A sex‐specific, COX‐derived/thromboxane receptor activator causes depolarization and vasoconstriction in male mice mesenteric resistance arteries

We investigated whether sex differences exist in cyclooxygenase‐dependent effects on membrane potential and relaxation in mice mesenteric resistance arteries. Mesenteric small arteries of 9‐ to 12‐week‐old, male and female, wild‐type mice, db/+ mice and diabetic db/db mice were mounted in myographs for measurements of isobaric diameter and smooth muscle cell membrane potential. Acetylcholine caused smaller dilation of arteries from male db/+ mice compared to arteries from female db/+ mice. In the presence of the NO synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME), acetylcholine‐induced dilation of arteries from males increased in the presence of indomethacin and the COX‐1‐specific inhibitor FR122047. The presence of indomethacin was also associated with a more negative membrane potential in arteries from males. In arteries from db/db mice, no sex differences were seen. In arteries from male but not female wild‐type mice, the thromboxane receptor blocker SQ29,548 increased relaxation to acetylcholine. In contrast to arteries from female mice, COX (most likely COX‐1)‐derived prostanoids and activation of thromboxane receptors counteract acetylcholine vasodilatation probably through increased smooth muscle depolarization in arteries from male mice. In mice with diabetes and pronounced endothelial dysfunction, inhibition of COX did not enhance acetylcholine vasodilatation.

[1]  M. Kuppusamy,et al.  Sex differences in the vascular function and related mechanisms: role of 17β-estradiol. , 2018, American journal of physiology. Heart and circulatory physiology.

[2]  J. Lykkesfeldt,et al.  Basic & Clinical Pharmacology & Toxicology Policy for Experimental and Clinical studies. , 2018, Basic & clinical pharmacology & toxicology.

[3]  M. Kuppusamy,et al.  Sex differences in the vascular function and related mechanisms: role of 17β-estradiol. , 2018, American journal of physiology. Heart and circulatory physiology.

[4]  C. Aalkjaer,et al.  Impaired endothelial calcium signaling is responsible for the defective dilation of mesenteric resistance arteries from db/db mice to acetylcholine. , 2015, European journal of pharmacology.

[5]  P. Vanhoutte,et al.  Endothelium‐mediated control of vascular tone: COX‐1 and COX‐2 products , 2011, British journal of pharmacology.

[6]  D. Mozaffarian,et al.  Diabetes and coronary heart disease as risk factors for mortality in older adults. , 2010, The American journal of medicine.

[7]  P. Vanhoutte,et al.  Endothelial dysfunction: a strategic target in the treatment of hypertension? , 2010, Pflügers Archiv - European Journal of Physiology.

[8]  P. Vanhoutte,et al.  COX‐1 and Vascular Disease , 2009, Clinical pharmacology and therapeutics.

[9]  Daniel Henrion,et al.  Activation of prostaglandin E2 EP1 receptor increases arteriolar tone and blood pressure in mice with type 2 diabetes. , 2009, Cardiovascular research.

[10]  A. Miner,et al.  Potential for control of detrusor smooth muscle spontaneous rhythmic contraction by cyclooxygenase products released by interstitial cells of Cajal , 2009, Journal of cellular and molecular medicine.

[11]  M. Gollasch,et al.  Cyclooxygenase-2–Derived Prostaglandin F2&agr; Mediates Endothelium-Dependent Contractions in the Aortae of Hamsters With Increased Impact During Aging , 2009, Circulation research.

[12]  A. Briones,et al.  Hypertension Increases Contractile Responses to Hydrogen Peroxide in Resistance Arteries through Increased Thromboxane A2, Ca2+, and Superoxide Anion Levels , 2009, Journal of Pharmacology and Experimental Therapeutics.

[13]  P. Vanhoutte,et al.  Endothelium‐dependent contractions: when a good guy turns bad! , 2008, The Journal of physiology.

[14]  M. Khazaei,et al.  Sulfaphenazole treatment restores endothelium-dependent vasodilation in diabetic mice. , 2008, Vascular pharmacology.

[15]  A. Hughes,et al.  Antiphase oscillations of endothelium and smooth muscle [Ca2+]i in vasomotion of rat mesenteric small arteries. , 2007, Cell calcium.

[16]  É. Thorin,et al.  A change in the redox environment and thromboxane A2 production precede endothelial dysfunction in mice. , 2007, American journal of physiology. Heart and circulatory physiology.

[17]  C. Triggle,et al.  Pharmacological characteristics of endothelium-derived hyperpolarizing factor-mediated relaxation of small mesenteric arteries from db/db mice. , 2006, European journal of pharmacology.

[18]  G. Tipoe,et al.  Endothelium-Dependent Contractions Occur in the Aorta of Wild-Type and COX2−/− Knockout But Not COX1−/− Knockout Mice , 2005, Journal of cardiovascular pharmacology.

[19]  J. Morrow,et al.  Acetylcholine‐induced endothelium‐dependent contractions in the SHR aorta: the Janus face of prostacyclin , 2005, British journal of pharmacology.

[20]  T. Hintze,et al.  Type 2 Diabetic Mice Have Increased Arteriolar Tone and Blood Pressure: Enhanced Release of COX-2–Derived Constrictor Prostaglandins , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[21]  S. Taddei,et al.  Endothelium‐dependent contractions in hypertension , 2005, British journal of pharmacology.

[22]  C. Garland,et al.  Thromboxane receptor stimulation associated with loss of SKCa activity and reduced EDHF responses in the rat isolated mesenteric artery , 2004, British journal of pharmacology.

[23]  E. Okon,et al.  In the presence of L‐NAME SERCA blockade induces endothelium‐dependent contraction of mouse aorta through activation of smooth muscle prostaglandin H2/thromboxane A2 receptors , 2002, British journal of pharmacology.

[24]  E. Masih-Khan,et al.  Influence of Type II Diabetes on Arterial Tone and Endothelial Function in Murine Mesenteric Resistance Arteries , 2001, Journal of Vascular Research.

[25]  Y. Liu,et al.  Selected contribution: Gender differences in the endothelin-B receptor contribution to basal cutaneous vascular tone in humans. , 2001, Journal of applied physiology.

[26]  T. Goto,et al.  The analgesic effect profile of FR122047, a selective cyclooxygenase-1 inhibitor, in chemical nociceptive models. , 2000, European journal of pharmacology.

[27]  M. Kähönen,et al.  Influence of gender on control of arterial tone in experimental hypertension. , 1998, American journal of physiology. Heart and circulatory physiology.

[28]  A. Bonev,et al.  Gender differences in coronary artery diameter involve estrogen, nitric oxide, and Ca(2+)-dependent K+ channels. , 1996, Circulation research.

[29]  K. Wu,et al.  Endothelium-dependent contractions are associated with both augmented expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin H2 in the SHR aorta. , 1995, Circulation research.

[30]  G. Rubanyi,et al.  Gender difference in endothelial dysfunction in the aorta of spontaneously hypertensive rats. , 1995, Hypertension.

[31]  B. Tesfamariam Free radicals in diabetic endothelial cell dysfunction. , 1994, Free radical biology & medicine.

[32]  P. Vanhoutte,et al.  Nitric oxide inactivates endothelium-derived contracting factor in the rat aorta. , 1992, Hypertension.

[33]  M. Ogletree,et al.  Pharmacological actions of SQ 29,548, a novel selective thromboxane antagonist. , 1985, The Journal of pharmacology and experimental therapeutics.