Effects of endothelin-1 on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.

The effects of endothelin-1 (ET-1) on renal function and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) were examined in anesthetized dogs, and comparisons were made with effects of Bay K 8644, a calcium channel agonist. RNS at a low frequency (0.5-2.0 Hz) produced significant decreases in urine flow and urinary excretion of sodium and increased NE secretion rates without influencing renal hemodynamics. RNS, at a high frequency of 2.5-5.0 Hz which diminishes renal hemodynamics, affected urine formation and NE secretion rate more potently than did low-frequency RNS. Intrarenal arterial infusion of ET-1 (1.0 ng/kg/min) decreased the baseline level of renal blood flow by 25% and that of urinary excretion of sodium by 54-69% but did not alter basal levels of NE secretion rate. During ET-1 infusion, low-frequency RNS-induced antidiuresis was observed to an extent similar to that seen without ET-1 infusion, whereas increase in NE secretion rate elicited by RNS was significantly inhibited by ET-1 infusion (45-65% of the values without ET-1 infusion). In addition, in the case of high-frequency RNS, ET-1 did not affect antidiuretic responses but did inhibit the increase in NE secretion rate by approximately 55%. In contrast, alterations in renal excretory responses and NE secretion rate elicited by RNS were not influenced by Bay K 8644 infusion (1.0 micrograms/kg/min), a dose that decreased renal blood flow to the same degree as did 1.0 ng/kg/min of ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory effect of nisoldipine on angiotensin-II-induced renal actions in anesthetized dogs

Renal effects of nisoldipine, a potent calcium channel blocker, were examined in anesthetized dogs. Intrarenal arterial infusion of nisoldipine (2, 10, and 50 ng/kg per min) had no effect on mean systemic blood pressure and heart rate and there was no significant change in renal hemodynamics during infusion of various doses of the drug. Urine flow and urinary excretions of sodium, chloride, and potassium were increased by nisoldipine in a dose-related manner. Fractional excretions of sodium and chloride were markedly elevated with the highest dose given thereby indicating that tubular reabsorptions of sodium and chloride were inhibited by nisoldipine. Nisoldipine (50 ng/kg per min) abolished the decreasing effects of angiotensin-II on glomerular filtration rate, urine flow, and urinary excretion of electrolytes but not the decrease in renal blood flow by the peptide. Angiotensin-II-induced reduction of fractional excretion of electrolytes was completely blocked by nisoldipine. Renal responses to norepinephrine were unaffected by nisoldipine. Thus, nisoldipine administered intrarenally to anesthetized dogs exerts a diuretic action by way of tubular effects, as is the case with other dihydropyridine calcium channel blockers. Nisoldipine seems to effectively antagonize the renal response to angiotensin-II. Thus, the preferential inhibition of angiotensin-II-induced antidiuresis may mean that nisoldipine interferes with stimulatory effects of angiotensin-II on the renal tubular reabsorption of electrolytes and water.     

Interaction between norepinephrine release and intrarenal angiotensin II formation during renal nerve stimulation in dogs

We examined possible interactions between intrarenal angiotensin II (ANG II) formation and norepinephrine (NE) release during renal sympathetic nerve stimulation (RNS) in anesthetized dogs. During 10 min of continuous RNS (1.5-2 Hz), the ANG II formation rates (ANG II-FR) and NE secretion rates (NE-SR) were determined at 1 and 10 min. Under control conditions, almost the same extent of increase in the NE-SR was observed at 1 and 10 min of RNS, whereas a significant increase in ANG II-FR was observed at 10 min but not at 1 min. During intrarenal arterial infusion of enalaprilat or losartan, the increase in NE-SR and reduction in renal blood flow at 10 min of RNS were suppressed, whereas the NE release and vasoconstriction responses at 1 min remained unaffected. The RNS-induced increases in ANG II-FR were completely abolished during infusion of enalaprilat. These results suggest that NE release on continuous RNS is enhanced by concomitantly formed ANG II, and this interaction depends on the time-related changes in intrarenal ANG II formation during RNS in the canine kidney.     

