Interleukin-1beta and neurogenic control of blood pressure in normal rats and rats with chronic renal failure.
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Increased sympathetic nervous system (SNS) activity plays a role in the genesis of hypertension in rats with chronic renal failure (CRF). The rise in central SNS activity is mitigated by increased local expression of neuronal nitric oxide synthase (NOS) mRNA and NO(2)/NO(3) production. Because interleukin (IL)-1beta may activate nitric oxide in the brain, we have tested the hypothesis that IL-1beta may modulate the activity of the SNS via regulation of the local expression of neuronal NOS (nNOS) in the brain of CRF and control rats. To this end, we first found that administration of IL-1beta in the lateral ventricle of control and CRF rats decreased blood pressure and norepinephrine (NE) secretion from the posterior hypothalamus (PH) and increased NOS mRNA expression. Second, we observed that an acute or chronic injection of an IL-1beta-specific antibody in the lateral ventricle raised blood pressure and NE secretion from the PH and decreased NOS mRNA abundance in the PH of control and CRF rats. Finally, we measured the IL-1beta mRNA abundance in the PH, locus coeruleus, and paraventricular nuclei of CRF and control rats by RT-PCR and found it to be greater in CRF rats than in control rats. In conclusion, these studies have shown that IL-1beta modulates the activity of the SNS in the central nervous system and that this modulation is mediated by increased local expression of nNOS mRNA. (+info)
Electrical activation of endothelium evokes vasodilation and hyperpolarization along hamster feed arteries.
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Endothelial cells are considered electrically unexcitable. However, endothelium-dependent vasodilators (e.g., acetylcholine) often evoke hyperpolarization. We hypothesized that electrical stimulation of endothelial cells could evoke hyperpolarization and vasodilation. Feed artery segments (resting diameter: 63 +/- 1 microm; length 3-4 mm) of the hamster retractor muscle were isolated and pressurized to 75 mmHg, and focal stimulation was performed via microelectrodes positioned across one end of the vessel. Stimulation at 16 Hz (30-50 V, 1-ms pulses, 5 s) evoked constriction (-20 +/- 2 microm) that spread along the entire vessel via perivascular sympathetic nerves, as shown by inhibition with tetrodotoxin, omega-conotoxin, or phentolamine. In contrast, stimulation with direct current (30 V, 5 s) evoked vasodilation (16 +/- 2 microm) and hyperpolarization (11 +/- 1 mV) of endothelial and smooth muscle cells that conducted along the entire vessel. Conducted responses were insensitive to preceding treatments, atropine, or N(omega)-nitro-L-arginine, yet were abolished by endothelial cell damage (with air). Injection of negative current (+info)
Activation of extracellular signal-regulated kinases, NF-kappa B, and cyclic adenosine 5'-monophosphate response element-binding protein in lung neutrophils occurs by differing mechanisms after hemorrhage or endotoxemia.
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Acute lung injury is frequently associated with sepsis or blood loss and is characterized by a proinflammatory response and infiltration of activated neutrophils into the lungs. Hemorrhage or endotoxemia result in activation of cAMP response element-binding protein (CREB) and NF-kappa B in lung neutrophils as well as increased expression of proinflammatory cytokines, such as TNF-alpha and macrophage-inflammatory peptide-2, by these cells. Activation of the extracellular regulated kinase (ERK) pathway occurs in stress responses and is involved in CREB activation. In the present experiments, hemorrhage or endotoxemia produced increased activation of mitogen-activated protein kinase kinase (MEK)1/2 and ERK2 (p42), but not of ERK1 (p44), in lung neutrophils. ERK1, ERK2, and MEK1/2 were not activated in peripheral blood neutrophils after hemorrhage or endotoxemia. Inhibition of xanthine oxidase led to further increase in the activation of MEK1/2 and ERK2 in lung neutrophils after hemorrhage, but not after endotoxemia. Alpha-adrenergic blockade before hemorrhage resulted in increased activation in lung neutrophils of MEK1/2, ERK1, ERK2, and CREB, but decreased activation of NF-kappa B. In contrast, alpha-adrenergic blockade before endotoxemia was associated with decreased activation of MEK1/2, ERK2, and CREB, but increased activation of NF-kappa B. Beta-adrenergic blockade before hemorrhage did not alter MEK1/2 or ERK1 activation in lung neutrophils, but decreased activation of ERK2 and CREB, while increasing activation of NF-kappa B. Beta-adrenergic inhibition before endotoxemia did not affect activation of MEK1/2, ERK1, ERK2, CREB, or NF-kappa B. These data indicate that the pathways leading to lung neutrophil activation after hemorrhage are different from those induced by endotoxemia. (+info)
In vivo demonstration of alpha(1A)-adrenoceptor subtype selectivity of KMD-3213 in rat tissues.
