Medvedeva Na

Vasorelaxant and antiplatelet activity of 4,7-dimethyl-1,2,5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide: role of soluble guanylate cyclase, nitric oxide and thiols

Certain heterocyclic N‐oxides are vasodilators and inhibitors of platelet aggregation. The pharmacological activity of the furoxan derivative condensed with pyridazine di‐N‐oxide 4,7‐dimethyl‐1,2,5‐oxadiazolo[3,4‐d]pyridazine 1,5,6‐trioxide (FPTO) and the corresponding furazan (FPDO) was studied. FPTO reacted with thiols generating nitrite (NO), S‐nitrosoglutathione and hydroxylamine (nitroxyl) and converted oxyHb to metHb. FPDO did not generate detectable amounts of NO‐like species but reacted with thiols and oxyHb. FPTO and FPDO haem‐dependently stimulated the activity of soluble guanylate cyclase (sGC) and this stimulation was inhibited by 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ) and by 0.1 mM dithiothreitol. FPTO relaxed noradrenaline‐precontracted aortic rings and its concentration‐response curve was biphasic (pIC50=9.03±0.13 and 5.85±0.06). FPDO was significantly less potent vasodilator (pIC50=5.19±0.14). The vasorelaxant activity of FPTO and FPDO was inhibited by ODQ. oxyHb significantly inhibited only FPTO‐dependent relaxation. FPTO and FPDO were equipotent inhibitors of ADP‐induced platelet aggregation (IC50=0.63±0.15 and 0.49±0.05 μM, respectively). The antiplatelet activity of FPTO (but not FPDO) was partially suppressed by oxyHb. The antiaggregatory effects of FPTO and FPDO were only partially blocked by sGC inhibitors. FPTO and FPDO (10–20 μM) significantly increased cyclic GMP levels in aortic rings and platelets and this increase was blocked by ODQ. Thus, FPTO can generate NO and, like FPDO, reacts with thiols and haem. The vasorelaxant activity of FPTO and FPDO is sGC‐dependent and a predominant role is played by NO at FPTO concentrations below 1 μM. On the contrary, inhibition of platelet aggregation is only partially related to sGC activation.

Role of sympathetic cholinergic pathway in the neurogenous control of tissue-type plasminogen activator release into the blood.

The changes in conductivity of skeletal muscle vessels of the hind leg and tissue-type plasminogen activator (t-PA) activity in outflowing blood after electrostimulation (5 V, 0.5 ms, 20 Hz, 30 s) at the L4-L5 level of the peripheral end of the transected isolated sympathetic chain were studied in experiments on anaesthetized cats. Stimulation of the sympathetic chain induced vasoconstriction and release of t-PA from the vascular wall into the blood. Pretreatment with the beta-adrenoblocker propranolol neither changed the character of vascular reactions nor blocked t-PA secretion. Efferent stimulation of the sympathetic chain against a background of alpha-adrenoceptor blockade by dihydroergotoxin increased blood flow and was accompanied by a rise in t-PA activity. The M-cholinergic blocker atropine suppressed both vascular relaxation and release of t-PA into the blood. Vasodilatation accompanied by t-PA secretion could be induced by intraarterial infusion of acetylcholine and blocked by atropine. The existence of a neurogenic mechanism controlling t-PA release from the vascular wall involving a sympathetic cholinergic pathway and connected with excitation of vascular M-cholinoceptors by acetylcholine is suggested.

Influence of sino-aortic barodenervation on the cardiovascular effects of imidazoline-like drugs.

Earlier findings have shown that hypotensive effects of centrally acting drugs, such as clonidine, are enhanced in animals after denervation of arterial baroreceptors. The purpose of this study was to investigate the dynamic of changes in arterial pressure, heart rate and hypotensive effects of clonidine, rilmenidine and moxonidine in Wistar rats after sino-aortic denervation (SAD) using radio-telemetry. SAD was followed by significant elevation of arterial pressure lability (the standard deviation of the mean arterial pressure), while the baseline mean arterial pressure (MAP) and heart rate in barodenervated rats (12 days after SAD) was similar to intact rats. The hypotension produced by clonidine, rilmenidine and moxonidine was much greater in SAD rats than in intact rats. The study suggests that baroreflex mechanisms are not only important for maintaining levels of blood pressure in the very short term, but also for buffering the effects of centrally acting antihypertensive drugs.

