Dissociation of hemodynamic and coronary arterial tolerance to nitroglycerin in dogs.
To investigate the development of tolerance to nitroglycerin (NTG), therapeutic doses of NTG (1 microgram/kg/min in group 1G and 10 micrograms/kg/min in group 10G) or vehicle alone (group 0G) were infused intravenously (i.v.) for 24 h into anesthetized mongrel dogs. The reduction of pulmonary artery pressure (PAP) by NTG was attenuated after the first 3 and 6 h of NTG infusion in groups 1G and 10G, respectively. At the end of infusion, coronary artery strips were excised for study of isometric tension responses to cumulative doses of NTG. The ED50 value for group 10G (17.5 +/- 2.9 nM) was greater than that for group 0G (5.2 +/- 1.1 nM, p < 0.001), but the ED50 value of group 1G (5.5 +/- 0.7 nM) was not. Maximum relaxation did not alter in the three groups. The concentration of cyclic GMP in the isolated coronary artery strips was measured by radioimmunoassay (RIA). Administration of 10(-8.5) M NTG increased the cyclic GMP level in group 0G (42.7 +/- 1.5%, p < 0.05) and group 1G (38.8 +/- 10.5%, p < 0.05), but not in group 10G (3.5 +/- 5.6%). The degree of increment in cyclic GMP corresponded with the relaxation response to 10(-8.5) M NTG. These results demonstrated the hemodynamic tolerance to NTG is different from vascular tolerance at therapeutic doses.
Miyauchi
N
N
First Department of Internal Medicine, Shiga University of Medical Science, Japan.
Takahashi
M
M
Fujioka
H
H
Kinoshita
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D004361:Drug Tolerance; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000502:physiology; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D011863:Radioimmunoassay
D005996:Nitroglycerin; D006152:Cyclic GMP