Thermoregulatory activity of sodium nitroprusside and arginine vasopressin

• 1.1. Thermal responses to sodium nitroprusside (SNP, 3 mg/kg/hr) and arginine vasopressin (AVP, 3μg/kg) were investigated in normothermic and febrile rabbits (LPS, 1μg/kg) at ambient temperature of 20.0 ±1.0°C. Furthermore, blood pressure after these drugs was tested on a separate group of animals.
• 2.2. I.v. infusion of SNP produced hypothermia and attenuated pyrogen fever. On the other hand, AVP increased body temperature and intensified the febrile response.
• 3.3. Both drugs affected in an opposite way blood pressure, i.e. SNP produced falls and AVP increases in this parameter.
• 4.4. The relationship between the activity of the vascular and thermoregulatory systems in normothermic or febrile state is discussed.

     

Inhibition of NO synthase induction by an anticancer drug 4′-epi-doxorubicin in rats

• 1.1. Nitric oxide (NO) plays various physiological roles in tumour tissues. Herein, we examined the effects of an anticancer drug 4′-epi-doxorubicin on NO synthase and the related responses in rat thoracic aorta, rat cerebellum and lung homogenates.
• 2.2. Treatment with an anticancer drug 4′-epi-doxorubicin in vitro or in vivo had little effect on the relaxation response to acetylcholine or nitroprusside in rat thoracic aorta.
• 3.3. Treatment with 4′-epi-doxorubicin in vitro or in vivo did not alter the constitutive NO synthase activity of rat cerebellum ([³H]-citrulline production from [³H]-arginine).
• 4.4. After inducible NO synthase had been induced by lipopolysaccharide, 4′-epi-doxorubicin also neither affected the relaxation response to L-arginine in rat thoracic aorta nor the enzyme activity of rat lung.
• 5.5. Coincubation with lipopolysaccharide and 4′-epi-doxorubicin in vitro prevented the development of relaxation response to L-arginine in rat thoracic aorta. Pretreatment with 4′-epi-doxorubicin in vivo also prevented the induction of inducible NO synthase by lipopolysaccharide in rat thoracic aorta and lung.
• 6.6. These results suggest that 4′-epi-doxorubicin selectively inhibits the induction of NO synthase without affecting constitutive and inducible NO synthase activities. This effect was discussed in relation to the anticancer and side effects of the drug.

     

Attenuation of tolerance to,and physical dependence on,morphine in the rat by inhibition of nitric oxide synthase

• 1.1. The effect of N^G-monomethyl-l-arginine (NMMA), an inhibitor of nitric oxide synthase (NOS), on the development of tolerance to and physical dependence on morphine was determined in the rat.
• 2.2. Male Sprague-Dawley rats were rendered tolerant to and dependent on morphine by the subcutaneous implantation of four morphine pellets (each containing 75 mg morphine base) during a 3 day period. Placebo pellet implanted rats served as controls.
• 3.3. Chronic administration of morphine resulted in the development of tolerance to the analgesic action of morphine. Twice daily injections of NMMA (4 or 8 mg/kg) attenuated the tolerance to morphine as evidenced by higher analgesic response in NMMA treated than in vehicle treated morphine tolerant rats.
• 4.4. Chronic administration of morphine also resulted in the development of physical dependence as evidenced by the appearance of a variety of symptoms including stereotyped jumping response following naltrexone injection. Concurrent treatment with NMMA inhibited naltrexone-induced jumping response but other responses like fecal boli formation, wet dog shakes, teeth chattering, rearing and ejaculations were not modified.
• 5.5. It is concluded that inhibition of NOS can attenuate the development of tolerance to, and physical dependence on, morphine in the rat. However, it appears that higher doses of NOS inhibitors are required in the rat than in the mouse for blockade of both tolerance and physical dependence processes.

