title: Effects of 3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-1-benzopyran (K-351) on smooth muscle cells and neuromuscular transmission in the canine mesenteric artery.
abstract: 1 The effects of K-351 on the electrical and mechanical responses were investigated in the canine mesenteric artery by isometric tension recording and the use of intracellular microelectrodes. The results were compared to the responses observed with other alpha-adrenoceptor blocking agents. 2 K-351 (greater than 3 X 10(-7)M) consistently inhibited the contraction evoked by perivascular nerve stimulation; however, K-351 had no effect on the contraction evoked by direct muscle stimulation, after pretreatment with 3 X 10(-7)M tetrodotoxin. 3 Phentolamine enhanced and prazosin had no effect on the amplitude of contraction evoked by perivascular nerve stimulation at a high frequency (over 1.0 Hz). Pretreatment with phentolamine inhibited the contraction evoked by lower frequencies of perivascular nerve stimulation (below 0.5 Hz). 4 The potency for the inhibition of the response to perivascular nerve stimulation was in the order of K-351 greater than phentolamine greater than prazosin, while the contractions induced by exogenously applied noradrenaline (5 X 10(-7)M) were inhibited in the order: prazosin greater than phentolamine greater than K-351. 5 K-351 (less than 3 X 10(-5)M) did not modify the resting membrane potential or the membrane resistance, as estimated from the change in the amplitude of electrotonic potentials in the smooth muscle cell membranes. 6 K-351 (greater than 3 X 10(-7)M) inhibited the amplitude of the first e.j.p. and e.j.ps after completion of the facilitation process following stimulation at frequencies over 0.25 Hz. 7 K-351 (less than 3 X 10(-5)M) did not modify the compound action potentials recorded from peripheral nerve bundles distributed on the mesenteric artery. 8 Phentolamine (greater than 1 X 10(-8)M) inhibited the first e.j.p. but this agent either inhibited or enhanced the amplitude of e.j.p. after completion of the facilitation process produced by repetitive stimulation below or over 1.0 Hz stimulus frequencies, respectively. Prazosin (1 X 10(-6)M) had no effect on e.j.ps evoked by perivascular nerve stimulation, at any stimulus frequency applied. 9 These results indicate that K-351 inhibits the extra-junctional adrenoceptor with a slightly weaker potency than prazosin or phentolamine, but that this agent has a potent action as an intra-junctional adrenoceptor blocking agent. Phentolamine acts mainly on the extra-junctional adrenoceptors and also has weak actions on intra-junctional adrenoceptors, as a blocking agent. This agent also inhibits the presynaptic alpha 2-adrenoceptor. Prazosin inhibits only the extra-junctional alpha 1-adrenoceptor.
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004285:Dogs; D005071:Evoked Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009469:Neuromuscular Junction / Q000187:drug effects*; D010646:Phentolamine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D011412:Propanolamines; D013779:Tetrodotoxin; C036089:nipradilol; D011224:Prazosin; D010646:Phentolamine