High alpha 1-adrenoceptor occupancy decreases relaxing potency of nifedipine by increasing myosin light chain phosphorylation.
It has been proposed that the decreased potency of Ca2+ channel blockers to produce relaxation in vascular tissues contracted at high alpha 1-adrenoceptor occupancy may be caused by activation of spare receptors. Results from the present study using isolated strips of rabbit renal arteries contracted with the alpha 1-adrenoceptor agonist phenylephrine (PhE) support this hypothesis and provide a cellular explanation for the phenomenon. PhE at 1 microM activated only 23% of the total alpha 1-adrenoceptor pool but produced maximum stress while increasing the extent of myosin light chain phosphorylation to 35%. Activation of additional (spare) alpha 1-adrenoceptors with 100 microM PhE produced an additional increase in the extent of myosin light chain phosphorylation, which reached 45%, but did not produce an additional increase in stress above that produced by 1 microM PhE. A complete [PhE]-response curve revealed a quasihyperbolic dependency of stress on myosin light chain phosphorylation; i.e., a roughly linear relation existed at [PhE] values below that producing maximum stress, and at higher concentrations, phosphorylation was further increased but stress was not. Interestingly, the Ca2+ channel blocker nifedipine (0.1 microM) reduced the increases in myosin light chain phosphorylation produced by both 1 and 100 microM PhE by the same amount, approximately 12%. Nifedipine also reduced the increases in [Ca2+]i produced by 1 and 100 microM PhE by the same amount. However, nifedipine reduced the level of stress produced by 100 microM PhE by only 17%, whereas the level of stress produced by 1 microM PhE was reduced by 63%.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, Eastern Virginia Medical School, Norfolk 23501.
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D000818:Animals; D002118:Calcium / Q000378:metabolism; D066298:In Vitro Techniques; D009218:Myosins / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D012077:Renal Artery / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine; D010738:Type C Phospholipases; D009218:Myosins; D009543:Nifedipine; D002118:Calcium