title: HEF-19-induced relaxation of colonic smooth muscles and the underlying mechanisms.
abstract: OBJECTIVE
  To investigate the relaxant effect of chromane HEF-19 on colonic smooth muscles isolated from rabbits, and the underlying mechanisms.
  
  
  METHODS
  The relaxant effect and action mechanisms of HEF-19 were investigated using descending colon smooth muscle of the rabbits. Preparations 1 cm long were mounted in 15-mL tissue baths containing Tyrode's solution, maintained at 37 ± 0.5 °C and aerated with a mixture of 5% CO2 in oxygen (Carbogen). The tension and amplitude of the smooth muscle strips were recorded after adding HEF-19 (10(-6), 10(-5) and 10(-4) mol/L). After cumulative administration of four antispasmodic agents, including acetylcholine chloride (Ach) (10(-4) mol/L), histamine (10(-4) mol/L), high-K(+) (60 mmol/L) and BaCl2 (8.2 mmol/L), HEF-19 (3 × 10(-7)-3 × 10(-4) mol/L) was added to investigate the relaxant effect of HEF-19. CaCl2 (10(-4)-2.5 × 10(-3) mol/L) was added cumulatively to the smooth muscle preparations pretreated with and without HEF-19 (1 × 10(-6) or 3 × 10(-6) mol/L) and verapamil (1 × 10(-7) mol/L) to study the mechanisms involved. Finally, phasic contraction was induced with ACh (15 × 10(-6) mol/L), and CaCl2 (4 × 10(-3) mol/L) was added to the smooth muscle preparations pretreated with and without HEF-19 (3 × 10(-6) mol/L or 1 × 10(-5) mol/L) and verapamil (1 × 10(-7) mol/L) in calcium-free medium to further study the underlying mechanisms.
  
  
  RESULTS
  HEF-19 (1 × 10(-6), 1 × 10(-5) and 1 × 10(-4) mol/L) suppressed spontaneous contraction of rabbit colonic smooth muscles. HEF-19 (3 × 10(-7)-3 × 10(-4) mol/L) relaxed in a concentration-dependent manner colonic smooth muscle preparations pre-contracted with BaCl2, high-K(+) solution, Ach or histamine with respective EC50 values of 5.15 ± 0.05, 5.12 ± 0.08, 5.58 ± 0.16 and 5.25 ± 0.24, thus showing a spasmolytic activity. HEF-19 (1 × 10(-6) mol/L and 3 × 10(-6) mol/L) shifted the concentration-response curves of CaCl2 to the right and depressed the maximum response to CaCl2. The two components contracted by Ach were attenuated with HEF-19 (3 × 10(-6) mol/L or 10(-5) mol/L) in calcium-free medium.
  
  
  CONCLUSIONS
  HEF-19 inhibited rabbit colonic smooth muscle contraction, probably through inhibiting opening of voltage-dependent Ca(2+) channels. HEF-19 reduced inflow and intracellular release of Ca(2+) ions.
authors: Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China. yuan2wei1@163.com
authors: Yuan-Yuan
authors: YY
authors: Wei
authors: Lu-Lu
authors: LL
authors: Sun
authors: Shou-Ting
authors: ST
authors: Fu
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D017609:Barium Compounds / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006632:Histamine / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D014700:Verapamil / Q000494:pharmacology
chemical_list: D017609:Barium Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002712:Chlorides; D002839:Chromans; D005765:Gastrointestinal Agents; C585953:HEF-19 chromane; C024986:barium chloride; D006632:Histamine; D014700:Verapamil; D002122:Calcium Chloride; D000109:Acetylcholine
keywords: Ca2+ channels; Colonic smooth muscle; Smooth muscle relaxation
references: Eur J Pharmacol. 2004 Apr 5;489(1-2):93-100
references: 15063160
references: Can J Physiol Pharmacol. 1981 Jun;59(6):541-7
references: 7296370
references: Br J Pharmacol. 1989 Aug;97(4):1174-81
references: 2551443
references: Pharmacol Rev. 1986 Dec;38(4):321-416
references: 2432624
references: Adv Physiol Educ. 2003 Dec;27(1-4):201-6
references: 14627618
references: J Physiol. 1981 Nov;320:347-61
references: 7320942
references: Eur J Pharmacol. 1987 Mar 3;135(1):69-75
references: 2436930
references: J Physiol. 2008 Nov 1;586(21):5047-61
references: 18787034
references: World J Gastroenterol. 2008 Feb 21;14(7):1077-83
references: 18286690
references: Am J Gastroenterol. 1987 Nov;82(11):1111-4
references: 3314483
references: Eur Rev Med Pharmacol Sci. 2012 Jan;16(1):25-37
references: 22338545
references: World J Gastroenterol. 2005 Jul 28;11(28):4414-8
references: 16038044
references: J Gastroenterol Hepatol. 2000 Aug;15(8):925-30
references: 11022835
references: J Physiol. 2005 Aug 1;566(Pt 3):645-56
references: 15905215
references: Eur J Pharmacol. 2001 Oct 5;428(2):251-9
references: 11675043
references: World J Gastroenterol. 2003 Mar;9(3):557-61
references: 12632518
references: J Physiol Pharmacol. 2004 Sep;55(3):639-50
references: 15381833
references: Life Sci. 2005 May 13;76(26):3089-105
references: 15850601
references: Life Sci. 1999;64(6-7):419-28
references: 10069505
references: Pharmacol Rev. 1997 Jun;49(2):157-230
references: 9228665
references: Can J Anaesth. 2002 Feb;49(2):151-64
references: 11823393
references: Dig Dis Sci. 1992 Jun;37(6):919-24
references: 1587197
references: Nature. 1994 Nov 17;372(6503):231-6
references: 7969467
references: Annu Rev Physiol. 1999;61:85-115
references: 10099683
references: Eur J Pharmacol. 1986 Oct 7;129(3):261-70
references: 3780843
references: Eur J Pharmacol. 1992 Jul 21;218(1):27-33
references: 1397033
references: Pharmacol Rev. 1986 Sep;38(3):227-72
references: 3022313