The dipeptide carnosine constricts rabbit saphenous vein as a zinc complex apparently via a serotonergic receptor.

1. The endogenous dipeptide carnosine (beta-alanyl-L-histidine), at 0.1-10 mM, provokes sustained contractures in rabbit saphenous vein rings with greater efficacy than noradrenaline (NA). 2. The effects of carnosine are specific; anserine and homocarnosine are ineffective, as are carnosine's constituent amino acids histidine and beta-alanine. 3. Maximum carnosine-induced tension is enhanced by Zn ions (e.g. to 127.5 +/- 13.1% of control at 10 microM total Zn concentration, Zntot) and the sensitivity to carnosine potentiated (mean [carnosine] required for half-maximal tension, K1/2, reduced from 1.23 mM to 17.0 microM carnosine with 15 microM Zntot). 4. The dipeptide apparently acts as a zinc-carnosine complex. The effects of carnosine at concentrations of 1 microM to 10 mM in the presence of 1-100 microM Zntot, can be described as a unique function of the concentration of Zn-carnosine, with an apparent K1/2 for the complex of 7.4 x 10(-8) M. 5. Contractures are reduced at low [Ca2+], unaffected by adrenoceptor antagonists, but can be blocked by serotonergic receptor antagonists including ketanserin and methiothepin. 6. Competition between albumin and carnosine for Zn ions, as might occur in plasma, can be demonstrated experimentally. 7. The mode of action of carnosine is virtually unique: a vascular muscle receptor apparently transduces the action of a dipeptide in the form of a metal chelate.

The relationship between the adrenoceptor and nonadrenoceptor-mediated effects of imidazoline- and imidazole-containing compounds.

This article brings together work on imidazoline or imidazole-containing compounds concerned with the pharmacology of alpha-adrenoceptors, principally on smooth muscle, to illustrate how imidazolines have contributed to the subclassification of alpha-adrenoceptors and how, against this background, attempts have been made to use this knowledge to uncover "nonadrenoceptor"-mediated biological effects of previously uncharacterized compounds, notably imidazole-containing dipeptides and "clonidine displacing substance" (CDS). Recent data are included on (1) the pharmacology of UK-14304, (2) nonadrenoceptor actions of phentolamine, (3) the pharmacology of tissue extracts containing imidazole-containing dipeptides and CDS activity, and (4) ligand binding data at I1 and I2 sites.

Extracellular ATP can activate autonomic signal transduction pathways in cultured equine sweat gland epithelial cells.

Changes in intracellular free calcium concentration ([Ca2+]i) were monitored in a cell line that was derived from the equine sweat gland epithelium. ATP and closely related compounds could increase [Ca2+]i with a rank order of potency of UTP > or = ATP > ADP >> AMP = adenosine = alpha,beta-methylene-ATP. The responses to ATP and to UTP were initiated by the release of calcium from an internal store and subsequently sustained by calcium influx. The rise in [Ca2+]i thus seems to be mediated by P2U receptors that are coupled to phosphoinositidase C. Some desensitisation of this response developed during repeated stimulation with ATP and this was blocked by staurosporine, an inhibitor of protein kinase C, and augmented by a phorbol ester which acts as an exogenous activator of this enzyme. A protein-kinase-C-dependent inhibitory pathway thus seems to become active during repeated stimulation with ATP. ATP and related compounds could also raise cellular cyclic AMP content. The order of potency was ATP > ADP = AMP = adenosine >> UTP, suggesting that this response is mediated via a separate subclass of P2 receptor. The present results demonstrate that ATP can activate autonomic signal-transduction pathways in cultured equine sweat gland cells and suggest that there may be a purinergic component to the control of secretory activity in the equine sweat gland.

Analysis of novel imidazoles from isolated perfused rabbit heart by two high-performance liquid chromatographic methods.

The paper reports two analytical high-performance liquid chromatographic methods to detect and quantify cardiac-derived histidyl derivatives. Method A relies on relative hydrophobicities as a basis of separation. Method B is an ion-pairing method in which the compounds are eluted in an entirely different order. Fractions collected from method A have been co-eluted in admixture in method B with authentic reference compounds. Thus the existence of the following imidazole ring-containing compounds derived from heart have been confirmed: N-acetylhistidine, N-acetyl-1-methylhistidine, N-acetylcarnosine, N-acetylhomocarnosine, homocarnosine, anserine, carnosine, balenine. Compounds were found in both tissue samples and perfusates.

