Bilateral kidney ligation abolishes pressor response to N(G)-nitro-D-arginine

We have shown that N(G)-nitro-D-arginine (D-NNA) is 50% as potent as N(G)-nitro-L-arginine (L-NNA) in causing pressor response and 2-3% as potent as L-NNA in inhibiting endothelium-dependent relaxation in vitro. These results suggest in vivo activation of D-NNA. Furthermore, the potency of D-NNA was markedly increased after it had been incubated with homogenate of the kidney, but not plasma or homogenate of the aorta, lungs or liver. This study examined if bilateral ligation of the kidneys attenuated the biological action of D-NNA. I.v. bolus of D-NNA (16 mg/kg), L-NNA (3 mg/kg) and norepinephrine (0.25-16 microg/kg) increased arterial pressure in sham-operated rats. Bilateral ligation of the kidneys abolished pressor response to D-NNA, but not L-NNA and norepinephrine. I.v. bolus D-NNA in sham-operated rats, but not kidney-ligated rats, inhibited relaxation response to acetylcholine in pre-constricted aortic rings ex vivo. These results indicate that the kidney is the primary organ which activates D-NNA.     

Possible dependence of pressor and heart rate effects of NG-nitro-L-arginine on autonomic nerve activity.

1. The effects of NG-nitro-L-arginine (L-NNA) on mean arterial pressure (MAP) and heart rate (HR) were investigated in conscious rats. 2. Intravenous bolus cumulative doses of L-NNA (1-32 mg kg-1) dose-dependently increased MAP. Both mecamylamine and phentolamine increased MAP responses to L-NNA, angiotensin II and methoxamine. Propranolol, reserpine, atropine and captopril did not affect MAP response to L-NNA. 3. A significant negative correlation of HR and MAP responses to L-NNA was obtained in control rats but not in rats pretreated with reserpine or mecamylamine. Significant negative correlations also occurred in the presence of atropine, propranolol, phentolamine or captopril. 4. A single i.v. bolus dose of L-NNA (32 mg kg-1) raised MAP to a peak value of 53 +/- 3 mmHg and the effect lasted more than 2 h; the rise and recovery of MAP were accompanied by significant decrease and increase in HR, respectively. While both phentolamine and mecamylamine increased peak MAP response to L-NNA, mecamylamine abolished the biphasic HR response and phentolamine potentiated the bradycardiac component of HR. 5. Blockade of the autonomic nervous and renin-angiotensin systems did not attenuate the pressor effects of L-NNA. However, the biphasic HR response to L-NNA is mediated via modulation of autonomic nerve activities.     

D-myo-inositol-1,2,6-trisphosphate is a selective antagonist of neuropeptide Y-induced pressor responses in the pithed rat.

The antagonistic effects of a new inositol phosphate derivative, D-myoinositol-1,2,6-trisphosphate (PP56), on pressor responses to preganglionic sympathetic nerve stimulation and exogenously administered phenylephrine or neuropeptide Y (NPY) were investigated in vivo in the pithed rat. In this model an intravenous (i.v.) bolus administration of PP56 (1-50 mg/kg) dose dependently inhibited the increase in mean arterial blood pressure (MAP) induced by a continuous infusion of NPY (2 micrograms/kg per min for 10 min). PP56 in a dose of 5 mg/kg i.v. bolus reduced the entire NPY dose-response curve (0.4-8 microgram/kg per min 10 min infusion) without any shift to the right indicating a non-competitive interaction. Furthermore, PP56 (10-50 mg/kg i.v.) was found to inhibit the pressor response to preganglionic sympathetic nerve stimulation and i.v. bolus injection of the alpha 1-adrenoceptor agonist, phenylephrine. The dose-response curves for increasing doses of phenylephrine and incremental preganglionic sympathetic nerve stimulation were not significantly altered by a lower dose of PP56 (5 mg/kg i.v. bolus). We conclude that PP56, representing a new class of synthetic drugs, can antagonize the actions of exogenous and endogenous NPY in vivo, an action which is specific for NPY within a limited dose range.     

