Effects of oxidizing and reducing agents on ovine pulmonary artery responses to nitric oxide donors, sodium nitroprusside and 3-morpholino-sydnonimine.

Nitrovasodilators-sodium nitroprusside (SNP; 10(-9)-10(-4) M) and 3-morpholino-sydnonimine (SIN-1; 10(-9)-10(-4) M) produced concentration-dependent relaxation of the fourth generation sheep pulmonary artery, preconstricted with 5-hydroxytryptamine (1 microM). Oxidizing agents [oxidized glutathione (GSSG, 1 mM) and CuSO4 (5 and 20 microM)] and reducing agents [dithiothreitol (DTT, 0.1 mM), ascorbic acid (1 mM) and reduced glutathione (GSH, 1 mM)] caused opposite effects on nitric oxide (NO)-induced vasodilation in the artery. Ascorbic acid and GSH potentiated the NO responses, while GSSG and CuSO4 inhibited relaxation caused by the nitrovasodilators. DTT, however, reduced the relaxant potency and efficacy of SNP and SIN-1. Pretreatment of the pulmonary artery strips with DTT (0.1 mM) inhibited SNP (10 microM)-induced Na(+)-K(+)-ATPase activity, while ascorbic acid (1 mM) and GSH (1 mM) had no effect either on basal or SNP (10 microM)-stimulated 86Rb uptake, an index of Na(+)-K(+)-ATPase activity, in ovine pulmonary artery. The results suggest that reducing agents like ascorbic acid may have beneficial effect in improving the vascular function under oxidative stress.

Hypothyroid state reduces calcium channel function in 18-day pregnant rat uterus.

Hypothyroidism significantly reduced the mean amplitude and increased the mean frequency of spontaneous rhythmic contractions in 18 day pregnant rat uterus. Nifedipine (10(-12)-10(-9) M) and diltiazem (10(-10)-10(-6) M) caused concentration related inhibition of the myogenic responses of the uterine strips obtained from both pregnant and hypothyroid state. However, nifedipine was less potent (IC50:2.11 x 10(-11) M) in pregnant hypothyroid state as compared to pregnant control (IC50: 3.1 x 10(-12) M). Similarly, diltiazem was less potent (IC50: 3.72 x 10(-9) M) in inhibiting the uterine spontaneous contractions in hypothyroid than in pregnant rat uterus (IC50:5.37 x 10(-10) M). A similar decrease in the sensitivity to nifedipine and diltiazem for reversal of K+ (100 mM)-induced tonic contraction and K(+)-stimulated 45Ca2+ influx was observed with these calcium channel antagonists in uterus obtained from hypothyroid pregnant rats compared to the controls. Nifedipine-sensitive influx of 45Ca(2+)-stimulated either by K+ (100 mM) or by Bay K8644 (1,4-dihydro-2,6-methyl-5-nitro-4-[2'-(trifluromethyl)phenyl]-3-pyridine carboxylic acid methyl ester) (10(-9) M) was significantly less in uterine strips from hypothyroid rats compared to controls. The results suggest that the inhibition of uterine rhythmic contractions may be attributable to a reduction in rat myometrial Ca2+ channel function in the hypothyroid state.

Effects of calcium channel blocker, mibefradil, and potassium channel opener, pinacidil, on the contractile response of mid-pregnant goat myometrium.

The present study was undertaken to investigate the in vitro influence of mibefradil, a calcium channel blocker, and pinacidil, a potassium channel opener, on pregnant goat myometrial spontaneous rhythmic contractility and contractions induced with the agonist, oxytocin. Longitudinal strips from the distal region of uterus, collected from goats at midgestation, were mounted in an organ bath for recording isometric contractions. Mibefradil (10(-8)-10(-4) M) or pinacidil (10(-10)-10(-4) M), added cumulatively to the bath at an increment of 1 log unit, caused concentration-dependent inhibition of the spontaneous rhythmic contractions of isolated uterine strips. The rhythmic contraction was, respectively, abolished at 100 and 10 microM concentrations of mibefradil and pinacidil. In a concentration-dependent manner, mibefradil (1 and 10 microM) antagonized the contractions elicited with oxytocin (10(-5)-10(-2) IU). Pretreatment of uterine strips with glibenclamide (10 microM), a selective KATP channel blocker, caused a rightward shift of the concentration-response curve of pinacidil with a concomitant decrease in its pD2 value. Pinacidil (0.3, 1 and 3 microM), in a concentration-related manner, antagonized the oxytocin (10(-5)-10(-2) IU)-induced contractile response. The inhibition of spontaneous rhythmic contractions and antagonism of oxytocin-induced contraction by mibefradil in the pregnant goat myometrium may be related to the antagonism of voltage-dependent Ca2+ channels, while by pinacidil suggests that KATP channel could be a therapeutic target for tocolysis.

Effect of centrally administered nitric oxide modulators in Brewer's yeast-induced nociception in rats.

Possible modulation of Brewer's yeast-induced nociception by centrally (icv) administered nitric oxide (NO) modulators, viz., NO synthase (NOS) inhibitors, NO precursor, donors, scavengers and co-administration of NO donor (SIN-1) with NOS inhibitor (L-NAME) and NO scavenger (Hb) was investigated in rats. Administration of NOS inhibitors and NO scavenger Hb increased the pain threshold capacity significantly, whereas NO donors SIN-1, SNP and NO precursor L-arginine were found to be hyperalgesic. D-arginine, the inactive isomer of L-arginine and methylene blue, inhibitor of soluble guanylate cyclase failed to alter the nociceptive behaviour in rats. Co-administration of SIN-1 with L-NAME and Hb found to increase the nociceptive threshold. The results indicate, that centrally administered NO modulators alter the nociceptive transmission induced by Brewer's yeast in rats.

