Biomedical subjects

A A Laniyonu

Publications and source records attributed to A A Laniyonu.

11 recordsLinked to original sources

PubMed1997

Endotoxin-induced microvascular leakage is prevented by a PAF antagonist and NO synthase inhibitor.

The hamster cheek pouch was used to determine the role of platelet activating factor (PAF) and nitric oxide (NO) in leukocyte adhesion and microvascular leakage of FITC-dextran following systemic administration of endotoxin. Endotoxin (5 mg/kg, i.v.) or vehicle was administered to the hamster 15 min after systemic pretreatment with either a PAF antagonist (Abbott-87648, .1 mg/kg, i.v.) or a nitric oxide synthase inhibitor (L-NAME, 30 mg/kg, i.v.), or 60 min after dexamethasone pretreatment (4 mg/kg, i.p.). Endotoxin alone caused rapid leakage of FITC-dextran from the vascular compartment into the tissue. This leakage was not preceded by either increased leukocyte rolling or adhesion in postcapillary venules. Pretreatment with the PAF antagonist, as well as with dexamethasone, completely blocked endotoxin-induced leakage. L-NAME also blocked endotoxin-induced leakage; however, more than 50% of the hamsters treated with L-NAME died within 2 h after endotoxin administration. These results suggest that PAF and NO are important mediators of microvascular leakage during endotoxemia and that their actions are not dependent on leukocyte adhesion to postcapillary venular endothelium.

Animals↗

PubMed1995

Vascular actions of thrombin receptor-derived polypeptides: structure-activity profiles for contractile and relaxant effects in rat aorta.

1. Using endothelium-denuded and intact rat aortic rings, we have determined the contractile and relaxant structure-activity profile for a series of thrombin receptor-derived polypeptides (TRPs) based on the human and rat receptor sequences: SFLLR (P5), SFLLR-NH2 (P5-NH2) SFFLR (Rat P5), SFFLR-NH2 (Rat P5-NH2), SFLLRNP (P7), SFLLRNP-NH2 (P7-NH2), SFFLRNP (Rat P7), SFFLRNP-NH2 (Rat P7-NH2), and SFLLRNPNDKYEPF (P14). 2. A contractile response to thrombin and the TRPs in the endothelium-denuded aortic tissue was minimal or absent in preparations obtained from animal weighing less than 180 g (< 6 weeks of age), but increased with animal size, plateauing in tissues derived from animals weighing between 320 and 420 g (about 9 to 14 weeks of age). In contrast, the contractile responses to KCl and noradrenaline did not differ in the tissues and relaxant responses to the TRPs in endothelium-intact aortic preparations were comparable for tissues obtained from either young (< or = 180 g) or older (> or = 320 g) animals. 3. The contractile response of the endothelium-denuded preparation to thrombin and the TRPs showed marked cross-desensitization: the relaxation response of the intact rings did not desensitize to the TRPs. 4. The relative potencies for the TRPs in the aortic contraction assay were comparable to those for the relaxation assay, but were distinct from the relative potencies we measured previously in a rat gastric longitudinal muscle contraction assay. Further, P5 behaved as a partial agonist in the aortic contraction assay, whereas it had been observed to be a full agonist in the gastric contraction assay. 5. The contractile activity of P5-NH2 in endothelium intact aortic rings was low or absent, but in the presence of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME), the contractions in the intact preparation were equivalent to the response of the endothelium-denuded preparation in the absence of L-NAME.6. The contractile response of the endothelium-denuded aortic preparation to P5-NH2 was inhibited by nifedipine and the kinase C antagonist, chelerythrine, but was resistant to the action of indomethacin,tetrodotoxin and the tyrosine kinase inhibitor, genistein.7 We conclude that the receptor system for the TRPs in the aortic smooth muscle elements, responsible for the contractile response, is similar to the aortic endothelial cell receptor responsible for the relaxation response, but is distinct from the receptor that we have previously characterized in gastric longitudinal smooth muscle, results pointing to the presence of receptor subtypes in the vascular and gastric smooth muscle elements.

Amino Acid Oxidoreductases↗

PubMed1994

Tyrosine kinase inhibitors and the contractile action of G-protein-linked vascular agonists.

