title: Effects of a new alpha-adrenoceptor blocking agent, ethyl-7-[4-(2-methoxyphenyl)-1-piperazinyl] heptanoate dihydrochloride (SGB-483), on smooth muscle and neuromuscular transmission in guinea-pig mesenteric artery.
abstract: The effects of ethyl-7-[4-(2-methoxyphenyl)-1-piperazinyl] heptanoate dihydrochloride (SGB-483) on the smooth muscle of the guinea-pig mesenteric artery were investigated using microelectrodes. The resting membrane potential was -70.3 +/- 2.1 mV.SGB-483 (10(-8)M - 10(-4)M) did not modify the membrane potential or membrane resistance, as estimated from measurement of current-voltage relationships. Noradrenaline (NA; above 10(-5)M) depolarized the membrane. After pretreatment with SBG-483 10(-5)M or prazosin 10(-6)M, the NA-induced depolarization of the membrane was inhibited; yohimbine (10(-5)M) was ineffective. Phenylephrine and NA (greater than 3 X 10(-7)M) but not clonidine (10(-6)M) contracted the artery. These contractions were inhibited by SGB-483. Following repetitive perivascular nerve stimulation, the amplitude of excitatory junction potentials (e.j.ps) increased to a certain steady state value (e.j.p.(s]. The amplitude of e.j.p.(s) was frequency-dependent. Application of SGB-483 (over 10(-8)M) enhanced the amplitude of e.j.p.(s), dose-dependently with no change in the amplitude of the first e.j.p. (e.j.p.(f] evoked by the first stimulus. After pretreatment with NA, the amplitudes of both e.j.p.(f) and e.j.p.(s) were inhibited, dose-dependently. Following pretreatment with SGB-483 (10(-6) - 10(-5)M), the NA-induced reduction in the amplitude of both e.j.p.(f) and e.j.p.(s) were reversed and the control values restored. Clonidine (10(-7)M) inhibited the amplitude of e.j.p.(f) and e.j.p.(s), and SGB-483 (10(-7)M) partially restored the amplitude of both. Yohimbine (10(-7)M) and phentolamine (10(-7)M) enlarged the amplitude of e.j.p.(s); the amplitude of e.j.p.(f) was inhibited by yohimbine and enlarged by phentolamine. Prazosin (10(-6)M) had no effect on the amplitude of either e.j.p.(f) or e.j.p.(s), at any given stimulus frequency. SBG-483 (10(-7)M) did not enhance the amplitudes of either e.j.p.(f) or e.j.p.(s) following pretreatment with phentolamine (10(-7)M) or yohimbine (10(-7)M) but did enhance the amplitude following pretreatment with prazosin (10(-7)M). SGB-483 possesses the property of an alpha 1- and alpha 2-adrenoceptor antagonist. The alpha-antagonistic action was apparent on post-junctional smooth muscle cells. The alpha 2-antagonistic action on neuromuscular transmission was mediated at pre-junctional nerve terminals to enhance the release of NA. The prejunctional actions of SGB-483 were more selective than those of yohimbine or phentolamine.
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D004347:Drug Interactions; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D008638:Mesenteric Arteries / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000502:physiology; D010646:Phentolamine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; C035927:SGB 483; D011224:Prazosin; D010646:Phentolamine