[Soluble guanylate cyclase in the molecular mechanism underlying the therapeutic action of drugs].

The influence of ambroxol--a mucolytic drug--on the activity of human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase and activation of both enzymes by NO-donors (sodium nitroprusside and Sin-1) were investigated. Ambroxol in the concentration range from 0.1 to 10 microM had no effect on the basal activity of both enzymes. Ambroxol inhibited in a concentration-dependent manner the sodium nitroprusside-induced human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase with the IC50 values 3.9 and 2.1 microM, respectively. Ambroxol did not influence the stimulation of both enzymes by protoporphyrin IX. The influence of artemisinin--an antimalarial drug--on human platelet soluble guanylate cyclase activity and the enzyme activation by NO-donors were investigated. Artemisinin (0.1-100 microM) had no effect on the basal activity of the enzyme. Artemisinin inhibited in a concentration-dependent manner the sodium nitroprusside-induced activation of human platelet guanylate cyclase with an IC50 value 5.6 microM. Artemisinin (10 microM) also inhibited (by 71 +/- 4.0%) the activation of the enzyme by thiol-dependent NO-donor the derivative of furoxan, 3,4-dicyano-1,2,5-oxadiazolo-2-oxide (10 microM), but did not influence the stimulation of soluble guanylate cyclase by protoporphyrin IX. It was concluded that the sygnalling system NO-soluble guanylate cyclase-cGMP is involved in the molecular mechanism of the therapeutic action of ambroxol and artemisinin.

[YC-1-like potentiation of nitric oxide-dependent activation of soluble guanylyl cyclase by adrenochrome].

The influence of adrenochrome and YC-1 on spermine NONO-induced activation of human soluble guanylyl cyclase was investigated. Adrenochrome (0.1-10 microM) had no effect on the basal activity, but it potentiated in concentration-dependent manner the spermine NONO-induced activation of this enzyme. Adrenochrome, like YC-1, sensitized guanylyl cyclase towards nitric oxide (NO) and produced the leftward shift of spermine NONO concentration responce curve. Addition of adrenochrome decreased the YC-1-induced leftward shift of spermine NONO concentration response curve. Adrenochrome also inhibited (by 63%) the enzyme activation by YC-1. These data demonstrates the possible competition between adrenochrome and YC-1. Thus, synergistic activation of NO-stimulated guanylyl cyclase activity by adrenochrome represents a new biochemical effect of this compound and indicates that adrenochrome may act as an endogenous regulator of NO-dependent stimulation of soluble guanylyl cyclase. This new property of adrenochrome, similar to YC-1, is necessary taking into account, especially under conditions of overproduction of adrenochrome in organism.

[Potentiation of NO-dependent activation of soluble guanylate cyclase by polyamines].

The influence of polyamines (putrescine, spermidine, spermine) on the activity of human platelet soluble guanylate cyclase and stimulation of the enzyme by sodium nitroprusside, YC-1 and their combination was investigated. All polyamines used stimulated the guanylate cyclase activity and potentiated its activation by sodium nitroprusside. The stimulatory effects of sodium nitroprusside and putrescine (or spermine) were additive; spermidine produced a synergistic activation and increased the additive effect. All polyamines investigated inhibited the activation of the enzyme by YC-1 and decreased the synergistic activation of sodium nitroprusside-stimulated guanylate cyclase activity by YC-1 with approximately the same efficiency. The revealed ability of polyamines investigated to potentiate and synergistically increase (similar to YC-1, but less effective) NO-dependent activation of soluble guanylate cyclase represents a new biochemical effect of these compounds, which should be taken into consideration, especially due to the endogenous nature of polyamines. The data obtained suggest, that the specific functions of polyamines in the processes of cell growth and diffentiation may be also related to the ability of these compounds to activate soluble guanylate cyclase and increase cGMP level.

[The activation of soluble guanylate cyclase by new NO donors as the basis of a directed search for new efficacious vasodilators and antiaggregants]. / Aktivatsiia rastvorimoi guanilattsiklazy novymi donorami NO kak osnova napravlennogo poiska novykh éffektivnykh vazodilatorov i antiagregantov.

The paper deals with the molecular mechanisms of antihypertensive and antiaggregatory actions of nitric oxide (NO). These effects of NO are shown to be directly associated with the activation of soluble guanylate cyclase and with the accumulation of 3',5'-guanosine monophosphate. The paper discusses the mechanism of activation of guanylate cyclase with new donors: the role and value of a nitrosyl-hemic complex formed in the interaction of guanylate cyclase with NO. New approaches to studying the mechanism of antihypertensive and antiaggregatory actions of the NO donors in question provided fundamental and priority data that lead to the development of the molecular bases of goal-oriented search and the synthesis of new effective vasodilators and antiaggregants. Examining the molecular mechanisms of targeted activation of soluble guanylate cyclase with new NO donors has revealed new enzyme activators that generate NO in the body and participate in the regulation of homeostasis and vascular tone.

[Nitric oxide: its role in the development of pregnancy complications and in their prevention in women with hypertension and chronic glomerulonephritis]. / Oksid azota: rol' v razvitii oslozhnenii beremennosti i v ikh profilaktike u zhenshchin s gipertonicheskoi bolezn'iu i khronicheskim glomerulonefritom.

The activity of NO-synthase and formation of NO (EDRF) were assessed by an increase in the activity of NO-dependent hyanilate cyclase in response to L-arginine in vitro in platelets of 61 pregnant females (39, 8 14 with essential hypertension, preeclampsia and healthy controls, respectively) and in 9 hypertensive nonpregnant females. Compared to healthy pregnant females, EDRF synthesis activity was inhibited in hypertensive gravidas but enhanced in preeclampsia patients. Effectiveness of exogenic donator NO (transdermal nitroglycerine, Nitroderm NNS 5) was studied in a randomised trial of 76 gravidas with essential hypertension (EH), EH and chronic glomerulonephritis (GN). 39 of them were given transdermal nitroglycerine, 37 received acetylsalicilic acid and curantil. The number of treatment failures was the same in both groups. The conclusion is made that nitro compounds are adequate for use in EH and chronic GN gravidas.