Ketamine enantiomers differentially relax isolated coronary artery rings

Background and objective: It has been shown that racemic ketamine increases coronary blood flow and that this effect is at least in part due to a direct vasorelaxing effect of this substance. This study was designed to determine whether ketamine might stereoselectively relax isolated porcine coronary arteries. Methods: Using the model of isolated vessels we studied the effects of S(+) ketamine, R(−) ketamine, and racemic ketamine (5‐500 μg mL−1) on artery strips pre‐contracted by either potassium chloride (KCl) or prostaglandin F2&agr; (PGF2&agr;). To elucidate possible mechanisms of action these experiments were repeated in the presence of one of the following compounds: Nω‐nitro‐L‐arginine (L‐NNA), indomethacin, glibenclamide, and tetraethylammonium (TEA) chloride, an inhibitor of the BKCa K+ channel. Results: Both isoforms and racemic ketamine relaxed isolated coronary arteries in a concentration‐dependent manner in concentrations beyond those used in clinical practice. S(+) ketamine exerted the strongest vasorelaxing effect, followed by racemic ketamine and R(−) ketamine. Pretreatment with L‐NNA, indomethacin, or glibenclamide did not alter the vasodilating properties of ketamine, whereas TEA chloride significantly attenuated the vasorelaxing effects of all the three forms of ketamine. Conclusions: Ketamine dilates coronary arteries in vitro when administered in high concentrations. There is a stereoselective difference with a stronger vasorelaxing effect of S(+) ketamine compared to racemic and R(−) ketamine. The impact of TEA chloride suggests that the activation of the BKCa channel may contribute to the vasodilating effect of ketamine.

[1]  G. Hellige,et al.  Ketamin hemmt die Wirkung von Vasokonstriktoren an isolierten Koronararterien , 2003 .

[2]  P. Murray,et al.  Inhibitory Effects of Etomidate and Ketamine on Adenosine Triphosphate–Sensitive Potassium Channel Relaxation in Canine Pulmonary Artery , 2003, Anesthesiology.

[3]  T. Akata,et al.  Mechanisms of Direct Inhibitory Action of Isoflurane on Vascular Smooth Muscle of Mesenteric Resistance Arteries , 2001, Anesthesiology.

[4]  G. Hellige,et al.  [Ketamine attenuates the contractile response to vasoconstrictors in isolated coronary artery rings]. , 2003, Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS.

[5]  H. Kinoshita,et al.  Ketamine Stereoselectively Affects Vasorelaxation Mediated by ATP-sensitive K+ Channels in the Rat Aorta , 2002, Anesthesiology.

[6]  T. Akata,et al.  Mechanisms of Direct Inhibitory Action of Ketamine on Vascular Smooth Muscle in Mesenteric Resistance Arteries , 2001, Anesthesiology.

[7]  S. Tanaka,et al.  Inhibitory Effects of Etomidate and Ketamine on Endothelium-dependent Relaxation in Canine Pulmonary Artery , 2001, Anesthesiology.

[8]  B. Nossaman,et al.  Analysis of ketamine responses in the pulmonary vascular bed of the cat , 2000, Critical care medicine.

[9]  A. Kaye,et al.  Pulmonary Vasodilation by Ketamine Is Mediated in Part by L-Type Calcium Channels , 1998, Anesthesia and analgesia.

[10]  S. Kojima,et al.  Ketamine Suppresses the Production and Release of Endothelin 1 from Cultured Bovine Endothelial Cells , 1998, Anesthesia and analgesia.

[11]  M. Bodelsson,et al.  Relaxant effects of propofol on human omental arteries and veins. , 1998, British journal of anaesthesia.

[12]  G. Lenz,et al.  Stereoselective Differences in the Vasorelaxing Effects of S(+) and R(‐) Ketamine on Rat Isolated Aorta , 1998, Anesthesiology.

[13]  G. Hellige,et al.  Influence of high‐dose ketamine on the vascular reactivity of human and porcine isolated coronary artery segments , 1997, Acta anaesthesiologica Scandinavica.

[14]  L. Missiaen,et al.  The Effects of Ketamine on Ca2+ Movements in A7r5 Vascular Smooth Muscle Cells , 1996, Anesthesia and analgesia.

[15]  C. Carlsson,et al.  The Effects of N-Methyl-D-Aspartate Agonists and Antagonists on Isolated Bovine Cerebral Arteries , 1996, Anesthesia and analgesia.

[16]  T. Lee,et al.  Vasoactive effects of ketamine on isolated rabbit pulmonary arteries. , 1995, Chest.

[17]  K. Miyasaka,et al.  Vasodilatory Effects of Ketamine on Pulmonary Arteries in Rats with Chronic Hypoxic Pulmoanry Hypertension , 1995, Anesthesia and analgesia.

[18]  C. Carlsson,et al.  Ketamine directly dilates bovine cerebral arteries by acting as a calcium entry blocker. , 1994, Journal of neurosurgical anesthesiology.

[19]  P. Vanhoutte,et al.  Endothelium-derived hyperpolarizing factor and endothelium-dependent relaxations. , 1993, American journal of respiratory cell and molecular biology.

[20]  J. Kampine,et al.  Differential Relaxant Effect of High Concentrations of Intravenous Anesthetics on Endothelin‐Constricted Proximal and Distal Canine Coronary Arteries , 1992, Anesthesia and analgesia.

[21]  K. Shimoji,et al.  Effects of thiopental, pentobarbital, and ketamine on endothelin-induced constriction of porcine cerebral arteries. , 1990, Anesthesiology.

[22]  N. Toda,et al.  Direct Effects of Ketamine on Isolated Canine Cerebral and Mesenteric Arteries , 1983, Anesthesia and analgesia.

[23]  E. Domino,et al.  Plasma Levels of Ketamine and Two of Its Metabolites in Surgical Patients Using a Gas Chromatographic Mass Fragmentographic Assay , 1982, Anesthesia and analgesia.

[24]  P. White,et al.  Pharmacology of Ketamine Isomers in Surgical Patients , 1980, Anesthesiology.

[25]  J. Folts,et al.  Systemic and coronary haemodynamic effects of ketamine in intact anaesthetized and unanaesthetized dogs. , 1975, British journal of anaesthesia.

[26]  D. Wong,et al.  An experimental study of the mechanism of action of ketamine on the central nervous system , 1974, Canadian Anaesthetists' Society journal.

[27]  D. Wong,et al.  An experimental study of the mechanism of action of ketamine on the central nervous system , 1974 .

[28]  E. Domino,et al.  Pharmacologic effects of CI‐581, a new dissociative anesthetic, in man , 1965, Clinical pharmacology and therapeutics.