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The present study was undertaken to characterize the in vivo alpha(1)-adrenoceptor binding of KMD-3213, a novel selective antagonist of alpha(1A)-adrenoceptors, in rat tissues by using a tritiated ligand with high specific activity, in comparison with that of [(3)H]prazosin. A significant degree of in vivo specific binding of [(3)H]KMD-3213 after i.v. injection of the radioligand (1. 4 nmol/kg) was seen in most rat tissues, except the cerebral cortex, spleen, and liver, which showed a little or no specific binding. There was a notable difference among tissues in the time course of specific [(3)H]KMD-3213 binding after i.v. injection of the ligand. The specific binding in the lung, kidney, and spleen was greatest at 10 min and declined rapidly with the disappearance of the ligand from the plasma. On the other hand, [(3)H]KMD-3213 binding in the submaxillary gland, vas deferens, and prostate attained peak levels at 60 min, and a considerable degree of binding was present even at 240 min. After i.v. injection of a similar dose (1.2 nmol/kg) of [(3)H]prazosin in rats, the in vivo specific binding in the submaxillary gland was greatest at 10 min and then it fell rapidly, whereas [(3)H]prazosin binding in the spleen attained a peak level at 60 min, and this was maintained even at 120 min. The AUC(0-120) values of the specific binding for [(3)H]KMD-3213, compared with those of [(3)H]prazosin, were markedly lower in the rat aorta, spleen, and liver, whereas the prostate, submaxillary gland, and lung showed significantly higher AUC(0-120) values of [(3)H]KMD-3213 compared with [(3)H]prazosin. Furthermore, the in vivo specific binding of [(3)H]KMD-3213 at dose ranges of 1.4 to 13.6 nmol/kg increased linearly in the prostate and submaxillary gland, but did not increase in a dose-dependent manner in the spleen. On the other hand, there was a dose-dependent increase in the in vivo specific binding of [(3)H]prazosin at doses of 1.2 to 10.6 nmol/kg in all tissues. The in vivo specific binding of [(3)H]KMD-3213 in rat tissues was reduced by concomitant i.v. injection of low doses of prazosin in a dose-dependent manner, but not by even a relatively high dose of yohimbine. In conclusion, the present study shows that KMD-3213 binds to the alpha(1A)-adrenoceptor subtype with a higher affinity than to the alpha(1B)- and alpha(1D)- subtypes under in vivo condition, thus leading to prostate selectivity. (+info)
Conducted vasoconstriction in rat mesenteric arterioles: role for dihydropyridine-insensitive Ca(2+) channels.
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The aim of this study was to evaluate the role of voltage-operated Ca(2+) channels in the initiation and conduction of vasoconstrictor responses to local micropipette electrical stimulation of rat mesenteric arterioles (28 +/- 1 microm, n = 79) in vivo. Local and conducted (600 microm upstream from the pipette) vasoconstriction was not blocked by TTX (1 micromol/l, n = 5), nifedipine, or nimodipine (10 micromol/l, n = 9). Increasing the K(+) concentration of the superfusate to 75 mmol/l did not evoke vasoconstriction, but this depolarizing stimulus reversibly abolished vasoconstrictor responses to current stimulation (n = 7). Addition of the T-type Ca(2+) antagonist mibefradil (10 micromol/l, n = 6) to the superfusate reversibly blocked local and conducted vasoconstriction to current stimulation. With the use of RT-PCR techniques, it was demonstrated that rat mesenteric arterioles <40 microm do not express mRNA for L-type Ca(2+) channels (alpha(1C)-subunit), whereas mRNA coding for T-type subunits was found (alpha(1G)- and alpha(1H)-subunits). The data indicate that L-type Ca(2+) channels are absent from rat mesenteric arterioles (<40 microm). Rather, the vasoconstrictor responses appear to rely on other types of voltage-gated, dihydropyridine-insensitive Ca(2+) channels, possibly of the T-type. (+info)
Alpha2-adrenoceptors modulating neuronal serotonin release: a study in alpha2-adrenoceptor subtype-deficient mice.
