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We evaluated the mechanisms of histamine-mediated adenylate cyclase stimulation in 18 human hearts obtained from cardiac transplant recipients or prospective donors. Mg2+ and guanyl nucleotide were required for histamine stimulation. In the presence of 10-5 M GTP, histamine produced a maximal stimulation of 1.54 +/- 0.06 times basal activity in left ventricle (39% of the isoproterenol maximum), which rose to 1.75 +/- 0.14 times basal activity (68% of the isoproterenol maximum) in the presence of a 10-5M concentration of the synthetic guanyl nucleotide 5'-guanylyl imidodiphosphate. Histamine stimulation of adenylate cyclase was antagonized by cimetidine (KB = 1.58 X 10-6 M) but not by H1-blocking doses of mepyramine or pyrrobutamine. The selective H2 agonist dimaprit stimulated adenylate cyclase to approximately the same extent as histamine, whereas a selective H1 agonist produced only minimal stimulation that was H2-mediated. The selective H2 agonist impromidine was a partial agonist and produced approximately 20-40% of maximal histamine stimulation at lower concentrations (10-7 and 10-6 M) and inhibition of histamine stimulation at higher concentrations (10-5 and 10-4 M). Histamine stimulated adenylate cyclase activity over the same dose range as that which produced a positive inotropic response in isolated papillary muscles. Under one set of assay conditions, contractile response and adenylate cyclase does-response curves were essentially super-imposable. We conclude that human myocardial adenylate cyclase is coupled to the H2 receptor and linked to the contractile response, whereas the H1 receptor does not mediate a biochemical or mechanical effect.

Regional and Urban Economics, P. N. BALCHIN and G. H. BULL, Harper & Row, London (1988). xiv + 249 pp. £8.95 (pbk). ISBN 0 06 318368 4.High Technology Industry and Innovative Environments: The European Experience, P. AYDALOT and D. KEEBLE (Eds.) Routledge and Kegan Paul, London (1988). 241 pp. £27.50 (hbk). ISBN 0 415 00414 4.Invisible Factors in Local Economic Development, P. B. DOERINGER D. G. TERKLA and G. C. TOPAKIAN, Oxford University Press, Oxford (1988). vii + 144 pp. £18.50 (hbk). ISBN 0 19 504965 9.Informatics and Regional Development, M. GIAOUTZI and P. NIJKAMP (Eds.), Avebury, Aldershot (1988). xiv + 344 pp. £29.50 (hbk). ISBN 0 566 05495 7.Tourism and Economic Development: Western European Experiences, A. M. WILLIAMS and G. SHAW (Eds.), Pinter, London (1988). xi + 257 pp. £25.00 (hbk). ISBN 1 85293 009 8.A Decision-Centred View of Environmental Planning, A. FALUDI, Pergamon, Oxford (1987). viii + 240 pp. £30.00 $54.00 (hbk). £12.95. $23.00 (pbk). ISBN 0 08 0326986 (hbk). ISBN 0 08 0349838 (pbk).Land and Housing Policies in Europe and the USA: A Comparative Analysis, G. HALLETT (Ed.), Routledge, London (1988). 216 pp. £27.50 (hbk). ISBN 0 415 00511 6.Faith in the City of Birmingham: An Examination of Problems and Opportunities Facing a City, BISHOP'S Council of the Diocese of Birmingham, The Paternoster Press, Exeter (1988). xiv + 158 pp. £3.50 (pbk). ISBN 0 85364 474 8.The Uncertain Future of the Urban Core, C. M. LAW, in association with E. K. GRIME, C. J. GRUNDY, M. L. SENIOR and J. N. TUPPEN, Routledge, London (1988). 253 pp. £32.50 (hbk). ISBN 0 415 00464 0.Urban Living: The Individual in the City, D. J. WALMSLEY, Longman Scientific and Technical, London, and Wiley, New York (1988). xiv + 204 pp. £7.95 (pbk). ISBN 0 582 30167 X.Urban Development and Regional Policy in India, V. SHUKLA, Himalaya Publishing House, Bombay (1988). xv + 158 pp. Rs 150.00 (hbk). No ISBN no. given.Planning Homes and Jobs: The Sheffield Report, Sheffield City Council, Department of Employment and Economic Development, University of Warwick (1988). 84 pp. £10.00 (pbk). ISBN 0 9513237 0 9.

