In experimental animals, coadministration of calcium (Ca) salts with β- adrenergic receptor agonists reduces the increased blood pressure and cyclic AMP (cAMP) produced by β-adrenergic receptor agonists alone. In patients, coadministration of these drugs reduces the increased cardiac output and blood glucose produced by selective administration of β-adrenergic agonists. The mechanism by which Ca might produce catecholamine resistance remains unclear. Healthy volunteers donated venous blood from which lymphocytes were isolated. The cAMP production was measured by radioimmunoassay under control conditions and after incubation with epinephrine or colforsin (forskolin) in the presence and absence of inhibitors. Epinephrine and colforsin produced concentration-dependent increases in cAMP production. Extracellular Ca concentration over the range from 0 to 8 mM did not inhibit basal cAMP production or that stimulated by either colforsin or epinephrine. The calcium channel agonist Bay K 8644 (50 μM) combined with normal extracellular Ca concentration significantly attenuated colforsin-induced increases in cAMP production. When barium was substituted for Ca in the extracellular fluid, the cAMP response to colforsin was restored, despite Bay K 8644. Inhibition of Ca channel permeability with cadmium or cobalt ions partially restored colforsin-stimulated cAMP production, despite the presence of extracellular Ca and Bay K 8644. These results suggest that entry of Ca ions through Ca channels attenuates adenylyl cyclase. The inhibition appears specific for Ca ions over other permeant divalent cations, and favors a possible physiologic role for the recently cloned Ca-inhibited adenylyl cyclase.
Bibliographical noteFunding Information:
Presented in part at “Ion Channels in the Cardiovascular System,” Chantilly, Va, October 1992, conference sponsored by National Heart, Lung, and Blood Institute and the American Association for the Advancement of Science; the 1993 meeting of the International Anesthesia Research Society, San Diego, Calif; and the 1993 meeting of the American Society of Anesthesiologists, Washington, DC.
- adenylyl cyclase
- bay K 8644
- colforsin (forskolin)
- cyclic adenosine monophosphate-(cAMP)