Cardiovascular Pharmacology Research Articles

Cardiovascular pharmacology in the post-blockbuster era

Cardiovascular pharmacology in the post-blockbuster era

Louis Ignarro

Circulation Research is pleased to inaugurate “Profiles in Cardiovascular Science” with this interview with Lou Ignarro, the son of poor Italian immigrants, who won the 1998 Nobel Prize. Lou is one of my favorite people, a wonderful combination of scientific prowess, human richness, genuineness, and unassumingness, that is both refreshing and rare among medical researchers. Perhaps the most poignant part of the interview is the end, when Lou states that neither of his parents ever attended school; that their son rose to become a Nobel laureate is not only extraordinary but also deeply inspiring. This should be a powerful lesson in motivation for all of us. — —Roberto Bolli In the 1970s and 1980s, a series of discoveries made independently by Louis Ignarro, Ferid Murad, and Robert Furchgott established that the highly reactive molecule nitric oxide (NO) was a somewhat unexpected yet important physiological mediator of blood vessel relaxation. First, in 1977, Murad showed that nitric oxide could increase intracellular levels of cyclic GMP,1 a signaling molecule previously shown to increase when blood pressure dropped.2 Then, in 1979, Ignarro showed that nitric oxide could relax vascular smooth muscles.3 Lastly, in 1980, Furchgott discovered a substance released from endothelial cells that relaxes blood vessels4 that was later discovered by Ignarro to be nitric oxide.5 This body of work led to the three researchers being jointly awarded the Nobel Prize. The work of Ignarro and colleagues has established nitric oxide as a key biological messenger. It is now recognized that nitric oxide is a paracrine and autocrine signaling molecule that regulates almost every biological process, including vascular homeostasis, cardiac metabolism, neurotransmission, carcinogenesis, immunity, and stem cell function. Changes in nitric oxide production have been found to be associated with the development of atherosclerosis, diabetes, and hypertension. Several …

40 abstracts relating to the Meeting of European Society of Cardiology Working Group on Cardiovascular Pharmacology and Drug Therapy & 3rd World Conference of International Academy of Cardiovascular Sciences June 18–19, 2009–Copenhagen, Denmark

Fundamental & Clinical PharmacologyVolume 24, Issue 1 p. 1-10 Free Access 40 abstracts relating to the Meeting of European Society of Cardiology Working Group on Cardiovascular Pharmacology and Drug Therapy & 3rd World Conference of International Academy of Cardiovascular Sciences June 18–19, 2009–Copenhagen, Denmark First published: 04 January 2010 https://doi.org/10.1111/j.1472-8206.2009.00792.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume24, Issue1February 2010Pages 1-10 RelatedInformation