In a porcine coronary artery helical strip preparation, the tyrosine kinase inhibitors genistein and tyrphostin (AG82) attenuated the contractile actions of angiotensin II, arginine vasopressin, epidermal growth factor--urogastrone, noradrenaline, and prostaglandin F2 alpha, under conditions where contractions due to acetylcholine and KCl were not affected. Both genistein and tyrphostin also caused a selective inhibition of angiotensin II action in rat aorta helical strips, without affecting KCl-mediated contractions. The IC50 values for the inhibition of contraction in the porcine coronary artery were in the range of 2-5 microM for genistein and 8-15 microM for tyrphostin. Comparable IC50 values were observed for the inhibitory effects of genistein on angiotensin II and prostaglandin F2 alpha action in the rat aorta, whereas much higher tyrphostin concentrations (IC50 > or = 40 microM) were required to block angiotensin II action in this preparation. Angiotensin II caused an elevation of phosphotyrosyl protein (antiphosphotyrosine Western blot) in the porcine coronary artery, which was reversed by genistein. In addition, porcine coronary artery derived membrane and cytosolic fractions exhibited sarcoma virus related tyrosine kinase activity, which was inhibited by both genistein and tyrphostin. Our data (i) document the selective inhibition by genistein and tyrphostin of the contractile action of some, but by no means all, G-protein-linked vascular agonists in porcine and rat arterial preparations, (ii) establish the presence of sarcoma virus related tyrosine kinase activity in the porcine coronary artery, and (iii) demonstrate angiotensin II mediated increases in phosphotyrosyl protein content in porcine coronary artery tissue. These data support the hypothesis that selected G-protein-linked contractile vascular agonists may act in part via the stimulation of nonreceptor tyrosine kinases. The data also indicate the complex actions of the tyrosine kinase inhibitors, even for the same agonist acting in vascular preparations obtained from different species.

Animals↗

PubMed1993

Role of the amino- and carboxyl-terminal domains of thrombin receptor-derived polypeptides in biological activity in vascular endothelium and gastric smooth muscle: evidence for receptor subtypes.

Using guinea pig gastric longitudinal muscle (GLM) and rat gastric longitudinal muscle (RLM) contractile assays and a rat aortic ring (RA) endothelium-dependent relaxation assay, we have examined the biological activities of a number of human and rat thrombin receptor-derived polypeptides (TRPs) modified at amino-terminal and carboxyl-terminal residues. Our study focused primarily on the human pentapeptide [S42FLLR46 (P5)], previously shown to retain full thrombin-like activity. Whereas N-acetylation (N-acetyl-P5) abolished biological activity in the GLM and RA assays, amidation or esterification of the carboxyl-terminal carboxyl group [P5-NH2, P5-OCH3, or S42FLLRNP48-NH2 (P7-NH2)] enhanced peptide potency by about 10-fold in both the GLM and RA assays, compared with the unmodified TRPs (P5 and P7). Removal from P5 of either the amino-terminal hydroxyl group of serine (to yield A42FLLR46) or both the amino-terminal hydroxyl group and the primary amino group of P5 [to yield propionyl-F43LLR46 (Pr-P4)] produced peptides that were active in both the GLM and RA assays. Substitution of the carboxyl-terminal guanidinium group of P5 with a less basic primary amino acid residue (S42FLLK46) resulted in a peptide with a lower potency than that of P5 in the GLM and RA assays, whereas substitution of D-arginine for L-arginine at the carboxyl terminus abolished biological activity. Substitution of norleucine for arginine (S42FLLNorleuN) resulted in a peptide active in the GLM but not in the RA assay. For selected agonists (Pr-P4, P5, P7, and P7-NH2), the potencies in the GLM and RA assays, relative to that of P5, differed; for the GLM the order was P7-NH2 > P7 > P5 congruent to Pr-P4, whereas for the RA the order was P7-NH2 > or = Pr-P4 >> P5 > or = P7. Data comparable to those obtained with the GLM assay were also obtained with a RLM assay, wherein the potency series was P7-NH2 > P7 > P5. The relative potencies of pentapeptides based on the rat receptor sequence [SFFLR (Ra-P5), SFFLR-NH2 (Ra-P5-NH2), and SFFLRNP (Ra-P7)] differed in the RLM and RA assays. In the RLM the order was Ra-P5-NH2 > P7-NH2 > P5-NH2 > Ra-P7 = P7 > P5 = Ra-P5, whereas in the RA the relative potency series was P7-NH2 > P5-NH2 > Ra-P5-NH2 > Ra-P7 > P5 > or = P7 > Ra-P5.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1992

Action of thrombin receptor polypeptide in gastric smooth muscle: identification of a core pentapeptide retaining full thrombin-mimetic intrinsic activity.