Effect of Chronic Administration of Estradiol on Responsiveness of Isolated Systemic and Pulmonary Blood Vessels from Ovariectomized Wistar Rats with Hypoxic Pulmonary Hypertension

The long-term (4 weeks) administration of estradiol (15 μg/kg/day) to ovariectomized female Wistar rats induced hypoxic pulmonary hypertension and significantly (p<0.05) diminished relaxation of perfused serotonin-preconstricted isolated vascular segments of the pulmonary artery in response to estradiol (10−6 M). At the same time, the isolated segments of systemic popliteal artery demonstrated a diminished response to serotonin and increased relaxation induced by acetylcholine (10−5 M) or estradiol (10−5 M) in comparison with preconstricted control vessels. Moderation of responsiveness to estradiol in pulmonary circulation can be one of the factors underlying the pro-hypertensive action of estradiol in female rats with hypoxic pulmonary hypertension.

Humoral factor(s) circulating in the blood of spontaneously hypertensive rats increases vascular tone and reduces constrictive responses of isolated rat caudal artery to stimulation of sympathetic fibers of the vascular wall

It is shown that the perfusion pressure in isolated rat caudal artery rises and constrictive responses to electrical stimulation decrease when the blood of normotensive Wistar-Kyoto rats perfusing the vessel was replaced by the blood of spontaneously hypertensive rats. The norepinephrine release from the sympathetic terminals is reduced.

Cardiac output and regional blood flow changes in alert rats with acute streptozotocin-induced diabetes

ing from lumbosacral osteochondrosis pain accompanied by ischialgia, although the anesthetic does not reach the pertinent sections of the spinal colunto or roots. It may be assumed that in these cases the therapeutic effect has to do with disengagement of the intraosseous receptors and, consequently, with limitation of afferent influences, alleviating the excitation process which is associated with root compression, muscle spasms, etc. Osteochondrous root syndromes are accompamied by changes of the bone tissue regional hemodyrmmics and an increase of the intraosseous pressure [4], which, as has been shown in this study, may promote a drop of the afferent reaction threshold for stimulation of nerve trunks and hence intensification of the pain syndrome.

PARAMETERS OF THE SYSTEMIC HEMODYNAMICS IN CONSCIOUS RATS WITH ACUTE STREPTOZOTOCIN DIABETES

The effect of acute streptozotocin-induced diabetes mellitus on the systemic hemodynamic parameters was studied in conscious rats by thermodilution technique. Male Wistar rats were made diabetic with a single intravenous injection of streptozotocin (STZ, 50 mg/kg). The most important finding of this work was the elucidation of the systemic vasodilation and increased cardiac index one day after STZ injection. Such alteration in hemodynamic parameters could result in the increased blood flow and capillary hypertension in some vascular beds and, therefore, be considered as a pathogenic factor in the development of diabetic microangiopathy.

Biphasic effect of endothelin-1 on coronary vascular resistance in anesthetized rats with an intact chest

Endothelin is one of the most effective vasoconstrictor endogenous peptides and was isolated from the supernatant of a culture of porcine aortic endothelial cells in 1988 [17]. This peptide causes constriction of both arteries and veins in rats [12], cats [11], dogs [7, 10], rabbits [13], guinea pigs [5], pigs [4], and man [2]. Expression of the endothelin gene arises under the influence of thrombin and catecholamines [17], indicating its possible involvement in the regulation of vascular tone in the course of various adaptive reactions. The effect of endothelin on coronary vascular tone has been studied in experiments in vitro on isolated preparations of the coronary arteries [2] and the isolated perfused heart [16]. In experiments in vivo, the coronary blood flow was recorded under open chest conditions [4, 9]. In that case the sucking action of the negative pressure is lost, and this introduces significant changes into the activity of the cardiovascular system. In the investigation described below we studied the effects of endothehn on coronary vascular resistance of anesthetized rats with an intact chest, and also the role of voltage-dependent Ca channels and of endogenous NO in these reactions.

Disturbance of sympathetic control of cardiovascular functions in rats with streptozocin-induced diabetes

Experimental diabetes causes considerable changes in the parameters of the systemic and regional hemodynamics in rats [4, 11, 13]. The causes of these changes may be disturbances of nervous control of the functions of the cardiovascular system due to the development of diabetic neuropathies [6, 15], and also changes in the contractile properties of the myocardium and smooth-muscle cells of the vessels [7, 10]. The aim of this investigation was to study the reactivity of the cardiovascular system of rats with streptozocin-induced diabetes to endogenous noradrenalin (NA) by measuring the parameters of the systemic and regional hemodynamics in conscious rats by the isotope-labeled microspheres method.