Triumph of the heart

Triumph of the heart: the story of statins by Jie Jack Li actually comprises several books in one — threads that run through the chapters as concurrent streams. The most compelling story recounts the checkered history of the development of the cholesterol-lowering drugs of the hydroxymethylglutaryl coenzyme A (HMGCoA) inhibitor family, also known as statins. This narrative illustrates the principle that most “breakthrough” drug development programs succeed despite, rather than because of, upper management and often depend on the ardent advocacy of individual scientists. The book describes the struggles of key protagonists in the development of statins. A few individuals emerge as heroes who pitted their passion and persistence against countervailing forces in their own industry. In one poignant passage, Akira Endo, the discoverer of statins, packs his office belongings and carries them out of his laboratories at the former Sankyo Corporation unaided; his colleagues had received instructions not to assist him after upper management discharged him. Such was Endo’s reward for having shown the creativity of targeting HMGCoA reductase, and for his persistence and dedication in developing the first statin. Likewise, the tableau of Roger Newton falling to his knees to plead for bringing atorvastatin into clinical evaluation at a 1990 meeting with senior executives at Parke-Davis appears more like a scene from a swashbuckler novel than from a corporate meeting room. Newton’s persistence and courage single-handedly saved the atorvastatin program from the drug development dustbin. The portrayal of the travails of the Parke-Davis medicinal chemistry team, directed by Bruce Roth, in developing atorvastatin gives the reader a glimpse into the hazardous undertaking of the design of new molecules suitable for use as drugs. A third hero of the statin development drama, Alfred Alberts of Merck, encountered fewer problems in developing lovastatin. But a decision by upper management put the clinical evaluation program on hold for several years, delaying the availability of the first statin on the market in the United States. If Alberts and his team had not had the good fortune of finding a “hit” in the 16th sample that they screened for HMGCoA reductase inhibition, they too might have encountered the kind of obstacles from management that plagued Endo and Newton. These three tales illustrate amply the human factor in drug development in Big Pharma, the role of chance, and the dependence of almost every successful drug development program on a “champion” who often persists despite internal opposition. Therein lies the value of Li’s story of statins. The other streams running through the book either seem tangential or have been better told before. Daniel Steinberg’s authoritative “interpretive history” of the “cholesterol hypothesis” of atherosclerosis, its challenges and ultimate vindication, remains unmatched (1). The sketches in Li’s book of the histories of various pharmaceutical firms are interesting, but forays into the development of antibiotics, steroid hormones, and epinephrine distract from the thrust of this tale, having little to do with statins or the heart. Venerable accounts describe better Paul Ehrlich’s development of the antisyphilitic agent Salvarsan and Alexander Fleming and Howard Florey’s work on penicillin, among other examples unrelated to cardiovascular pharmacology dwelt upon in Li’s book (2). Li’s background as a medicinal chemist shines through in his detailed depiction of the academic genealogy of key contributors to the chemistry discussed in this book. He relishes the details of the chemical challenges, including the complexities of chiral syntheses. These long digressions will not interest general medical or lay audiences, but they will engage more chemically minded readers. The “chemical” passages compel most when they furnish unvarnished views into scientists’ human foibles and how they influence the research enterprise. Given Li’s background and interest in drugs that target lipid metabolism, some of the book’s factual lapses seem surprising. The discussion of fibrate-statin interactions does not mention the defect in glucuronidation of some statins, particularly due to gemfibrozil. One allusion to the ENHANCE trial (which assessed the effect of ezetimibe plus simvastatin versus simvastatin alone on carotid intima-media thickness) misrepresents the end point as “reducing coronary heart disease.” The editorial comments characterizing as sad or regrettable the FDA halt on laropiprant (a prostaglandin D receptor antagonist intended to decrease niacin’s side effects) detract from the book’s balance. Finally, the use of brand names rather than generic designations lends a commercial patina to the text, although an appendix of the names does provide a concordance. Despite these drawbacks, Triumph of the heart provides documentation of some of the “oral history” of the story behind the story of statin development. The depiction of the champions of this important undertaking affirms their critical contributions to lowering cardiovascular morbidity and mortality worldwide. Their uphill battles bear notice by pharmaceutical executives as they struggle to find the path for the future of their industry.

Cardiovascular and smooth muscle pharmacology in the next decade

OPINION article Front. Pharmacol., 19 May 2010Sec. Cardiovascular and Smooth Muscle Pharmacology https://doi.org/10.3389/fphar.2010.00001

Chapter 1 - The Cardiovascular Physiology and Pharmacology of Endothelin-1

One year after the discovery in 1980 that the endothelium was obligatory for acetylcholine to relax isolated arteries, it was clearly shown that the endothelium could also promote contraction. In 1988, Dr Yanagisawa's group identified endothelin-1 (ET-1) as the first endothelium-derived contracting factor. The circulating levels of this short (21 amino acids) peptide were quickly determined in humans and it was reported that in most cardiovascular diseases, circulating levels of ET-1 were increased and ET-1 was then recognized as a likely mediator of pathological vasoconstriction in human. The discovery of two receptor subtypes in 1990, ET(A) and ET(B), permitted optimization of bosentan, which entered clinical development in 1993, and was offered to patients with pulmonary arterial hypertension in 2001. In this report, we discuss the physiological and pathophysiological role of endothelium-derived ET-1, the pharmacology of its two receptors, focusing on the regulation of the vascular tone and as much as possible in humans. The coronary bed will be used as a running example, but references to the pulmonary, cerebral, and renal circulation will also be made. Many of the cardiovascular complications associated with aging and cardiovascular risk factors are initially attributable, at least in part, to endothelial dysfunction, particularly dysregulation of the vascular function associated with an imbalance in the close interdependence of NO and ET-1, in which the implication of the ET(B) receptor may be central.