Biological activation of NG-nitro-D-arginine by kidney homogenate

N^G-nitro-L-arginine (L-NNA) and D-NNA have been shown to inhibit endothelium-dependent relaxation. This study examined if the inhibitory effect of L-NNA or D-NNA on relaxation is increased following incubation of the drug with the supernatant of tissue homogenates. Acetylcholine (ACh) caused concentration-dependent relaxation of pre-constricted rat aortic rings with maximum relaxation of 95%. Maximum relaxations to ACh were reduced to 71 and 37% in the presence of D-NNA (40 μM) and L-NNA (1 μM), respectively. Relaxation to ACh was further reduced to 18% in the presence of D-NNA that was incubated for 1 h with the supernatant of kidney homogenate, but unaffected by D-NNA incubated with the supernatant of trichloroacetic acid-denatured kidney homogenate. Incubation of L-NNA (1 μM) with either kidney supernatant or denatured kidney supernatant for 1 h did not affect its inhibitory effect on ACh-induced relaxation. Neither 1 h’s incubation with plasma, or supernatants of liver, lungs or aorta homogenates affected the inhibitory action of D-NNA (40 or 120 μM) on ACh-induced relaxation. After D-NNA was incubated in kidney supernatant, its inhibitory effect on ACh-induced relaxation of the aorta was abolished by pretreatment of the aorta with L-arginine (L-Arg) but not D-Arg suggesting involvement of the L-Arg pathway. The results suggest that D-NNA is converted by the kidney to a compound that acts similar to L-NNA. There appears to be little conversion of L-NNA to D-NNA. Received: 21 April 1997 / Accepted: 20 June 1997     

NG-hydroxy-L-arginine prevents the haemodynamic effects of nitric oxide synthesis inhibition in the anaesthetized rat.

1. We have investigated the effects of L-hydroxy-L-arginine (L-HOArg), an intermediate in the biosynthesis of nitric oxide (NO) from L-arginine (L-Arg), on the haemodynamic effects (systemic blood pressure and renal blood flow) of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in the anaesthetized rat. 2. L-Arg or L-HOArg (3 mg kg-1 min-1), but not D-arginine (D-Arg) or NG-hydroxy-D-arginine (D-HOArg), elicited a slight but significant increase in total renal blood flow (RBF) of 11 +/- 2% and 11 +/- 1%. Since mean arterial blood pressure (MAP) did not change this dose of L-Arg or L-HOArg resulted in a reduced renal vascular resistance (RVR) of the same magnitude. 3. Bolus injections of L-NAME, at 0.3 or 1 mg kg-1 i.v., produced a significant fall in RBF of 11 +/- 2% and 32 +/- 5% and an increase in MAP of 7 +/- 3 mmHg and 22 +/- 5 mmHg, respectively. Consequently, RVR was elevated by 21 +/- 5% and 52 +/- 10%. 4. L-Arg or L-HOArg (3 mg kg-1 min-1) reduced the L-NAME-induced (0.3 or 1 mg kg-1) falls in RBF and increases in RVR by more than 65%. Neither D-Arg nor D-HOArg (3 mg kg-1 min-1) had any significant effect on the changes in RBF or RVR induced by L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)     

肾脏是体内N~G-D-硝基精氨酸单向手性转化的主要器官

目的　研究NG D 硝基精氨酸 (NG nitro D arginine,D NNA)在体内发生手性转化的的部位。方法　考察肾脏结扎对于D NNA诱导大鼠动脉压升高活性的变化 ,并运用毛细管电色谱 (capillaryelectrochromatography ,CEC)分析技术测定D NNA在体内手性转化的情况。结果　肾脏结扎使大鼠完全丧失对D NNA (32mg·kg-1)升高血压反应 ,但不影响由NG L 硝基精氨酸 (NG nitro L arginine ,L NNA)(16mg·kg-1)引起的升压反应。而D NNA/肾匀浆孵育液(32mg·kg-1)则可使肾脏结扎大鼠产生升压反应。CEC血药检测证实D NNA在大鼠体内转化生成L NNA ,而L NNA在体内未被代谢生成D NNA ;肾脏结扎则使D NNA的手性转化大量减少。结论　D NNA在大鼠体内可单向代谢转化L NNA ,肾脏是D NNA发生手性转化的主要器官     

Incomplete inhibition of the pressor effects of endothelin-1 and related peptides in the anaesthetized rat with BQ-123 provides evidence for more than one vasoconstrictor receptor.