Effects of bradykinin on renal nerve stimulation-induced antidiuresis and norepinephrine overflow in anesthetized dogs

We examined effects of bradykinin on antidiuresis and norepinephrine overflow induced by renal nerve stimulation (RNS) in anesthetized dogs, with or without blockade of the B2 receptor by Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin) or the endogenous nitric oxide generation by N(G)nitro-L-arginine (NOARG), a nitric oxide synthase inhibitor. RNS (0.5-2.0 Hz) produced significant decreases in urine flow, urinary and fractional excretions of sodium, and increases in norepinephrine secretion rate (NESR), without affecting systemic and renal hemodynamics. Intrarenal arterial infusion of bradykinin (5 ng/kg per minute) significantly suppressed the RNS-induced antidiuresis and increase in NESR. Hoe 140 (100 ng/kg per minute) did not affect the RNS-induced renal actions, but in the presence of Hoe 140, bradykinin-induced suppressive actions on reductions in urine formation and increases in NESR in response to RNS were abolished. RNS during intrarenal arterial infusion of NOARG (40 microg/kg per minute) led to potent reductions in urine formation and decreased renal blood flow and glomerular filtration rate. Simultaneously, NESR was markedly increased. During NOARG infusion, bradykinin-induced decreases in renal actions elicited by RNS were markedly attenuated. These findings suggest that bradykinin suppresses the RNS-induced norepinephrine overflow and renal actions via nitric oxide production mediated by activation of B2 receptor. Renal noradrenergic neurotransmission may be inhibited by bradykinin at the prejunctional level, when its local production in the kidney is enhanced.     

The role of endogenous angiotensin II in antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.

We examined the possible involvement of endogenous angiotensin II (ANG II) in norepinephrine (NE) overflow and antidiuresis induced by renal nerve stimulation (RNS). RNS at a frequency of 0.5-2.0 Hz, which did not influence renal hemodynamics, produced significant reductions in urine flow and urinary excretion of sodium, and elevations in NE secretion rate (NESR) and renin secretion rate (RSR). Intrarenal arterial (i.r.a.) infusion of phentolamine (10 micrograms/kg/min) abolished the RNS-induced antidiuresis. In dogs receiving captopril (15 micrograms/kg/min i.v.), RNS-induced antidiuresis and increase in NESR were significantly attenuated. The i.r.a. administration of propranolol at 5 micrograms/kg/min, a dose that inhibited completely the RNS-induced increase in RSR, did not influence the alterations in NESR and urine formation in response to RNS. During ANG II infusion (1 ng/kg/min i.r.a.), RNS produced a reduction in urine formation and an increase in NESR, at a magnitude similar to that seen without ANG II infusion. These results suggest that RNS at a low frequency increased the NESR and RSR without affecting renal hemodynamics and that the antidiuretic effect was probably produced via the activation of postsynaptic alpha-adrenoceptors, but not via the ANG II receptor, located on the renal tubules. The release of NE appears to be modulated by ANG II through the activation of a facilitatory prejunctional mechanism, which is maximally stimulated by endogenously and locally generated basal levels of ANG II.     

Effects of K-351 on adrenergically induced renin release and renal vasoconstriction in anesthetized dogs

Effect of 3-4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-1-b enzopyran (K-351) infused into the renal artery on renin release during graded renal nerve stimulation (RNS) was investigated in pentobarbital-anesthetized dogs. K-351 (20 micrograms/min) produced significant suppression of the RNS-induced renin release; the renin secretion responses to RNS at lower frequencies (0.5 and 1 Hz) were almost abolished, and those at the highest frequency (3 Hz) were attenuated. K-351 also suppressed an increase in renal vascular resistance during RNS at 3 Hz. The same extent of inhibition in the renin secretion response to RNS was also obtained during infusion of DL-propranolol (100 micrograms/min). Inhibitory effect of K-351, prazosin, or phentolamine on the renal vasoconstriction induced by RNS and norepinephrine (NE) injected into the renal artery, an approximately 50% reduction in renal blood flow, was also assessed. K-351 and prazosin exerted a greater inhibitory effect on RNS-than on NE-induced vasoconstriction, and the opposite was true of phentolamine. The potency of K-351 in reducing the vasoconstriction due to RNS or NE was roughly estimated to be 10-30 times less than that of prazosin. These results suggest that K-351 shares beta- and alpha-adrenoceptor blocking properties, which effectively contribute to the suppression of adrenergically induced renin release and renal vasoconstriction.     

