Inotropic Action Research Articles

Curcumin alone not combined with piperine exerts cardioprotective effects in pressure-overload rats by increasing glucagon-like peptide-1 receptor signaling and additional properties

Background and aimCurcumin has shown significant cardiovascular protective effects. However, the low bioavailability limits its practical application. As a natural bioenhancer, piperine is expected to increase the bioavailability of curcumin, and then, enhance its beneficial effects. Meanwhile, glucagon-like peptide-1 receptor (GLP-1R) signaling has been confirmed to be involved in the regulation of cardiovascular events. Herein, this study aimed to investigate whether piperine could enhance the beneficial effects of curcumin in pressure-overload rats and whether GLP-1/GLP-1R signaling is involved in their action mechanism. Methods and resultsMale Sprague-Dawley (SD) adult rats were subjected to abdominal aortic constriction (AAC) surgery to 16 weeks, which elevated blood pressure and induced cardiac hypertrophy. Curcumin (100 mg/kg/day) or/and piperine (20 mg/kg/day) were orally given for 4 weeks from the 17th week after AAC surgery. Curcumin alone treatment significantly lowered blood pressure, ameliorated cardiovascular remodeling, improved left ventricular performance and endothelium-dependent vascular relaxation. Accompanied by these results, GLP-1R expression in the myocardium was up-regulated. Piperine alone also exhibited a certain positive inotropic cardiac activity, but the effect was less significant. The combination of curcumin and piperine didn't show enhanced cardiovascular protective effects relative to curcumin, along with decreased fasting serum GLP-1 level and GLP-1R expression in the myocardium. ConclusionCurcumin exerts cardiovascular protective effects in pressure-overload rats by upregulating GLP-1R, and inhibiting of GLP-1/GLP-1R signaling pathway may be related to the limited beneficial effects of combination of curcumin and piperine. This study provides a new thinking that oral administration of some spices may affect cardiovascular function by modulating the GLP-1/GLP-1R system in a mode of gut-heart axis regulation.

Use of Inotropes and vasopressors in Septic Shock: When, Why, and How?

Septic shock, a severe and sometimes fatal condition caused by systemic infection, demands immediate and focused therapies to restore hemodynamic stability and prevent organ failure. The use of vasopressors and inotropes has become the foundation in the treatment of septic shock, with the goal of reversing the vasodilatory condition and increasing cardiac contractility.
 Vasopressors are an effective class of medications that cause vasoconstriction and hence increase mean arterial pressure (MAP). Norepinephrine is recommended as the first-line agent to use in septic shock. However, many medications have both vasopressor and inotropic actions, distinguishing them from inotropes, which increase heart contractility.
 Inotropes work by increasing cardiac contractility and thereby increasing cardiac output. Dobutamine is still the mainstay of treatment based on the latest SCCM guidelines.
 This review provides a comprehensive overview of the rationale, indications, doses and major side effects surrounding the administration of these pharmacological agents in septic shock.
 Our team extensively explored various databases regarding this subject. We concluded that the most trustworthy sources for our study were articles indexed in PubMed. We thoroughly examined these articles and synthesized the information within our review.
 We recommend that more trials are needed to compare the effectivity of dobutamine compared to other inotropes in the setting of septic shock as the latest guidelines are based on a shortage of randomized control trials. Also the literature should emphasize the importance of continuous hemodynamic monitoring during vasopressor therapy, highlighting the necessity for personalized changes to reach and maintain target blood pressure targets.

The antiarrhythmic activity of amino acid-containing derivatives of 1,4-naphthoquinone

In recent times, the issue of cardiac arrhythmia disturbances has garnered increasing attention from researchers. Pharmacotherapy continues to be the primary method for treating rhythm disturbances; however, its effectiveness is often limited due to the common side effects associated with many antiarrhythmic drugs, among which negative inotropic action plays a significant role. One direction in the development of antiarrhythmic agents involves the targeted search for new drugs among agents with metabolic effects. The aim of this study was to investigate the antiarrhythmic activity using models of occlusion and reperfusion arrhythmias in cats, aconitine arrhythmias in rats, and calcium chloride ventricular fibrillation in rats of five original amino acid-containing derivatives of 1,4-naphthoquinone, synthesized at the Lviv Polytechnic Institute under the guidance of Ph.D. A.P. Kartoflitska. The conducted research indicated that the studied compounds exhibit antiarrhythmic effects. The enhancement of the antiarrhythmic activity occurred primarily in those arrhythmia models where metabolic disorders play a significant role in the pathogenesis.

