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Division of Respiratory Medicine, City Hospital, Nottingham NG5 1PB, United Kingdom
Airway smooth muscle (ASM) hypertrophy and
hyperplasia are important determinants of bronchial responsiveness in
asthma, and agents that interfere with these processes may prevent
airway remodeling. We tested the hypothesis that activators of soluble and particulate guanylyl cyclases would inhibit human ASM cell (HASMC)
proliferation. We report that the nitric oxide (NO) donors S-nitroso-N-acetylpenicillamine
(SNAP; 10
6 to
104 M) and sodium
nitroprusside (105 to
103 M) and human atrial
natriuretic peptide [ANP-(1
28);
108 to
106 M], which
activate soluble and particulate guanylyl cyclases, respectively,
inhibited serum- and thrombin-induced proliferation of cultured HASMCs.
The antimitogenic effect of SNAP was reversed by hemoglobin
(105 M), an NO scavenger,
suggesting that NO donation was involved. The antiproliferative effects
of SNAP and ANP-(128) were potentiated by the cGMP-specific
phosphodiesterase zaprinast and mimicked by 8-bromo-cGMP
(106 to
103 M), suggesting that
cGMP-dependent mechanisms were involved. However, first, ANP-(128)
produced a smaller antiproliferative effect than SNAP in contrast to
their abilities to elevate cGMP, and second, rat ANP-(104126), which
binds selectively to ANP clearance receptors without elevating cGMP,
had a small antiproliferative effect, suggesting that cGMP-independent
mechanisms were also involved. These results provide
evidence for a novel antiproliferative effect of NO and ANP in HASMCs
mediated through cGMP-dependent and cGMP-independent mechanisms.
nitric oxide; atrial natriuretic peptide; asthma; guanosine 3',5'-cyclic monophosphate; hypertrophy; hyperplasia
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