Increased nitric oxide concentrations in posterior hypothalamus and central sympathetic function on nitrate tolerance following subcutaneous nitroglycerin.
The present study was to examine the distributions of nitric oxide (NO) in the brain regions and peripheral vessels following subcutaneously administered nitroglycerin (NTG) and determine the noradrenergic activity and the role of central sympathetic function in acute nitrate tolerance. Tolerance to NTG was produced by subcutaneous (sc) administration of 4.0 mg NTG as four separate hourly pulse injections of 1.0 mg each in male (5-8 months) Sprague-Dawley rats. Rats in sham-treated group received sc injections of saline. Rats were killed by sodium pentobarbital (150 mg/kg, ip) at 10 min after last sc injection. The brain, gracilis muscle, aorta, superior mesenteric artery, coronary artery, and pulmonary vessels were quickly removed. Concentrations of nitrite (NO2-), nitrate (NO3-), and total NO2- plus NO3- (NOx-) were quantified in the micropunches of the anterior hypothalamus, the posterior hypothalamus (PH), the nucleus tractus solitarius, the lateral reticular nucleus, and the vessels in a blinded fashion. The central actions of acute tolerance to NTG were also determined using blockades of sympathetic functions in conscious rats. Four separate hourly pulse sc injections of 1.0 mg NTG produced a marked shift of the dose-response curve for arterial pressure depression induced by intravenous injection of the challenge doses of NTG. The same doses of sc NTG caused increases in NOx- [92+/-16% (mean +/- SE)] and NO3- productions (77+/-15%) in the PH, but did not significantly change in other brain regions (n = 6). NOx- and NO3- productions were significantly enhanced in the superior mesenteric artery, aorta, coronary artery, and pulmonary vessels following sc NTG, but were not altered in gracilis muscle by the treatment. The tolerance responses to arterial pressure depression were attenuated by intravenous administration of either prazosin (300 microg/kg), an alpha1-adrenoceptor antagonist, or chlorisondamine (10 mg/kg), a sympathetic ganglion blockading agent (n = 5-6). The results suggest that acute NTG tolerance predominately increases NO production in the PH. NO production was also markedly enhanced in the large and middle vessels but not in small vessels during acute NTG tolerance. The arterial pressure tolerance to NTG was reversed by blockade of central sympathetic function. We conclude that NO formation is increased in the PH following systemically administered NTG and NO in the PH may facilitate central sympathetic functions which contribute to nitrate tolerance.
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Department of Obstetrics and Gynecology, UCLA School of Medicine, Harbor-UCLA Medical Center, Torrance, California 90502, USA. MA@AFP76.HUMC.edu
Ignarro
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D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D007034:Hypothalamus, Posterior / Q000378:metabolism*; D007279:Injections, Subcutaneous; D008297:Male; D009566:Nitrates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D009566:Nitrates; D014665:Vasodilator Agents; D009569:Nitric Oxide; D005996:Nitroglycerin