Effects of hallucinogenic drugs on the human heart.

Hallucinogenic drugs are used because they have effects on the central nervous system. Their hallucinogenic effects probably occur via stimulation of serotonin receptors, namely, 5-HT2A-serotonin receptors in the brain. However, a close study reveals that they also act on the heart, possibly increasing the force of contraction and beating rate and may lead to arrhythmias. Here, we will review the inotropic and chronotropic actions of bufotenin, psilocin, psilocybin, lysergic acid diethylamide (LSD), ergotamine, ergometrine, N,N-dimethyltryptamine, and 5-methoxy-N,N-dimethyltryptamine in the human heart.

Further Quinolizidine Derivatives as Antiarrhythmic Agents- 3.

Fourteen quinolizidine derivatives, structurally related to the alkaloids lupinine and cytisine and previously studied for other pharmacological purposes, were presently tested for antiarrhythmic, and other cardiovascular effects on isolated guinea pig heart tissues in comparison to well-established reference drugs. According to their structures, the tested compounds are assembled into three subsets: (a) N-(quinolizidinyl-alkyl)-benzamides; (b) 2-(benzotriazol-2-yl)methyl-1-(quinolizidinyl)alkyl-benzimidazoles; (c) N-substituted cytisines. All compounds but two displayed antiarrhythmic activity that was potent for compounds 4, 1, 6, and 5 (in ascending order). The last compound (N-(3,4,5-trimethoxybenzoyl)aminohomolupinane) was outstanding, exhibiting a nanomolar potency (EC50 = 0.017 µM) for the increase in the threshold of ac-arrhythmia. The tested compounds shared strong negative inotropic activity; however, this does not compromise the value of their antiarrhythmic action. On the other hand, only moderate or modest negative chronotropic and vasorelaxant activities were commonly observed. Compound 5, which has high antiarrhythmic potency, a favorable cardiovascular profile, and is devoid of antihypertensive activity in spontaneously hypertensive rats, represents a lead worthy of further investigation.

BPIFB4 and its longevity-associated haplotype protect from cardiac ischemia in humans and mice

Long-living individuals (LLIs) escape age-related cardiovascular complications until the very last stage of life. Previous studies have shown that a Longevity-Associated Variant (LAV) of the BPI Fold Containing Family B Member 4 (BPIFB4) gene correlates with an extraordinarily prolonged life span. Moreover, delivery of the LAV-BPIFB4 gene exerted therapeutic action in murine models of atherosclerosis, limb ischemia, diabetic cardiomyopathy, and aging. We hypothesize that downregulation of BPIFB4 expression marks the severity of coronary artery disease (CAD) in human subjects, and supplementation of the LAV-BPIFB4 protects the heart from ischemia. In an elderly cohort with acute myocardial infarction (MI), patients with three-vessel CAD were characterized by lower levels of the natural logarithm (Ln) of peripheral blood BPIFB4 (p = 0.0077). The inverse association between Ln BPIFB4 and three-vessel CAD was confirmed by logistic regression adjusting for confounders (Odds Ratio = 0.81, p = 0.0054). Moreover, in infarcted mice, a single administration of LAV-BPIFB4 rescued cardiac function and vascularization. In vitro studies showed that LAV-BPIFB4 protein supplementation exerted chronotropic and inotropic actions on induced pluripotent stem cell (iPSC)-derived cardiomyocytes. In addition, LAV-BPIFB4 inhibited the pro-fibrotic phenotype in human cardiac fibroblasts. These findings provide a strong rationale and proof of concept evidence for treating CAD with the longevity BPIFB4 gene/protein.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 33.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 33.

Evaluation of Biological Activity Exerted by Dibenzo[b,e]Thiophene-11(6H)-One on Left Ventricular Pressure Using an Isolated Rat Heart Model.

