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M J Ryan

Publications and source records attributed to M J Ryan.

At least 19 recordsLinked to original sources
PubMed1992

Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors.

A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.

Animals↗
PubMed1992

Design and synthesis of potent, selective, and orally active fluorine-containing renin inhibitors.

A series of primate renin inhibitors containing difluorocarbinol and difluoroketone groups at the P1-P1' position have been synthesized and studied both in vitro and in vivo. In vitro, the compounds were evaluated as inhibitors of monkey renin and the closely related aspartic proteinase, cathepsin D (bovine), as a measure of enzyme selectivity. Interestingly, the difluoroketone derivatives showed greatly reduced selectivity compared with the corresponding alcohols. However, selectivity could be enhanced by judicious choice of other substituents. Sites influencing selectivity, included not only P2, which is well-known to strongly affect selectivity, but also the P4, P1-P1', and P2' sites. These results make possible the design of inhibitors with a greater selectivity for either renin versus cathepsin D. In vivo several of the compounds in the difluoroketone series have shown good oral activity in the salt depleted normotensive cynomolgus monkey model.

Administration, Oral↗
PubMed1992

Eccentric exercise training as a countermeasure to non-weight-bearing soleus muscle atrophy.

Although various exercise paradigms have been tested, none has completely prevented muscle atrophy during non-weight bearing. Because loaded eccentric contractions occur during normal daily activity but are absent during non-weight bearing, this investigation tested whether eccentric resistance training could prevent soleus muscle atrophy during non-weight bearing. Adult female rats were randomly assigned to either weight bearing +/- intramuscular electrodes or non-weight bearing +/- intramuscular electrodes groups. Electrically stimulated maximal eccentric contractions (4 sets of 6 repetitions at approximately 0.2 fiber lengths/s, 128 degrees range of motion) were performed on anesthetized animals at 48-h intervals during the 10-day experiment. Non-weight bearing significantly reduced soleus muscle wet weight (28-31%) and noncollagenous protein content (30-31%) compared with controls. Eccentric exercise training during non-weight bearing attenuated but did not prevent the loss of soleus muscle wet weight and noncollagenous protein by 77 and 44%, respectively. The potential of eccentric exercise training as an effective and highly efficient counter-measure to non-weight-bearing atrophy is demonstrated in the 44% attenuation of soleus muscle noncollagenous protein loss by eccentric exercise during only 0.035% of the total non-weight-bearing time period.

Adrenal Glands↗
PubMed1992

Call patterns and basilar papilla tuning in cricket frogs. I. Differences among populations and between sexes.

Male cricket frogs (Acris crepitans) produce a broad-band, high frequency advertisement call with a single spectral peak (the dominant frequency). We measured the dominant frequencies of male calls from six populations in central Texas and one from Indiana and compared them to the tuning of basilar papilla afferents in males and females. Averaging over all populations, mean call dominant frequency was 3.69 kHz, mean male basilar papilla tuning was 3.63 kHz, and mean female basilar papilla tuning was 3.17 kHz. Among populations, mean dominant frequency varied from 3.56 kHz to 3.82 kHz. Dominant frequencies were slightly higher in the more eastern Texas populations occupying pine forest habitats than in the more western populations occupying open grassland habitats. Changes in dominant frequency in a population coincided with changes in tuning of both male and female basilar papillae. Furthermore, within populations females were tuned on average lower than males and lower than the mean dominant frequency of calls in their own population. We suggest that the coincident changes in calls and basilar papilla tuning plus the sexual difference in tuning indicate that female mate choice would be directed toward males from her home population with low frequency calls or toward males from foreign populations with average calls lower in frequency than those in her home population. This in turn suggests that any gene flow between populations would be biased from east to west and from forest to open habitats.

Animals↗
PubMed1992

Call patterns and basilar papilla tuning in cricket frogs. II. Intrapopulation variation and allometry.

We determined the influence of body size on the male advertisement call's dominant frequency and basilar papilla's (BP) tuning in male and female cricket frogs (Acris crepitans) in two Texas populations (Wimberley and Stengel Ranch). In both populations, call and tuning characters correlated negatively with body size; females were larger than males and their BPs were tuned to a lower frequency. Analysis of covariance showed that neither the sex difference in tuning nor the population differences in calls or tuning were due to the difference in body size alone, but instead represented differences in the allometric relationships of each character with body size. The analysis implied that differences between sexes or populations were due more to shifts in the Y-intercept rather than the slope of the relationship with body size. This suggests a developmental model in which sexes or populations possess resonant structures in the ear or larynx with similar growth rates but different starting points or initial growth phases, resulting in different frequency characteristics as adults. The examination of the relationship between female BP tuning and male call dominant frequency predicts potentially different patterns of sexual selection in the two populations, with the Wimberley population males subject to much greater directional selection for low frequency calls.

