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Both alpha and beta adrenoceptor-mediated components contribute to final inotropic response to norepinephrine in rat
T Skomedal1, I G Schiander, J B Osnes
1Department of Pharmacology, University of Oslo, Norway.
Insights
Norepinephrine
Area of Science:
- Pharmacology
- Cardiovascular Physiology
Background:
- Alpha and beta adrenoceptor blockers are used to study norepinephrine's effects.
- Previous studies struggled to isolate alpha adrenoceptor contributions to norepinephrine's inotropic response.
Purpose of the Study:
- To unmask and quantify alpha and beta adrenoceptor-mediated inotropic components of norepinephrine.
- To investigate the interaction between alpha and beta adrenoceptor pathways.
Main Methods:
- Isolated paced rat papillary muscles were used.
- Norepinephrine stimulation was followed by sequential or simultaneous addition of adrenoceptor blockers (timolol and prazosin).
- Reversal responses were studied to determine receptor contributions.
Main Results:
- Norepinephrine's inotropic response comprises distinct beta (approx. 75%) and alpha (approx. 25%) adrenoceptor-mediated components.
- Sequential blockade revealed both components, while simultaneous blockade rapidly reversed the response.
- Concomitant stimulation of both receptor types resulted in reduced expression of each component, indicating mutual inhibition.
Conclusions:
- The study successfully quantified the distinct alpha and beta adrenoceptor contributions to norepinephrine's inotropic effect.
- Mutual inhibition between alpha and beta adrenoceptor pathways was observed.
- This explains previous difficulties in demonstrating the alpha adrenoceptor component during unopposed beta adrenoceptor stimulation.
Abstract:
The classical approach of displacing the dose-response curve by an alpha adrenoceptor blocker has most often failed to demonstrate a contribution of an alpha adrenoceptor-mediated component in the final inotropic response to norepinephrine unless the beta adrenoceptors are extensively blocked. To unmask and quantify the inotropic components in the response to norepinephrine, we took a different approach by studying reversal responses to appropriate adrenoceptor blockers in isolated paced rat papillary muscles maximally stimulated by norepinephrine. The inotropic response to norepinephrine was rapidly reversed by simultaneous addition of the beta adrenoceptor blocker timolol and the alpha adrenoceptor blocker prazosin. When the adrenoceptor blockers were added sequentially, both alpha and beta adrenoceptor-mediated components in the inotropic response to norepinephrine could be demonstrated: one beta adrenoceptor-mediated component (timolol sensitive only) that represented about 75% of the inotropic response and one alpha adrenoceptor-mediated component (prazosin sensitive only) that represented about 25% of the inotropic response. When one adrenoceptor population was eliminated by giving one of the adrenoceptor blockers before norepinephrine, the inotropic response in this situation could be completely reversed by the other adrenoceptor blocker. The expression of both alpha and beta adrenoceptor-mediated components was significantly less during concomitant receptor stimulation than when the respective receptor populations were stimulated separately. Thus, there was apparently a mutual inhibition of one component upon the other. Although the beta adrenoceptor-mediated inotropic component clearly was the dominating one, the present observations will explain the difficulties in demonstrating an alpha adrenoceptor-mediated component during unopposed beta adrenoceptor stimulation in the inotropic response to norepinephrine in earlier studies.