Biomedical subjects

S Cellek

Publications and source records attributed to S Cellek.

26 records · Page 2Linked to original sources

PubMed1996

cGMP mediates the vascular and platelet actions of nitric oxide: confirmation using an inhibitor of the soluble guanylyl cyclase.

The L-arginine:nitric oxide (NO) pathway is believed to exert many of its physiological effects via stimulation of the soluble guanylyl cyclase (SGC); however, the lack of a selective inhibitor of this enzyme has prevented conclusive demonstration of this mechanism of action. We have found that the compound 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) inhibits the elevation of cGMP induced by the NO donor S-nitroso-DL-penicillamine in human platelets and rat vascular smooth muscle (IC50 = 10-60 nM and <10 nM, respectively) and that this is accompanied by prevention of the platelet inhibitory and vasodilator actions of NO donors. ODQ also inhibited the antiaggregatory action of NO generated by the platelets but did not affect the action of prostacyclin or that of a cGMP mimetic. In addition, ODQ inhibited the vasodilator actions of endogenously released NO and of NO generated after induction of NO synthase in vascular preparations. It did not, however, affect the increase in vascular smooth muscle cGMP or the dilatation induced by atrial natriuretic factor. ODQ had no effect on NO synthase activity, nor did it react with NO. It did, however, potently (IC50 approximately 10 nM) inhibit the activity of the SGC in cytosol obtained from crude extract of rat aortic smooth muscle. Thus ODQ prevents the actions of NO on platelets and vascular smooth muscle through its potent inhibitory effect on the SGC.

Animals↗

PubMed1996

Inhibition of nitrergic relaxations by a selective inhibitor of the soluble guanylate cyclase.

1. The actions of 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), a specific inhibitor of the soluble guanylate cyclase (SGC), were investigated in the rabbit anococcygeus muscle. 2. ODQ (1 nM-1 microM) inhibited in a concentration-dependent manner the relaxations induced by electrical field stimulation (EFS; 50 V, 0.3 ms duration, 1 Hz, for 5 s, every 120 s). 3. ODQ (1 microM) also inhibited the relaxations elicited by EFS (50 V, 0.3 ms duration, 1, 2.5, 5, 10 Hz, for 5 s) and sodium nitroprusside (SNP; 1 microM) without affecting those induced by isoprenaline (1 microM), atrial natriuretic peptide (ANP; 100 nM) or an analogue of cyclic GMP (8-pCPT-cyclic GMP; 500 microM). 4. ODQ (1 microM) inhibited the elevations in the concentration of cyclic GMP induced by SNP or EFS, but not by ANP. ODQ did not affect the concentrations of cyclic AMP. 5. Nitrergic relaxation in this tissue appears, therefore, to be mediated via activation of SGC.

Animals↗

PubMed1995

Characterization of nitrergic neurotransmission during short- and long-term electrical stimulation of the rabbit anococcygeus muscle.

1. Isolated preparations of rabbit anococcygeus muscle were exposed to electrical field stimulation (EFS; 50V, 0.3 ms duration, 0.08-40 Hz) for periods of 1-60 s (short-term EFS) or 10 min-2 h (long-term EFS). 2. Both short- and long-term EFS caused a contractile response which was enhanced by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (L-NOARG), showing that it is modulated by endogenous NO. 3. In preparations treated with scopolamine and guanethidine and in which a constrictor tone was induced by histamine, both short- and long-term EFS resulted in relaxation of the tissue. 4. Such relaxations were reversed by tetrodotoxin (TTX), omega-conotoxin, inhibitors of NO synthase and the NO scavenger, oxyhaemoglobin, indicating that they are neuronal in origin and nitrergic in nature. 5. The relaxations to long-term EFS persisted for the duration of the stimulation and were associated with sustained release of oxidation products of NO (NOx). The EFS-induced release of NOx was decreased by N-iminoethyl-L-ornithine (L-NIO), an inhibitor of NO synthase, and by TTX. 6. Inhibitors of NO synthase, in addition, increased the basal tone of the tissue and reduced the basal output of NOx. The basal output of NOx was also reduced by TTX. 7. Long-term EFS which induces approximately 50% of the maximum relaxation could be enhanced by addition of L-, but not D-, arginine to the perfusion medium. 8. These data show that there is a continuous basal release of NO from nitrergic nerve terminals which maintains a relaxant tone in the rabbit anococcygeus muscle. 9. In addition, NO is released during short- and long-term EFS which further relaxes the preparation and modulates sympathetic transmission. Activation of the L-argimne: NO pathway for periods up to2 h does not exhaust nitrergic transmission in any appreciable way.

Adenosine Triphosphate↗

PubMed1990

Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone: an insight into endotoxin shock.