Effects of nifedipine on renin release and renal function in anesthetized dogs

The effects of nifedipine, classed as a calcium entry blocker, on urinary excretion and renin release were investigated in anesthetized dogs. Nifedipine was infused into one renal artery for three consecutive 10-min periods, at incremental rates of 0.3, 1, and 3 micrograms/min. Intrarenal infusion of nifedipine (3 micrograms/min) produced marked increases in urine flow rate (by 200%) and in urinary sodium (by 210%) and potassium (by 40%) excretion rates of the infused kidney without changes in mean systemic blood pressure, heart rate, glomerular filtration rate, and filtration fraction. Urinary osmolarity was slightly decreased by the drug, but this change was not statistically significant. There were no consistent changes in these parameters for the contralateral noninfused kidney. Renin secretion rate was increased to three times the preinfusion level during infusion of the highest nifedipine dose. The blood flow to the infused kidney was increased, and ipsilateral renal vascular resistance was simultaneously decreased upon nifedipine infusion. These results suggest that a nonhypotensive dose of nifedipine causes an increase in renin secretion and that this drug has a striking effect on the reabsorption of sodium and water by the renal tubules.     

Effects of NKH477 on renal nerve stimulation-induced responses in anesthetized dogs

The present study was undertaken to explore the possible neuroprotective effect of the selective alpha2-adrenoceptor agonist, dexmedetomidine in a rat model of focal cerebral ischemia. The effect of dexmedetomidine (9 microg kg(-1)) on infarct volume was assessed and compared to that of glutamate receptor antagonists cis-4(phosphonomethyl)-2-piperidine carboxylic acid (CGS-19755) (20 mg kg(-1)) or 2,3-dihydro-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (50 mg kg(-1)). Dexmedetomidine decreased total ischemic volume by 40% in the cortex (P<0.05) compared to NaCl-treated control rats, whereas NBQX reduced the infarct by 73% in the cortex (P<0.001) and by 43% in the striatum (P<0.01). Dexmedetomidine infusion was associated with some minor degree of hyperglycemia and hypotension. Drug-induced kidney changes were only seen in NBQX-treated rats. These results suggest that dexmedetomidine reduced ischemic volume despite causing a minor increase in blood glucose concentrations and hypotension. Its neuroprotective efficacy was better than that produced by CGS-19775, and dexmedetomidine was safer with respect to kidney toxicity when compared to NBQX.     

Renin release induced by a nonvasoconstrictor dose of phenylephrine is independent of the renal prostaglandin system in anesthetized dogs

We examined the relationship between prostaglandin (PG) production and renin release induced by a nonvasoconstrictor dose of an alpha-agonist, phenylephrine, in anesthetized dogs. Intrarenal infusion of phenylephrine (1 microgram/min) did not affect systemic blood pressure or renal blood flow, but increased the renin secretion rate about twofold. The effect of phenylephrine on renin release was abolished by the intrarenal infusion of the alpha-antagonist phentolamine (50 micrograms/min), but was not affected by the intravenous administration of the PG synthetase inhibitor indomethacin (5 mg/kg). Urine flow and urinary sodium excretion rate were not altered by phenylephrine. These results suggest that a nonvascular and nontubular alpha-adrenoceptor mechanism, which is independent of the renal PG system, may be involved in renin release.     

Effects of GABA on noradrenaline release and vasoconstriction induced by renal nerve stimulation in isolated perfused rat kidney.