A section devoted to profiles of renowned teachers and to the recognition and accomplishments of physiology teachers within the society

A section devoted to profiles of renowned teachers and to the recognition and accomplishments of physiology teachers within the society

John Feely

John Feely

Significance of initial blood pressure and comorbidity for the efficacy of a fixed combination of an angiotensin receptor blocker and hydrochlorothiazide in clinical practice

Two-thirds of all patients with arterial hypertension need drug combinations to achieve blood pressure (BP) goals. Fixed combinations have high efficacy and result in high patient compliance. 300 mg irbesartan plus 25 mg hydrochlorothiazide (HCTZ) has been investigated only in clinical trials but not in daily practice. A multicenter, noninterventional, noncontrolled observational study with 8123 patients seen by 1604 physicians in daily practice. BP reduction (office measurements), co-morbid disease and tolerability were documented over a 6-month observational period. At mean baseline BP of 161 +/- 15/94 +/- 10 mmHg, administering of fixed combination resulted in a substantial BP reduction averaging 28 +/- 15/14 +/- 10 mmHg (P < 0.001). Decrease of systolic BP ran parallel with increasing systolic baseline BP (Spearman's Rho -0.731; P < 0.0001; diastolic BP vs diastolic baseline BP Rho 0.740; P < 0.0001), independent from patient characteristics (age, obesity, diabetes or nephropathy) but enhanced with short history of hypertension (P < 0.0001 vs long history), prior beta blockers (P = 0.001 vs prior angiotensin receptor blockers [ARBs]), prior calcium channel blockers (P = 0.046 vs prior ARBs) and no prior medication (P = 0.012 vs prior ARBs). High compliance (>98%) and low incidence of adverse events (0.66%) were documented. The fixed combination of 300 mg irbesartan with 25 mg HCTZ was efficacious and tolerable in an unselected patient population in primary care.

Editor's Note

HomeCirculationVol. 120, No. 13Editor's Note Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBEditor's Note Samuel Z. Goldhaber, MD and Joseph Loscalzo, MD, PhD Samuel Z. GoldhaberSamuel Z. Goldhaber Search for more papers by this author and Joseph LoscalzoJoseph Loscalzo Search for more papers by this author Originally published29 Sep 2009https://doi.org/10.1161/CIRCULATIONAHA.109.899757Circulation. 2009;120:1168Editor’s NoteThe Editors of Circulation wish to remind our readers about 2 special sections of our journal: Clinician Update and the Patient Page. Clinician Update serves as case-based learning of important topics in cardiology geared to readers who are not specialists in that particular area. The section is especially pertinent for general cardiologists and for those cardiovascular medicine specialists who wish to retain overall familiarity with cardiovascular medicine. Recent contributions to this section have included a broad range of topics: clopidogrel resistance, coronary artery spasm, ventricular assist devices, coronary stents, and health literacy. Articles in Clinician Update are always published in the Print Edition of Circulation and are also posted on our Web site under the journal’s Special Sections (http://circ.ahajournals.org/misc/special.shtml). For an example of a recent Clinician Update, please see the one in this issue by Badiwala et al, titled “Surgical Management of Ischemic Mitral Regurgitation.”The Patient Page is geared to nonprofessionals, especially to patients and their families. Articles are written with a minimum of medical jargon and are focused on providing the same type of “take-home message” that a cardiovascular specialist might provide to a patient and family during an outpatient office visit or family meeting during a hospitalization. Recent topics have included the following: venous thromboembolism prevention, warfarin anticoagulation, implantable cardioverter-defibrillator recalls, aortic dissection, and hospital quality of care. Articles in the Patient Page section are posted on our Web site (http://circ.ahajournals.org/misc/special.shtml) and are available for downloading at no charge and without any restriction.The Editors welcome submissions to either section of Circulation. Instructions to authors are posted on our Web site (http://circ.ahajournals.org/misc/ifora.shtml). Previous Back to top Next FiguresReferencesRelatedDetailsCited By Huang Q, Zhang J, Liang L, Lan Z, Huo T and Li S (2015) The Significance of Neuregulin-1/ErbB Expression in Autogenous Vein Grafts in a Diabetic Rat Model, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0000000000000279, 66:3, (300-306), Online publication date: 1-Sep-2015. September 29, 2009Vol 120, Issue 13 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.109.899757 Originally publishedSeptember 29, 2009 PDF download Advertisement SubjectsAcute Coronary Syndromes

