Does Cyclic AMP Mediate Rat Urinary Bladder Relaxation by Isoproterenol?

Abstract

Cyclic AMP is the prototypical second messenger of ␤-adrenergic receptors, but recent findings have questioned its role in mediating smooth muscle relaxation upon ␤-adrenergic receptor stimulation. We have investigated the signaling mechanisms underlying ␤-adrenergic receptor-mediated relaxation of rat urinary bladder. Concentration-response curves for isoproterenolinduced bladder relaxation were generated in the presence or absence of inhibitors, with concomitant experiments using passive tension and KCl-induced precontraction. The adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536; 1 M), the protein kinase A inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7; 10 M), N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89; 1 M), and Rp-adenosine 3Ј,5Ј-cyclic monophosphorothioate (Rp-cAMPS; 30 M), and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; 3 M) produced only minor if any inhibition of relaxation against passive tension or KClinduced precontraction. Among various potassium channel inhibitors, BaCl 2 (10 M), tetraethylammonium (3 M), apamin (300 nM), and glibenclamide (10 M) did not inhibit isoproterenol-induced relaxation. Some inhibition of the isoproterenol effects against KCl-induced tone but not against passive tension was seen with inhibitors of calcium-dependent potassium channels such as charybdotoxin and iberiotoxin (30 nM each). A combination of SQ 22,536 and ODQ significantly inhibited relaxation against passive tension by about half, but not that against KCl-induced tone. Moreover, the combination failed to enhance inhibition by charybdotoxin against KCl-induced tone. We conclude that cAMP and cGMP each play a minor role in ␤-adrenergic receptor-mediated relaxation against passive tension, and calcium-dependent potassium channels play a minor role against active tension.During the storage phase of the micturition cycle, the urinary bladder must accommodate increasing amounts of urine without major elevation of intravesical pressure. This enhancement of bladder compliance requires relaxation of smooth muscle cells of the detrusor, which is controlled by reflex pathways involving an efferent activity of the sympathetic nervous system, particularly the hypogastric nerve originating from spinal cord segments Th12-L2 (Michel and Peters, 2004). Norepinephrine released from the hypogastric nerves primarily acts upon ␤-adrenergic receptors in the urinary bladder to promote relaxation during the storage phase. Therefore, ␤-adrenergic receptor activation is considered to be the most important physiological mechanism mediating urinary bladder relaxation during the filling/storage phase of the micturition cycle (Yamaguchi, 2002;Andersson, 2004).Several recent reports have investigated the ␤-adrenergic receptor subtypes mediating urinary bladder relaxation in several species. Atypical ␤-adrenergic receptors, i.e., ␤ 3 and/or other non-␤ 1 -non-␤ 2 subtypes, seem to be important for bladder relaxation in all species, b...

Control of Urinary Drainage and Voiding

“…The canonical signaling pathway for b-ARs is through elevation of cAMP and generally results in smooth muscle relaxation. It appears likely that activation of the b 3 -receptor may involve interactions with other cellular signaling proteins, such as K channels (60). There appears to be good evidence for both cAMP-dependent, as well as independent, effects (61).…”

Prospective pharmacologic therapies for the overactive bladder

“…However, there is evidence suggesting that in the bladder Kþ channels, particularly BK ca channels, may be more important in -AR mediated relaxation than cAMP [Frazier et al 2008;Frazier et al 2005;Uchida et al 2005;Hudman et al 2000].…”

Bladder Contractility Is Mediated by Different K+ Channels in the Urothelium and Detrusor Smooth Muscle

“…On the other hand, stimulation with a β-adrenergic agonist elicits bladder relaxation (6). Growing evidence points to a role of K + channels in β-adrenoceptor-mediated bladder relaxation (7,8). Direct relaxant effects of K + -channel openers, for example, rilmakalim and ZD0947, have also been demonstrated in CCh-precontracted detrusor strips (9,10).…”

“…Phasic contractions in the detrusor are under negative influences of K v , BK, IK, and SK channels (2,4,14). Functional relationship between K + channels and β-adrenoceptor-mediated detrusor relaxations have also been studied (7,8,22). Information on K + channel-mediating effects in detrusor contractions is relatively scarce by comparison.…”