Effects of Various Selective Phosphodiesterase Inhibitors on Carbachol-Induced Contraction and Cyclic Nucleotide Contents in the Guinea Pig Gall Bladder

Abstract

ABSTRACT. The effects of various selective phosphodiesterase (PDE) inhibitors on muscle contractility and cyclic nucleotide contents in the guinea pig gall bladder were investigated. Various selective PDE inhibitors, vinpocetine (type 1), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, type 2), milrinone (type 3), Ro20-1724 (type 4), and zaprinast (type 5), inhibited CCh-induced contractions in a concentration-dependent manner. The rank order of potency for the gall bladder was Ro20-1724 > vinpocetine > EHNA >milrinone > zaprinast, which was different from that of the trachea, taenia coli, and aorta. In the presence of CCh (0.3 µM), vinpocetine, milrinone, and Ro20-1724 each increased cAMP content, but not cGMP. By contrast, zaprinast increased cGMP content, but not cAMP, and EHNA increased both cAMP and cGMP contents. These results suggest that vinpocetine-, milrinone-, and Ro20-1724-induced relaxation was correlated with cAMP, zaprinast-induced relaxation was correlated with cGMP, and that EHNA-induced relaxation was correlated with cAMP and cGMP in the guinea pig gall bladder. In conclusion, the effect of PDE inhibitors in the guinea pig gall bladder was different from those in smooth muscles, such as the trachea, taenia coli, and aorta. KEY WORDS: cAMP, cGMP, Gall bladder, PDE inhibitor.J. Vet. Med. Sci. 67 (7): [659][660][661][662][663][664][665] 2005 Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are important second messengers, and have been associated with smooth muscle relaxation [5]. These cyclic nucleotides are synthesized by adenylyl cyclase or guanylyl cyclase, and are degraded by phosphodiesterase (PDE). Currently, PDEs are classified into 11 families [3,6,23], and selective PDE inhibitors have been found [4]. It has been reported that the relaxation induced by these selective PDE (type 1-type 5) inhibitors is involved in the increases in cAMP and/or cGMP contents in vascular [14], tracheal [16], urinary [15,22], and intestinal smooth muscle [10,11]. Since PDE1 and 2 hydrolyze cAMP and/or cGMP [3], it is thought that type 1 and type 2 inhibitor-induced relaxations may be correlated with increases in cAMP and/or cGMP in smooth muscles. It has been reported that vinpocetine (type 1 inhibitor) induced relaxation in the rabbit aorta through the increase in cGMP content [1,7], and in the rat urinary bladder [15] and guinea pig taenia coli [10] through an increase in the cAMP content. There have been few reports indicating that relaxation induced by EHNA (type 2 inhibitor) is associated with the increases in the cyclic nucleotide contents of smooth muscle [9,11,13].Additionally, the relationship of relaxation induced by these selective inhibitors and cyclic nucleotides is less clear in the smooth muscle of the gastrointestinal tract. Barnette et al. [2] assessed the activity of PDE families and the relaxation induced by the PDE3, 4, and 5 inhibitors in canine colonic smooth muscle. They showed that PDE3 and 4 inhibitors decreased the hydrolysis of cAMP, that the PDE5 inhib...

PDE4 and PDE5 regulate cyclic nucleotide contents and relaxing effects on carbachol-induced contraction in the bovine abomasum

“…It has been reported that rolipram (type 4) potently relaxed electrical field stimulation-induced contraction in the cat gastric fundus [1]. Ro20-1724 inhibited CCh-induced contraction in the bovine abomasum (in the present study) and guinea pig gall bladder [14] potently, but poorly in the guinea pig ileum [12] and taenia coli [13]. These data suggested that the functional distributions of PDE4 isozymes of gastrointestinal smooth muscles differ by organ.…”

“…Moreover, the PDE1-5 isozymes have selective inhibitors [5], and selective inhibitors for PDE7 and 9 have also been made recently and commercialized. It has been shown that the potency of the relaxation induced by these PDE inhibitors differed in many smooth muscles including gastrointestinal smooth muscles [1, 12,13,14, 22]. Therefore, we investigated the effects of selective PDE inhibitors for PDE1-5, 7 or 9 on CCh-induced contractions of the smooth muscles in the bovine abomasum.…”

“…On the other hand, selective inhibitors for PDE1-5 also inhibited agonist-induced contraction dose-dependently in gastrointestinal smooth muscle, zaprinast (type 5) was most effective in the guinea pig taenia coli [13] and ileum [12], and Ro20-1724 (type 4) was most effective in the guinea pig gall bladder [14]. In the present study, selective PDE inhibitors inhibited CCh-induced contraction in the bovine abomasum, dose-dependently, and Ro20-1724 (type 4) and vardenafil (type 5) were more effective than the other PDE inhibitors.…”

“…Currently, PDEs are classified into 11 families [3], and selective PDE inhibitors have been developed [5]. It has been reported that the relaxation induced by these selective PDE (type 1 to 5) inhibitors is involved in the increases in cAMP and/or cGMP contents in vascular [17], tracheal [19], urinary [18, 23], gastrointestinal [1, 12,13,14, 22] and iris smooth muscle [26]. However, to our knowledge, there have been few reports showing the effects of selective PDE7 and/or PDE9 inhibitors in smooth muscle contractions.…”

Characterization of inhibitors of phosphodiesterase 1C on a human cellular system

“…PDE1 enzymes have been reported to be involved in heterogeneous functions such as smooth muscle cell proliferation (PDE1C [5]), Cl – secretion by human colonic epithelial cells [9], interleukin (IL)‐13 production by CD3/CD28‐stimulated human T‐lymphocytes [10], the acrosome reaction of human spermatozoa [11], lipopolysaccharide‐induced IL‐6 release from alveolar epithelial cells [12], glucose‐induced insulin secretion from insulinoma cells [8], contraction of ureteral smooth muscle cells [13], hypoxic pulmonary remodeling [14], granulocyte–macrophage colony‐stimulating factor‐induced human monocyte‐to‐macrophage differentiation (PDE1B [15]), and gall bladder relaxation [16].…”