On the Road to iPS Cell Cardiovascular Applications

See related article, pages 648–656 The ability to generate induced pluripotent stem (iPS) cells from somatic cells by the overexpression of a limited number of stem cell-related genes has generated great excitement and interest in the biomedical research community including cardiovascular researchers. The pioneering study by Yamanaka and colleagues showing that overexpression of Oct3/4 , Sox2 , Klf4 , and c-Myc could reprogram mouse fibroblasts to a pluripotent state similar to that of embryonic stem (ES) cells opened major new avenues of research.1 This epigenetic reprogramming was rapidly extrapolated to the human system using either the same combination of reprogramming factors or a slightly different combination of transgenes ( OCT4 , NANOG , SOX2 , LIN28 ).2–4 Like embryonic stem (ES) cells, iPS cells can be used for basic developmental biology research and also as a cell source to generate theoretically unlimited quantities of desired cell types such as cardiomyocytes. Such differentiated cells types can be used in a wide range of basic research studies and potentially in clinical applications, which not only include cellular therapies but also drug discovery and safety testing. One appealing aspect of human iPS cells compared to human ES cells is that they can be more readily generated without specialized expertise and access to human embryos, which also avoids the ethical challenges associated with human embryo research. Potentially the most powerful advantage of iPS cells over ES cells is that they can be generated from any patient to produce genetically identical pluripotent cells that can create human disease models or generate patient-specific cells for therapy. Already a number of iPS cell human disease models have been generated,5,6 and proof-of-principle iPS cellular therapies have been pioneered in mouse models.7–9 Despite the speed at which the iPS cell field is racing forward, we …

Validation of the rabbit telemetry model for cardiovascular safety pharmacology studies

Validation of the rabbit telemetry model for cardiovascular safety pharmacology studies

The Göttingen minipig in cardiovascular safety pharmacology—A consortia project preliminary report

The Göttingen minipig in cardiovascular safety pharmacology—A consortia project preliminary report

Channeling a New Focus for Heart Failure: Insights Into Ion Channels

Channeling a New Focus for Heart Failure: Insights Into Ion Channels

Gender Aspects in Cardiovascular Pharmacology

The influence of biological sex on pharmacokinetics and pharmacodynamics has been previously described for each step of the metabolic cascade of pharmaceuticals. Women and men display differences in distribution, metabolism, and excretion of drugs for several biologic reasons. Estrogens are relevant in these processes, but cannot be regarded as the only responsible mechanism. Sex differences in the incidence of adverse drug reactions and pharmacotoxicity have also been reported for several classes of drugs and specifically for several cardiovascular preparations. Given the high incidence of cardiovascular conditions and thus the broad use of these drugs in the general population, these reports have to be considered of relevance to public health. Nonetheless, increased knowledge has not translated into the development and implementation of gender-specific pharmacologic guidelines which appear as the only effective strategy to minimize the incidence of sex-specific side effects and adverse drug reactions. In the present review, we analyze the basic aspects of sex-specific pharmacodynamics and present several examples of gender dimorphism in cardiovascular drugs. We also suggest measures to analyze and possibly improve current therapeutic strategies.