Synergism of histidyl dipeptides as antioxidants.

Histidyl dipeptides such as carnosine (beta-alanyl-L-histidine) and homocarnosine (gamma-amino-butyryl-L-histidine) are reported at millimolar concentrations in several mammalian tissues (O'Dowd et al., 1988; House et al., 1989), but their precise physiological function, or functions, is uncertain. These compounds are known to be potent buffers at physiological pH (Davey, 1960). They are also able to restore functional capacity to fatigued muscle preparations, stimulate some glycolytic enzymes and maintain coupling between mitochondrial oxidation and phosphorylation (Severin, 1964). Histidyl dipeptides may also have antioxidant activity, though this finding is controversial. For example, Aruoma et al. have argued that these compounds, individually, are unable to scavenge superoxide (O2-.), hydrogen peroxide (H2O2) or hypochlorous acid (HOCl) at rates which could offer antioxidant protection in vivo. Since there is a range of these histidyl dipeptides within mammalian tissue we have investigated possible synergism between them in respect of antioxidant activity. Our results show that combining histidine-containing compounds at near physiological concentrations results in synergistic antioxidant activity.

Analysis of carnosine, homocarnosine, and other histidyl derivatives in rat brain.

Isocratic reverse-phase analytical HPLC has been used to examine naturally occurring imidazoles of rat brain. Elution of brain extracts with a phosphate buffer mobile phase from columns packed with Hypersil ODS (5 microns) resulted in good separation of the well-documented brain imidazole-containing dipeptides carnosine and homocarnosine. Measured concentrations corresponded to published values. Several further peaks observed had properties consistent with those of N-acetyl derivatives of compounds related to carnosine and homocarnosine. N-Acetyl forms not commercially available were prepared and their identities verified by nuclear magnetic resonance spectroscopy. A number of these had chromatographic properties identical to those of compounds in brain extracts. Fractions corresponding to some of the peaks were examined using staining systems specific for certain chemical features and compared with results obtained for commercial or synthetic standards. The results of these tests supported the chromatographic data. Thus, chromatographic and microchemical evidence is presented for the existence of N-acetyl forms of histidine, 1-methylhistidine, carnosine, anserine, and homocarnosine in rat brain.

Detection, characterisation, and quantification of carnosine and other histidyl derivatives in cardiac and skeletal muscle.

Isocratic reverse phase analytical high performance liquid chromatography (HPLC) has been used to examine naturally occurring imidazoles of cardiac and skeletal muscles. Elution of muscle extracts with a phosphate buffer mobile phase from columns packed with hypersil ODS (5 micron) resulted in good separation of the skeletal muscle imidazole-containing dipeptides carnosine and anserine. Measured concentrations corresponded to published values. N-Acetyl forms that were not commercially available were prepared from their parent compounds and their identities verified by NMR-spectroscopy. Examination of frog cardiac muscle confirmed the presence of N-acetylhistidine and also indicated the presence of its 1-methyl derivative. Extracts of mammalian cardiac muscle were examined by HPLC which indicated the presence of low concentrations of carnosine but substantial amounts of N-acetyl forms of histidine, 1-methylhistidine, carnosine and anserine. Fractions corresponding to the numerous peaks were examined using staining systems specific for certain chemical features and compared to results obtained for commercial or synthetic standards. Results of these tests supported the chromatographic data. The total concentrations in cardiac muscle of these imidazole-containing substances (approx. 10 mM) is sufficient to alter significantly the sensitivity of their contractile apparatus to calcium ions.

The distribution of DMBA and its dihydrodiols in tissues of control and Sudan-III-treated Long-Evans rats after the injection (i.v.) in vivo of a leukaemogenic dose of the hydrocarbon.

