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The newly discovered peptide, brain natriuretic factor (BNF), caused a concentration-dependent increase (up to 400-fold) in intracellular cyclic GMP levels in cultured endothelial, smooth muscle and fibroblast cells. The extent of cGMP augmentation was comparable to that produced by atria1 natriuretic factor (ANF). The activity of the membrane-bound guanylate cyclase of different rat tissues and cultured cells was markedly stimulated by the peptide and the addition of ATP potentiated the stimulation. As opposed to tissue particulate guanylate cyclase, the enzyme in cell membranes was slightly more sensitive to activation by BNF than to stimulation by ANF. On bovine aortic smooth muscle (BASM) cells, specific high-affinity binding sites (B,,,u = 398 fmol/lW cells, Kd =0.52 nM) for BNF were observed for which ANF could compete with apparently equal affinity. These results suggest that activation of the cGMP pathway constitutes a common mechanism of action for both BNF and ANF.

1. In order to investigate exercise-induced changes of beta 2-adrenoceptors on human leukocyte subsets, beta-adrenoceptor density was determined as specific binding of [125I]-iodocyanopindolol to granulocytes, monocytes, B and T lymphocytes of six subjects immediately before and after exercise and after 30 min of rest. 2. A 10 min graded bicycle exercise with a workload of 50-250 W caused a transient increase of granulocytes, monocytes, B and T cells of about 32, 43, 120 and 25%, respectively. 3. While the number of beta 2-adrenoceptors in granulocytes remained unchanged, beta-adrenoceptor densities in B cells, T cells and monocytes increased from pre-exercise mean values of 2730, 870 and 2400 binding sites/cell to 3500, 1230 and 3220 binding sites/cell, respectively, under physical stress. The rise in receptor numbers was accompanied by an enhanced isoprenaline-stimulated cyclic AMP formation in unfractionated mononuclear leukocytes (MNL) of about 26% as well as by a 2-3-fold increase in plasma catecholamine levels. Cell concentrations, beta 2-adrenoceptor numbers and adrenergic responsiveness returned to normal after 30 min rest. 4. Administration of 60 mg prednisone 2 h before exercise resulted in granulocytosis and lymphopenia with a preponderant effect on the exercise-induced rise in B cells and monocytes. Corticosteroids showed no effect on stress-induced changes of beta 2-adrenoceptors and responsiveness. 5. It is concluded that exercise-induced increases in beta 2-adrenoceptor density and adrenergic responsiveness of unfractionated MNL are caused by a release of receptor-enriched cells into the circulation, particularly of B lymphocytes and monocytes which carry the highest beta 2-adrenoceptor density.

The interactions of the nitrovasodilators, endothelium-dependent vasodilators, and atrial peptides with cGMP synthesis have proved to be useful and important leads to the functions of cGMP and signal transduction mechanisms. Although considerable progress has been made, many important questions remain to be answered. Nevertheless, the guanylate cyclase-cGMP system clearly represents an important second-messenger system that mediates the effects of numerous agents.