Journal of autonomic pharmacology最新文献

1. When pretreated for 1 min, with Cd2+ at low concentrations (0.001-0.01 mM), there was a parallel rightward shift of Ca2+ concentration-curves in guinea-pig taenia coli in K+-depolarized Ca2+-free medium. However, when pretreated for 30 min, Cd2+ reduced the maximal Ca2+ response size. 2. The application of 0.01 mM Cd2+ for 1, 5 and 30 min in Ca2+-free, K+-medium reduced to the same degree the Ca uptake after addition of 3 mM Ca2+. The inhibitory action on the tension by Cd2+ however, became greater as the pretreatment time with Cd2+ increased. 3. Within 5 min of Cd2+ (0.01 mM) treatment, Cd2+ chiefly bound to the cell membrane, however, with a longer duration (30 min), Cd2+ entered the cytoplasm where EDTA could not reach. 4. Cd2+ above 0.0005 mM reduced dose-dependently the respiration of isolated mitochondria. 5. These results suggest that with short duration exposure (1-5 min) of taenia coli cells to Cd2+, the interference with Ca2+ entry through voltage-dependent Ca2+ channels is predominant but for longer exposure times, intracellular actions of Cd2+ contribute to its inhibitory effects.

In the pigeon oesophageal smooth muscle electrical field stimulation (EFS), in the presence of atropine and guanethidine, evoked TTX-sensitive inhibitory effects on both the electrical and mechanical activity. N(omega)-Nitro L-arginine (L-NA) (0.1-100 microM), an inhibitor of nitric oxide synthase, reduced the inhibitory EFS-evoked effects. Sodium nitroprusside (SNP) (10 microM), a NO-donor, mimicked the effects evoked by EFS. Apamin (1 microM) perfusion did not modify the inhibitory effects induced by SNP. Cystamine (10 microM), a guanylate-cyclase inhibitor, reduced the inhibitory effects elicited by EFS. This study shows a possible role for NO in the non-adrenergic non-cholinergic (NANC) inhibitory responses induced by EFS in the pigeon oesophagus.

1. We hypothesized that acetylcholine would attenuate the metabolic effect of increasing cAMP and decreasing cGMP on cardiac myocyte O2 consumption (VO2) in dog, and this effect would be altered in left ventricular hypertrophy (LVH) produced by aortic valve placation. 2. Steady-state VO2 of a suspension of ventricular myocytes from control (n = 7) and LVH (n = 6) dogs was measured by Clark O2 electrodes during electrical stimulation (5 ms, 1 Hz, in 2 mm Ca2+). Cyclic AMP and cyclic GMP were determined by radioimmunoassay. Cellular cAMP was increased by forskolin (adenylate cyclase stimulator) and cGMP was decreased by LY83583 (guanylate cyclase inhibitor) both at 10(-7,-6,-5,-4) M with and without 10(-6) M acetylcholine. 3. Baseline cGMP level in LVH (62 +/- 10 fmol 10(-5) myocytes) was significantly greater than that in control (20 +/- 3), although the myocyte VO2 (356 +/- 39 nL O2 min(-1) 10(-5) myocytes) and cAMP levels (3.9 +/- 0.6 nmol 10(5-1) myocytes) were similar to control (312 +/- 23 and 6.9 +/- 3.1). 4. Forskolin increased myocyte cAMP in both control and LVH myocytes and increased VO2 by 51 +/- 13 in control and 91 +/- 65 in LVH myocytes. LY83583 decreased myocyte cGMP levels in control and LVH myocytes and increased VO2 by 128 +/- 57 in control and 43 +/- 26 in LVH myocytes. 5. Acetylcholine altered the cAMP, cGMP, and VO2 levels in control to 2.4 +/- 0.4, 30 +/- 3 and 213 +/- 27 and LVH to 2.5 +/- 0.3, 85 +/- 9 and 261 +/- 32. Acetylcholine attenuated the maximal effects of forskolin on VO2 to 32 +/- 27 in control and 66 +/- 56 in LVH myocytes. Acetylcholine also decreased the maximal effects of LY83583 to 82 +/- 50 in control and 19 +/- 19 in LVH myocytes. 6. The positive metabolic effects of both increases in myocyte cAMP and decreases in cGMP were blunted by acetylcholine. There was a significant increase in myocyte cGMP with forskolin in LVH myocytes. Acetylcholine decreased the increased myocyte VO2 caused by elevated cAMP or decreased cGMP in both control and LVH myocytes, although the absolute decrease in cAMP was reduced and the absolute values of cGMP were higher in LVH myocytes.