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1. The release-inhibiting alpha2-adrenoceptors of cerebral serotoninergic axons were studied in mice. Slices of the hippocampus or the occipito-parietal cortex from NMRI mice, from mice lacking the alpha2A/D-, the alpha2B-, the alpha2C- or both the alpha2A/D- and the alpha2C-adrenoceptor, and from mice sharing the genetic background of the receptor-deficient animals (WT) were preincubated with [3H]-serotonin and then superfused and stimulated electrically, in most experiments by trains of 8 pulses at 100 Hz. 2. The concentration-response curves of the alpha2-adrenoceptor agonist medetomidine were virtually identical in hippocampal slices from NMRI and WT mice, with maximally 70% inhibition and an EC50 of about 2 nM. In hippocampal slices from NMRI mice, phentolamine and rauwolscine were equipotent antagonists against medetomidine. 3. The effect of medetomidine was greatly reduced, with maximally 20% inhibition, in hippocampal slices from alpha2A/D-adrenoceptor-deficient mice; was slightly reduced, with maximally 59% inhibition, in hippocampal slices from alpha2C-adrenoceptor-deficient mice; was not changed in hippocampal slices from alpha2B-adrenoceptor-deficient mice; and was abolished in hippocampal slices from mice lacking both the alpha2A/D- and the alpha2C-adrenoceptor. 3. Similar results were obtained in: (i) occipito-parietal slices from NMRI and alpha2A/D-adrenoceptor-deficient mice and (ii) hippocampal slices that were preincubated with [3H]-serotonin in the presence of oxaprotiline to rule out cross-labelling of noradrenergic axons. 5. The serotoninergic axons of the mouse brain possess both alpha2A/D-heteroreceptors, which predominate, and alpha2C-heteroreceptors but lack alpha2B-adrenoceptors. The situation resembles the coexistence of alpha2A/D- and alpha2C-autoreceptors but lack of alpha2B-autoreceptors at the noradrenergic axons of mice. (+info)
Periovulatory changes in catfish ovarian oestradiol-17beta, oestrogen-2-hydroxylase and catechol-O-methyltransferase during GnRH analogue-induced ovulation and in vitro induction of oocyte maturation by catecholoestrogens.
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In the catfish Heteropneustes fossilis and Clarias batrachus, ovarian oestrogen-2-hydroxylase (OE-2-H) activity increased significantly at 8 h after the injection of an ovulatory dose (0.15 microg/g body weight) of a mammalian GnRH analogue ([d -Ala(6)-Pro(9)]-LHRH ethylamide) and was restored to the 0 h (control) level after egg-stripping at 16 h. On the other hand, ovarian oestradiol-17beta (OE2) level and catechol-O-methyltransferase (COMT) activity decreased significantly at 8 h. While the OE2 level was restored to the 0 h level, COMT activity increased significantly at 16 h. Changes in ovarian OE2 level and enzymes indicate higher synthesis of 2-hydroxylated catecholoestrogens and their degradation during the periovulatory period. Under in vitro conditions, the synthetic catecholoestrogens (CEs, 2- and 4-hydroxylated oestradiol17beta and oestrone (OE1)) induced germinal vesicle break down (GVBD) in a dose- (0.01-10 microg/ml) and duration- (1-36 h) dependent manner, the mean values of the responses being in the order 2-OH OE2>4-OH OE2> 2-OH OE1>4-OH OE1. The CE-induced GVBD response (8 h induction) was not blocked by prior and subsequent incubations with steroid synthesis inhibitors (cyanoketone, epostane and aminoglutethimide) up to 36 h, suggesting that de novo steroidogenesis is not essential for the response. The percentage of GVBD response to 2-h induction by CEs was significantly inhibited by actinomycin D (a transcriptional inhibitor) and cycloheximide (a translational inhibitor), indicating the involvement of both RNA and protein synthesis. The CE-induced 8-h stimulation of GVBD was mildly blocked by propranolol, the beta-adrenergic inhibitor, suggesting the response was partly mediated through a beta-adrenergic receptor mechanism. Incubations with phentolamine, an alpha-adrenergic inhibitor, did not interfere with the CE-induced GVBD response. The results demonstrate CE-related enzymatic changes in teleost (catfish) ovaries and maturation-inducing substance activity of CEs. (+info)
A clinical comparative study on effects of intracavernous injection of sodium nitroprusside and papaverine/phentolamine in erectile dysfunction patients.
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AIM: To study the effect of intracavernous sodium nitroprusside (SNP), a nitric oxide (NO) donor, on penile erection. METHODS: Forty-two patients with erectile dysfunction (ED) were randomly assigned to receive SNP 300 micrograms or the control drugs (papaverine 30 mg + phentolamine 1 mg) intracavernously crosswise one week apart. The penile length, circumference and hardness after the administration of the experimental and control drugs were assessed and compared statistically. RESULTS: (1) There was no significant difference between the changes in penile length and circumference in the two occasions; (2) In 25 SNP and 28 control cases, the hardness of the penis was scored above 100 as evaluated by the Virag method (P > 0.05); (3) The duration of erection in the controls was longer than that in the SNP, but there were three priapism in the controls and not a single one in the SNP; (4) there was no apparent change in the heart rate and blood pressure in both occasions; other side effects were minimal except slight local pain in a few controls. CONCLUSION: SNP facilitates relaxation of the penile smooth muscle and penile erection without significant side effects. SNP may be used in ED patients that experience pain and priapism with papaverine/phentolamine. (+info)