Some studies show that some Dibenzo derivatives can produce changes in the cardiovascular system; however, its molecular mechanism is not very clear. The objective of this investigation was to evaluate the inotropic activity of ten Dibenzo derivatives (compounds 1 to 10) on either perfusion pressure or left ventricular pressure. Biological activity produced by the Dibenzo derivatives on either perfusion pressure or coronary resistance was evaluated using an isolated rat heart. In addition, the molecular mechanism of biological activity produced by compound 4 (Dibenzo[b,e]thiophene-11(6H)-one) on left ventricular pressure was determined using both Bay-k8644 and nifedipine as pharmacological tools in an isolated rat heart model. The results showed that Dibenzo[b,e]thiophene-11(6H)-one increases perfusion pressure and coronary resistance at a dose of 0.001 nM. Besides, other data display that Dibenzo[b,e]thiophene-11(6H)-one increases left ventricular pressure in a dose-dependent manner (0.001 to 100 nM) and this effect was similar to biological activity produced by Bay-k8644 drug on left ventricular pressure. However, the effect exerted by Dibenzo[b,e]thiophene-11(6H)-one was inhibited in the presence of nifedipine at a dose of 1 nM. All these data suggest that Dibenzo[b,e]thiophene-11(6H)-one increase left ventricular pressure through calcium channel activation. In this way, Dibenzo[b,e]thiophene-11(6H)-one could be a good candidate as positive inotropic agent to heart failure.

The Role of Heart Rate Variability (HRV) in Different Hypertensive Syndromes

Cardiac innervation by the parasympathetic nervous system (PNS) and the sympathetic nervous system (SNS) modulates the heart rate (HR) (chronotropic activity) and the contraction of the cardiac muscle (inotropic activity). The peripheral vasculature is controlled only by the SNS, which is responsible for peripheral vascular resistance. This also mediates the baroreceptor reflex (BR), which in turn mediates blood pressure (BP). Hypertension (HTN) and the autonomic nervous system (ANS) are closely related, such that derangements can lead to vasomotor impairments and several comorbidities, including obesity, hypertension, resistant hypertension, and chronic kidney disease. Autonomic dysfunction is also associated with functional and structural changes in target organs (heart, brain, kidneys, and blood vessels), increasing cardiovascular risk. Heart rate variability (HRV) is a method of assessing cardiac autonomic modulation. This tool has been used for clinical evaluation and to address the effect of therapeutic interventions. The present review aims (a) to approach the heart rate (HR) as a CV risk factor in hypertensive patients; (b) to analyze the heart rate variability (HRV) as a "tool" to estimate the individual risk stratum for Pre-HTN (P-HTN), Controlled-HTN (C-HTN), Resistant and Refractory HTN (R-HTN and Rf-HTN, respectively), and hypertensive patients with chronic renal disease (HTN+CKD).

Digoxin monitoring and toxicity management

Digoxin is a chemical derived from the plant Digitalis purpurea, more commonly known as foxglove, and belongs to the class of medicines known as cardiac glycosides​[1]​. Digoxin is used to treat a variety of cardiovascular conditions and provides inotropic activity (i.e. alters the force or energy of the heart muscle’s contractions) in the management of […]

The Effects of Curcumin on Mechanical Functions and Cardiac Contractility in Isolated Rat Hearts.

Curcumin is a bioactive compound that has well-known pharmacological activities. Numerous studies have shown that curcumin provides potential cardiovascular benefits through a variety of mechanisms.The present study aims to discuss different concentrations of curcumin's impact on mechanical functions and cardiac contractility in isolated perfused rat hearts. The hearts were isolated under sodium thiopental (50 mg/kg) anesthesia and perfused with a modified Krebs-Henseleit solution (mK-Hs). After stabilization, curcumin was applied in concentrations of 0.1, 1, and 10 µM. In isolated rat hearts, indexes of + dP / dt max, LVDP, MAP, and LVEDP were evaluated for cardiac contractility and ventricular function. All curcumin concentrations reduced +dP/dtmax and LVDP. Ten µM curcumin also significantly decreased heart rate. Curcumin (1 and 10 µM) increased LVEDP and reduced MAP amplitude with a concomitant increase in MAP duration. Curcumin at all concentrations did not affect dMAPdtmax and dMAPdtmin. Our results might suggest that curcumin at higher concentrations (≥ 1 µM) increases LVEDP with a negative chronotropic effect and decreases MAP amplitude with an increase in MAP duration. There is sufficient evidence from this study that Curcumin possesses an adverse inotropic action. Different disease models should support the pathophysiological role of Curcumin on cardiac contraction.