     

Some cyclic nucleotides reduce phenylephrine-induced and phorbol ester-induced constriction of the rat anterior mesenteric artery

• 1.1. Vasoconstrictor responses to phenylephrine (PE) and to 12-deoxyphorbol 13-phenylacetate in the rat isolated perfused anterior mesenteric artery were inhibited by pretreating the artery with isoprenaline (ISOP), sodium nitroprusside or 8-bromoguanosine 3′:5′-cyclic monophosphate, but not with 8-bromoadenosine 3′:5′-cyclic monophosphate.
• 2.2. The inhibitory effect of ISOP toward the response to PE was less prominent after pretreating the artery with a selective inhibitor of cyclic GMP-dependent kinase.
• 3.3. The vasorelaxant effect of ISOP was enhanced by pretreating the artery with an inhibitor of nitric oxide synthase.

     

Role of nitric oxide in nonadrenergic,noncholinergic relaxation of whole tracheal tube preparations isolated from guinea pigs

• 1.1. Frequency-dependent nonadrenergic, noncholinergic (NANC) relaxant responses were induced by transmural stimulation of whole tracheal tube preparations.
• 2.2. Responses at lower frequencies (⩽10 Hz) were abolished by L-nitroarginine methyl ester (L-NAME).
• 3.3. Responses at higher frequencies (⩾20 Hz) consisted of a rapid, short-lasting relaxation, followed by a slow, long-lasting relaxation. The former and the latter were reduced by L-NAME and α-chymotrypsin, respectively.
• 4.4. α-Chymotrypsin had little effect on the magnitude of NANC responses, but reduced the duration of responses at higher frequencies (⩾20 Hz).
• 5.5. The results suggest that NANC relaxation of guinea pig trachea may be mediated primarily by nitric oxide, with and without concomitant release of vasoactive intestinal peptide or related peptides, and nitric oxide may act as predominant mediator providing the magnitude of relaxant response.

     

Nitric oxide,prostaglandin, and sensory neurons in gastric mucosal blood flow response during acid secretion in rats

• 1.1. The mechanism underlying the increase of gastric mucosal blood flow (GMBF) during acid secretion induced by pentagastrin was investigated in anesthetized rats, in relation to nitric oxide (NO), prostaglandin (PG), and sensory neurons.
• 2.2. An intravenous infusion of pentagastrin at 60 μg/kg/h (submaximal dose) produced an increase of acid secretion and GMBF as determined by laser Doppler flowmetry, and the GMBF response was totally attenuated when the acid secretion was inhibited by omeprazole or when the luminal H⁺ was removed by mucosal perfusion with glycine (200 mM).
• 3.3. Prior administration of N^G-nitro-L-arginine methyl ester (L-NAME, 5 mg/kg, IV), a NO synthase inhibitor, significantly mitigated the GMBF response to pentagastrin, without any influence on acid secretion, and this effect was antagonized by coadministration of L-arginine (500 mg/kg IP).
• 4.4. The increase of GMBF during pentagastrin infusion also was significantly mitigated by indomethacin (5 mg/kg, SC) or sensory deafferentation following capsaicin pretreatment, had no effect on the acid secretion, and was totally inhibited by the combined treatments with indomethacin plus L-NAME in addition to sensory deafferentation.
• 5.5. Pentagastrin infusion for 8 hr did not by itself cause any macroscopic damage in the stomach, but additional treatments with L-NAME, and indomethacin plus sensory deafferentation provoked severe lesions in the gastric mucosa.
• 6.6. These results suggest that the increase of GMBF induced by submaximal dose of pentagastrin totally depends on luminal H⁺. This process seems to be mediated by endogenous NO and PGs, as well as capsaicin-sensitive sensory neurons, and to play a pivotal role in maintaining mucosal integrity during acid secretion.