We examined effects of gamma-aminobutyric acid (GABA) on vasoconstriction and noradrenaline (NA) release induced by electrical renal nerve stimulation (RNS) in the isolated pump-perfused rat kidney. RNS (1 and 2 Hz for 2.5 min each, 0.5-ms duration, supramaximal voltage) increased renal perfusion pressure (PP) and renal NA efflux. GABA (3, 10 and 100 microM) attenuated the RNS-induced increases in PP by 10-40% (P<0.01) and NA efflux by 10-30% (P<0.01). GABA did not affect exogenous NA (40 and 60 nM)-induced increases in PP. The selective GABA(B) agonist baclofen (3, 10 and 100 microM) also attenuated the RNS-induced increases in PP and NA efflux, whereas the RNS-induced responses were relatively resistant to the selective GABA(A) agonist muscimol (3, 10 and 100 microM). The selective GABA(B) antagonist 2-hydroxysaclofen (50 microM), but not the selective GABA(A) antagonist bicuculline (50 microM), abolished the inhibitory effects of GABA (10 microM) on the RNS-induced responses. The selective alpha2-adrenoceptor antagonist rauwolscine (10 nM) enhanced the RNS-induced responses. GABA (3, 10 and 100 microM) potently attenuated the RNS-induced increases in PP by 40-60% (P<0.01) and NA efflux by 20-50% (P<0.01) in the presence of rauwolscine. Prazosin (10 and 30 nM) suppressed the RNS-induced increases in PP by about 70-80%. Neither rauwolscine (10 nM) nor GABA (10 microM) suppressed the residual prazosin-resistant PP response. These results suggest that GABA suppresses sympathetic neurotransmitter release via presynaptic GABA(B) receptors, and thereby attenuates adrenergically induced vasoconstriction in the rat kidney.     

Effect of presynaptic alpha-adrenoceptor blockade on responses to cardiac nerve stimulation in anesthetized dogs.

Phentolamine caused significant potentiation of chronotropic responses to cardioaccelerator nerve stimulation (CANS) in pentobarbital-anesthetized dogs without impairing neuronal reuptake of norepinephrine. In a separate group of dogs, desipramine produced slight augmentation of CANS responses which were potentiated further by phentolamine administration. These results provide support for the hypothesis that presynaptic alpha-adrenergic receptors play an inhibitory role in sympathetic neurotransmission and demonstrate that this mechanism is also functioning during stimulation of the cardioaccelerator nerve in pentobarbital-anesthetized dogs.     

Effects of cardiac sympathetic nerve stimulation during adrenergic blockade on infarct size in anesthetized dogs

beta-Adrenergic blockade has been shown to limit myocardial infarct size (IS) in anesthetized dogs. The objective of the present study was to determine whether sympathetic activation in the presence of beta-adrenergic blockade would alter IS. Chloralose-anesthetized dogs were divided into five groups. All hearts were neurally decentralized and paced at 150 beats/min. The circumflex coronary artery was ligated distal to the first major branch. Group 1 (n = 5) had no treatment. Group 2 (n = 6) received timolol (0.2 mg/kg) intravenously before and throughout occlusion. Group 3 (n = 7) underwent left stellate stimulation (LSS; 8 Hz, 5 ms, 7-10 V) immediately following coronary artery occlusion and for the duration of occlusion. Group 4 (n = 5) received timolol in addition to LSS. Group 5 animals (n = 6) received prazosin (0.5 mg/kg i.v.) and timolol before circumflex occlusion and LSS following coronary artery occlusion. After 6 h, Evans blue dye was injected into the left atrium while the circumflex artery distal to the ligation was simultaneously perfused with saline. Hearts were rapidly excised, and the left ventricle was sliced and photographed. IS was determined and expressed as a percentage of the area at risk by planimetry. The following mean +/- SEM values were measured: Group 1, 23.5 +/- 5.3; Group 2, 34.2 +/- 1.4; Group 3, 31.4 +/- 7.8; Group 4, 59.3 +/- 3.9; and Group 5, 25.6 +/- 5.3%. Significant differences were found between Group 4 and all other groups (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

八肽胆囊收缩素对大鼠颈动脉窦神经传入放电的抑制作用(英文)

目的　观察八肽胆囊收缩素 (CCK 8)是否通过直接抑制颈动脉窦压力感受器放电活动而影响心血管功能。方法　在麻醉雄性大鼠隔离灌流颈动脉窦区条件下记录窦神经传入放电及积分。结果　①CCK 80 .1,0 .5和 1.0 μmol·L- 1使压力感受器机能曲线向右下方移位 ,曲线最大斜率和窦神经传入放电积分最大值均明显减小 ,表明CCK 8可剂量依赖性抑制颈动脉窦压力感受器活动。②预先灌流CCK 8非特异性受体阻断剂丙谷胺 10 0 μmol·L- 1或钙通道开放剂BayK86 440 .5 μmol·L- 1可部分阻断CCK 80 .5 μmol·L- 1对颈动脉窦压力感受器放电活动的抑制作用。预先灌流一氧化氮合酶抑制剂L NAME不能阻断CCK 8的效应。结论　CCK 8可直接抑制大鼠颈动脉窦压力感受器传入神经放电活动。其机制可能为CCK 8作用于颈动脉窦区相应的受体后 ,对牵张敏感性通道产生抑制作用。     

