Novel Actions of Nonsteroidal Anti-Inflammatory Drugs on Vascular Ion Channels: Accounting for Cardiovascular Side Effects and Identifying New Therapeutic Applications.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used medications for the treatment of both acute and chronic pain. Selective cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib (Celebrex(®)), rofecoxib (Vioxx(®)), and diclofenac, have been among the most widely prescribed NSAIDs because they prevent the generation of prostaglandins involved in inflammation and pain, but avoid some of the gastrointestinal complications associated with less selective COX-1/COX-2 inhibitors. In 2004, rofecoxib (Vioxx(®)) was voluntarily withdrawn from the market because of adverse cardiovascular side effects. This led to an explosion of research into the cardiovascular effects of the 'coxibs', which revealed differential cardiovascular risk profiles among the members of this drug class. The differential risk profiles may relate to the tendency of some of the drugs to elevate blood pressure (BP). An important component of BP regulation is dependent on the contractile state of vascular smooth muscle cells (VSMCs), which is controlled to a large extent by the activities of KCNQ (Kv7 family) potassium channels and L-type calcium channels. Our recently published data indicate that celecoxib, but not rofecoxib or diclofenac, at therapeutically relevant concentrations, acts as a Kv7 potassium channel activator and a calcium channel blocker, causing relaxation of VSMCs and decreasing vascular tone. These vasorelaxant ion channel effects may account for the differential cardiovascular risk profiles among the different COX-2 inhibitors. We further speculate that these properties may be exploited for therapeutic benefit in the treatment of cardiovascular diseases or other medical conditions.

[1]  S. Selvin,et al.  The burden, trends, and demographics of mortality from subarachnoid hemorrhage , 1998, Neurology.

[2]  J. Hwang,et al.  Prevention of nonsteroidal anti-inflammatory drug-induced gastropathy , 2008, Journal of Gastroenterology.

[3]  Ramón Martínez-Mármol,et al.  Skeletal muscle Kv7 (KCNQ) channels in myoblast differentiation and proliferation. , 2008, Biochemical and biophysical research communications.

[4]  S. Olesen,et al.  The KCNQ5 potassium channel from mouse: a broadly expressed M-current like potassium channel modulated by zinc, pH, and volume changes. , 2005, Brain research. Molecular brain research.

[5]  Maria Virginia Soldovieri,et al.  Molecular pharmacology and therapeutic potential of neuronal Kv7-modulating drugs. , 2008, Current opinion in pharmacology.

[6]  A. Wei,et al.  Molecular Cloning and Functional Expression of KCNQ5, a Potassium Channel Subunit That May Contribute to Neuronal M-current Diversity* , 2000, The Journal of Biological Chemistry.

[7]  D. Trask,et al.  Celecoxib toxicity is cell cycle phase specific. , 2007, Cancer research.

[8]  L. Pardo,et al.  Role of Voltage-gated Potassium Channels in Cancer , 2005, The Journal of Membrane Biology.

[9]  C. Cooke,et al.  A Retrospective Review of the Effect of COX-2 Inhibitors on Blood Pressure Change , 2003, American journal of therapeutics.

[10]  G. Loussouarn,et al.  Kv7.1 (KCNQ1) properties and channelopathies , 2008, The Journal of physiology.

[11]  A. Dumont,et al.  New insights into the causes and therapy of cerebral vasospasm following subarachnoid hemorrhage. , 2008, Drug discovery today.

[12]  P. Gorelick,et al.  Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomized clinical trials. , 2007, The American journal of cardiology.

[13]  G. Parmigiani,et al.  The Consensus Coding Sequences of Human Breast and Colorectal Cancers , 2006, Science.

[14]  J. Roh,et al.  Effects of celecoxib on volumes of hematoma and edema in patients with primary intracerebral hemorrhage , 2009, Journal of the Neurological Sciences.

[15]  H. Lerche,et al.  Nervous system KV7 disorders: breakdown of a subthreshold brake , 2008, The Journal of physiology.

[16]  M. Schwake,et al.  Molecular expression and pharmacological identification of a role for Kv7 channels in murine vascular reactivity , 2007, British journal of pharmacology.

[17]  F. Lang,et al.  Ion Channels in Cell Proliferation and Apoptotic Cell Death , 2005, The Journal of Membrane Biology.

[18]  Shunqi Yan,et al.  Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents. , 2002, Journal of the National Cancer Institute.

[19]  L. Cribbs,et al.  Vascular KCNQ Potassium Channels as Novel Targets for the Control of Mesenteric Artery Constriction by Vasopressin, Based on Studies in Single Cells, Pressurized Arteries, and in Vivo Measurements of Mesenteric Vascular Resistance , 2008, Journal of Pharmacology and Experimental Therapeutics.

[20]  D. Rhoney,et al.  Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage: An Overview of Pharmacologic Management , 2006, Pharmacotherapy.

[21]  M. Diringer,et al.  Clinical review: Prevention and therapy of vasospasm in subarachnoid hemorrhage , 2007, Critical care.

[22]  Zhiguo Wang.  Roles of K+ channels in regulating tumour cell proliferation and apoptosis , 2004, Pflügers Archiv.

[23]  A. Schönthal.  Antitumor properties of dimethyl-celecoxib, a derivative of celecoxib that does not inhibit cyclooxygenase-2: implications for glioma therapy. , 2006, Neurosurgical focus.

[24]  I. Greenwood,et al.  Electrophysiological and functional effects of the KCNQ channel blocker XE991 on murine portal vein smooth muscle cells , 2005, British journal of pharmacology.

[25]  A. Gurney,et al.  KCNQ Modulators Reveal a Key Role for KCNQ Potassium Channels in Regulating the Tone of Rat Pulmonary Artery Smooth Muscle , 2009, Journal of Pharmacology and Experimental Therapeutics.

[26]  L. Cribbs,et al.  Differential Effects of Selective Cyclooxygenase-2 Inhibitors on Vascular Smooth Muscle Ion Channels May Account for Differences in Cardiovascular Risk Profiles , 2009, Molecular Pharmacology.

[27]  L. Marnett.  The COXIB experience: a look in the rearview mirror. , 2009, Annual review of pharmacology and toxicology.

[28]  L. Cribbs,et al.  Vasopressin stimulates action potential firing by protein kinase C-dependent inhibition of KCNQ5 in A7r5 rat aortic smooth muscle cells. , 2007, American journal of physiology. Heart and circulatory physiology.

[29]  Thomas C. Chen,et al.  Celecoxib analogs that lack COX-2 inhibitory function: preclinical development of novel anticancer drugs , 2008, Expert opinion on investigational drugs.

[30]  F. Ruschitzka,et al.  Selective COX-2 Inhibitors and Renal Injury in Salt-Sensitive Hypertension , 2005, Hypertension.

[31]  H. Krum,et al.  Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. , 2005, Archives of internal medicine.

[32]  A. Gurney,et al.  Pulmonary vasoconstrictor action of KCNQ potassium channel blockers , 2006, Respiratory research.

[33]  P. McGettigan,et al.  Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. , 2006, JAMA.

[34]  Thomas J. Jentsch,et al.  KCNQ5, a Novel Potassium Channel Broadly Expressed in Brain, Mediates M-type Currents* , 2000, The Journal of Biological Chemistry.

[35]  L. Laine.  Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. , 2001, Gastroenterology.