractions induced by PNS on pretreated with verapamil ($10^{-6}{\sim}5{\times}10^{-6}M$) were not changed by $\alpha$,$\beta$-Me ATP ($10^{-4}M$). These results demonstrate that the neurogenic phasic contractions induced by PNS are due to adrenergic-, cholinergic- and $P_{2X}$-purinergic receptors and the origin of $Ca^{2+}$ on $P_{2X}$-purinoceptor mediated muscle contraction is extracellular $Ca^{2+}$ through plasmalemmal $Ca^{2+}$ channels.
Natasha Cordeiro dos Santos;Aquiles Assuncao Camelier;Anne Karine Menezes;Victor Durier Cavalcanti de Almeida;Roberto Rodrigues Bandeira Tosta Maciel;Fernanda Warken Rosa Camelier
Tuberculosis and Respiratory Diseases
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v.87
no.3
/
pp.261-281
/
2024
Cardiovascular comorbidity is common in individuals with chronic obstructive pulmonary disease (COPD). This factor interferes with pharmacological treatment. The use of β-blockers has been proposed for their known cardioprotective effects. However, due to their adverse reactions, and the risk of causing bronchospasm, there is reluctance to use them. To summarize existing evidence on the effects of β-blocker use in COPD associated with cardiovascular comorbidities in relation to disease severity, exacerbation, and mortality outcomes. EMBASE, Medline, Lilacs, Cochrane Library, and Science Direct databases were used. Observational studies that evaluated the effects of β-blockers on individuals with COPD and cardiovascular comorbidities, and related disease severity, exacerbations, or mortality outcomes were included. Studies that did not present important information about the sample and pharmacological treatment were excluded. Twenty studies were included. Relevance to patient care and clinical practice: The use of β-blockers in individuals with COPD and cardiovascular disease caused positive effects on mortality and exacerbations outcomes, compared with the results of individuals who did not use them. The severity of the disease caused a slight change in forced expiratory volume in 1 second. The odds ratio for mortality was 0.50 (95% confidence interval [CI], 0.39 to 0.63; p<0.00001), and for exacerbations, 0.76 (95% CI, 0.62 to 0.92; p=0.005), being favorable to the group that used β-blockers. Further studies are needed to study the effect of using a specific β-blocker in COPD associated with a specific cardiovascular comorbidity.
Journal of Physiology & Pathology in Korean Medicine
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v.27
no.1
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pp.112-117
/
2013
We studied the modulation of pacemaker activities by Samchulkunbi-tang (SCKB) in cultured interstitial cells of Cajal (ICC) from murine small intestine with the whole-cell patch-clamp technique. Externally applied SCKB produced membrane depolarization in the current-clamp mode. The pretreatment with $Ca^{2+}$-free solution and thapsigargin, a $Ca^{2+}$-ATPase inhibitor in endoplasmic reticulum, abolished the generation of pacemaker potentials and suppressed the SCKB-induced action. The application of flufenamic acid (a nonselective cation channel blocker) abolished the generation of pacemaker potentials by SCKB. However, the application of niflumic acid (a chloride channel blocker) did not inhibit the generation of pacemaker potentials by SCKB. In addition, the membrane depolarizations were inhibited by not only GDP-${\beta}$-S, which permanently binds G-binding proteins, but also U-73122, an active phospholipase C inhibitor. These results suggest that SCKB modulates the pacemaker activities by nonselective cation channels and external $Ca^{2+}$ influx and internal $Ca^{2+}$ release via G-protein and phospholipase C-dependent mechanism. Therefore, the ICC are targets for SCKB and their interaction can affect intestinal motility.
Seo, Sang Hun;Mai, Xuan-Lan;Le, Thi-Anh-Tuyet;Kim, Kyeong Ho
Analytical Science and Technology
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v.34
no.1
/
pp.9-16
/
2021
In the group of commonly prescribed β-blocker drugs, one of the enantiomers is generally relatively more active than the others. This study aims to develop a technique for the chiral analysis of select β-blockers based on proton nuclear magnetic resonance (1H-NMR) spectrometry. (S)-2-Tert-butyl-2-methyl-1,3-benzodioxole-4-carboxylic acid ((S)-TBMB) was synthesized and utilized as a chiral derivatizing agent. Pure β-blocker enantiomers were isolated from racemates by semi-preparative liquid chromatography prior to derivatization. The reaction time and concentration of (S)-TBMB were controlled to improve the derivatization procedure. No racemization was found during the analysis. High-performance liquid chromatography (HPLC) analysis was also performed for comparative purposes. High agreement between the NMR and HPLC methods was achieved in the determination of (R)-metoprolol in a standard solution of the (S) isomer.
Adenosine has been reported to provide cytoprotection in the central nervous systems as well as myocardium by activating cell surface adenosine receptors. However, the exact target and mechanism of its action still remain controversial. The present study was performed to examine whether adenosine has a protective effect against $A{\beta}$-induced injury in neuroglial cells. The astrocyte-derived human neuroglioma cell line, A172 cells, and $A{\beta}_{25{\sim}35}$ were employed to produce an experimental $A{\beta}$-induced glial cell injury model. Adenosine significantly prevented $A{\beta}$-induced apoptotic cell death. Studies using various nucleotide receptor agonists and antagonists suggested that the protection was mediated by $A_1$ receptors. Adenosine attenuated $A{\beta}$-induced impairment in mitochondrial functional integrity as estimated by cellular ATP level and MTT reduction ability. In addition, adenosine prevented $A{\beta}$-induced mitochondrial permeability transition, release of cytochrome c into cytosol and subsequent activation of caspase-9. The protective effect of adenosine disappeared when cells were pretreated with 5-hydroxydecanoate, a selective blocker of the mitochondrial ATP-sensitive $K^+$ channel. In conclusion, therefore we suggest that adenosine exerts protective effect against $A{\beta}$-induced cell death of A172 cells, and that the underlying mechanism of the protection may be attributed to preservation of mitochonarial functional integrity through opening of the mitochondrial ATP-sensitive $K^+$ channels.
Background: Preclinical studies have demonstrated that ${\beta}$-adrenergic receptor antagonists could improve the prognosis of breast cancer. However, the conclusions of clinical and pharmacoepidemiological studies have been inconsistent. This review was conducted to re-assess the relationship between beta-adrenoceptor blockers and breast cancer prognosis. Materials and Methods: The literature was searched from PubMed, EMBASE and Web of Nature (Thompson Reuters) databases through using key terms, such as breast cancer and beta-adrenoceptor blockers. Results: Ten publications met the inclusion criteria. Six suggested that receiving beta-adrenoceptor blockers reduced the risk of breast cancer-specific mortality, and three of them had statistical significance (hazard ratio (HR)=0.42; 95% CI=0.18-0.97; p=0.042). Two studies reported that risk of recurrence and distant metastasis (DM) were both significantly reduced. One study demonstrated that the risk of relapse-free survival (RFS) was raised significantly with beta-blockers (BBS) (HR= 0.30; 95% CI=0.10-0.87; p=0.027). One reported longer disease-free interval (Log Rank (LR)=6.658; p=0.011) in BBS users, but there was no significant association between overall survival (OS) and BBS (HR= 0.35; 95% CI=0.12-1.0; p=0.05) in five studies. Conclusions: Through careful consideration, it is suggested that beta-adrenoceptor blockers use may be associated with improved prognosis in breast cancer patients. Nevertheless, larger size studies are needed to further explore the relationship between beta-blocker drug use and breast cancer prognosis.
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