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Inhibition of beta- but not alpha 1-mediated adrenergic responses in isolated hearts and cardiomyocytes by nitric oxide and 8-bromo cyclic GMP.
Cardiovasc Res. 1996 Sep; 32(3):622-9.CR

Abstract

OBJECTIVES

The study was carried out to assess the effect of nitric oxide (NO) generation or inhibition of NO synthase on the cardiac response to beta- and alpha 1-adrenergic agonists. In addition, we determined the effects of the cell-permable analogue of cGMP, 8-bromo-cGMP (8Br-cGMP).

METHODS

Experiments were done in electrically-paced isolated perfused rat hearts as well as in ventricular myocytes. Hearts were exposed to either the beta-adrenoceptor agonist, isoproterenol (0.1 microM), or the alpha 1-adrenoceptor agonist, phenylephrine (2 microM in the presence of equimolar concentrations of propranolol), either with each drug alone or in the presence of the NO donors S-nitrosoacetylpenicillamine (SNAP, 10 microM) and 3-morpholino-sydnonimine (SIN-1, 10 microM), the NO synthase inhibitor L-NAME (10 microM) or 8Br-cGMP (50 microM). These concentrations of SNAP and 8Br-cGMP increase tissue cGMP levels approximately 3-fold after 15 min treatment. Myocardial contractility was assessed by determining left ventricular pressure with a fluid-filled balloon inserted into the left ventricle. Similar experiments were performed in myocytes in which cell shortening and intracellular calcium transients were determined although concentrations of isoproterenol and phenylephrine in myocytes were higher (1 and 5 microM, respectively) than those used in isolated hearts in order to achieve optimum responses.

RESULTS

In isolated hearts isoproterenol increased developed pressure by about 50%, which was totally prevented by SNAP and SIN-1 and unaffected by L-NAME. 8Br-cGMP, however, did not significantly diminish the positive inotropic effect of isoproterenol. Phenylephrine increased developed pressure of isolated hearts by about 30%, but this was totally unaffected by either SNAP, SIN-1 or 8Br-cGMP. In myocytes, isoproterenol significantly increased the calcium transient by more than 50% and cell shortening by about 70%. Both effects were significantly attenuated by SNAP, SIN-1 and 8Br-cGMP but unaffected by L-NAME. Phenylephrine significantly increased cell shortening and the calcium transient, but these responses were unaffected either by SNAP or 8Br-cGMP.

CONCLUSION

The present study demonstrate that NO as well as guanylate cyclase inhibitors and, to a lesser extent, 8Br-cGMP attenuate beta-receptor-mediated cardiac responses and supports the concept that NO serves as an endogenous regulator of beta-mediated effects of catecholamines in the heart. In addition, our findings suggest that the antiadrenergic effects of NO are restricted to these receptors but likely do not involve alpha 1-mediated effects.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8881523

Citation

Ebihara, Y, and M Karmazyn. "Inhibition of Beta- but Not Alpha 1-mediated Adrenergic Responses in Isolated Hearts and Cardiomyocytes By Nitric Oxide and 8-bromo Cyclic GMP." Cardiovascular Research, vol. 32, no. 3, 1996, pp. 622-9.
Ebihara Y, Karmazyn M. Inhibition of beta- but not alpha 1-mediated adrenergic responses in isolated hearts and cardiomyocytes by nitric oxide and 8-bromo cyclic GMP. Cardiovasc Res. 1996;32(3):622-9.
Ebihara, Y., & Karmazyn, M. (1996). Inhibition of beta- but not alpha 1-mediated adrenergic responses in isolated hearts and cardiomyocytes by nitric oxide and 8-bromo cyclic GMP. Cardiovascular Research, 32(3), 622-9.
Ebihara Y, Karmazyn M. Inhibition of Beta- but Not Alpha 1-mediated Adrenergic Responses in Isolated Hearts and Cardiomyocytes By Nitric Oxide and 8-bromo Cyclic GMP. Cardiovasc Res. 1996;32(3):622-9. PubMed PMID: 8881523.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of beta- but not alpha 1-mediated adrenergic responses in isolated hearts and cardiomyocytes by nitric oxide and 8-bromo cyclic GMP. AU - Ebihara,Y, AU - Karmazyn,M, PY - 1996/9/1/pubmed PY - 1996/9/1/medline PY - 1996/9/1/entrez SP - 622 EP - 9 JF - Cardiovascular research JO - Cardiovasc Res VL - 32 IS - 3 N2 - OBJECTIVES: The study was carried out to assess the effect of nitric oxide (NO) generation or inhibition of NO synthase on the cardiac response to beta- and alpha 1-adrenergic agonists. In addition, we determined the effects of the cell-permable analogue of cGMP, 8-bromo-cGMP (8Br-cGMP). METHODS: Experiments were done in electrically-paced isolated perfused rat hearts as well as in ventricular myocytes. Hearts were exposed to either the beta-adrenoceptor agonist, isoproterenol (0.1 microM), or the alpha 1-adrenoceptor agonist, phenylephrine (2 microM in the presence of equimolar concentrations of propranolol), either with each drug alone or in the presence of the NO donors S-nitrosoacetylpenicillamine (SNAP, 10 microM) and 3-morpholino-sydnonimine (SIN-1, 10 microM), the NO synthase inhibitor L-NAME (10 microM) or 8Br-cGMP (50 microM). These concentrations of SNAP and 8Br-cGMP increase tissue cGMP levels approximately 3-fold after 15 min treatment. Myocardial contractility was assessed by determining left ventricular pressure with a fluid-filled balloon inserted into the left ventricle. Similar experiments were performed in myocytes in which cell shortening and intracellular calcium transients were determined although concentrations of isoproterenol and phenylephrine in myocytes were higher (1 and 5 microM, respectively) than those used in isolated hearts in order to achieve optimum responses. RESULTS: In isolated hearts isoproterenol increased developed pressure by about 50%, which was totally prevented by SNAP and SIN-1 and unaffected by L-NAME. 8Br-cGMP, however, did not significantly diminish the positive inotropic effect of isoproterenol. Phenylephrine increased developed pressure of isolated hearts by about 30%, but this was totally unaffected by either SNAP, SIN-1 or 8Br-cGMP. In myocytes, isoproterenol significantly increased the calcium transient by more than 50% and cell shortening by about 70%. Both effects were significantly attenuated by SNAP, SIN-1 and 8Br-cGMP but unaffected by L-NAME. Phenylephrine significantly increased cell shortening and the calcium transient, but these responses were unaffected either by SNAP or 8Br-cGMP. CONCLUSION: The present study demonstrate that NO as well as guanylate cyclase inhibitors and, to a lesser extent, 8Br-cGMP attenuate beta-receptor-mediated cardiac responses and supports the concept that NO serves as an endogenous regulator of beta-mediated effects of catecholamines in the heart. In addition, our findings suggest that the antiadrenergic effects of NO are restricted to these receptors but likely do not involve alpha 1-mediated effects. SN - 0008-6363 UR - https://www.unboundmedicine.com/medline/citation/8881523/Inhibition_of_beta__but_not_alpha_1_mediated_adrenergic_responses_in_isolated_hearts_and_cardiomyocytes_by_nitric_oxide_and_8_bromo_cyclic_GMP_ DB - PRIME DP - Unbound Medicine ER -