The fentanyl/etomidate-anaesthetised beagle (FEAB) dog: A versatile in vivo model in Cardiovascular Safety Research

The purpose of conducting cardiovascular safety pharmacology studies is to investigate the pharmacological profiles of new molecular entities (NMEs) and provide data that can be used for optimization of a possible new drug, and help make a selection of NMEs for clinical development. An anaesthetised dog preparation has been used for more than two decades by our department to measure multiple cardiovascular and respiratory parameters and to evaluate different scientific models, leading to more in-depth evaluation of drug-induced cardiovascular effects. An anaesthetic regime developed in house (induction with lofentanil, scopolamine and succinylcholine, and maintenance with fentanyl and etomidate) gives us a preparation free of pain and stress, with minimal effects on the cardiovascular system. This anaesthetic regime had minimal influences on circulating catecholamine levels, on the baroreflex sensitivity, and on all measured basal parameters compared to conscious dogs. All parameters were stable for at least 3 h, with acceptable tolerance intervals, evaluated over 99 safety studies with 3 vehicle treatments (saline, 10% and 20% hydroxypropyl-beta-cyclodextrin). This translates into a highly sensitive model for detecting possible drug-induced effects of NMEs with different mechanisms of action such as: Ca-, Na-, I Kr-, I Ks-channel blockers, K- and Ca-channel activators, α1- and β-agonists, and muscarinic antagonists. Fentanyl in combination with etomidate is a successful anaesthetic regime in humans [ Stockham, R.J., Stanley, T.H., Pace, N.L., King, K., Groen, F. & Gillmor, S.T. (1987). Induction of anaesthesia with fentanyl or fentanyl plus etomidate in high-risk patients. Journal of Cardiothoracic Anesthesia. 1(1), 19–23.]. In the anaesthetised dog, QT correction factors (Van de Water correction and body temperature correction) and risk factors (total, short-term and long-term instability) have been evaluated, using this regime [Van de Water, A., Verheyen, J., Xhonneux, R. & Reneman, R. (1989). An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. Journal of Pharmacological Methods, 22, 207–217.; van der Linde, H.J., Van Deuren, B., Teisman, A., Towart, R. & Gallacher, D.J. (2008). The effect of changes in core body temperature on the QT interval in beagle dogs: A previously ignored phenomenon, with a method for correction. British Journal of Pharmacology, 154, 1474–1481.; van der Linde, H.J., Van de Water, A., Loots, W., Van Deuren, B., Lu, H.R., Van Ammel, K., et al. (2005) A new method to calculate the beat-to-beat instability of QT duration in drug-induced long QT in anaesthetised dogs. Journal of Pharmacological and Toxicological Methods, 52, 168–177.]. Furthermore, this anaesthetic protocol has been used to create different scientific models (long QT, short QT) with different specific end-points (ventricular fibrillation, adrenergic- or pause-dependent TdP) and also their specific precursors: e.g. aftercontractions, phase 2 EADs, phase 3 EADs, DADs, T-wave morphology changes, T-wave alternans, R-on-T, transmural and interventricular dispersion [Gallacher, D.J., Van de Water, A., van der Linde, H.J., Hermans, A.N., Lu, H.R., Towart, R., et al. (2007). In vivo mechanisms precipitating torsade de pointes in canine model of drug-induced long QT1 syndrome. Cardiovascular Research, 76–2, 247–256.]. This paper gives a brief overview of the stability, reproducibility, sensitivity and utility of a well-validated anaesthetised dog model.