7,12-Dimethylbenz[a]anthracene (DMBA) is a potent leukaemogenic agent in Long-Evans rats when it is administered i.v. in vivo. The prior oral administration of Sudan III [1(p-phenylazo-phenylazo)-2-naphthol] protects animals from the leukaemogenic effects of this compound. Sudan-III-treatment resulted in an increased rate of removal of DMBA from the livers and blood of treated animals and resulted in a reduced level of accumulation of the hydrocarbon in its presumed target tissue, the bone marrow. The regio-selective hepatic metabolism of DMBA was altered in Sudan-III-treated animals, thus only trans-3,4-dihydro-3,4-dihydroxy-DMBA was recovered from the livers of control animals whereas only trans-8,9-dihydro-8,9-dihydroxy-DMBA was recovered from the livers of Sudan-III-treated animals. The distribution of DMBA dihydrodiols in the blood and in the bone marrow was found to reflect the findings in the liver. DMBA, when incubated with rat bone marrow cells in vitro, was metabolized to probable phenolic compounds but no evidence whatsoever was found for dihydrodiol formation in these cells. Taken together these results are consistent with a model in which Sudan-III-induced alterations in the regio-selective hepatic metabolism of DMBA are responsible for the protection against leukaemogenesis afforded by the administration of that compound. The probable mechanism of protection is the induction in liver of a cytochrome P450, probably P450c.

The metabolism in vitro of 7,12-dimethylbenz[a]-anthracene by human bone marrow.

The leukaemogenic polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]-anthracene (DMBA) has been incubated with human bone marrow cells. It was found that these cells could metabolise DMBA to a number of products and that the process was dependent upon incubation time and upon cell number. Different bone marrow fractions from the same individual formed different DMBA dihydrodiols. Evidence was obtained that suggested that conjugation of DMBA metabolites with glucuronic acid occurred during incubation with bone marrow cells. The differential site-specific metabolism of DMBA by human bone marrow fractions may have implications for future epidemiological studies.

The reification of age: Age stratification theory and the passing of the autonomous subject.

Sociology has always been charactereized by a joint interest in social structures and individual lives as well as in their interaction. Social gerontology, however, has developed in a lopsided manner with disproportionate attention focused on individual attitudes and behavior. The principal sociological theory of aging, the age stratification model (ASM), has failed to provide an adequate structuralist counterpoint to the prevailing reductionism in social gerontology. The problem with the ASM lies in its preoccupation with a functionalist understanding of structure that is grounded in the concept of role. Because of its view of structure as a framework of social roles, the ASM neglects the realm of autonomous individual activity and the corresponding dialectics between social action and social structures. To remedy this neglect of micro-macro linkage in the ASM, Seve's concept of use-time is presented as the basis of an alternative theory of aging and age relations.

Alterations in the metabolism of 7,12-dimethylbenz[a]anthracene and various xenobiotics by rat hepatic microsomes following Sudan III treatment in vivo.

Sudan III treatment of Long-Evans rats results in increased hepatic monooxygenase activity using ethoxycoumarin and aniline as substrates. Monooxygenase activity towards amino-pyrine and nitrosodimethylamine is not affected. Sudan III treatment results in increased microsomal cytochrome P448 and increased amounts of a protein band which comigrates with purified cytochrome P448 during SDS polyacrylamide gel electrophoresis. The proportions of the different dihydrodiols formed during the incubation of 7,12-dimethylbenz[a]anthracene with microsomes vary between untreated and treated animals. Thus, extracts of microsomes from untreated rats were found to contain materials with chromatographic properties identical to those of the 3,4-dihydrodiol and the 5,6-dihydrodiol when examined on two different h.p.l.c. systems. Extracts of microsomes from Sudan III treated animals were found to contain materials with chromatographic properties identical to those of the 5,6-dihydrodiol and the 8,9-dihydrodiol when similarly examined. These findings suggest that the protective effect of Sudan III against DMBA induced leukaemia is mediated by an alteration in monooxygenase activity.

Mental illness and the aged stranger.

Sociological investigations of mental illness in older populations have been largely concerned with the causes and consequences of morale and life satisfaction. Satisfaction with life and "good morale" are widely viewed as reasonable indicators of mental health. Apart from the definitional problems inherent in this approach, the focus on morale has effectively diverted greater research attention from more serious issues of mental health in older populations, such as schizophrenia, personality disorders, and depression. The intent of this paper is to evaluate the dominant mental health paradigms within social gerontology; to synthesize some existing threads of a political economy/social control approach to these issues; and, finally, to argue that the act of growing old in capitalist societies brings increased risk of mental illness not because of drift, selection, or stress but, rather, because of the exclusion of the aged from labor markets and the physical and ideological "strangeness" of the aged.

Beneficence and the aged.