     

Catalepsy induced by nitric oxide synthase inhibitors

• 1.1. Previous study showed that N^G-nitro-l-arginine (l-NOARG), an inhibitor of nitric oxide synthase, induces catalepsy in a dose-dependent manner in male albino-Swiss mice.
• 2.2. The objective of the present work was to further investigate this effect, extending it to other NOS inhibitors.
• 3.3. Results showed that l-NOARG (40–80 mg/kg IP), N^G-nitro-l-arginine methylester (l-NAME, 40–160 mg/kg IP) or N^G-monomethyl-l-arginine (l-NMMA, 80 mg/kg IP) were able to induce catalepsy in mice. The effect of l-NOARG (40 mg/kg) was antagonized by pretreatment with l-arginine (300 mg/kg), but not by d-arginine (300 mg/kg). The catalepsy-inducing effect of l-NOARG suffered rapid tolerance, showing a significant decrease after two days of chronic treatment (40 mg/kg IP, twice a day).
• 4.4. The results suggest that interference with the formation of nitric oxide induces significant motor effects in mice.

     

Indomethacin does not modify the role of nitric oxide on blood pressure regulation of SHR

• 1.1. The endothelium-dependent relaxation is impaired in spontaneously hypertensive rats (SHR) by the release of a vasoconstrictor prostanoid. We evaluated whether such a vasoconstrictor prostanoid is masking the vasodilatation induced by nitric oxide (NO).
• 2.2. For this we observed, in SHR, whether indomethacin (INDO) modified both the pressor response to the inhibition of NO biosynthesis with l-nitro-arginine methyl ester (l-NAME) and the acute hypotensive response to acetylcholine.
• 3.3. INDO did not modify basal mean arterial pressure (MAP), either the pressor response to l-NAME, or the depressor response to acetylcholine.
• 4.4. It shows that, in awake SHR, a vasoconstrictor prostanoid, did not seem to affect the acute regulatory function of NO on MAP.

     

Nitric oxide release and long term potentiation at synapses in autonomic ganglia

• 1.1. Long-term potentiation (LTP) of synaptic transmission in autonomic ganglia is reviewed, together with the possible role of nitric oxide (NO) in this process.
• 2.2. Calcium levels in preganglionic nerve terminals are elevated during at least the induction phase of LTP following a tetanus as well as during LTP induced by transmitter substances acting on the nerve terminals. Of the large number of calcium-dependent processes in the nerve terminal that might affect transmitter release, only calcium-calmodulin has been shown to be important in both the induction and maintenance of LTP.
• 3.3. The possibility that there is a decrease in the open time of nerve-terminal potassium channels following a tetanus, leading to an increase in duration of the terminal action potential and hence an increase in calcium influx and transmitter release is considered. There is little evidence for such an effect as yet for preganglionic nerve terminals.
• 4.4. Phosphorylation of potassium channels by cAMP-dependent protein kinase can lead to their inactivation with consequent action potential broadening in some systems. Exogenous cAMP enhances synaptic efficacy at preganglionic nerve terminals. Whether this occurs through an inactivation of potassium channels is not known.
• 5.5. Nitric oxide (NO) synthase is present in both sympathetic ganglia and the ciliary ganglia. NO increases synaptic efficacy in both ganglia. In at least the case of ciliary ganglion this is due to elevation of quantal secretion.
• 6.6. NO can in some conditions increase the terminal action potential duration in ciliary ganglia, probably through decrease in the Ic potassium current. There is evidence that this happens through cGMP modulating cAMP phosphodiesterases, thereby affecting cAMP phosphorylation of the Ic channel.
• 7.7. Blocking NO synthase markedly decreases LTP following a tetanus in the ciliary ganglion. The possibility is considered that NO is released from the terminal during a tetanus and through altering cAMP phosphorylation of Ic enhances transmitter release.