Central serotonergic and histaminergic modulation of peripheral inflammation and nociception in rats.

Possible central serotonergic and histaminergic modulation of acute peripheral inflammation was investigated in rats, adopting the formaldehyde-induced acute pedal inflammation as an experimental model. Intracerebroventricular (icv) administration of central inhibitory neurotransmitter, serotonin and its precursor, 5-hydroxytryptophan (5-HTP) attenuated the oedema volume and exudate protein content alongwith augmentation in pain threshold. On the contrary, cyproheptadine, a 5-HT-receptor antagonist and selective serotonin synthesis inhibitor, parachlorophenylalanine (PCPA) produced oedema augmenting and pro-nociceptive effects besides elevating the protein content of the exudate. Centrally administered histamine attenuated pedal oedema, nociception as well as protein concentration in oedema fluid. Cimetidine, an H2 histaminergic receptor blocker did not produce any significant effect on inflammation.

Central noradrenergic and cholinergic modulation of formaldehyde-induced pedal inflammation and nociception in rats.

Possible central noradrenergic and cholinergic modulation of acute peripheral inflammation was investigated in rats, adopting the formaldehyde-induced pedal inflammation as the experimental model. Intracerebroventricularly (icv) administered noradrenaline (NA), alpha-adrenoceptor agonist, L-phenylephrine, alpha-2 adrenoceptor agonist, clonidine and non-selective beta-adrenoceptor blocker, propranolol, suppressed formaldehyde-induced inflammation producing a decrease in oedema volume and increase in pain threshold. Conversely, both noradrenergic neuron degenerator, 6-hydroxydopamine (6-OHDA) and non-selective alpha-adrenoceptor antagonist, phenoxybenzamine produced an increase in paw oedema along with an augmentation of pain. Significant oedema augmenting effects were also produced by central excitatory neurotransmitter, acetylcholine (ACh) on icv administration. ACh also produced pro-nociceptive action. An ACh antagonist, scopolamine and ACh synthesis inhibitor, hemicholinium-3 (HC) reduced pedal oedema and produced analgesia. The results of this study indicate that central NA exerts an inhibitory effect on peripheral oedema and pain whereas, ACh has an augmenting effect on formaldehyde-induced peripheral inflammation.

Effects of adenosine on contractility and 45Ca-uptake in rat urinary bladder.

Effects of adenosine on K+ and ACh-stimulated contractility and 45Ca uptake were studied in the rat urinary bladder smooth muscle and were compared with those of nifedipine. Both adenosine (10(-5) M) and nifedipine (10(-7) M/10(-8) M) significantly inhibited the contractions elicited by K+ (10(-2)-32 x 10(-2) M), Ca2+ (10(-4)-3 x 10(-2 M) in K(+)-depolarized preparations and ACh (10(-9) M-3 x 10(-3) M). Further, adenosine (10(-5) M) significantly (P < 0.05) inhibited K+ (10(-1) M)-stimulated 45Ca-uptake in the bladder strips. However, it had little effect on inward 45Ca movement resulting from ACh (10(-4) M)-induced stimulation. On the other hand, nifedipine (10(-7) M) significantly (P < 0.001) reduced both K+ and ACh-induced 45Ca-uptake in this tissue. It is concluded that the calcium channel blocking action of adenosine is limited to Ca2+ uptake through voltage operated calcium channels, while receptor operated calcium channels activated by muscarinic receptor stimulation appear to be insensitive to the purine.

Effect of nifedipine and dipyridamole on K+ and NA stimulated 45Ca-uptake into rabbit aortic strips.

The effect of dipyridamole (DPM), a purine nucleoside uptake inhibitor, on the K+ and noradrenaline (NA)-stimulated 45Ca-uptake into Rabbit aortic strips was studied and compared with that of nifedipine (NFD). DPM (10(-6) M) significantly (P < 0.02) inhibited 45Ca-uptake in aortic strips stimulated with K+ (10(-1) M). However, it had less significant effect on NA (10(-4) M)-stimulated 45Ca-uptake. The percentage inhibition was 80 and 57 in K+ and NA-stimulated 45Ca-uptake, respectively. Similarly, NFD (10(-7) M) caused significant (P < 0.01, P < 0.05) decrease in K+ (0.060 +/- 0.009) and NA (0.082 + 0.01, mM)-stimulated 45Ca-uptake. The percentage inhibition by NFD was 98 and 64 in K+ and NA-stimulated 45Ca-uptake, respectively. The results suggest that DPM inhibits Ca2+ influx occurring through Voltage Operated Calcium Channels (VOCCs) but it has little effect on Receptor Operated Calcium Channels (ROCCs).

Vascular permeability increasing action of the saline extract of Dictyocaulus filaria--a preliminary report.

The cutaneous hypersensitivity reaction in sheep infected with Dictyocaulus filaria was investigated. The saline extract of the worms increased the cutaneous capillary permeability in both the infected and uninfected control animals. Similar increase in the permeability was also observed in uninfected healthy rabbits. The results suggest that the vascular permeability increasing action of the worm extract is, partly, due to histamine release.

In vitro anthelmintic action of some indigenous medicinal plants on Ascardia galli worms.

Different parts of ten indigenous medicinal plants were screened for their in vitro anthelmintic activity against Ascaridia galli worms of the birds. Preparations from Carica papaya, Sapindus trifoliatus, Butea frondosa and Momordica charantia were more effective than piperazine hexahydrate.