Animals↗
PubMed1991

N6-substituted adenosine receptor agonists: potential antihypertensive agents.

Adenosine is known to exert a wide range of pharmacological effects including hypotension. This effect of adenosine suggested that modified analogues of adenosine might provide useful antihypertensive agents. Thus, we prepared a series of novel N6-benzocycloalkyladenosines and studied their receptor binding and antihypertensive activity. The structure-activity relationship study shows that the adenosine analogues having the hydrophobic phenyl moiety one carbon away from the C6-nitrogen have modest affinity and selectivity for the A1 receptor, whereas those with the phenyl moiety two carbons away from the C6-nitrogen have excellent affinity and selectivity for the A1 receptor. Many of these analogues showed excellent antihypertensive activity with a wide range of effects on heart rate. There is no direct correlation between the receptor binding affinities and antihypertensive activity; however, it is more closely associated with A1 than A2 affinity. The bradycardic effect of these agonists seems to be due to the A1 affinity. From this set, compound 3 was further evaluated in secondary antihypertensive screens. It lowered the blood pressure dose dependently with effects lasting for over 20 h following administration of a 30 mg/kg dose. Compound 3 was also effective in lowering blood pressure in a renal hypertensive rat model. Thus, appropriately modified N6-substituted adenosines represent a novel class of antihypertensive agents.

Adenosine↗
PubMed1991

Development of a high renin model of hypertension in the cynomolgus monkey.

Hypertension was produced in cynomolgus monkeys by reducing blood flow to the left kidney by 60% via renal artery stenosis (2-kidney, 1-clip). Significant increases in mean arterial blood pressure (MABP) were observed within two to three weeks. Maximum increase (from 95 +/- 6 mmHg to 130 +/- 7 mmHg) occurred at about four to six weeks following renal artery stenosis and was sustained for more than 24 weeks. Plasma renin activity (PRA) was elevated concomitantly with the increase in MABP. PRA was raised to 42 +/- 3 ng angiotensin I/ml/hr six weeks after renal artery stenosis from a control PRA of 3 +/- 0.7 ng angiotensin I/ml/hr. At six months post renal artery stenosis, PRA was 33.4 +/- 4.2 ng angiotensin I/ml/hr. The angiotensin II (AII) receptor antagonist saralasin, the angiotensin I converting enzyme inhibitor captopril, and the renin inhibitor CGP 38,560 produced sustained reductions in MABP. The antihypertensive response to the renin inhibitor CGP 38,560 was associated with a reduction in PRA of greater than 99%, and a greater than 90% reduction in immunoreactive AII. These studies demonstrate that high-renin hypertension can be induced in the cynomolgus monkey. This pathological model provides a useful method for investigating the antihypertensive effects of agents which antagonize the renin-angiotensin system in a nonhuman primate.

Angiotensin II↗
PubMed1990

Sexual selection for sensory exploitation in the frog Physalaemus pustulosus.

The sensory bases of species and population mate preferences are well known; in frogs properties of the female auditory system influence such preferences. By contrast, there is little understanding of how sensory characteristics could result in sexual selection within a population. One possible mechanism is that females are more sensitive to male courtship signals that deviate from the population mean. We document this mechanism in the frog Physalaemus pustulosus. Female basilar papilla tuning is biased toward lower-than-average frequencies in the 'chuck' portion of the male's call, explaining female preference for the lower-frequency chucks produced by larger males. The tuning does not differ between P. pustulosus and its close relative P. coloradorum, a species in which males never evolved the ability to produce chucks; thus the female tuning evolved before the chuck and therefore the chuck played no role in the evolution of the preference. This allows us to reject two popular hypotheses for the evolution of this female preference (runaway sexual selection and natural selection) in favour of a third: sexual selection for sensory exploitation.

Animals↗
PubMed1990

Peroxyl radical-dependent epoxidation of cyclopenteno[c,d]pyrene.