1. To investigate the relationship between the autonomic drive to the heart and heart rate variability, as evaluated by power spectral analysis, we studied the effect of clonidine (300 microg), a central sympatholytic agent, on heart rate variability. 2. Six healthy subjects (mean age 31 +/- 3 years) were studied in the supine and the sitting position (15 min each) on two different occasions, respectively, before and after clonidine administration. Using an autoregressive approach, the low frequency (LF) and the high frequency (HF) components of power spectral analysis were measured, and their ratio was calculated. Blood pressure was monitored throughout the study and plasma catecholamines were measured at the end of each period. 3. Before clonidine, assumption of the sitting position induced increases in LF, LF/HF ratio, blood pressure and plasma noradrenaline. Clonidine induced remarkable reductions in the normalized values of the LF component and the LF/HF ratio in both the resting and the sitting position (supine: LF = -68%, LF/HF ratio = -80%; sitting: LF = -23%, LF/HF ratio = -55%) without affecting the central frequencies of LF and HF components. Blood pressure and plasma catecholamines also significantly decreased after clonidine. 4. These results support the hypothesis that the LF component of HRV, expressed in normalized units, is an indicator of the sympathetic control of the heart. In addition, this component seems to be largely of central origin, because it is markedly reduced by the central sympatholytic action of clonidine.

1. In conscious fasted rabbits the insulin secretory response induced by the intravenous infusion of the alpha1-adrenoceptor agonist, amidephrine (10 microg kg(-1) min(-1)) was blocked by the simultaneous administration of clonidine (2 microg kg(-1) min(-1) i.v.). 2. The excitatory effect of amidephrine (10 microg kg(-1) min(-1)) on insulin secretion was similarly suppressed by the concomitant infusion of the selective alpha2-adrenoceptor agonist UK14304 (1 microg kg(-1) min(-1)). Both, the increase in blood glucose and the inhibition of insulin secretion found with UK14304 when infused alone were antagonized in rabbits previously treated with the very selective alpha2-adrenoceptor antagonist 2-methoxyidazoxan (1.5 microg kg(-1) min(-1)). 3. The combined administration of amidephrine (3 microg kg(-1) min(-1)) and isoprenaline (0.3 microg kg(-1) min(-1)) evoked a potentiated increase in insulin plasma levels in the face of a weak hyperglycaemia, an established reduction in blood pressure and tachycardia. 4. The potentiated insulin secretory response derived from alpha1- and beta-adrenoceptor stimulation was blunted by clonidine administration. In its presence a sustained hyperglycaemic response was found. 5. The increase in plasma lactate levels resulting from dual adrenoceptor stimulation (amidephrine: 10 microg kg(-1) min(-1) + salbutamol: 0.3 microg kg(-1) min(-1)) was smaller than the expected should addition or potentiation occurred. 6. Our results point to a possible physiological role played by alpha2-adrenoceptors on insulin secretion, since their stimulation by the endogenous catecholamines could lead to inhibition of insulin release, masking any potentiated response that otherwise should have appeared from alpha1- and beta-adrenoceptor stimulation.

1. The antilesion actions of two antimuscarinic drugs on ethanol-induced gastric injury and mucosal integrity were examined in male rats. Histological examinations were made and gastric emptying rates determined after in vivo administration of the drugs to conscious rats. In anaesthetized rats, with an ex vivo gastric chamber, effects on gastric transmucosal potential difference, Evan's blue leakage and Na+ output were examined. 2. In conscious animals, atropine (1 mgkg-1, i.p.) and pirenzepine (1 mgkg-1, i.p.) both significantly reduced macroscopic lesion formation, but not microscopic damage and functional alterations, caused by orally administered absolute ethanol. Moreover, these drugs did not show any effect on the basal gastric adherent mucus level, nor the depleting action of ethanol on both adherent mucus and the mucosal mucus layer. Nevertheless, both atropine and pirenzepine significantly reduced gastric emptying rate. 3. In anaesthetized animals, pirenzepine but not atropine increased the basal transmucosal potential difference (PD); however, it could not prevent the ethanol-induced drop in PD. Furthermore, the inhibitory action of ethanol on sodium ion output from the gastric mucosa was not attenuated by these drugs. Pirenzepine, however, significantly lessened the increase in vascular permeability caused by 100% ethanol. This action was not shared by atropine. 4. These findings indicate that both atropine and pirenzepine exert their antilesion actions through the relaxation of the stomach. Pirenzepine also preserves the integrity of the gastric mucosal vasculature, which is distinct from the action of atropine. The protective action of these drugs occurs only at the macroscopic level.