High Tech America: The What, How, Where and Why of Sunrise Industries, A. MARKUSEN, P. HALL and A. GLASMEIER, George Allen and Unwin, Hemel Hempstead, Herts. (1986). xvii + 227 pp. £20.00 (hbk). ISBN 0 04 338139 1.Handbook of Urban and Regional Economics, P. NIJKAMP (Ed.), North-Holland, Amsterdam (1986). xxii + 702 pp. US$ 65.00/Dfl. 215.00 (hbk). ISBN 0 444 87969 2.Energy, Planning and Urban Form, S. OWENS, Pion, London (1987). 118 pp. £9.00 (pbk). ISBN 0 850 861187.Land at the Centre: Choices in a Fast-Changing World, J. C. HOLLIDAY, Shepheard-Walwyn, London (1986). xiii + 241 pp. £7.95 (pbk). ISBN 0 05683 084 4.Lay Participation in a Local Public Inquiry: A Sociological Case Study, N. HUTTON, Gower, Aldershot, Hants. (1986). x + 203 pp. £18.50 (hbk). ISBN 0 566 05192 3.The Designation of Cumbernauld New Town: A Case Study of Central-Local Government Relationships in Scotland During the 1950s, C. CARTER and M. KEATING, Open University, Social Sciences Working Paper 2, Milton Keynes (1986). 100 pp. £2.50. No ISBN given.Western Europe: Economic and Social Studies, R. KING, Harper & Row, London (1987). x + 222 pp. £6.95 (pbk). ISBN 0 06 318364 1.The British Transport Industry and the European Community, P. MACKIE, D. SIMON and A. WHITEING, Gower, Aldershot, Hants. (1987). xvi + 184 pp. £22.50 (hbk). ISBN 0 566 05368 3.Jura Separatism in Switzerland, J. R. G. JENKINS, Clarendon Press, Oxford (1987). xv + 221 pp. £25.00 (hbk). ISBN 0 19 823247 0.Uneven Development and Regionalism: State, Territory and Class in Southern Europe, C. HADJIMICHALIS, Croom Helm, Beckenham, Kent (1986). 343 pp. £29.95 (hbk). ISBN 0 7099 3700 8.West European Population Change, A. FINDLAY and P. WHITE (Eds.), Croom Helm, Beckenham, Kent (1986). xv + 253 pp., £25.00 (hbk). ISBN 0 7009 3667 2.Decentralization and Change in Contemporary France, M. KEATING and P. HAINSWORTH, Gower, Aldershot, Hants. (1986). 143 pp. £17.50 (hbk). ISBN 0 566 05206 7.Self-Reliant Development in Europe, M. BASSAND, E. A. BRUGGER, J. M. BRYDEN, J. FRIEDMAN and B. STUCKEY (Eds.), Gower, Aldershot, Hants. (1986). vi + 234 pp. £17.50 (hbk). ISBN 0 566 05095 1.Contemporary Studies of Migration: Proceedings of the Second British-Dutch Symposium on Population Geography, 1983, B. VAN DER KNAAP and P. WHITE (Eds.), Geo Books, Norwich (1986). 184 pp. No price given. ISBN 0 96094 192 2.

Prenalterol (beta 1-agonist), denopamine (beta 1-agonist), and zinterol (beta 2-agonist) were partial agonists of adenylate cyclase (AC) stimulation in human ventricular myocardium obtained from nonfailing chambers whose beta 1/beta 2 receptor subtype ratio was approximately 80/20. At a concentration less than its low affinity (beta 2) Kl, betaxolol, a highly selective beta 1-antagonist, inhibited isoproterenol (non-selective agonist), denopamine, and prenalterol stimulation of AC, indicating that isoproterenol, denopamine, and prenalterol are all capable of stimulating AC through beta 1-receptor activation. At a concentration less than its low affinity (beta 1) Kl, ICI 118,551, a highly selective beta 2-agonist, inhibited both isoproterenol and zinterol stimulation of AC, indicating that isoproterenol and zinterol stimulate AC through beta 2-receptors. Zinterol stimulation of AC was mediated entirely by beta 2-receptors, inasmuch as 10(-7) M betaxolol had no effect on the zinterol dose-response curve and ICI 118,551 produced a degree of blockade (KB = 5.2 +/- 1.6 X 10(-9) M), consistent with the beta 2-receptor Kl of the latter (2.0 +/- .4 X 10(-9) M, p, not significant). In nonfailing myocardium, analysis of beta 1 versus beta 2 stimulation by the nonselective agonist isoproterenol revealed that the numerically small (19% of the total) beta 2 fraction accounted for the majority of the total adenylate cyclase stimulation. In failing ventricular chambers with a beta 1/beta 2 receptor subtype ratio reduced from 82/19 (nonfailing) to 64/36 (p less than 0.001) and a beta 1-receptor density reduced by 61% (p less than 0.001), maximal denopamine stimulation was reduced by 49% (p less than 0.001). Moreover, in preparations from failing heart, the component of denopamine stimulation that was inhibited by 10(-7) M betaxolol (beta 1 component) was reduced by 77% (p less than 0.05). Finally, in preparations derived from failing ventricular myocardium, beta 2-receptor density was not significantly decreased, but zinterol stimulation of AC was reduced by 32% (p less than 0.05). We conclude that heart failure results in subsensitivity to both selective beta 1 and beta 2 stimulation of adenylate cyclase, with beta 1 subsensitivity due to selective beta 1 receptor down-regulation and beta 2 subsensitivity due to partial uncoupling of beta 2 receptors from subsequent events in the beta 2-adrenergic pathway.