Loss of Intracellular and Intercellular Synchrony of Calcium Release in Systolic Heart Failure

Normal contraction of cardiac muscle requires a coordinated cellular mechanical response to the electric pacemaker signal that begins in the sinoatrial node and spreads through the conduction system and ultimately across the ventricular myocardium via gap junctions. In ventricular myocytes, depolarization by the action potential causes clusters of L-type calcium channels (LCCs) to open, allowing a small amount of Ca to enter the diadic cleft space between the sarcolemma and the sarcoplasmic reticulum (SR). When the Ca concentration in this space becomes sufficiently high to gate ryanodine receptors (RyRs), they open and release SR Ca into the cytoplasm, so that it can bind to and activate myofilaments, resulting in force development. Each cluster of LCCs on the sarcolemma, its opposing cluster of RyRs across the 10- to 12-nm diameter diadic cleft space, and associated SR regulatory proteins is a couplon.1 According to the local control theory of cardiac excitation-contraction (EC) coupling, couplons are activated independently. Independent activation of couplons depends on the extent of LCC activation, providing a mechanism for regulation of contractile force by stochastic recruitment of couplons.2 In systolic heart failure, numerous cellular defects in EC coupling and Ca regulation have been identified that contribute to contractile dysfunction (and ventricular arrhythmias), although there is a host of other major abnormalities leading to loss of force development, including fibrosis,3 defective energy metabolism,4 pH changes,5 heterogeneous conductance across connexin hemichannels,6 and defects in sarcomeric proteins.7 Thus, it is important to keep in mind that no single defect can explain the contractile dysfunction of systolic failure. Article see p 223 Recent studies of defective EC coupling in heart failure have addressed not only reductions in the extent and kinetics of Ca released in response to the action potential (ie, reduced recruitment of couplons and …

β-Erythropoietin Effects on Ventricular Remodeling Left and Right Systolic Function, Pulmonary Pressure, and Hospitalizations in Patients Affected With Heart Failure and Anemia

Eugenosedin-B is able to block serotonin (5-HT) and alpha/beta receptors and to inhibit platelet aggregation. In Wistar rats, intravenous injections of eugenosedin-B (2.4, 7.2, 12 micromoL/kg) caused a dose-dependent decrease in blood pressure and heart rate. In contrast, intracisternal injection of eugenosedin-B (0.3, 0.03 micromoL) and an alpha2-antagonist yohimbine (0.03 micromoL) increased blood pressure and heart rate. Eugenosedin-B and yohimbine prevented hypotension induced by intracisternal injection of an alpha2-agonist clonidine (38 pmol). In in vitro experiments, eugenosedin-B (10, 10, 10 M) competitively antagonized norepinephrine-, clonidine-, and 5-HT (10 to 10 M)-induced vasocontractions in isolated rat aorta. It also competitively antagonized the isoproterenol (10 to 10 M)-induced positive inotropic effects in isolated rat atrium. These findings clearly suggest that eugenosedin-B possesses alpha1, alpha2, beta1, and 5-HT2A receptor blocking activities. In isolated rabbit ear artery sensitized with 16 mM K, eugenosedin-B antagonized 5-nonyloxytryptamine- and 5-HT-induced vasocontractions, indicating it also blocked 5-HT1B and 5-HT2A receptors. In radioligand-binding experiments, eugenosedin-B had significant binding affinities on alpha1, alpha2, beta1, 5-HT1B, and 5-HT2A receptors. In human platelets, eugenosedin-B inhibited epinephrine and 5-HT-induced aggregations. It also had competitive binding effects in human platelet with [H]yohimbine (alpha2), [H]ketanserin (5-HT2A). We conclude that hypotensive and vasorelaxant effects of eugenosedin-B can be attributed to its multiple actions on the blockade of 5-HT1B, 5-HT2A, alpha1/2 and beta1 receptors, and its ability to reduce platelet aggregation attributed to its blockade of alpha2 and 5-HT2A receptors.