     

Comparison of the pharmacological response of human corpus cavernosal tissue with the response of rabbit cavernosal tissue

• 1.1. This study directly compares the response of cavernosal tissue obtained from sexually mature rabbits with the response of human corpus cavernosal tissue obtained during implant surgery for psychogenic impotence (five individual samples) to field stimulation and specific autonomic agonists.
• 2.2. At 2 g basal tension, field stimulation of the rabbit corpus cavernosal tissue produced a frequency dependent biphasic response consisting of an initial relaxation followed by contraction. Low frequency stimulation induced primarily relaxations whereas high frequency stimulation induced primarily contractions. FS of human corpus cavernosal tissue induced a frequency dependent contraction.
• 3.3. In general, the rabbit corpus cavernosal strips showed a significantly greater degree of spontaneous activity than the strips of human cavernosal tissue.
• 4.4. Phenylephrine stimulated a rapid and sustained increase in basal tension in both tissues. Although the isolated strips weighed the same, the magnitude of the response of the rabbit tissue was significantly greater than the response of the human tissue.
• 5.5. For both tissues, FS relaxations were completely inhibited by L-NAME showing that the relaxations were mediated by nitric oxide. Similarly, for both tissues, nitroprusside, ATP, and bethanechol induced similar dose-response relaxations of pre-stimulated tissue.
• 6.6. In conclusion, the major difference between the response of human and rabbit tissue to various forms of stimulation was that isolated strips of human corporal tissue responded to FS with contractions at all frequencies whereas the rabbit tissue responded to the relaxations at low frequencies of stimulation; a clear bi-phasic response at intermediate frequencies; and contraction at high frequencies.

     

Dietary ginsenosides improve endothelium-dependent relaxation in the thoracic aorta of hypercholesterolemic rabbit

• 1.1. Endothelium-dependent relaxation to acetylcholine was impaired in aortic rings from cholesterol-fed rabbits as compared to rabbits fed with a control diet.
• 2.2. The dietary treatment of rabbits with ginsenosides did not affect endothelium-dependent relaxation to acetylcholine but did effect the relaxation in cholesterol-fed rabbits.
• 3.3. Dietary treatment of rabbits with ginsenosides did not alter the relaxations to sodium nitroprusside and the contractions to norepinephrine in rings without endothelium from both control and cholesterol-fed rabbits.
• 4.4. Ginsenoside feeding had no significant effect on the plasma lipid levels in both control and cholesterol-fed rabbits.
• 5.5. These results suggest that dietary supplementation of rabbits with ginsenosides improve the endothelium-dependent relaxation to acetylcholine in the aortic blood vessels in cholesterol-fed rabbits. This beneficial effect of ginsenosides feeding cannot be explained by a facilitation of the cyclic GMP effector pathway in the smooth muscle or by an enhanced cholesterol metabolism but may involve an increased production of nitric oxide by endothelial cells.

     

Cellular and Molecular Mechanisms of Nitric Oxide–Induced Heart Muscle Relaxation

• 1.The nitric oxide (NO) donor S-nitro-N-acetyl-penicillamine (SNAP) inhibits Helix aspersa heart activity and relaxes muscles.
• 2.K-free saline and ouabain both depress SNAP-induced relaxation in most experiments, but in a few preparations they either had no effect or potentiated SNAP-induced relaxation.
• 3.Na-K pump reactivation following preincubation in K-free saline leads to the pronounced transient relaxation of heart muscle, the magnitude of which depends on the duration of preincubation.
• 4.0.1 mM SNAP inhibited the ouabain sensitive part of ⁸⁶Rb uptake, which reflects Na-K pump activity. This inhibition is potentiated by phospholipase C.
• 5.SNAP increased cGMP levels in the heart.
• 6.These results indicate that SNAP-induced relaxation depends on Na and Ca gradients across the membrane, which suggests that Na:Ca exchange is involved in the mechanisms of SNAP-induced relaxation. It is postulated that SNAP elicits its inhibitory effect on the heart through a cGMP-dependent Na:Ca exchange.