We have used a guinea pig gastric longitudinal (LM) smooth muscle bioassay system to evaluate the contractile activities of a previously described thrombin receptor-derived polypeptide, S42FLLRNPNDKYEPF55 (one-letter amino acid code) (TRP42-55) and of a series of peptides derived from this sequence. The contractile activities of the polypeptides were compared with the actions of thrombin. Shortened peptides of the sequences S42FLLRNPND50, S42FLLRN47, and S42FLLR46 (TRP42-46) all exhibited contractile activities that were equivalent to or greater than those of the parent polypeptide, TRP42-55. Both TRP42-55 and TRP42-46 mimicked the action of thrombin, in terms of two different signal transduction pathways that were activated either in the LM preparation or in the related but distinct gastric circular muscle assay. In the LM preparation, the peptide FSLLR also exhibited appreciable, but much reduced, activity. Minimal activity was exhibited in the LM by the sequence SFLLA, but the lysine-containing analogue S42FLLK46 was about one fifth as potent as TRP42-46. In contrast, the receptor-derived sequences S42FLL45, S42FL44-NH2, F43LLR46, and S42ALLR46, as well as arginine-containing polypeptides beginning with the SF motif, SFRG and SFRGHITR, were inactive in the LM bioassay system, at concentrations of greater than or equal to 200 microM, as either agonists or antagonists against TRP42-55. In addition to its actions in the LM and circular muscle preparations, the active pentapeptide, TRP42-46, also exhibited thrombin-mimetic intrinsic activity in a rat aortic arterial ring relaxation bioassay, whereas the pentapeptide S42FLLA46 and the tetrapeptide S42FLL45 were inactive. We conclude that the intrinsic biological activity of the thrombin receptor-derived peptide resides in the pentapeptide TRP42-46 and that the phenylalanine and arginine residues at positions 43 and 46 play key roles in the activity of this pentapeptide in smooth muscle systems.

Amino Acid Sequence↗

PubMed1989

Naloxone-insensitive inhibitory and excitatory effects of opioid agonists in the rat isolated uterus.

Morphine (3 x 10(-6)-10(-3) M) produced a concentration-dependent inhibition of both spontaneous rhythmic contractions and tonic contraction induced by potassium chloride (KCl) (50 mM) in rat isolated uterus. Uteri at the metoestrus phase were the most sensitive to the inhibitory effect of morphine. Morphine-induced relaxation was characterized by a post-wash tonic contraction. The mu-specific opioid agonist, D-alaglymepheglycol (DAGO) (4 x 10(-8)-1.2 x 10(-5) M) did not affect spontaneous rhythmic contraction but produced a partial inhibition of the KCl depolarized uterus. There was no post-wash contraction following DAGO. In contrast to the inhibition produced by both morphine and DAGO, methionine enkephalin (8 x 10(-7)-2.4 x 10(-5) M) produced a concentration-dependent contraction of the KCl depolarized uterus. Naloxone up to 100 microM, propranolol (10 microM), flurbiprofen (50 microM) and metiamide (10 microM) did not affect either the relaxation produced by morphine and DAGO or the contraction produced by methionine enkephalin. The results showed that the opioid agonists may have non-receptor mediated direct effects on the rat uterus.

Animals↗

PubMed1986

Interaction by bendrofluazide with acetylsalicylic acid.

The effects of aspirin and bendrofluazide alone and in combination were studied on the diuresis, natriuresis, kalliuresis and excretion of salicylates in normal human volunteers. The simultaneous administration of both drugs in a sequence of aspirin-bendrofluazide was accompanied by a reduction in the kalliuretic effect of aspirin without any significant effects on the natriuresis, kalliuresis and diuresis induced by bendrofluazide. Concomitant administration of both drugs produced marked increases in the amount of salicylate excreted over the experimental session, being highest (58.3%) with an aspirin-bendrofluazide sequence, and lowest (30.3%) when injected simultaneously (suggesting antagonism by bendrofluazide). The results suggest interference by bendrofluazide with the excretion of salicylate but not vice versa.

Adult↗

PubMed1984

Interaction between frusemide and aspirin.

