From the Institute of Physiology I, University of Heidelberg (Germany).
Correspondence to Dr J. Zanzinger, I. Physiologisches Institut, Im Neuenheimer Feld 326, D-69120 Heidelberg, FRG. E-mail zanzing{at}novsrv1.pio1.uni-heidelberg.de
Background—Endogenous
nitric oxide (NO) reduces sympathetic vasoconstriction by attenuating
neuronal excitability in the brain stem and inhibition of
postganglionic neurotransmission. We studied whether this modulation of
sympathetic circulatory control by NO may be altered during chronic
administration of NO donor drugs in pigs.
Methods and Results—Nitrate tolerance was induced by oral
administration of isosorbide dinitrate (ISDN, 4 mg/kg per day for 4
weeks) in eight pigs. Four of them were chronically instrumented for
the measurement of mean arterial blood pressure and cardiac
output in the conscious state. ISDN treatment caused
hemodynamic tolerance to NO donors and significantly
increased the hypotensive responses to pharmacologic ganglionic
blockade in conscious pigs. In general anesthesia,
ISDN-treated animals and age-matched controls (n=5) had similar
baseline renal sympathetic nerve activity and in both groups neither
inhibition of NO synthases (NOS) nor administration of NO donors to the
brain stem by intracerebroventricular
(ICV) infusions caused significant changes in baseline renal
sympathetic nerve activity. However, whereas
sympathoexcitatory responses to glutamate (0.5
mL, 0.1 mol/L, ICV) or electrical stimulation of somatic nerve
afferents were significantly potentiated by central NOS inhibition and
attenuated by NO donors in controls, these treatments no longer had
significant effects in ISDN-treated pigs. Furthermore, reflex
sympathetic activation in response to intravenous NO donor
treatment was more pronounced in nitrate tolerant animals, which
suggests loss of central sympathoinhibitory effects of NO.
Subsequent histology on brain stem slices with
NADPH-diaphorase as NOS marker revealed significant
reduction of NOS density in ISDN-treated pigs.
Conclusions—Long-term administration of organic nitrates reduces
the number of NO-producing neurons in the brain stem and causes loss of
inhibitory effects of NO on sympathetic excitability. This
component of tolerance to organic nitrates may be important in patients
confronted frequently with sympathetic activation caused by mental
and/or physical stressors.
© 1998 American Heart Association, Inc.
Basic Science Reports
Impaired Modulation of Sympathetic Excitability by Nitric Oxide After Long-term Administration of Organic Nitrates in Pigs
Key Words: nitric oxide • brain • nervous system
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