     

Different roles of endothelium-derived substances on inhibiting platelet aggregation in whole blood

• 1.1. The inhibitory effects of adenosine, nitroprusside (a nitric oxide donor) and prostacyclin on collagen induced rabbit platelet aggregation were studied under two different conditions: in whole blood with an impedance method and in platelet-rich plasma (PRP) with a turbidimetric method.
• 2.2. All substances tested were less potent in whole blood than in PRP, and the differences in IC₅₀ value between whole blood and PRP were not of the same order of magnitude; adenosine (669-fold), nitroprusside (54-fold) and prostacyclin (2-fold).
• 3.3. These results imply that (a) some other, as yet unknown, factors in blood modulate the platelet aggregation; (b) adenosine and nitric oxide act close to the endothelium, and (c) prostacyclin acts as a relatively long lasting circulating hormone.

     

The effect of Lithium on endothelial-dependent relaxation in rat isolated aorta

• 1.1. In endothelium-containing rings of rat aorta, precontracted by phenylephrine, addition of acetylcholine (Ach), resulted in a concentration-dependent relaxation through the release of endothelial dependent relaxing factors, including nitric oxide (IC₅₀ = 8.41 μM).
• 2.2. Pretreatment of the tissues with 20 μM indomethacin, significantly decreased the relaxation.
• 3.3. Preincubation of the preparations in medium solution in which sodium has been partially replaced by 0.5 mM lithium, significantly reduced Ach-induced endothelial dependent relaxation (EDR).
• 4.4. Lithium (2 mM) in medium, significantly increased Ach-induced relaxation.
• 5.5. As is shown in this study, lithium has two opposite actions on EDR, with the dose of 0.5 mM inhibiting, while the dose of 2 mM potentiates EDR. Thus it seems that the action of lithium on EDR is mediated through two separate mechanisms.

     

Physostigmine and modulators of nitric oxide system on the mean arterial pressure of the spontaneously hypertensive rat

• 1.1. A slow intravenous infusion of L-arginine (3 mg kg⁻¹) lasting one hr produced significant hypotension in urethane-anaesthetized spontaneously hypertensive rats (SHRs).
• 2.2. A slow intravenous infusion of N^G-nitro-l-arginine methyl ester (l-NAME) (3 mg kg⁻¹ h⁻¹) did not produce any significant change in the mean arterial pressure during infusion. After stopping infusion of l-NAME, a slowly developing increase of the mean arterial pressure was observed during the following 40 min.
• 3.3. The pressor response to physostigmine (20, 40 and 80 μg kg⁻¹, IV), injected during a slow intravenous infusion of either l-arginine or l-NAME, was not changed.
• 4.4. l-arginine and l-NAME depressed the pressor responses to physostigmine, if physostigmine was injected after the end of a 1-hr infusion.
• 5.5. Acute pretreatment with increasing doses of physostigmine markedly affected the blood pressure response to L-arginine (i.e., L-arginine-caused hypotension was more pronounced), but only slightly that to l-NAME.
• 6.6. In conclusion, l-arginine, as a donor of NO, produced hypotension by itself and also decreased, but not significantly, the central cholinergically-mediated hypertension (CCMH) produced by physostigmine. It is quite possible that the peripheral NO released by l-arginine antagonized the increased adrenergic activity in the CCMH. This does happen in normotensive rats, but to a lesser degree than in SHRs, as shown in the current experiments.
• 7.7. Also, our results show that inhibition of endogenous NO biosynthesis using l-NAME does not necessarily lead to pressor response in vivo, at least in SHRs. It is concluded that l-arginine-nitric oxide pathways operate in SHRs, as well as in normotensive Wistar rats, but their role in modulating cholinergically-mediated regulation of the mean arterial pressure is less pronounced in SHRs than in normotensive animals.

