Katsuhito Ogawa

Mechanism of xanthine-induced relaxation of guinea-pig isolated trachealis muscle

1 Four 3‐alkylxanthines (3‐methylxanthine, 3‐n‐propylxanthine (enprofylline), 3‐n‐butylxanthine and 3‐iso‐butylxanthine) and four 1‐methyl‐3‐alkylxanthines (1‐methyl‐3‐methylxanthine (theophylline), 1‐methyl‐3‐n‐propylxanthine, 1‐methyl‐3‐n‐butylxanthine and 1‐methyl‐3‐iso‐butylxanthine (IBMX)), were compared in terms of cyclic AMP phosphodiesterase (PDE) inhibition and trachealis muscle relaxation. The relationship between xanthine structure and cyclic AMP PDE inhibition was also studied. 2 Xanthine induced relaxation of guinea‐pig isolated trachealis muscle was measured against spontaneous tone. 3 The four 1‐methyl‐3‐alkylxanthines were each significantly more potent than the corresponding 3‐alkylxanthines in relaxing the isolated trachealis muscle. The 1‐methyl‐3‐alkylxanthines were similarly more potent than the corresponding 3‐alkyl derivatives in inhibiting low Km cyclic AMP PDE. There was a strong positive correlation between low Km cyclic AMP PDE inhibition and the tracheal smooth muscle relaxation evoked by the xanthine derivatives. 4 Since methylation of the 1‐position of each 3‐alkylxanthine increased the potency of the derivative in inhibiting low Km cyclic AMP PDE and in relaxing trachealis muscle and since a strong positive correlation was observed between the relaxant EC50 and the Ki value of each xanthine derivative, it is suggested that low Km cyclic AMP PDE inhibition by xanthines plays an important role in their tracheal relaxant effect.

Potentiation of atrial natriuretic peptide‐stimulated cyclic guanosine monophosphate formation by glucocorticoids in cultured rat renal cells

1 The effect of steroid hormones on atrial natriuretic peptide (ANP)‐stimulated cyclic guanosine monophosphate (cyclic GMP) formation was studied in cultured rat renal cells. 2 ANP increased cyclic GMP formation in a dose‐dependent manner, while cyclic AMP was not changed by ANP. 3 Steroid hormones did not affect basal cyclic GMP levels in cultured rat renal cells. 4 Dexamethasone at 10−8m increased ANP (human and rat ANP)‐stimulated cyclic GMP dose‐dependently in cultured rat renal cells. Cortisol, corticosterone and aldosterone at a concentration of 10−7m also potentiated ANP‐stimulated cyclic GMP formation, although triiodothyronine, oestradiol and testosterone were ineffective. Potentiation of ANP action by these steroids seems to parallel glucocorticoid activity. 5 Dexamethasone did not affect cyclic GMP formation stimulated by sodium nitroprusside which stimulates soluble guanylate cyclase in the cytosol. Therefore, the potentiating action of dexamethasone may be mediated through the action on particulate guanylate cyclase at the plasma membrane. 6 It is suggested that the diuretic action of glucocorticoids may, at least in part, be mediated through the potentiating effect of glucocorticoids on cyclic GMP response to ANP.

Diuretics modify [Arg8]vasopressin-stimulated cAMP but not atrial natriuretic peptide-stimulated cGMP formation in renal cells.

The present study was undertaken to examine whether sulfonamide-derived diuretics affect [Arg8]vasopressin (AVP)-stimulated or atrial natriuretic peptide (ANP)-stimulated cyclic nucleotide formation in cells cultured from rat or dog kidney. In rat renal cells, all four sulfonamide-derived diuretics examined significantly suppressed 10(-9) M AVP-stimulated cAMP formation at concentrations of 10(-4) and 10(-3) M, while basal cAMP formation was unchanged by the diuretics. When cells were stimulated with 10(-7) M AVP, low ceiling diuretics (indapamide and trichlormethiazide) did not suppress cAMP formation, while high ceiling diuretics (furosemide and azosemide) significantly suppressed cAMP formation at concentrations of 10(-4) and 10(-3) M. The suppressive effect of the diuretics on AVP-stimulated cAMP formation in vitro paralleled the reported diuretic potency of the agents in vivo. In dog renal cells, all four diuretics significantly suppressed 10(-9) M AVP-stimulated cAMP formation at concentrations from 10(-6) to 10(-5) M, while these diuretics did not change basal cAMP levels. High ceiling diuretics suppressed 10(-7) M AVP-stimulated cAMP formation, whereas low ceiling diuretics did not. The difference in effective doses between rats and dogs seems to be consistent with the species difference observed in vivo. None of the diuretics affected basal levels of intracellular cGMP or ANP-stimulated cGMP formation in cultured rat renal cells. In addition to the inhibition of the Na/K/Cl co-transporter, it is suggested that most sulfonamide-derived diuretics act, at least in part, by inhibiting the actions of AVP.