nitroarginine and methylatropine

The aim of the present study was to characterize the muscarinic receptor subtype mediating nonadrenergic noncholinergic (NANC) relaxations in the rabbit anococcygeus muscle (RAM) by the use of muscarinic receptor agonists and a battery of key muscarinic antagonists. In addition, experiments were carried out to identify the NANC neurotransmitter(s) involved in the inhibitory NANC neurotransmission. In preparations with histamine-raised tone, the nonselective muscarinic agonists (pD2 values) (+)-muscarine (5.23), cis-dioxolane (5.16), oxotremorine M (4.95) and carbachol (4.06) produced concentration-dependent relaxations corresponding to 72.6-85.0% of the histamine-induced precontraction. In contrast, the subtype-preferring (M1/M4 over M2 and M3 receptors) agonists 4-(3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343), (S)-4-(dimethylamino)-1-methyl-2-butynyl-N-(3-chlorophenyl)carbamate methobromide [(S)-BN 228], (R)- and (S)-N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide [(R)- and (S)-BM 5] showed no or rather low [(S)-BN 228] muscarinic activity. The low potencies, together with the ineffectiveness of some agonists, indicated a low effective receptor reserve associated with the relaxant response. No contractile responses to (+)-muscarine were observed neither in unstimulated nor in precontracted preparations suggesting that the existence of an excitatory postjunctional muscarinic receptor may be excluded. The nicotinic antagonist hexamethonium had no influence on relaxant responses to (+)-muscarine, but abolished relaxations elicited by (-)-nicotine. This demonstrates that the RAM contains also nicotinic acetylcholine receptors (AchRs) mediating inhibitory NANC responses. Relaxations induced by the stimulation of muscarinic and nicotinic AchRs as well as by electrical field stimulation (EFS) were completely abolished by tetrodotoxin and were also sensitive to the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L-NOARG), indicating that NO plays an important role as an inhibitory NANC transmitter in RAM. All muscarinic antagonists investigated did not influence the histamine-induced precontraction, but shifted the concentration-response curve of (+)-muscarine to the right in a parallel fashion. Schild analysis yielded regression lines of unit slope, indicating competitive antagonism. The following rank order of antagonist potencies (pA2 values) was found: 11-([4-[4-(diethylamino)-butyl]-1-piperidinyl]-acetyl-5,1

Topics: Animals; Atropine Derivatives; Electric Stimulation; Hexamethonium; In Vitro Techniques; Male; Muscarine; Muscarinic Agonists; Muscarinic Antagonists; Muscle Relaxation; Muscle, Skeletal; Nicotine; Nitric Oxide; Nitroarginine; Rabbits; Receptor, Muscarinic M4; Receptors, Muscarinic; Receptors, Nicotinic; Tetrodotoxin

Externally applied acetylcholine (ACh) in human corpus cavernosum has been shown to cause endothelium-dependent smooth muscle relaxation. Changes in isometric tension in rabbit cavernous smooth muscle strips mounted in organ bath chambers were monitored in the presence of blocking agents. Nitric oxide (NO) is known as an endothelium-derived relaxation factor (EDRF). Addition of specific inhibitors of nitric oxide synthesis, such as L-n-monomethyl arginine (L-NMMA) at 5 x 10(-4) mol/l.. or L-n-nitro arginine (L-NOARG) at 2 x 10(-4) mol/l. to strips precontracted with phenylephrine (PE) at 3.16 x 10(-6) mol/l. led to significant increases in tension. In the presence of L-NMMA or L-NOARG, relaxing effects of ACh at 10(-8)-3.16 x 10(-5) mol/l. mediated by muscarinic receptors were almost completely abolished. These data indicate that rabbit cavernous smooth muscle is under the control of basal NO release. They constitute strong evidence that cholinergically induced endothelial formation of NO plays a crucial role in relaxing cavernous smooth muscle.

Topics: Acetylcholine; Animals; Arginine; Atropine Derivatives; Endothelium; In Vitro Techniques; Male; Methylene Blue; Muscle Relaxation; Muscle, Smooth; Nitric Oxide; Nitroarginine; omega-N-Methylarginine; Parasympatholytics; Penis; Rabbits