Effects of isoproterenol on contraction and membrane potential of gastric smooth muscle were studied in stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY). Circular muscle preparation from the gastric fundus developed tonic contraction by re-administration of Ca²⁺ to a nominally Ca²⁺-free solution. The contraction was inhibited by nifedipine or nicardipine. Isoproterenol induced relaxation when it was applied to the Ca²⁺-induced contraction. The amplitude of isoproterenol-induced relaxation was concentration-dependent. Propranolol 10^-6M abolished the relaxation induced by isoproterenol 10^-7M. In the preparation from SHRSP, the amplitude of isoproterenol-induced relaxation was smaller than that from WKY between 3×10^-9 and 10^-7M. Forskolin, an adenylate cyclase activator, induced concentration-dependent relaxation. There was no difference in the relaxation induced by forskolin between preparations from WKY and SHRSP. Dibutilyl cyclic AMP, a membrane permeable analogue of cyclic AMP, also induced similar relaxation in preparations from WKY and SHRSP. Resting membrane potential of smooth muscle cell was not different between preparations from WKY and SHRSP. Isoproterenol hyperpolarized the membrane concentration-dependently. Isoproterenol-induced hyperpolarization in the preparation from SHRSP was smaller than that from WKY between 10^-8 and 10^-6M. When the membrane was depolarized by Tyrode’s solution containing 40mM K⁺, isoproterenol-induced hyperpolarization was almost abolished. In this condition, the isoproterenol-induced relaxation was inhibited partly, however, there was no difference in the amplitude of relaxation between preparations from WKY and SHRSP. Therefore, isoproterenol-induced hyperpolarization contributed at least partly to the relaxation. Forskolin hyperpolarized the membrane by the same amplitude in the preparations from WKY and SHRSP. These results indicate that a decrease in hyperpolarization may contribute to the decreased relaxation by isoproterenol in the preparation from SHRSP.

View full abstract

In the present study, we tried to determine what effects were induced by β-adrenoceptor agonists on 40mM KCl-induced rhythmic contraction and to clarify which β-adrenoceptor subtypes are involved in the regulation of ureter motility in the guinea pig by using in vitro functional analysis. 40mM KCl-induced rhythmic contraction was abolished by papaverine (10^-6M), nicardipine (10^-5M) and cromakalim (10^-5M), but was not influenced by atropine (10^-6M). Isoprenaline decreased the amplitude, and changed the pattern of 40mM KCl-induced rhythmic contraction in concentration-dependent manner. These results suggest the posslbility that the stimulation of β-adrenoceptors may regulate the ureteral peristalsis. Salbutamol (selective β₂-AR agonist) and CGP12177 (β_{1, 2}-AR antagonist and β₃-AR partial agonist) were also effective in decreasing the amplitude and changing the pattern of the rhythmic contraction. The pD₂ values of agonists were 7.57 (isoprenaline), 5.80 (CGP12177) and 7.63 (salbutamol), respectively. The concentration-response curves of isoprenaline and salbutamol were rightward shifted by the presence of propranolol, and the apparent pA₂ values for propranolol against isoprenaline and salbutamol were 7.12 and 6.29, respectively. These results suggest that inhibition for 40mM KCl-induced rhythmic contraction of the ureter by isoprenaline and salbutamol mediated mainly via atypical β-adrenoceptor subtype.

View full abstract

1 Activation of β-adrenoceptors causes relaxation of the urinary bladder and contraction of the external urethral sphincter, which consists of fast-contracting skeletal muscles. A β₂-adrenoceptor agonist, clenbuterol, recently has been developed as a therapeutic drug for the treatment of urinary incontinence, however β₂-adrenoceptor agonists have undesirable effects on cardiac and striated muscle function. 2 In this study, we compared the effects of the β₂-adrenoceptor agonist, clenbuterol and of a novel β₂-adrenoceptor agonist, GS332, on urinary bladder and external urethral sphincter function in rat, rabbit and human. We also determined the distrubution of β₃-adrenoceptors in human urinary bladder and external urethral sphincter, using radioligand-binding techniques. 3 Clenbuterol induced marked relaxations in rat, rabbit and human urinary bladder smooth muscles and also induced marked contractions in rat periurethral striated muscles (external urethral sphincter), while GS332 induced marked relaxations in rat and human, but not in rabbit, urinary bladder smooth muscles and induced small contractions in rat periurethral striated muscles. 4 The radioligand-binding studies showed presence of β₂- and β₃-adrenoceptors in human urinary bladder, external urethral sphincter and abdominal rectus muscles. The affinities of GS332 were the highest in urinary bladder and the lowest in the skeletal (abdominal rectus) muscles, while the affinities of clenbuterol were similar in urinary bladder, external urethral sphincter and the skeletal (abdominal rectus) muscles. 5 These results suggest that GS332 could, similarly clenbuterol, have a role in the treatment of urinary frequency and urinary incontinence.

View full abstract

Endothelium-dependent relaxation of aorta and carotid artery from stroke-prone spontaneously hypertensive rats (SHRSP) and the effect of chronic treatment of SHRSP with perindopril, an angiotensin converting enzyme inhibitor, on endothelium-dependent relaxation were studied. Endothelium-dependent relaxation was induced by acetylcholine (ACh) in preparations of SHRSP and normotensive Wistar Kyoto rats (WKY) precontracted with noradrenaline. The ACh-induced relaxation in both preparations was abolished by L-nitroarginine. The ACh-induced relaxation was impaired in preparations from SHRSP and contraction was observed at high concentrations of ACh. In the presence of indomethacin, impairment of endothelium-dependent relaxation in SHRSP was minimized and the contraction was inhibited. The relaxation with sodium nitroprusside did not differ between the preparations from WKY and SHRSP. Treatment of SHRSP with perindopril (2 mg/kg/ day) for 6 weeks decreased systolic blood pressure and improved the ACh-induced relaxation of aorta and carotid artery. The treatment inhibited the contraction by higher concentrations of ACh in the presence of L-nitroarginine. These results indicate that the impairment of endothelium-dependent relaxation in aorta and carotid artery of SHRSP may be caused by the reduced availability of nitric oxide. The perindopril-treatment may prevent these changes in SHRSP.

View full abstract