Positive chronotropic action of HCN channel antagonism in human collecting lymphatic vessels.

Spontaneous action potentials precede phasic contractile activity in human collecting lymphatic vessels. In this study, we investigated the expression of hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels in human collecting lymphatics and by pharmacological inhibition ex vivo tested their potential role in controlling contractile function. Spontaneous and agonist‐evoked tension changes of isolated thoracic duct and mesenteric lymphatic vessels—obtained from surgical patients with informed consent—were investigated by isometric myography, and ivabradine, ZD7288 or cesium were used to inhibit HCN. Analysis of HCN isoforms by RT‐PCR and immunofluorescence revealed HCN2 to be the predominantly expressed mRNA isoform in human thoracic duct and mesenteric lymphatic vessels and HCN2‐immunoreactivity confirmed protein expression in both vessel types. However, in functional experiments ex vivo the HCN inhibitors ivabradine, ZD7288, and cesium failed to lower contraction frequency: conversely, all three antagonists induced a positive chronotropic effect with concurrent negative inotropic action, though these effects first occurred at concentrations regarded as supramaximal for HCN inhibition. Based on these results, we conclude that human collecting vessels express HCN channel proteins but under the ex vivo experimental conditions described here HCN channels have little involvement in regulating contraction frequency in human collecting lymphatic vessels. Furthermore, HCN antagonists can produce concentration‐dependent positive chronotropic and negative inotropic effects, which are apparently unrelated to HCN antagonism.

Substantial impact of 3-iodothyronamine (T1AM) on the regulations of fluorescent thermoprobe-measured cellular temperature and natriuretic peptide expression in cardiomyocytes

There is growing interest in 3-iodothyronamine (T1AM), an active thyroid hormone metabolite, that induces negative inotropic and chronotropic actions in the heart and exerts systemic hypothermic action. We explored the direct impact of T1AM on cardiomyocytes with a focus on the regulation of the intracellular temperature and natriuretic peptide (NP) expression. A thermoprobe was successfully introduced into neonatal rat cardiomyocytes, and the temperature-dependent changes in the fluorescence intensity ratio were measured using a fluorescence microscope. After one-hour incubation with T1AM, the degree of change in the fluorescence intensity ratio was significantly lower in T1AM-treated cardiomyocytes than in equivalent solvent-treated controls (P < 0.01), indicating the direct hypothermic action of T1AM on cardiomyocytes. Furthermore, T1AM treatment upregulated B-type NP (BNP) gene expression comparable to treatment with endothelin-1 or phenylephrine. Of note, ERK phosphorylation was markedly increased after T1AM treatment, and inhibition of ERK phosphorylation by an MEK inhibitor completely cancelled both T1AM-induced decrease in thermoprobe-measured temperature and the increase in BNP expression. In summary, T1AM decreases fluorescent thermoprobe-measured temperatures (estimated intracellular temperatures) and increases BNP expression in cardiomyocytes by activating the MEK/ERK pathway. The present findings provide new insight into the direct myocardial cellular actions of T1AM in patients with severe heart failure.

