Long-lasting hypotensive action of stable preparations of dinitrosyl-iron complexes with thiol-containing ligands in conscious normotensive and hypertensive rats.
Previously we established the hypotensive action of nitric oxide donors, dinitrosyl-iron complexes (DNIC) with thiol-containing ligands, stored in frozen solution at 77K. In the present study, we tested recently designed water soluble dry powder preparations of DNICs keeping their characteristics in dry air for a long time. The complexes dissolved in PBS were injected intravenously into normotensive Wistar and spontaneously hypertensive SHR rats. The average arterial pressure (AAP) was recorded through preliminary implanted catheter in a carotid artery. The initial hypotensive action of DNIC with cysteine (DNIC-cys) was comparable to action of nitroprusside (SNP) but, in contrast to the latter, lasted for 20-120min depending on a doze. The blood DNIC content as detected by electronic paramagnetic resonance steadily decreased at this time. The hypotensive action of S-nitrosocysteine was similar to SNP while binding of iron in DNIC by batophenantroline-disulphonate prevented its hypotensive effect. These data suggest that long-lasting hypotensive action of DNICs may be caused by stable protein-bound DNICs forming in the process of transfer of Fe(+)(NO(+))(2) moieties from low-molecular DNICs to thiol protein ligands. The relative initial dose-dependent effect of DNIC-cys was similar in Wistar and SHR but secondary AAP reduction was more profound in SHR. A substitution of cysteine in DNIC by thiosulphate resulted in markedly less initial AAP reduction while long-lasting effect was similar and substitution by glutathione smoothed initial AAP decline and stabilized AAP level in the second phase. Prolonged AAP reduction induced by DNIC-cys was considerably shortened in narcotized rats. Thus, dry preparations of DNICs preserve prolonged hypotensive activity.
Lakomkin
Vladimir L
VL
Russian Cardiologic Research and Production Complex, Russian Ministry of Health, Moscow, Russia.
Vanin
Anatoly F
AF
Timoshin
Alexander A
AA
Kapelko
Valery I
VI
Chazov
Evgeny I
EI
D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007022:Hypotension / Q000139:chemically induced; D007501:Iron / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds; D014851:Wakefulness; D014867:Water / Q000737:chemistry
D000959:Antihypertensive Agents; D008024:Ligands; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D013438:Sulfhydryl Compounds; D014867:Water; C073661:dinitrosyl iron complex; D007501:Iron