1. The effects of the ETA receptor antagonist, BQ-123 on blood pressure changes induced by various members of the endothelin (ET)/sarafotoxin (SX) peptide superfamily were investigated in the anaesthetized rat. 2. ET-1 (1 nmol kg-1, i.v. bolus) induced a sustained increase in mean arterial pressure (MAP, maximum increase 44 +/- 3 mmHg). Intravenous injection of BQ-123 at 0.2, 1.0 or 5.0 mg kg-1 5 min before ET-1 inhibited the pressor response by 18, 50 and 61%, respectively. The ET-1 pressor response was inhibited by 75% when the peptide was given 60 min after the start of a 120 min i.v. infusion of BQ-123 (0.2 mg kg-1 min-1). 3. In addition to ET-1, BQ-123 (1 mg kg-1, i.v. bolus) attenuated the pressor responses to big ET-1 (1 nmol kg-1, i.v., bolus, maximum increase in MAP: 68 +/- 7 mmHg), ET-3 (3 nmol kg-1, i.v., bolus, maximum response: 30 +/- 3 mmHg), SX6b (1 nmol kg-1, i.v., bolus, maximum response: 41 +/- 5 mmHg) and SX6c (1 nmol kg-1, i.v., bolus, maximum response: 24 +/- 4 mmHg) by 65, 60, 88 and 50%, respectively. 4. With the exception of big ET-1, all the peptides used in this study induced an initial transient depressor response (-32 +/- 3 mmHg, n = 18). Although BQ-123 (1 mg kg-1, i.v., bolus) did not affect the absolute magnitude of the fall in MAP, the ETA receptor antagonist significantly prolonged the depressor responses induced by ET-3 and SX6b.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of nitric oxide in 5-HT3 receptor agonist-induced fluid accumulation in jejunum and colon of anesthetized rats

Objectives:

The aim of the present study was to investigate the involvement of nitric oxide in 5-HT₃ receptor agonist-induced fluid accumulation in jejunum and colon of anesthetized rats.

Materials and Methods:

Fluid movement in jejunum and colon were determined simultaneously in the same rat, by modifying the Beubler method. Nω-nitro-L-arginine (L-NNA, 20 mg/kg, s.c) alone and in combination with L-arginine (L-Arg, 150 mg/kg s.c) or D-arginine (D-Arg, 150 mg/kg, s.c) were administered 30 min before administration of 1-PBG (18.5 μg/kg, i.v).

Results:

Intravenous administration of 1-phenylbiguanide (1-PBG) induced a net secretion of fluid in both jejunum and colon. 1-PBG had a more prominent secretory effect in the colon, causing a three-fold increase in volume of fluid secreted/g of colon than in the jejunum. Pretreatment with (L-NNA) prevented the 1-PBG-induced fluid accumulation in both jejunum and colon. The inhibitory effect of L-NNA on 1-PBG-induced fluid accumulation was reversed by L-Arg but not by D-Arg.

Conclusion:

These results provide evidence that nitric oxide plays an important role in 5-HT₃ receptor agonist-induced fluid accumulation in jejunum and colon of anesthetized rats.     

Effect of genistein on cardiovascular responses to angiotensin II in conscious unrestrained rats

Soybeans contain genistein, a phytoestrogen that may have beneficial effects in coronary artery disease, osteoporosis, and breast cancer. In vitro studies demonstrated that genistein reduced vascular smooth muscle contractions to angiotensin II. We tested the hypothesis that genistein attenuates the overall cardiovascular responses to angiotensin II via nongenomic mechanisms in conscious rats. Mean arterial blood pressure (MAP) was recorded from conscious unrestrained Sprague-Dawley rats (n = 26) approximately 48 hours after surgery. Cumulative dose response curves to angiotensin II (10-200 ng/kg/min) were constructed before and after i.v. treatment with genistein given as a single bolus dose of 160 microg/kg or 1500 microg/kg, or as a loading dose of 160 microg/kg followed by an infusion at a rate of 20 microg/kg. Angiotensin II infusions were associated with graded increases in arterial pressure ranging between 0+/-1 and 35+/-4 mm Hg. These pressor responses were accompanied by significant dose-dependent decreases in heart rate. None of the genistein treatment regimens significantly affected the pressor responses to angiotensin II. Accordingly, we conclude that short-term i.v. treatment with genistein does not depress pressor responsiveness to angiotensin II.     