     

Influence of opiate tolerance and calcium channel antagonists on the antinociceptive effects of L-arginine and NG-nitro L-arginine

• 1.1. The antinociceptive effects induced by L-arginine (L-Arg 300–600 mg sc) or N^G-nitro-L-arginine (NOArg 20–70 mg sc) in mice were assessed by the hot-plate test.
• 2.2. The antinociception induced by both agents was antagonized by naloxone. L-Arg significantly reduced the effects of the largest doses of morphine (3, 5, and 10 mg/kg) or pentazocine (7.5, 15, and 30 mg/kg).
• 3.3. Morphine antagonized L-Arg-induced antinociception but did not change the responses to NOArg.
• 4.4. Diltiazem (10 mg/kg) or verapamil (10 mg/kg) decreased L-Arg antinociceptive responses, whereas the effects of NOArg were enhanced.
• 5.5. The antinociceptive effects of L-Arg and NOArg were also tested in mice rendered tolerant to morphine or pentazocine. Whereas the effect of L-Arg were lower in tolerant animals, the responses to NOArg were unchanged.
• 6.6. The results suggest the involvement of opiate mechanisms and NO synthesis in L-ARG-induced antinociception and a lesser influence of opiate mechanisms in the antinociception induced by NOArg.

     

Amplifying effect of serotonin on contractile responses in rat aorta and depletion of intracellular Ca-stores

• 1.1. Serotonin, 1 μM, induces a contractile response in isolated rat aorta in the presence or absence of extracellular Ca.
• 2.2. In Ca-free media, the fast phasic contraction is lower in magnitude and further addition of serotonin evokes no response.
• 3.3. Recovery of the contractile response in Ca-free medium is obtained by a 40 min incubation in Ca-containing solution.
• 4.4. In Ca, Mg-free medium, the response to serotonin is significantly higher than that obtained in the presence of Mg.
• 5.5. An amplifying effect of serotonin on the contractile responses induced by serotonin itself or by noradrenaline was observed in Ca-containing but not in Ca-free solution.

     

Endothelium-derived hyperpolarizing factor does not contribute to the decrease in endothelium-dependent relaxation in the aorta of streptozotocin-induced diabetic rats

• 1.1. We examined the contribution of endothelium-derived hyperpolarizing factor (EDHF) to the impairment of endothelium-dependent relaxation caused by acetylcholine (ACh) in the aorta of streptozotocin-induced diabetic rats, by using N^ω-nitro-l-arginine methylester (L-NAME) and tetraethylammonium chloride (TEA) to inhibit nitric oxide (NO) and EDHF, respectively.
• 2.2. ACh-induced relaxation of the aorta decreased in diabetic rats. In contrast, sodium nitroprusside-induced relaxation was the same in diabetic rats and control rats.
• 3.3. Treatment with 5 × 10⁻⁷ M L-NAME resulted in a right shift of the dose-response curves of ACh-induced relaxation in the aorta. The shift was greater in the control aorta.
• 4.4. Treatment with 5 × 10⁻⁴ M TEA resulted in a similar right shift in both the control and diabetic aorta.
• 5.5. Therefore, while endothelium-derived NO appears to contribute to the impairment of ACh-induced endothelium-dependent relaxation in the aorta of diabetic rats, EDHF does not

.     

Effect of cyproheptadine treatment on conditioned avoidance response in female rats

• 1.1. The percentage of conditioned avoidance response was higher during proestrus compared to diestrus.
• 2.2. Cyproheptadine (CPH) significantly enhanced avoidance behavior during diestrus.
• 3.3. On the other hand, CPH treatment did not alter avoidance behavior during proestrus.
• 4.4. Serum progesterone and testosterone levels were determined at the end of 60 trials for acquisition of conditioned avoidance response after prolonged (12–15 days) CPH treatment (0.5 mg/kg for 24 h per os (p.o.).
• 5.5. Prolonged CPH treatment lowered adrenal testosterone levels, and rats with impaired avoidance had higher testosterone and progesterone levels.
• 6.6. The results of this study indicate a positive role for CPH in the acquisition of avoidance response during diestrus, and a negative effect of progesterone and adrenal testosterone on the avoidance response.