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The study examined the effects of hyperpolarization-activated funny current (If) on HR and coronary flow in Langendorff-isolated hearts from newborn rats. Blockade of If current with ZD7288 changed the examined cardiac parameters. The blocker in a concentration of [10.sup.-9] M decreased HR by 26.8% (p [less than or equal to] 0.05). In concentrations [10.sup.-8], [10.sup.-7], [10.sup.-6], and [10.sup.-5] M ZD7288 produced minor differently directed effects. In a concentration of [10.sup.-5] M, ZD7288 reduced coronary flow in the isolated heart (p [less than or equal to] 0.01). In other concentrations, the blocker produced no significant effects on coronary flow.

[This corrects the article DOI: 10.1371/journal.pone.0251658.].

Ivabradine is a unique agent that is distinct from beta-blockers and calcium channel blockers as it reduces heart rate without affecting myocardial contractility or vascular tone. Ivabradine is a use-dependent inhibitor targeting the sinoatrial node. It is approved for use in the United States as an adjunct therapy for heart rate reduction in patients with heart failure with reduced ejection fraction. In this scenario, ivabradine has demonstrated improved clinical outcomes due to reduction in heart failure readmissions. However, there has been conflicting evidence from prospective studies and randomized controlled trials for its use in stable ischemic heart disease regarding efficacy in symptom reduction and mortality benefit. Ivabradine may also play a role in the treatment of patients with inappropriate sinus tachycardia, who often cannot tolerate beta-blockers and/or calcium channel blockers. In this review, we highlight the evidence for the nuances of using ivabradine in heart failure, stable ischemic heart disease, and inappropriate sinus tachycardia to raise awareness for its vital role in the treatment of select populations.

BACKGROUND: Inappropriate sinus tachycardia (IST) is an arrhythmic complication observed after coronary artery bypass graft (CABG) surgery which left untreated, commonly increases chances of postoperative stroke. The primary study objective was comparing effectiveness of beta blocker-metoprolol; a specific If blocker-ivabradine and its combination in patients who develop IST as a complication following CABG. MATERIALS AND METHODS: An open-labeled, investigator initiated, clinical study was conducted on 150 patients who developed IST (heart rate [HR] >100 beats/min) following elective CABG surgery. The patients were randomized into three treatment groups. Group I - received ivabradine (5 mg), Group II - metoprolol (25 mg), and Group III - ivabradine (5 mg) and metoprolol (25 mg). Treatment was given orally, twice a day for 7 days in all the three groups postoperatively. Primary endpoints were comparative effectiveness in HR and blood pressure reduction following treatment. RESULTS: IST was diagnosed by an electrocardiogram (12-lead) considering morphological features of P-wave and with 32% increase from baseline HR in all the three groups. Compared to IST arrthymic rate, HR was reduced in all groups following respective treatment (P = 0.05). Reduction in HR was significant (P < 0.05) in combination group followed by ivabradine which was significantly greater than metoprolol treated group. None of the treatments clinically changed the systolic, diastolic and mean blood pressure till discharge. No surgery/treatment-related complications were observed in any groups. CONCLUSION: Ivabradine stands as a pharmacological option for controlling HR and rhythm without associated side effects in postoperative CABG patients with IST.

Background Myocardial injury is a major cause of death after noncardiac surgery and is associated with long-term cardiovascular outcomes. Perioperative tachycardia increases this risk. Although perioperative beta blockers prevent myocardial injury, they increase the risk of death and stroke, which analyses suggest is due to a significant increase in hypotension. Ivabradine, a selective heart rate-lowering drug, may offer a safer alternative. The primary objective of the PREVENT-MINS trial is to determine whether perioperative administration of ivabradine is superior to placebo for the prevention of myocardial injury after noncardiac surgery (MINS) in patients with or at risk of atherosclerotic disease having noncardiac surgery.  Methods The PREVENT-MINS trial is a multicentre, parallel-group, blinded, placebo-controlled trial conducted in 26 hospitals in Poland. It will enroll 2500 patients aged ≥ 45 years undergoing noncardiac surgery with at least one risk factor for myocardial injury. Participants will be randomized in a 1:1 ratio to receive ivabradine 5 mg orally twice daily for 7 days starting 1 h before surgery or placebo. The primary outcome is MINS within 30 days after randomization; independent experts will adjudicate this outcome. Secondary outcomes include vascular complications, mortality, haemodynamics, and quality of life at 30 days. Additional tertiary and 1-year outcomes will assess long-term cardiovascular and surgical complications. Analyses will follow an intention-to-treat approach. For the primary outcome, a chi-squared test will be conducted, with results presented as unadjusted relative risk (RR) accompanied by 95% confidence intervals (CIs) and p -values.  Discussion This trial will generate high-quality, generalizable data due to its large population and rigorous design, including blinding. Moreover, it will be one of the first large-scale trials specifically focused on preventing MINS. Trial registration ClinicalTrials.gov NCT05279651. Registered on 4 March 2022. 

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5–7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain ( p  = 0.7479), HPT ( p  = 0.7501), area of PMH ( p  = 0.1052) or flare size ( p  = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller ( p  < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

QX-314 is a positively charged lidocaine derivative with the membrane-impermeant property. This compound applied at the intracellular side has been shown to suppress the voltage-gated Na[sup.+] current (I [sub.Na]), while lidocaine itself acts to suppress the hyperpolarization-activated cation current (I [sub.h]). To what extent this drug may exert any effects on various plasmalemmal ionic currents still remains largely unknown. This investigation focused on the impact of QX-314 on ionic currents in GH[sub.3] cells derived from pituitary tumors. This compound applied extracellularly was noted to differentially suppress the amplitude of transient and late I [sub.Na] with an IC[sub.50] value of 93 and 42 μM, respectively. In GH[sub.3] cells dialyzed with QX-314 (10 μM), the I [sub.Na(T)] amplitude evoked by a brief depolarizing step was decreased, and its inactivation was increased. Moreover, QX-314, when applied extracellularly at 100 μM, diminished the amplitude of the I [sub.h] current with an IC[sub.50] of 68 μM. Intracellular dialysis with QX-314 also suppressed I [sub.h] amplitude; moreover, the later application of oxaliplatin reversed this suppression. As cells were extracellularly and continually exposed to QX-314, the magnitude of the erg-mediated K[sup.+] current (I [sub.K(erg)]) was also effectively suppressed with an IC[sub.50] value of 73 μM. Furthermore, upon intracellular dialysis with QX-314 (10 μM), the degree of the voltage-dependent hysteresis (Hys[sub.(V)]) of I [sub.K(erg)] during the long-lasting isosceles-triangular ramp voltage was decreased; during continued exposure to QX-314, further extracellular bath additions of PD118057 (10 μM) counteracted QX-314-induced suppression. However, the extracellular addition of QX-314 (100 μM) mildly suppressed the outward delayed rectifier K[sup.+] current in GH[sub.3] cells. Collectively, QX-314 effectively suppressed I [sub.Na], I [sub.h], and I [sub.K(erg)] in GH[sub.3] cells, a model of endocrine function, and these actions may contribute to their physiological functions, if similar effects are observed in vivo.