TY - JOUR
T1 - Analysis of vasodilator responses to novel nitric oxide donors in the hindquarters vascular bed of the cat
AU - Bivalacqua, Trinity J.
AU - Champion, Hunter C.
AU - De Witt, Bracken J.
AU - Saavedra, Joseph E.
AU - Hrabie, Joseph A.
AU - Keefer, Larry K.
AU - Kadowitz, Philip J.
PY - 2001
Y1 - 2001
N2 - Controlled release of nitric oxide (NO·) may be useful in the treatment of a variety of vascular disorders. NO· donors of the diazeniumdiolate family with different rates of spontaneous NO· release have been synthesized. In the current study responses to seven diazeniumdiolate NO· donors (DEA/NO·, DETA/NO·, OXI/NO·, PIPERAZI/NO·, PROLI/NO·, SPER/NO·, and SULFI/NO·) were investigated in the hindquarters vascular bed of the cat. Intravenous injections of all NO· donors caused dose-dependent decreases in systemic arterial pressure and the rank order of potency was SNP > DEA/NO· > PIPERAZI/NO· > SPER/NO· > PROLI/NO· > OXI/NO·. Injections of all NO· donors into the hindlimb perfusion circuit caused dose-related decreases in hindquarters perfusion pressure that were similar to the order of potency in decreasing systemic arterial pressure. The rank order of the time required for the response to return to 50% of the maximal decrease in pressure (T1/2) and total duration of action of the NO· donors was SPER/NO· > PIPERAZI/NO· > DEA/NO· > OXI/NO· > DETA/NO· > PROLI/NO· > SULFI/NO·. After treatment with the NO· synthase inhibitor, Nω-nitro-L-arginine methyl ester (100 mg/kg, i.v.), hindlimb vasodilator responses to the NO· donors were not significantly different, but vasodilator responses to acetylcholine were significantly reduced. After treatment with zaprinast (2 mg/kg, i.v.), a type V cyclic 3′, 5′-guanosine monophosphate-specific phosphodiesterase inhibitor, the duration of vasodilator responses to the NO· donors, as measured by T1/2, was increased significantly, whereas the duration of the response to the β2-adrenergic receptor agonist albuterol was unchanged. These data suggest that diazeniumdiolate NO· donors are endothelium-independent, directly stimulate soluble guanylate cyclase, and decrease vascular resistance by increasing cyclic 3′, 5′-guanosine monophosphate levels in the hindquarters vascular bed of the cat.
AB - Controlled release of nitric oxide (NO·) may be useful in the treatment of a variety of vascular disorders. NO· donors of the diazeniumdiolate family with different rates of spontaneous NO· release have been synthesized. In the current study responses to seven diazeniumdiolate NO· donors (DEA/NO·, DETA/NO·, OXI/NO·, PIPERAZI/NO·, PROLI/NO·, SPER/NO·, and SULFI/NO·) were investigated in the hindquarters vascular bed of the cat. Intravenous injections of all NO· donors caused dose-dependent decreases in systemic arterial pressure and the rank order of potency was SNP > DEA/NO· > PIPERAZI/NO· > SPER/NO· > PROLI/NO· > OXI/NO·. Injections of all NO· donors into the hindlimb perfusion circuit caused dose-related decreases in hindquarters perfusion pressure that were similar to the order of potency in decreasing systemic arterial pressure. The rank order of the time required for the response to return to 50% of the maximal decrease in pressure (T1/2) and total duration of action of the NO· donors was SPER/NO· > PIPERAZI/NO· > DEA/NO· > OXI/NO· > DETA/NO· > PROLI/NO· > SULFI/NO·. After treatment with the NO· synthase inhibitor, Nω-nitro-L-arginine methyl ester (100 mg/kg, i.v.), hindlimb vasodilator responses to the NO· donors were not significantly different, but vasodilator responses to acetylcholine were significantly reduced. After treatment with zaprinast (2 mg/kg, i.v.), a type V cyclic 3′, 5′-guanosine monophosphate-specific phosphodiesterase inhibitor, the duration of vasodilator responses to the NO· donors, as measured by T1/2, was increased significantly, whereas the duration of the response to the β2-adrenergic receptor agonist albuterol was unchanged. These data suggest that diazeniumdiolate NO· donors are endothelium-independent, directly stimulate soluble guanylate cyclase, and decrease vascular resistance by increasing cyclic 3′, 5′-guanosine monophosphate levels in the hindquarters vascular bed of the cat.
KW - Diazeniumdiolate
KW - Feline
KW - NO donors
KW - Regional vascular bed
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U2 - 10.1097/00005344-200107000-00013
DO - 10.1097/00005344-200107000-00013
M3 - Article
C2 - 11444495
AN - SCOPUS:0034944985
SN - 0160-2446
VL - 38
SP - 120
EP - 129
JO - Journal of cardiovascular pharmacology
JF - Journal of cardiovascular pharmacology
IS - 1
ER -