The present paper reexamines the modernization hypothesis, focusing principally on the issues of whether and why the relative status and prestige of old people is lower in late 20th century industrial societies than it was during the preceding century. It is argued that the status of most old people, whether considered in absolute or relative terms, is indeed higher now than earlier. No longer bound by the usual norms of reciprocity governing social interaction, old people benefit by a renascence of the norm of beneficence. The very old, in other words, receive more than they are owed under the norm of reciprocity. For the young-old, however, the norm of reciprocity continues in effect. Because of this, and the tightening in eligibility criteria for programs of social support, the position of the young-old is less a function of age than it is of social class.

Socialization to violence among the aged.

This paper addresses the issue of the attitudinal consequences of fear and victimization by focusing on the degree to which people of different ages expresses approval of violent behavior. It is our argument that the experience of victimization socializes the individual to a view as constituting an effective strategy for resolving interpersonal conflict. Data from a national sample of the noninstitutionalized adult population of the United States support this argument, at least for respondents under 60. Older people are less likely to be victims of crime than younger persons, more likely to report fear of crime, and more disapproving of violent behavior. Older victims, however, do not evidence the same attitudinal response as younger victims. Younger victims are generally less disapproving of violence than youthful non-victims; the difference between older victims and non-victims, however, is in the opposite direction. This finding is explained as a specific instance of the lesser impact across the life cycle of period effects on attitudes.

Exchange rates and old people.

This paper extends earlier work on aging as a process of exchange by focusing on the issue of exchange rates and how they are negotiated. Intergenerational social exchange is conceptualized as a "boundary crossing" in which the older partner must learn the decision rules appropriate to interaction within a younger stratum. Because of the power differential that, in many cases, favors the middle-aged partner, the "discourse" governing the exchange is typically that of the younger exchange partner. Age is an "exportable" status characteristic, one that is used to assess the legitimacy of a person's claim for a certain level of reward. Old age places the exchange partner in a double bind. Access to power resources declines with age, placing the person in the unenviable position of negotiating from weakness. In addition, those resources which he/she does possess are exchanged for less than they would be if held by a younger person.

Sociological functionalism, exchange theory and life-cycle analysis: a call for more explicit theoretical bridges.

There has been a notable lack of articulation between mainstream sociological theory and the work of social gerontologists. This paper suggests four reasons for this, and reviews the basic assumptions and applications to gerontology of two well-established frameworks in sociological theory: structural-functionalism and exchange. With more rigorous and systematic integration of gerontological data with social and social psychological theory, more comprehensive explanations of life course phenomena would result. Moreover, the age variable would be considerably by other sociologists as less of a control and more of a relevant variable in its own right.

The problems of generations: and generational analysis.

The focus of this paper is two fold: 1. conceptual and methodological problems underlying the life-span sociology literature that heretofore have not been discussed; and 2. application of the generational analysis model to the question of life cycle change in personal values. Specifically, we address the issues of whether (1) value change over the life course is a result of period shifts or individual maturation and (2) differences in values among age strata are a function of cohort experience or individual maturation (aging). Utilizing data from the Detroit Area Studies, four measures of values were constructed. The analyses shows that on only one of the four dependent measures was aging directly implicated in the findings. However, cohort differences and period effects were found to have a significant effect on the distribution of several of the value indices. The data are consistent with Mannheim's observation that older cohorts are affected by social change although the relative degree of observed change is much greater among the young.

Aging in minority populations. An examination of the double jeopardy hypothesis.

The plight of minority aged has been characterized by many as one of double jeopardy: in addition to the disadvantages imposed by their minority group status, the minority aged are said also to experience the devaluation in status associated with old age in our society. Other research has indicated, however, that the gaps between minority and majority individuals tend to decline with age, such that the status disparity between white and minority aged actually may have decreased from middle to old age. To test these competing hypotheses, a series of health, income, life satisfaction, and social participation variables (interaction with family, kin, neighbors, and friends) was examined with data from a large (N = 1269) sample of middle-aged and older blacks, Mexican Americans and whites in Los Angeles County. Differences among the three ethnic groups were found which, in some cases, constituted a case of "double jeopardy" for minority aged. On variables measuring life satisfaction or frequency of contact with relatives, however, the extent of ethnic variation declined across age strata, indicating some support for the "age as leveler" hypothesis.