Cardiac Ischemia On-a-Chip: Antiarrhythmic Effect of Levosimendan on Ischemic Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Ischemic heart disease (IHD) is one of the leading causes of mortality worldwide. Preserving functionality and preventing arrhythmias of the heart are key principles in the management of patients with IHD. Levosimendan, a unique calcium (Ca2+) enhancer with inotropic activity, has been introduced into clinical usage for heart failure treatment. Human-induced pluripotent cell-derived cardiomyocytes (hiPSC-CMs) offer an opportunity to better understand the pathophysiological mechanisms of the disease as well as to serve as a platform for drug screening. Here, we developed an in vitro IHD model using hiPSC-CMs in hypoxic conditions and defined the effects of the subsequent hypoxic stress on CMs functionality. Furthermore, the effect of levosimendan on hiPSC-CMs functionality was evaluated during and after hypoxic stress. The morphology, contractile, Ca2+-handling, and gene expression properties of hiPSC-CMs were investigated in response to hypoxia. Hypoxia resulted in significant cardiac arrhythmia and decreased Ca2+ transient amplitude. In addition, disorganization of sarcomere structure was observed after hypoxia induction. Interestingly, levosimendan presented significant antiarrhythmic properties, as the arrhythmia was abolished or markedly reduced with levosimendan treatment either during or after the hypoxic stress. Moreover, levosimendan presented significant protection from the sarcomere alterations induced by hypoxia. In conclusion, this chip model appears to be a suitable preclinical representation of IHD. With this hypoxia platform, detailed knowledge of the disease pathophysiology can be obtained. The antiarrhythmic effect of levosimendan was clearly observed, suggesting a possible new clinical use for the drug.

A study of gonadal dysfunction in women with thyroid disease

Background: Thyroid diseases are among the commonest endocrine disorders. It effects growth, embryonic development, tissue differentiation, maturation, metabolism, increases chronotropic and inotropic action of heart. The aim was to study gonadal dysfunction in women with thyroid disease; to study levels of FSH, LH, prolactin, estrogen and testosterone in hypothyroid and hyperthyroid.Methods: All participants fulfilling the inclusion criteria were interviewed as per proforma and medical details were recorded in proforma sheet and patients were subjected to necessary blood investigations.Results: Among 80 study subjects, majority were in the age group 26-35 years (60.1%) and majority had overt hypothyroid disease (72.5%). Symptoms of hypothyroid subjects mainly were fatigue, weight gain, hair loss, oligomenorrhea. Hyperthyroid subjects had fatigue, palpitations, oligomenorrhea, polymenorrhea. Prolactin had positive correlation with TSH in hypothyroid subjects, their LH, FSH levels were normal and sex steroid levels were low. In contrary, majority of the hyperthyroid subjects had normal prolactin and FSH, high LH and high sex steroid levels.Conclusions: The study demonstrated that thyroid disease in women causes menstrual abnormalities due to altered gonadotropin patterns which in turn alter ovarian hormone pattern. Hypothyroidism is associated with hyperprolactinemia leading to anovulation and abnormal menstrual cycle. Hyperthyroidism is associated with increased levels of LH, estrogen and testosterone with normal levels of PRL and FSH. Screening, identifying and correcting thyroid disease should be undertaken to prevent infertility as early as possible.

CHRONOTROPIC, INOTROPIC, AND RADICAL SCAVENGING ACTIVITY OF Curcuma heyneana EXTRACT BY MOLECULAR DOCKING SIMULATION AND In-vitro STUDY ON THE HEART OF Fejervarya cancrivora FROG

The β-1 adrenergic receptor belongs to GPCRs which communicates via the Gs-α subunit, thus initiating the cAMPdependent pathway through the upregulation of adenylyl cyclase. The activation of the β-1 adrenergic receptor in the heart triggers the activation of the sinoatrial node and atrioventricular nodes, hence escalating heart rate (positive chronotropic) and contractility (positive inotropic). Flavonoids and terpenes have been reported for their inotropic effect in animal models. In this work, we examined the chronotropic and inotropic activity of Curcuma heyneana Valeton and Zijp rhizome by determining the molecular interaction between the bioactive compounds, namely, αsitosterol, stigmasterol, quercetin, and curcumenol, with human G-protein-coupled receptor kinase 2 (hGRK2), and in vitro study of C. heyneana extract on the heart of crab-eating Fejervarya cancrivora frog. Moreover, the total phenol content in the extract and the radical scavenging activity were also determined. The results indicated that C. heyneana positively contains phenolic compounds and weakly inhibits the radicals of the DPPH reagent (IC50 = 320.0 µg/mL). The molecular docking study revealed that α-sitosterol and quercetin have the best interaction with important residues in hGRK2, similar to that of the enzyme’s inhibitor. C. heyneana decreases the heart rate and increases the heart contractility of crab-eating F. cancrivora frogs. Based on these findings, C. heyneana is the potential in helping the heart pump more blood to fulfill the oxygen demands, but with lesser heartbeats, thus it is useful for patients with cardiovascular disorders.

