Pressor Effect of Intracerebroventricular 4-Aminopyridine on the Systemic Arterial Pressure in the Rabbit

A K+-channel blocker, 4-aminopyridine(4-AP) increases neurotransmitter release from motor nerve terminals and has been shown to restore neuromuscular transmission in the myasthenic syndrome. It has been reported that the intravenous injection of 4-AP in the myasthenic patients caused many central adverse effects including anxiety and restlessness, but did not affect the blood pressure. The aim of this study was to observe the effect of intracerebroventricularly administered 4-AP on the blood pressure and to elucidate the mechanism of the action in urethane-anesthetized rabbits. Intracerebroventricular(icv) 4-AP produced pressor effects in a dose-dependent fashion, but intravenous(iv) 4-AP of the same dose did not altered the blood pressure. Tetraethylammonium, a K+-channel blocker which differs from 4-AP structurally, had little effect on the blood pressure, but 3,4-diaminopyridine, another derivative of the aminopyridine, produced pressor effect similar to 4-AP. The pressor effect of icv 4-AP was not affected by the treatment with iv phenoxybenzamine and chlorisondamine, and in bilateral adrenalectomized rabbits. These results suggest that the 4-AP pressor effect is not related to the periphral sympathetic nerve nor adrenal gland. The pretreatment with icv phentolamine and prazosin did not altered the 4-AP pressor. However, the icv 4-AP pressor effect was significantly attenuated by the treatment with icv yohimbine, and significantly potentiated by the treatment with icv clonidine. The treatment with icv diltiazem markedly inhibited the icv 4-AP pressor effect. It is concluded that 4-AP-sensitive K+-channels in rabbit brain might play a role in the regulation of blood pressure and that the 4-AP pressor effect is closely related to the central alpha2-adrenoceptors and L-type calcium channels.

Action mechanisms of NANC neurotransmitters in smooth muscle of guinea pig ileum

The relaxation induced by stimulation of the inhibitory non-adrenergic, non-cholinergic (iNANC) nerve is mediated by the release of iNANC neurotransmitters such as nitric oxide (NO), vasoactive intestinal peptide (VIP) and adenosine triphosphate (ATP). The mechanisms of NO, VIP or ATP-induced relaxation have been partly determined in previous studies, but the detailed mechanism remains unknown. We tried to identify the nature of iNANC neurotransmitters in the smooth muscle of guinea pig ileum and to determine the mechanism of the inhibitory effect of nitric oxide. We measured the effect of NO-donors, VIP and ATP on the intracellular Ca2+ concentration((Ca2+)i), by means of a fluorescence dye (fura 2) and tension simultaneously in the isolated guinea pig ileal smooth muscle. Following are the results obtained. 1. Sodium nitropnisside (SNP: 10(-5) M) or S-nitro-N-acetyl-penicillamine (SNAP: 10(-5) M) decreased resting (Ca2+)i and tension of muscle. SNP or SNAP also inhibited rhythmic oscillation of (Ca2+)i and tension. In 40mM K+ solution or carbachol (CCh:10(-6) M)-induced precontracted muscle, SNP decreased muscle tension. VIP did not change (Ca2+)i and tension in the resting or precontracted muscle, but ATP increased resting (Ca2+)i and tension in the resting muscle. 2. 1H-(1,2,4)oxadiazol(4,3-a)quinoxalin-1-one (ODQ:1 muM), a specific inhibitor of soluble guanylate cyclase, limited the inhibitory effect of SNP. 3. Glibenclamide (10 muM), a blocker of KATP channel, and 4-aminopyridine (4-AP:5 mM), a blocker of delayed rectifier K channel, apamin (0.1 muM), a blocker of small conductance KCa. channel had no effect on the inhibitory effect of SNP. Iberiotoxin (0.1 muM), a blocker of large conductance KCa channel, significantly increased the resting (Ca2+)i, and tension, and limited the inhibitory effect of SNP. 4. Nifedipine (1 muM) or elimination of external Ca2+ decreased not only resting (Ca2+)i and tension but also oscillation of (Ca2+)i and tension. Ryanodine (5 muM) and cyclopiazonic acid (10 muM) decreased oscillation of (Ca2+)i and tension. 5. SNP decreased Ca2+ sensitivity of contractile protein. In conclusion, these results suggest that 1) NO is an inhibitory neurotransmitter in the guinea pig ileum, 2) the inhibitory effect of SNP on the (Ca2+)i and tension of the muscle is due to a decrease in (Ca2+)i by activation of the large conductance KCa channel and a decrease in the sensitivity of contractile elements to Ca2+ through activation of G-kinase.