We have reported previously that cyclopenteno[c,d]pyrene (CPP), an environmentally prevalent polycyclic aromatic hydrocarbon, is activated as a bacterial mutagen by several model systems which generate peroxyl radicals. In this report we present our findings on the chemical fate of CPP in these activating systems. The peroxyl radical systems employed are microsomal prostaglandin H synthase and arachidonic acid, the hematin-catalyzed decomposition of a lipid hydroperoxide, and the autoxidation of the sulfite anion. Reverse-phase HPLC analysis of stable products of CPP metabolism yielded qualitatively identical profiles from the first two systems. The three major products from these systems were analyzed by UV/visible and fluorescence spectroscopy, and a mass spectrum was obtained for the most abundant product. Based on these spectral analyses and on chromatographic behavior, the three products were identified as the cis- and trans-isomers of 3,4-dihydroxy-3,4-dihydro-CPP and 4-keto-(3H)-CPP. The identities of these products and their quantitative distributions relative to the epoxide hydrolase activities present in the microsomal system and the hematin system clearly establish 3,4-epoxy-CPP as the key intermediate and probable active mutagen generated in the peroxyl radical-dependent metabolism of CPP. This epoxidation of the activated aliphatic double bond of CPP extends the known range of peroxyl radical-dependent oxygenations by demonstrating the direct, one-step activation of a carcinogenic, environmentally relevant hydrocarbon. Strikingly different results are obtained in the sulfite-dependent system. The epoxide-derived metabolites seen with the peroxyl radical systems are very minor products. Instead, two product peaks elute near the solvent fron on reverse-phase HPLC. These are apparently monohydroxy-CPP sulfonates. Such products may form either by the direct addition of the sulfite anion radical to the activated double bond of CPP or by peroxyl radical-dependent epoxidation of CPP followed by nucleophilic addition of sulfite. Precedent for both of these reactions has been reported with analogous benzo[a]pyrene derivatives. The occurrence of these radical-dependent transformations in intact mammalian systems has not been investigated, but the ability of all three model systems employed to convert CPP to potent bacterial mutagens implies that these pathways should be studied further.

Animals↗
PubMed1990

Sulfite enhancement of diolepoxide mutagenicity: the role of altered glutathione metabolism.

Sulfur dioxide is a cocarcinogen for benzo[a]pyrene in the respiratory tract of rats and hamsters. Sulfur dioxide exists under physiological conditions as the sulfite ion. Sulfite enhances the mutagenic potency of (+-)-7r,8t-dihydroxy-9t,-10t- epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) and 7r,8t-dihydroxy-9c10c-epoxy-7,8,9,10-tetrahydrobenzo[a]py ren e (syn-BPDE) in Salmonella typhimurium strains TA98 and TA100. This enhancement of diolepoxide mutagenicity is observed with sulfite concentrations between 1 and 20 mM, and the concentration dependence is identical for the two diolepoxides. Half-maximal enhancement of mutagenicity occurs at approximately 5 mM sulfite. Sulfite is neither toxic nor mutagenic to the bacteria under these conditions. The enhancement of diolepoxide mutagenicity requires that the bacteria be exposed to sulfite prior to the addition of the diolepoxide. Simultaneous addition of sulfite and diolepoxide significantly decreases the enhancing effect, and addition 15 min after the diolepoxide virtually abolishes the effect. This is consistent with sulfite serving to increase the efficiency of processes leading to DNA modification by the diolepoxides, rather than some effect subsequent to DNA adduct formation. Direct evidence for this hypothesis was provided by determining the effect of sulfite on mutagenicity and DNA binding in TA98 using [3H]anti-BPDE. Exposure of the bacteria to 10 mM sulfite for 5 min prior to the addition of the labeled mutagen led to as much as 170% increase in DNA binding levels relative to parallel incubations without sulfite. Corresponding increases in mutagenicity were seen as well. As sulfite can affect the glutathione/glutathione-S-transferase systems, the primary cellular defense against BPDE, the effect of sulfite on these pathways in Salmonella was determined. When strain TA98 was treated with N-acetoxy-2-acetamidofluorene, a direct-acting mutagen not scavenged by glutathione, prior addition of 10 mM sulfite to the bacteria had no effect on resultant viability or mutagenicity. Assessment of the bacterial glutathione levels revealed that 10 mM sulfite treatment results in an 82% decrease in the concentration of the cosubstrate. We were, however, unable to detect diolepoxide-glutathione conjugates in any of our incubations. Moreover, the presence of sulfite leads to significant trapping of the diolepoxide in the form of sulfonate derivatives. Based on these data, we conclude that the depletion of glutathione does indeed play a role in the enhancement of diolepoxide mutagenicity in S. typhimurium.(ABSTRACT TRUNCATED AT 400 WORDS)

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1988

Metabolic activation of cyclopenteno[c,d]pyrene by peroxyl radicals.