Use of Aconitum Herbal Medicine for Pain Control in Musculoskeletal Disease

Objectives This review was conducted to study use of Aconitum herbal medicine for pain control in musculoskeletal disease. Methods Musculoskeletal disease is a major factor of social cost increase and physical disability. Various drugs, surgery and imaging are being overused regardlessly. Aconitum herbal plants are one of the most toxic Korean traditional herbs. However, they could be utilized effectively on patients with appropriate processing and decocting time. We searched Korean medicine literature to see various features of aconitum herbal plants and tried to find the utilization of the plants in effective way for pain control in musculoskeletal disease. Results Aconitum herbal plants needs to be used carefully because of intoxication which could lead to severe damage to human body. Processing of these toxic plants could minimize the harm and raise the benefits, such as relieving various types of pain and positive inotropic action. Further studies with clearer evidence and discovering aftereffects of processing in more details are needed. Conclusions Aconitum herbal plants could dedicate to controlling pain in musculoskeletal disease with various forms and appropriate processing.

Clinical Update on Vasopressors and Titration Strategies.

Clinical Update on Vasopressors and Titration Strategies.

The Impact of Glucocorticoid Therapy on Guideline-Directed Medical Treatment Titration in Patients Hospitalized for Heart Failure with Low Blood Pressure: A Retrospective Study.

BackgroundPositive inotropic and renal protective actions of glucocorticoids have been observed clinically. Therefore, glucocorticoids may be used in patients with heart failure and low blood pressure (HF-LBP).MethodsThe medical records of 144 consecutive patients with HF-LBP who received glucocorticoids as an adjunctive treatment to facilitate the up-titration of β-blocker and angiotensin-converting enzyme inhibitor were reviewed.ResultsAfter four weeks of treatment, the metoprolol and captopril (or equivalent) dosages were progressively and consistently increased from 25 (interquartile range [IQR] = 12.5–75 mg/day) to 100 mg/day (IQR = 50–178.8 mg/day) and from 0 (IQR = 0–25 mg/day) to 12.5 mg/day (IQR = 0–50 mg/day), respectively. There was a remarkable beneficial hemodynamic response to the glucocorticoid treatment signified by an increase in blood pressure and decrease in heart rate. The average heart rate decreased by 6 beat per minute (bpm) (0.5–16 bpm), and the mean arterial blood pressure increased from 74.06 ± 7.81 to 78.85 ± 7.91 mmHg. We also observed an improvement in renal function and an increased diuretic response following glucocorticoid treatment. As a result, the left ventricular ejection fraction increased from 28.92 ± 8.06% to 33.86 ± 8.76%, and the diuretic response increased from 776.7 mL/40 mg furosemide (IQR = 133.8–2000 mL) to 4000 mL/40 mg furosemide on day 28 (IQR = 2200–5925 mL).ConclusionThe use of glucocorticoid treatment to maintain hemodynamic and renal functional targets when titrating guideline-directed medical treatment in patients with HF-LBP may be safe, effective, and feasible.

Description of the Mechanism of Positive Inotropic Action of the Isoquinoline Alkaloid F-18

This study evaluated the mechanism of inotropic effect of an isoquinoline alkaloid derivative, 1-(2´-bromine-4´,5´-dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline (F-18) using electrically stimulated rat left ventricular papillary muscle of rat. The F-18 alkaloid have been shown to have positive inotropic effect on papillary muscle contraction activity, IC50 value -14,6 µM. Са2+L-channel blocker - nifedipine was used in experiments. Inotropic effects of F-18 isoquinoline alkaloid on cardiomyocytes were suggested, based on results obtained in experiments carried in cardiomyocytes SR Ca2+- transport systems modulation.