alpha 1-adrenoceptor-mediated negative inotropy of adrenaline in rat myocardium.

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1. The effect of alpha- and beta-adrenoceptor stimulation on isotonic contraction was investigated on right ventricular papillary muscles of the rat, stimulated at a rate of 0.5 Hz. 2. Adrenaline (0.5 microM) induced a slight but significant negative inotropic effect: shortening decreased from 0.137 +/- 0.058 to 0.122 +/- 0.059 muscle lengths (mean +/- S.D.; -11%, P < 0.0001) and maximum shortening velocity from 2.9 +/- 1.2 to 2.7 +/- 1.3 muscle lengths s-1 (-7%, P < 0.025). 3. The negative inotropic effect of adrenaline was enhanced after blocking the beta-adrenoceptors with 50 microM atenolol. On the other hand, exposure to adrenaline after blocking the alpha-adrenoceptors with 50 microM phentolamine resulted in an increase in shortening as well as in maximum shortening velocity. 4. Stimulation of the beta-adrenoceptors with 0.5 microM isoprenaline caused marked positive inotropic effects, whereas stimulation of the alpha 1-adrenoceptors with 0.5 microM phenylephrine regularly resulted in a long-lasting decrease in shortening and maximum shortening velocity. 5. 1,2-Dioctanoyl-sn-glycerol (1,2-DOG) and adrenaline induced an activation of protein kinase C (PKC) with translocation of this enzyme from the cytosol to the sarcolemma. 6. Activation of PKC with 10 microM 1,2-DOG and 0.5 microM adrenaline was accompanied by a decrease in shortening and maximum shortening velocity. Inhibition of PKC with 0.1 microM staurosporine abolished the negative inotropic effect of adrenaline. 7. From these results we conclude that a low dose of adrenaline stimulates not only beta-but also alpha-adrenoceptors and that the observed negative inotropic effect of adrenaline is mediated by alpha 1-adrenoceptors, linked to the diacylglycerol-PKC signal transduction pathway.

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