The relationship between vascular tone and the induction by endotoxin of a nitric oxide (NO) synthase was studied in vitro in rings of rat thoracic aorta. In rings with and without endothelium there was a time-dependent induction of NO synthase accompanied by both spontaneous and L-arginine-induced relaxation and by reduced contractility to phenylephrine. These effects, which were attributable to the presence of endotoxin in the Krebs' buffer, were attenuated by cycloheximide, polymyxin B and inhibitors of NO synthase. Furthermore, dexamethasone inhibited the induction of NO synthase and the consequent effects on vascular tone. These findings indicate that prevention of the induction of NO synthase by glucocorticoids may be an important component of their therapeutic action.

Amino Acid Oxidoreductases↗

PubMed1986

Cholesterol feeding attenuates endothelium-dependent relaxation response to acetylcholine in the main pulmonary artery of chickens.

The endothelium-dependent relaxation in response to acetylcholine was significantly less in pulmonary artery strips from chickens fed 5% cholesterol for 4 weeks than in strips from animals fed an 'ordinary' diet. No relaxation was observed in the strips from either group when the endothelium was disrupted or the strips were pretreated with hydroquinone. These results indicate that the relaxing effect of acetylcholine is endothelium-dependent and that hypercholesterolemia leads to an impairment of the endothelium-mediated relaxation response of the pulmonary artery strips to acetylcholine.

Acetylcholine↗

PubMedDate not supplied

Investigation of cavernosal smooth muscle dysfunction in low flow priapism using an in vitro model.

The effects of hypoxia (pO2: 50 mmHg), acidosis (pH: 6.9) or glucopenia (absence of glucose) in vitro on the tone of the rabbit corpus cavernosum were investigated. The recovery of smooth muscle contractility following exposure to these conditions was also assessed. Hypoxia, acidosis or glucopenia alone or in combination showed a sustained reduction in the tone. Reperfusion of tissue strips showed complete recovery of smooth muscle tone for all conditions except when hypoxia and glucopenia were combined or when hypoxia, glucopenia and acidosis were used in combination. Incomplete recovery of tone was associated with a significant reduction in tissue ATP concentrations and an increase in the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling)-positive nuclei. This indicates that following reversal of hypoxia, acidosis and glucopenia, failure of conventional alpha-adrenergic agonists to produce tumescence in low flow priapism is associated with irreversible smooth muscle cell dysfunction, which is linked to ATP reduction and smooth muscle cell death.

Acidosis↗

PubMedDate not supplied

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Autonomic Nervous System↗

PubMedDate not supplied

Nitrergic-noradrenergic interaction in penile erection: a new insight into erectile dysfunction.

Penile erection is regulated by two opposing systems: noradrenergic (anti-erectile) and nitrergic (pro-erectile) neurotransmission. Noradrenaline released from sympathetic nerves causes contraction of the blood vessels and smooth muscle of the penile corpus cavernosum, thus leading to detumescence of the penis. Nitric oxide (NO) released from nitrergic nerves causes relaxation of the smooth muscle of the corpus cavernosum, thus allowing engorgement of blood into the cavernous space and leading to erection. Nitrergic neurotransmission is known to modulate noradrenergic responses. We have recently shown that the degree of this modulation varies among species. In the human corpus cavernosum, noradrenergic responses are under nitrergic control, such that even pharmacological concentrations of noradrenaline fail to show an effect when nitrergic neurotransmission is operating. This situation is similar in the monkey and rabbit, where nitrergic neurotransmission does not merely modulate but actually controls the sympathetic responses; however it differs in the rat, mouse and dog where the sympathetic system is predominant. Our recent work has demonstrated that the interaction between the two systems occurs in the smooth muscle, suggesting a physiological antagonism. Our observations suggest that the key element in this interaction is intracellular calcium in the smooth muscle. The nitrergic pathway causes a decrease in intracellular calcium concentrations thus leading to relaxation of the smooth muscle. Noradrenergic stimulation, in contrast, elicits an increase in the intracellular calcium concentrations thus leading to a contraction. The neuronal pathway which controls the concentrations of intracellular calcium in the smooth muscle determines the dominance of that pathway over the other. Nitrergic dominance over noradrenergic system in the human corpus cavernosum also suggests a key role for this interaction in the pathophysiology of erectile dysfunction. Indeed, a nitrergic-noradrenergic imbalance in favor of the noradrenergic system has been implicated in penile tissues from patients with erectile dysfunction. However, the mechanism of this imbalance is not fully understood. In addition, since the present study has demonstrated that phosphodiesterase type V inhibitors can enhance and prolong the nitrergic control of noradrenergic responses, such compounds may have therapeutic potential in impotence, where defective nitrergic transmission is accompanied by increased noradrenergic activity.

Journal Article↗