Possible role of cAMP, cGMP and [Ca 2+] i during NANC relaxation in the cat airway smooth muscle

Abstract

To investigate the possible role of cyclic nucleotides and [Ca 2+] i in non-adrenergic non-cholinergic (NANC) relaxations evoked by electrical field stimulation (EFS) in the cat airway, we studied the effects of specific phosphodiesterase (PDE) type IV or V inhibitors on the biphasic-NANC relaxations, the correlation between NANC relaxation and changes in intracellular levels of cAMP and cGMP ([cAMP] i and [cGMP] i), and measured changes in [Ca 2+] i during the NANC relaxation. EFS (repetitive stimuli at 20 Hz, 1 or 4 ms pulse duration, 50 V) applied to the bronchial smooth muscle during contraction induced by 5-HT (10 −5 M) in the presence of atropine (10 −6 M) and guanethidine (10 −6 M) elicited biphasic NANC relaxations. Zaprinast (>3×10 −7 M), a specific PDE type V inhibitor, preferentially enhanced the amplitude of the first component of the NANC relaxations. However, rolipram (>3×10 −7 M) enhanced both the first and second component of the NANC relaxation to a similar extent. In the trachea, EFS evoked monophasic NANC relaxation accompanied by a concomitant accumulation of [cAMP] i and [cGMP] i. Pretreatment with rolipram (3×10 −6 M) enhanced the accumulation of [cAMP] i and amplitude of NANC relaxation evoked by EFS. However, zaprinast did not affect the amplitude of NANC relaxation although it significantly increased the levels of [cGMP] i. N ω -Nitro- l-arginine methylester ( l-NAME; 10 −5 M) completely suppressed the accumulation of [cGMP] i but only partly suppressed the NANC relaxation evoked by EFS. In contrast, EFS significantly enhanced [cAMP] i in the presence of l-NAME. During NANC relaxation, time-dependent decrease in [Ca 2+] i occurred, which was partly suppressed by l-NAME. These results indicate that NANC relaxation is associated with concomitant accumulation in both [cAMP] i and [cGMP] i, and decrease in [Ca 2+] i. However, the timing of the action of [cGMP] i and [cAMP] i in NANC relaxations differs in the central and peripheral airway.