1. The aim of this study was a pharmacological characterization of the multiple NANC inhibitory transmission systems producing relaxation of the circular muscle of guinea-pig proximal colon. In the presence of atropine (1 microM), guanethidine (3 microM) and of the tachykinin NK1 and NK2 receptor antagonists, SR 140333 (0.3 microM) and MEN 10627 (1 microM), respectively, electrical field stimulation (EFS) produced a frequency-dependent (0.1-3 Hz) relaxation. During a cumulative frequency-response curve, the maximal relaxant effect was produced at 3 Hz and approached the maximal relaxation to 1 microM isoprenaline. In the presence of both apamin (0.3 microM) and L-nitroarginine (L-NOARG, 100 microM), EFS failed to evoke relaxation up to 1 Hz; at 1-10 Hz, a slowly developing relaxation ensured which approached 50% of the Emax to isoprenaline. The EFS-evoked NANC relaxation, either in the presence or absence of apamin and L-NOARG, was unaffected by in vitro capsaicin pretreatment (10 microM for 15 min). 2. Three protocols of EFS were developed for further pharmacological analysis: (a) EFS at 1 Hz for 5 s in the presence of L-NOARG, producing a transient fast apamin-sensitive relaxation; (b) EFS at 1 Hz for 5 s in the presence of apamin, producing a transient fast L-NOARG-sensitive relaxation; and (c) EFS at 10 Hz for 5 s in the presence of both apamin and L-NOARG, producing a transient but slowly developing and more sustained relaxation. 3. The neutral endopeptidase inhibitor, thiorphan (1-10 microM), enhanced and prolonged the apamin- and L-NOARG-resistant NANC relaxation produced by EFS at 10 Hz, without affecting that evoked at 1 Hz in the presence of apamin or L-NOARG. The angiotensin converting enzyme inhibitor, captopril (1-10 microM) was without effect. 4. The cAMP analogue inhibitor of protein kinase A, Rp-cAMPs (100-300 microM) significantly reduced and shortened the NANC relaxation produced by 10 Hz EFS in the presence of L-NOARG without affecting that produced by 1 Hz EFS in the presence of apamin or L-NOARG. 5. The inhibitor of sarcoplasmic reticulum Ca-ATPase, cyclopiazonic acid (CPA, 3-10 microM for 60 min) abolished the 1 Hz EFS-induced relaxation in the presence of L-NOARG, and greatly inhibited that produced by 10 Hz EFS in the presence of both apamin and L-NOARG. The relaxation produced by 1 Hz EFS in the presence of apamin was inhibited by about 32% at 10 microM only. 6. Nifedipine (1 microM) did not affect the EFS-induced NANC relaxations. In the presence of nifedipine, tetraethylammonium (TEA, 1 mM) enhanced the 1 Hz EFS-induced relaxation in the presence of L-NOARG (158% of control) and that produced by 10 Hz EFS in the presence of apamin and L-NOARG (215% of control) while that evoked by 1 Hz EFS in the presence of apamin was slightly affected (109% of control). 7. In the presence of atropine, guanethidine, SR 140333 and MEN 10627, bath application of human vasoactive intestinal polypeptide (VIP, 0.1 nM-10 nM) produced a

1. All previous studies on the effects of changes in sodium intake on the renal dopamine (DA) response (increase in urinary DA output) have used sudden, large changes in oral sodium intake. The present study was designed to study the role of renal DA and the suppression of sympathetic nervous system activity in the natriuretic response to step-wise, gradual increases in sodium intake. 2. Seven healthy, male Chinese subjects (23-25 years) were studied. During the 12-day study period (day -3 to 8), subjects were given the same basic diet containing 1900 calories, 75 g protein, 20 mmol sodium and 45 mmol potassium. From days 1 to 8, subjects also received 'Slow sodium' tablets (Ciba-Geigy) equivalent to 50 mmol on day 1, 100 mmol on day 2, 150 mmol on day 3,200 mmol on day 4, 250 mmol on day 5, and 300 mmol on days 6 to 8. Body weight was recorded and blood pressure was measured after lying supine for 10 min in the morning before breakfast on entry and at the end of the low and high sodium intake periods. Urine was collected for 24 h on day -3 and from days 0 to 8 for the measurement of sodium, potassium, creatinine, free DA and free noradrenaline (NA). 3. After 4 days of sodium restriction, mean arterial pressure (mean +/- SEM) had decreased from 83.0 +/- 1.3 to 79.4 +/- 0.5 (P < 0.05) and body weight from 70.2 +/- 3.1 to 68.3 +/- 3.0 (P < 0.02). Following sodium loading, MAP and body weight did not change, but pulse rate had decreased from 64.1 +/- 2.8 to 57.4 +/- 2.6 (P < 0.02). 4. There was a 13-fold increase in sodium excretion (P < 0.02) by the last day of the high sodium intake period. There were no significant changes in urine volume and urinary excretion of potassium, creatinine and free DA throughout the high sodium intake period. In contrast, there was a 19.9-26.5% decrease in urine NA 4 and 6 days after the start of the increase in sodium intake. 5. Healthy Chinese subjects do not have a renal DA response to gradually increasing sodium intake over an 8-day period. Any tendency to hypervolaemia-related rises in blood pressure during the high sodium intake period may be partly offset by a reduction in sympathetic nervous system activity.