Effect of K+ channel Blocker on Vasodilation by Halothane / 대한마취과학회지

Halothane is a popular inhalation anesthetics in practice, which has been reported to cause a vasodilation through a direct depressant action on vascular smooth muscle, or by an indirect attenuation of vasoconstrictor activity. The membrane potential of the vascular smooth muscle cell is mainly regulated by the flow of Ca2+ and K+ ions through specialized channels. The purpose of this study was to determine whether blockade of the K+ channel alter the response to halothane vasodilating action. This study was done with rat thoracic aorta in tissue bath. Isometric tension of the ring (3~4 mm in length) was recorded. In halothane alone group (n=15), after precontraction with norepinephrine (10(-7) M), ring was exposed with halothane 0.7%, 1.5%, 2.1% concentration for 15 minutes, sequentially. The procedure of calcium activated K+ channel blocker pretreated group (n=12) was same manner as halothane alone group after tetraethylammonium (TEA 20 mM) pretreatment. The result of this study was shown to followings; 1) Vasodilation correlate with halothane concentration (p<0.05). 2) Vasodilation in tetraethylammonium (TEA) pretreated group also augmented 'significantly (p<0.05). 3) Especially, in the halothane 1.5%, 2.1%, the presence of TEA significantly potentiate vasodilating effect: halothane alone group, -35%, -53%: TEA group, -47%, -71%(p<0.05). These result demonstrate that: 1) halothane induce relaxation of rat aorta. 2) K+ charinel blokade potentiate the vasodilating effect of halothane.

Effects of Acid-Base Balance on the Isolated Rabbit Vascular Tone / 대한마취과학회지

The effects of acidosis and alkalosis on vascular smooth muscle contractions were studied. Ring segments(3-4 mm in length) of rabbit abdominal aorta and pulmonary artery were mounted in the tissue bath(for respiratory study) and superfusion device(for metabolic study) for isometric tension recording. Respiratory acidosis and alkalosis were obtained by increasing and lowering the PCO2(80 and 15 mmHg, respectively). Metabolic acidosis and alkalosis were obtained by lowering and increasing the HCO3 concentration(12 and 50 mEq/l, respectively). After precontraction with norepinephrine(10-7 M), Vessels were exposed to acidosis and alkalosis for 30 minutes. The study was done with and without endothelium. The mechanism of vasorelaxation and vasoconstriction were confirmed with Ca2+ activated K+ channel blocker and Ca2+ free Krebs solution. The results were as follows: 1) Respiratory and metabolic acidosis induced significant vasorelaxation in both group of abdominal aorta and pulmonary artery(p<0.05). In endothelium intact group, vasorelaxation was greater than endothelium removed group. especially in respiratory acidosis was statistically significant(p<0.05). 2) Respiratory and metabolic alkalosis induced significant vasoconstriction in both group of abdominal aorta and pulmonary artery(p<0.05). In endothelium intact group, vasoconstriction was lesser than endothelium removed group, but was not statistically significant. 3) Acidosis induced vasorelaxation was blocked by tetraethylammonium(TEA). 4) Alkalosis induced vasoconstriction was blocked by Ca2+ free Krebs solution. These results suggested that: 1) Acidosis induced vasorelaxation. 2) alkalosis induced vasoconstriction 3) Vasorelaxation during acidosis was induced by K+ efflux through the Ca2+ activated K' channel. 4) Vasoconstriction during alkalosis was induced by Ca2+ influx.

The Effect of Tetraethylammonium Chloride on the Impulse Conduction Block by bupivacaine / 대한마취과학회지

Potassium channel blockers slow depolarization, broaden the action potential, and thus pro- mote the open and inactivated Na+ channel states. The ability of local anesthetics to reduce the amplitude of compound action potential(CAP) of rat sciatic nerve was examined in the presence and absence of teteraethylammonium chloride(TEA) that selectively block K+ channels, In the presence of 1.3X10-5 M bupivacaine that inhibit the CAP by 22.5% at tonic stimulation, the addition of TEA(10-1M) increased this inhibition by another 27.5% and increased another 50% by phasic stimulation(20Hz). Also, dose response curve of bupivacaine in the presence of TEA(10-1M) showed marked shift to left of curve. The re- covery kinetics of bupivacaine in the presence of various coneentration of TEA(10-2-10-1M) showed marked delay of recovery(2X10-2 M), reocurrence of inhibition(90min,5X10-2 M), even no recovery(10-1M). TEA alone slightly depolarized the resting membrane which was represented as increment of CAP height from 0.9%(3min) to 12.3%(80min), and broadened mid-peak amplitude width by 2 times in 5X10-1M, 5.3 times in 1M. These experiments directly demonstrated that TEA potentiated the inhibition of CAP by bupivacaine and showed the poesibility of mixture of TEA and local anesthetics to potenti- ate impulse conduction blockade.