PMID- 8797140
OWN - NLM
STAT- MEDLINE
DCOM- 19970106
LR  - 20191210
IS  - 0160-2446 (Print)
IS  - 0160-2446 (Linking)
VI  - 28
IP  - 1
DP  - 1996 Jul
TI  - Thapsigargin inhibits the response to acetylcholine and substance P but does not 
      interfere with the responses to endothelium-independent agents.
PG  - 82-8
AB  - We investigated the influence of the Ca(2+)-ATPase inhibitor thapsigargin (TG) on 
      the vasorelaxant response to different endothelium-dependent and 
      endothelium-independent relaxing agents in an isolated thoracic aorta preparation 
      of the rabbit, precontracted by norepinephrine (NE). Pretreatment with 100 microM 
      L-arginine methyl ester (L-NAME) an inhibitor of nitric oxide (NO) synthesis, 
      completely prevented acetylcholine (ACh)-induced relaxation; the inactive 
      stereoisomer D-NAME did not modify the effect of ACh. The exposure of the 
      preparations to 1 microM TG induced a slowly developing slight increase in the 
      basal tension during 30-min contact. The same concentration of TG also slightly 
      reduced the response to the subsequent administration of NE. The antagonist 
      effect of TG on the ACh response was concentration dependent in the range between 
      0.1 and 10 microM. A 30-min pretreatment with 1 microM TG appeared to be 
      sufficient to induce a consistent antagonism of the ACh (0.01-10 microM) 
      concentration-relaxant effect curve, since an increase to 60 min did not produce 
      a further significant increment in the degree of the antagonist effect. The 
      concentration-dependent relaxation induced by substance P (SP 0.1-3 nM) was also 
      significantly antagonized by 1 microM TG. The effect of the calcium ionophore 
      A23187 (0.01-1 microM) was reduced by the Ca(2+)-ATPase inhibitor only at the 
      higher concentrations tested (0.3-1 microM). However, a 30-min contact time with 
      1 microM TG was completely ineffective in antagonizing the concentration-relaxant 
      response curves to the two nitrovasodilators sodium nitroprusside (SNP 0.1-100 
      microM) and nitroglycerin (NTG 1-300 nM) and to the cyclic GMP analogue 
      8-Bromo-cyclic GMP (3-100 microM). The effects of the beta-adrenoceptor agonist 
      isoprenaline (ISO 0.1-10 microM) and of the direct adenylate cyclase activator 
      forskolin (FK 0.01-10 microM) were also completely unaffected by 1 microM TG. 
      These results demonstrate that TG affects the response to agents that induce an 
      endothelium-dependent relaxation through receptor-dependent calcium mobilization. 
      However, they do not support the hypothesis that sarcoplasmic pump activity is 
      essential for the development of a vasorelaxant response to 
      endothelium-independent agents.
FAU - Amerini, S
AU  - Amerini S
AD  - Department of Preclinical and Clinical Pharmacology, University of Florence, 
      Italy.
FAU - Filippi, S
AU  - Filippi S
FAU - Parenti, A
AU  - Parenti A
FAU - Ziche, M
AU  - Ziche M
FAU - Ledda, F
AU  - Ledda F
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cardiovasc Pharmacol
JT  - Journal of cardiovascular pharmacology
JID - 7902492
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Vasodilator Agents)
RN  - 33507-63-0 (Substance P)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 7.2.2.10 (Calcium-Transporting ATPases)
RN  - G59M7S0WS3 (Nitroglycerin)
RN  - N9YNS0M02X (Acetylcholine)
SB  - IM
MH  - Acetylcholine/*pharmacology
MH  - Animals
MH  - Aorta/*drug effects/physiology
MH  - Calcium-Transporting ATPases/*antagonists & inhibitors
MH  - Drug Interactions
MH  - Endothelium, Vascular/*drug effects/physiology
MH  - Enzyme Inhibitors/*pharmacology
MH  - In Vitro Techniques
MH  - Male
MH  - Nitroglycerin/pharmacology
MH  - Rabbits
MH  - Substance P/*pharmacology
MH  - Thapsigargin/*pharmacology
MH  - Vasodilation
MH  - Vasodilator Agents/*pharmacology
EDAT- 1996/07/01 00:00
MHDA- 1996/07/01 00:01
CRDT- 1996/07/01 00:00
PHST- 1996/07/01 00:00 [pubmed]
PHST- 1996/07/01 00:01 [medline]
PHST- 1996/07/01 00:00 [entrez]
AID - 10.1097/00005344-199607000-00013 [doi]
PST - ppublish
SO  - J Cardiovasc Pharmacol. 1996 Jul;28(1):82-8. doi: 
      10.1097/00005344-199607000-00013.