Tumor Necrosis Factor-α and Its Receptors 1 and 2

In healthy hearts, tumor necrosis factor-α (TNF-α) concentration is low, and TNF-α is mainly located in endothelium and resident mast cells.1 TNF-α receptors (TNFRs) 1 (TNFR1) and 2 (TNFR2) are expressed on most cardiac cells, including cardiomyocytes.2 During myocardial ischemia, preformed TNF-α is released within minutes from resident mast cells and macrophages.3 With persistent ischemia, TNF-α also originates from cardiomyocytes.4 In rats after myocardial infarction (MI), TNFR1 density is increased for 10 days, whereas TNFR2 density remains unchanged.5 In contrast, TNFR1 and TNFR2 are both downregulated in the failing heart, whereas soluble TNFRs are increased6 owing to proteolytic cleavage of cardiomyocyte TNFR and release from circulating exosome-like vesicles.7 Increased soluble TNFRs decrease TNF-α bioactivity while at the same time prolonging its half-life.8 Article p 1386 TNF-α contributes to both reversible (contractile dysfunction4,9) and irreversible (MI) injury.1 Preischemic treatment with TNF-α antibodies10 or soluble TNFR1,11 permanent TNF-α knockout,12 or knockout of TNFR1 but not TNFR213 all reduce infarct size. The latter finding highlights the functional difference of TNFR1 and TNFR2 activation for ischemia/reperfusion injury: Only TNFR1 signaling is detrimental (Figure). Figure. Signaling cascade activated (→) or inhibited (⊣) by TNFR1 (red) or TNFR2 (blue) activation. sTNFR1 indicates soluble TNFR1; sTNFR2, soluble TNFR2; S1-P, sphingosine-1-phosphate; NF-κB, nuclear factor-κB; SOCS3, suppressor of cytokine signaling 3; ROS, reactive oxygen species; Akt-P, phosphorylated Akt, a homologue of the transforming v-Akt; NADPH-Ox, NADPH oxidase; STAT3-P, phosphorylated signal transducer and activator of transcription; Jnk-P, phosphorylated c-jun N-terminal kinase; p38-P, phosphorylated mitogen-activated protein kinase; Erk-P, phosphorylated extracellular signal-regulated kinase; PKC, protein kinase C; CamK, calcium/calmodulin-dependent kinase; MMP-2/9, matrix metalloproteinases 2 and 9; and IL-6, interleukin 6. Red indicates proteins involved in apoptosis; purple, proteins involved in growth; green, …

Combined L-/T-Type Calcium Channel Blockers

Opening of the voltage-dependent Ca2+ channels permits influx of Ca2+ across the plasma membrane, triggering diverse physiological processes. These channels are widely distributed in the cardiovascular system, constituting the main route for Ca2+ entry essential for excitation and contraction. Ten unique α1 subunits, grouped in 3 families (CaV1, CaV2, and CaV3), that encode the low-voltage–activated T-type and the high-voltage–activated L-, N-, P/Q- and R-type Ca2+ channels, have been identified.1,2 L-type Ca2+ channels are predominantly expressed in the hearts and peripheral vasculature and serve as the preferred molecular target of the initial Ca2+ channel antagonists in the treatment of hypertension.3 Recently, a growing body of evidence has accumulated depicting important roles of T-type Ca2+ channels in the regulation of cardiovascular function, such as generation of pacemaker potential and regulation of arterial resistance.3,4 T-type Ca2+ channels are found in various cell types, including neurons, cardiomyocytes, vascular smooth muscle cells, and endocrine cells, where they participate in a variety of physiological processes, such as low-threshold Ca2+ spike generation, action potential firing, pacemaking, impulse conduction, maintenance of myogenic tone, cell proliferation, and hormone secretion.1 In addition to their predominant role in the regulation of vascular function, T-type Ca2+ channels are also involved in cardiomyocyte growth and survival.3 T-type Ca2+ channel blockers are capable of interrupting certain pathological hypertrophic signaling pathways, including calcineurin-mediated nuclear factor of activated T cells–3 activation.1 The importance of voltage-dependent Ca2+ channels is demonstrated by the clinical efficacy of Ca2+ channels blockers in certain disease conditions, as well as the widespread distribution and function of these channels.1 Three classes of chemically distinct L-type Ca2+ channel blockers have been widely used clinically depending on their biophysical and conformation-dependent interactions …