In both cell culture based model systems and in the failing human heart, beta-adrenergic receptors ( beta-AR) undergo agonist-mediated down-regulation. This decrease correlates closely with down-regulation of its mRNA, an effect regulated in part by changes in mRNA stability. Regulation of mRNA stability has been associated with mRNA-binding proteins that recognize A + U-rich elements within the 3'-untranslated regions of many mRNAs encoding proto-oncogene and cytokine mRNAs. We demonstrate here that the mRNA-binding protein, AUF1, is present in both human heart and in hamster DDT1-MF2 smooth muscle cells and that its abundance is regulated by beta-AR agonist stimulation. In human heart, AUF1 mRNA and protein was significantly increased in individuals with myocardial failure, a condition associated with increases in the beta-adrenergic receptor agonist norepinephrine. In the same hearts, there was a significant decrease (approximately 50%) in the abundance of beta1-AR mRNA and protein. In DDT1-MF2 cells, where agonist-mediated destabilization of beta2-AR mRNA was first described, exposure to beta-AR agonist resulted in a significant increase in AUF1 mRNA and protein (approximately 100%). Conversely, agonist exposure significantly decreased (approximately 40%) beta2-adrenergic receptor mRNA abundance. Last, we demonstrate that AUF1 can be immunoprecipitated from polysome-derived proteins following UV cross-linking to the 3'-untranslated region of the human beta1-AR mRNA and that purified, recombinant p37AUF1 protein also binds to beta1-AR 3'-untranslated region mRNA.

In membrane preparations derived from primary cultures of chick myocardial cells, beta adrenergic receptors modeled for a single low-affinity site for both betaxolol (beta-1-selective) and ICI 118551 (beta-2-selective) displacement of [125I]iodocyanopindolol (ICYP), indicating that the chick beta receptor is pharmacologically distinct from both mammalian beta-1 and beta-2 adrenergic receptors with respect to these antagonists. However, the highly beta-1-selective compound CGP 20712A was able to distinguish two binding sites on ICYP competition curves, a high-affinity "beta-1 site" (75%) and a low-affinity "beta-2 site" (25%). Also, in chick heart cell membranes the relative ability of agonists to displace ICYP produced a profile typical of beta-1 adrenergic receptors with a rank order of potency or efficacy of: isoproterenol greater than epinephrine = norephinephrine. When agonist-mediated adenylyl cyclase stimulation was assessed the order of potency was slightly different, isoproterenol greater than epinephrine greater than or equal to norepinephrine. Additionally, antagonism of isoproterenol stimulation of adenylyl cyclase by CGP 20712A yielded a Kb value (1.16 +/- 0.35 x 10(-7) M) intermediate between the high and low-affinity binding sites of CGP 20712A, suggesting that the low-affinity site is coupled to adenylyl cyclase. In membrane preparations of frog myocardial cells, ICYP/antagonist competition curves modeled for a mixed population of receptors, with subtype percentages varying from 50:50 beta-1:beta-2 to 100% beta-2 depending on the specific antagonist used and the individual cell preparation. For ICYP/agonist competition binding experiments the relative ability to displace ICYP was isoproterenol greater than epinephrine = norepinephrine, a profile typical of beta-1 adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined alpha-1 adrenergic receptor density in ventricular myocardium from nonfailing and failing human hearts, utilizing the alpha-1 radioligand [125I]IBE2254. The alpha-1 receptor population comprised a relatively small portion of the total adrenergic receptors, 14.6 +/- 1.9%. However, in failing human ventricular myocardium the alpha-1 adrenergic receptor population constituted a much greater portion, 27.3 +/- 2.1% (P less than .01). The reason for the increased proportion of alpha-1 adrenergic receptors was not that the total concentration of alpha-1 receptors was increased, but instead was due to selective down-regulation of the beta-1 adrenergic receptor population. Beta-2 adrenergic receptors behaved similarly to alpha-1 adrenergic receptors in the failing human heart, and were increased in proportion and unchanged in total number. Additionally, the ability of alpha-1 stimulation to increase the incorporation of label from [3H]inositol into inositol phosphates was examined in tissue homogenates. Maximal doses of norepinephrine produced only marginal stimulation of phosphatidylinositol hydrolysis, in contrast to a more substantial response produced by muscarinic stimulation. We conclude that human ventricular myocardium contains alpha-1 adrenergic receptors that 1) are of relatively low density, 2) are unchanged in density by heart failure and 3) mediate relatively low-level stimulation of phosphatidylinositol hydrolysis.

We investigated the effects of clentiazem, a 1,5-benzothiazepine calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and fibrosis of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P < .05), and attenuated the ventricular ischemic lesions and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced cardiac injury, possibly through its effect on the adrenergic pathway.