The effects of the combination of aspirin and frusemide were studied on salicylate excretion by aspirin and on the diuresis and excretion of K+ and Na+ by frusemide in normal human subjects. There was a paradoxical net reduction in the natriuresis induced by aspirin, from 29.4 +/- 3.57 m-equiv and frusemide from 31.9 +/- 1.27 to 23.7 +/- 1.56 m-equiv on combined administration. Frusemide caused a reduction of the kalliuretic effect induced by aspirin from 48.86 +/- 8.36 to 18.3 +/- 3.76 m-equiv. The amount of salicylate excreted over a 3-hr period gave increases of 9.6 and 12.0% when aspirin was administered before frusemide and vice versa, respectively, while there was a 30.4% reduction when administered concomitantly.

Adult↗

PubMed1984

Effects of p-chlorophenylalanine on the sensitivity of rat intestine to agonists and on intestinal 5-hydroxytryptamine levels during Nippostrongylus brasiliensis infection.

Infection of rats with the nematode N. brasiliensis caused non-specific increases in maximum response of isolated intestine to acetylcholine and 5-hydroxytryptamine (5-HT), and a specific subsensitivity to 5-HT. Intestinal levels of 5-HT, measured fluorimetrically, increased approximately 2 fold during infection. Treatment of infected rats with parachlorophenylalanine (PCPA) depleted the gut of 5-HT, and prevented the specific subsensitivity to the amine but not the increases in maximum response. Depletion of intestinal 5-HT did not prevent the immune expulsion of the parasites. It is concluded that the specific subsensitivity of the gut is due to the elevated levels of 5-HT during infection, but that the increased maximum responses are due to some other factor. Further, the lack of effect of PCPA on parasite rejection casts doubt on the proposed role of 5-HT in this process.

Acetylcholine↗

PubMed1984

Studies on the contributive effects of the different constituents of cow's urine concoction in rats (Part I).

The effects of cow's urine concoction (CUPR) and of the concoction in distilled water (CUPRw) were assessed on convulsion and the effects of each of the constituents in cow's urine or distilled water was also assessed. The basic procedure involved was observing for convulsion, the time of its occurrence and its duration, and time for recovery or death following the administration of the concoction and each of its constituents in distilled water or cow's urine. The results showed that the CUPR paradoxically induced convulsion while the CUPRw did not. Of the individual constituents (in either medium) tobacco gave appreciable results on the convulsion, thus suggesting that it is the active ingredient. In instances where convulsion was recorded, its onset and duration followed with or without death, is a function of the dose employed. The administration of cow's urine and some of the constituents alone produced no remarkable results, though when given in randomized combination some significant findings were recorded. It is suggested that the possibility of interaction between the various constituents is high and that there is a differential solubilization of the constituents in the media, thus bringing about qualitative and quantitative differences in the observations. The claim by the herbalists that the concoction is effective in eliminating convulsions is questionable as we observed that the concoction obtained from three different herbalists did not protect against strychnine-induced convulsion.

Animals↗

PubMed1984

Studies on the contributive effects of the different constituents of cow's urine concoction in rats (Part II).

The effects of cow's urine concoction (CUPR) with cow's urine as the diluting medium and of the same concoction with distilled water as the diluting medium (CUPRw), together with each of the constituents in both media were assessed on such parameters as reaction to spinal cord reflexes e.g. startle, nociception and righting, limb abduction, locomotor anomaly and limb paralysis. The basic procedure involved eliciting the spinal reflexes under the influence of the concoction and its constituents and recording the presence or absence of the reflexes. In addition, the accompanying musculoskeletal defects were recorded. The results showed that the CUPR affected all the parameters positively while the CUPRw also had positive effects on the parameters with the exception of response to startle reflex. It was tobacco leave alone that gave appreciable results on all the parameters, suggesting that it is the active ingredient. Cow's urine alone gave no appreciable results, neither did the administration of some other constituents of the concoction in distilled water or cow's urine affected the parameters appreciably. As was observed for convulsion in our previous report, there seems to be an interaction between the constituents of the concoction as far as effects on righting reflex were concerned. No interaction seems to result on the observations for the startle reflex and musculoskeletal observations. There was also a qualitative difference between the concoction in the two media on righting reflex. While CUPR caused a loss of righting reflex at 3 ml/kg body weight and above, CUPRw at doses twice as high did not affect the righting reflex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