Acute cardiovascular effects of the alpha2-adrenoceptor antagonist, idazoxan, in rats: influence of the basal sympathetic tone

Intravenous administration of the alpha2-adrenoceptor antagonist, idazoxan, elicits variable cardiovascular effects, depending on experimental conditions. In this study, the effects of idazoxan were investigated in rats with high, low, or no basal sympathetic tone. In a group of conscious Sprague-Dawley rats (n = 9), mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nervous activity (RSNA) were recorded. Idazoxan (250 microg/kg, i.v.) induced a transient decrease in MAP (-12+/-3 mm Hg) that was accompanied by increases in HR (49+/-14 beats/min) and RSNA (53+/-14%). In six of nine rats, a light pentobarbitone anesthesia was given. Basal RSNA was decreased (6.0+/-1.3 microV from 12.8+/-4.1 microV; p<0.05), and the depressor effect of idazoxan was reversed to a pressor effect (21+/-6 mm Hg) associated with bradycardia (-16+/-8 beats/min) and sympathoinhibition (-56+/-15%). In eight conscious intact rats, idazoxan (250 microg/kg, i.v.) attenuated by approximately 40% the pressor response to the selective alpha1-adrenoceptor agonist, cirazoline (0.5 microg/kg, i.v.). In three groups of six to seven ganglion-blocked (chlorisondamine, 2.5 mg/kg, i.v.) conscious rats, idazoxan dose-dependently increased mean arterial pressure (MAP: 39+/-2, 55+/-3, and 69+/-4 mm Hg at 125, 250, and 500 microg/kg, i.v., respectively) with minimal changes in HR. In contrast, the noradrenaline-releasing agent, tyramine (62.5, 125, and 250 microg/kg, i.v.), dose-dependently increased both MAP and HR. The alpha1-adrenoceptor antagonist, prazosin (1 mg/kg, i.v.; n = 8) blunted by approximately 70% (p<0.01) the pressor effect of 250 microg/kg idazoxan. It is concluded that in rats with high sympathetic tone, idazoxan has depressor effects, most likely related to its peripheral alpha-adrenoceptor antagonist properties. In rats with low or no sympathetic tone, idazoxan induced pressor responses mainly secondary to its partial agonist activity at vascular postjunctional alpha1-adrenoceptors.     

Effects Of L-Arginine And Furosemide On Blood Pressure And Renal Function In Volume-Expanded Rats

1. The aim of the present study was to investigate the effects of L-arginine (L-Arg) on blood pressure and water and electrolyte excretion in control and extracellular fluid volume-expanded rats (10% bodyweight with 0.9% NaCl) and to determine whether diuretic treatment with furosemide (FUR) can be optimized by the administration of L-Arg in this model. 2. Both groups of animals were anaesthetized, divided into groups and treated with either 7.5 mg/kg FUR, 250 mg/kg L-Arg, 1 mg/kg NG-nitro-L-arginine methyl ester (L-NAME), FUR + L-NAME or FUR + L-Arg. Mean arterial pressure (MAP), diuresis, natriuresis and kaliuresis were determined. 3. Extracellular fluid volume expansion induced no changes in MAP in control and volume-expanded rats (92+/-6 vs 100+/-8 mmHg, respectively). The hypotension induced by FUR in control and volume-expanded rats (69+/-7 and 76+/-5 mmHg, respectively) was significantly (P < 0.01) enhanced by the administration of L-Arg (54+/-3 and 64+/-3 mmHg, respectively). 4. Injection of L-NAME increased MAP and diminished diuresis, natriuresis and kaliuresis in both groups. 5. Furosemide-induced water and electrolyte excretion was blunted by the administration of L-NAME. 6. The combination of L-Arg + FUR increased diuresis induced by FUR alone (control rats: 29.33+/-1.68 vs 12.91+/- 0.41 microL/min per 100 g, respectively; volume-expanded rats: 248.5+/-25.4 vs 112,6+/-8.3 microL/min per 100 g, respectively; P < 0.01). 7. The administration of the combination of L-Arg + FUR promoted a decrease in the sodium/water excretion ratio compared with the administration of FUR alone (control rats: 0.230+/-0.018 vs 0.45+/-0.03, respectively, P < 0.001; volume-expanded rats: 0.091+/-0.010 vs 0.22+/-0.03, respectively, P < 0.01). 8. The potassium/water excretion rate induced by FUR alone and in the presence of L-Arg followed a pattern similar to that seen for natriuresis (control rats: 0.35+/-0.05 vs 0.20+/-0.05 microEq/min per 100 g, respectively; volume-expanded rats: 0.045+/-0.008 vs 0.014+/-0.003 microEq/min per 100 g, respectively; P < 0.01). 9. The decrease in the electrolyte/water excretion ratio observed with FUR + L-Arg in volume-expanded rats was greater than in control animals. 10. The results of the present study show that the administration of FUR with L-Arg contributes to enhanced hypotensive and diuretic effects of FUR, thus diminishing the relative electrolyte excretion in normal conditions and in extracellular fluid volume expansion.     