Renal vascular and sympathetic nerve responses to hypotension induced by platelet-activating factor in anesthetized dogs

This experiment was designed to determine renal sympathetic and renal vascular responses to platelet-activating factor (PAF)-induced hypotension in anesthetized dogs with and without systemic baroreceptor denervation. The left kidney was perfused at a constant flow, and renal perfusion pressure and efferent left renal sympathetic nerve activity were measured simultaneously. Intrarenal injection of PAF (1.25−5.0×10⁻² μg/kg, N = 6) produced a dose-dependent increase in renal perfusion pressure without any change in systemic blood pressure. An intravenous injection of PAF (10 μg/kg) to intact animals (n = 7) caused an initial increase in renal nerve activity (157±14%) followed by a gradual reduction below baseline (72±7%) with concomitant systemic hypotension (from 116±7 to 46±6 mmHg). Renal perfusion pressure increased significantly from 84±2 to 161±33 mmHg concomitant with an increase in renal nerve activity at 1 min and was maintained at this elevated level throughout the experiment. Similar responses of renal nerve activity and renal perfusion pressure were found in animals with complete systemic baroreceptor denervation (n = 7). These renal suggest that renal vascular response during PAF-induced hypotension may presumably be mediated by a direct vasoconstrictor effect of PAF on the renal vasculature and that baroreceptor reflex is not involved in either renal sympathetic or renal vascular changes.     

丹皮酚对麻醉犬冠脉结扎致心肌梗死的保护作用

目的观察丹皮酚对冠脉结扎致实验性心肌梗死犬的影响。方法结扎犬左冠状动脉前降支造成急性心肌梗死模型,观察丹皮酚对心肌梗死面积、梗死程度、磷酸肌酸激酶同工酶及超氧化物歧化酶(SOD)、丙二醛(MDA)的影响。结果丹皮酚能够明显减小心肌梗死面积、降低心肌梗死程度、减少心肌酶的释放,同时可以提高血清中SOD的活力,增强清除自由基能力,降低血清中MDA的含量,减轻脂质过氧化损伤的程度。结论丹皮酚具有明显的抗心肌缺血作用,其作用机制可能是通过稳定细胞膜,抑制缺血心肌的膜损伤,增加自由基清除,降低脂质过氧化等发挥作用。     

Atrial natriuretic peptide suppresses renal vasoconstriction induced by angiotensin II and norepinephrine in dogs.

Atrial natriuretic peptide (ANP, 10 and 50 ng/kg per min), infused into the renal artery, suppressed decreases in renal blood flow induced by intrarenal arterial injection of angiotensin II (Ang II, 25-100 ng) and norepinephrine (NE, 0.25-1 microgram) in anesthetized dogs. Sodium nitroprusside (SNP, 0.1-5.0 micrograms/kg per min) slightly attenuated the blood flow response to Ang II but not the response to NE. 8-Bromo cyclic GMP (8bcGMP, 0.5-25 micrograms/kg per min) did not suppress the blood flow response to Ang II. Although at a high dose ANP attenuated the blood flow response to Bay K 8644 (1-4 micrograms), nifedipine pretreatment (20 micrograms/kg plus 1 microgram/kg per min i.v.) did not affect the inhibitory effect of ANP on the NE-induced response. The vaso-inhibitory effects of ANP therefore could not be related exclusively to stimulation of cGMP production or inhibition of voltage-dependent Ca2+ channels.     

Atrial natriuretic factor inhibits norepinephrine release evoked by sympathetic nerve stimulation in isolated perfused rat mesenteric arteries

The effect of atrial natriuretic factor (ANF) on [3H]norepinephrine release evoked by sympathetic nerve stimulation was examined in the isolated perfused rat mesenteric arteries. ANF (1 nM to 0.1 microM) caused a dose-dependent inhibition of [3H]norepinephrine release during nerve stimulation. The present result indicates that ANF inhibits noradrenergic neurotransmission in the rat mesenteric arteries through a prejunctional mechanism. This prejunctional effect of ANF may in part contribute to its vasodilation action.