The conversion of cyclopento[c,d]pyrene (CPP) to forms which are mutagenic to Salmonella typhimurium strain TA98 has been demonstrated in systems which generate peroxyl radicals. The systems examined included prostaglandin H synthase (PHS) and arachidonic acid, 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid (15-HPETE) and hematin, and the autoxidation of the sulfite ion. In all cases concentration-dependent activation of CPP was observed at hydrocarbon concentrations between 10 and 100 microM. Neither CPP nor the peroxyl radical systems alone were mutagenic or toxic to the tester strain. The use of hydroxygen peroxide with PHS, a peroxidative system which does not yield peroxyl radicals, does not activate CPP. The involvement of a CPP epoxide was examined using 1,1,1-trichloropropene-2,3-oxide. Addition of this epoxide hydrolase inhibitor to incubations of CPP with the PHS/arachidonic acid system resulted in a 210% increase in induced revertants relative to the system in the absence of the inhibitor. The addition of pure rat liver microsomal epoxide hydrolase to incubations of CPP with the 15-HPETE/hematin system resulted in a concentration-dependent loss of mutagenicity, further supporting the intermediacy of an epoxide. The site of metabolism of CPP is the cyclopenteno double bond based on the formation of products which display distinct pyrene-type fluorescence spectra. The involvement of the cyclopenteno double bond also is shown by the inability of the 15-HPETE/hematin system to activate 3,4-dihydrocyclopenteno[c,d]pyrene as a mutagen. CPP is the first environmentally-relevant carcinogenic hydrocarbon found to be activated directly by peroxyl radical systems without prior biotransformation to a diol derivative by the cytochrome P-450 system. These findings expand the range of potentially toxic substrates to be considered for activation by peroxyl radical pathways.

Animals↗
PubMed1988

A method of detecting oesophageal intubation or confirming tracheal intubation.

A method of testing the location of an endotracheal tube, in the trachea or oesophagus, was subjected to trial. The test involves drawing back on the plunger of a 50 ml syringe connected with airtight fittings to the endotracheal tube connector, with the endotracheal tube cuff deflated. The ability to withdraw 30 ml of air confirms tracheal intubation. When marked resistance to withdrawal of the plunger occurs and on release the plunger rebounds to its original position the oesophagus has been intubated. The method was 100% accurate in fifty intubations, 25 tracheal and 25 oesophageal. The technique has been in routine use by one author for several years without giving an incorrect answer and enthusiastic use by other authors is producing the same result.

Adult↗
PubMed1987

The clinical importance of subnormal folate levels in epileptic patients on anticonvulsant therapy.

A neurological theory was obtained and examination performed on 62 outpatient epileptics on anticonvulsant therapy. Blood counts, folate and B12 assays were performed on all patients and on a control group of 59 adult non-epileptic neurological outpatients. None of the anticonvulsant treated group had clinical peripheral neuropathy; there was one patient with microcytic anaemia and one with normochromic, normocytic anaemia. In 5 of this group the mean corpuscular volume (MCV) was slightly raised but there was no significant overall difference from the control group. In 17 patients serum folate was subnormal and in 7 the red cell folate was subnormal and this was significantly different to the control group (P less than 0.001). Vitamin B12 levels were normal in all subjects. It is concluded that despite subnormal measured folate levels, there is no increased incidence of clinical peripheral neuropathy or of significant macrocytosis. In view of this, we recommend that folate replacement should not be given to non anaemic asymptomatic patients, with subnormal folate levels, on anticonvulsant therapy.

Adolescent↗
PubMed1986

Gastrointestinal bleeding in competitive runners.

Competitive runners have been shown to develop previously undescribed clinical conditions, including "runner's anemia." This has been shown to be an iron-deficiency anemia of several etiologies including gastrointestinal bleeding. Although 8-23% of runners have been shown to have guaiac-positive stools after a marathon, the incidence of significant and prolonged bleeding is unknown. We report four cases of competitive runners with iron-deficiency anemia, gastrointestinal bleeding coinciding with running, and no definitive gastrointestinal pathology despite extensive evaluation.

Adult↗
PubMed1986

Synchronized calling in a treefrog (Smilisca sila). Short behavioral latencies and implications for neural pathways involved in call perception and production.

A neotropical treefrog, Smilisca sila, exhibits an unusual ability to synchronize its calling with that of neighbors such that calls often overlap temporally. Call playback experiments measured the latency to evoked calling in response to one-note and two-note mating calls. Approximately one-half of the responses overlapped the one-note stimulus call, while 20% overlapped the two-note stimulus call. Minimum response latencies were 55 ms and 78 ms in response to the one-note and two-note calls, respectively. These data were used to evaluate the efficacy of proposed neural pathways involved in call recognition and production. Based on neural and behavioral latencies presented in those studies, it is suggested that the proposed pathways for call recognition and production might not accommodate the short behavioral latencies in S. sila. One possible explanation for this discrepancy is that call detection is decoupled from call recognition, the former requiring a shorter neural pathway thus permitting a shorter behavioral latency.

Animals↗