Biological properties of the antagonist SRI 63-441 in the PAF and endotoxin models of hypotension in the rat and dog

Intravenous administration of platelet-activating factor (PAF) produces dose-dependent hypotension in several species. We have evaluated a recently developed PAF antagonist, SRI 63-441, for its ability to inhibit the hypotensive effect of PAF in the rat and dog. In the rat, 100 ng/kg PAF produced a 38.6 +/- 5.1% decrease in carotid mean arterial pressure (MAP), followed by a 3.2 +/- 0.7 min recovery period for MAP to return to baseline values. SRI 63-441 reduced the hypotension response in the rat, where the ED50 values for inhibition of MAP were 0.16 mg/kg i.v. and 0.19 mg/kg i.v. for the recovery period. Dogs challenged with 1.5 micrograms/kg PAF i.v. demonstrated a 52 +/- 8% decrease in MAP that persisted for at least 15 min. The ED50 for inhibition of MAP by SRI 63-441 was 0.20 mg/kg i.v. Following injection of tritium-labeled SRI 63-441, 56.8 +/- 2.4% of the dose was recovered in the urine and 43.2 +/- 8.9% in the feces in the rats while in dogs 38.7 +/- 5.6% and 60.9 +/- 23.5% of the dose was excreted in the urine and feces, respectively. In the rat model of endotoxin-induced hypotension, SRI 63-441 given 1 min after a 5 mg/kg endotoxin challenge (which produced a 52 +/- 7% decrease in MAP), reversed the systemic effects, with an ED50 of 0.18 mg/kg i.v. The ED50 for reversal 6 min after endotoxin injection was 0.01 mg/kg. These results of inhibition and reversal by SRI 63-441 strongly implicate PAF as a pivotal mediator of hypotension and shock.     

Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 1. Acute treatments are active in the forced swim test.

Previous studies have demonstrated that antagonists at the NMDA receptor are as efficacious as tricyclic antidepressants in pre-clinical antidepressant screening procedures and in blocking or reversing the behavioral deficits associated with animal analogs of major depressive symptomatology. The NMDA receptor complex gates Ca2+, which interacts with calmodulin to subsequently activate nitric oxide (NO) synthase. We hypothesized that NO synthase antagonists might display antidepressant-like properties, similar to NMDA receptor antagonists. We examined the effects of N(G)-nitro-L-arginine (L-NNA), its dextrorotatory enantiomer, D-NNA, N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA) at doses from 1 to 30 mg/kg in the forced swim test in mice. We now report that NO synthase antagonists are as efficacious as imipramine (15 mg/kg) in reducing the duration of immobility in the mouse forced swim test. The effects of NO synthase antagonists, as well as those of imipramine were blocked by pre-treatment with L-arginine (L-Arg) (500 mg/kg). In contrast to imipramine, the NO synthase antagonists were without effect on locomotor activity over the dose range active in the forced swim test (3-10 mg/kg). Likewise, L-Arg was without effect on locomotor activity. These data support the hypothesis that NO synthase antagonists possess antidepressant properties and may represent a novel class of therapeutics for major depressive disorders.     

The involvement of endothelium-derived relaxing factor in the regulation of renal cortical blood flow in the rat.

1. In the present study the role of endogenous nitric oxide (NO) was investigated, in the regulation of renal cortical blood flow (RCBF) in vivo in anaesthetized rats under conditions in which prostacyclin involvement had been eliminated. 2. Infusions of the NO synthesis inhibitor NG-monomethyl-L-arginine (MeArg) at 1 or 3 mg kg-1 min-1, i.v., produced significant decreases in RCBF of 29 +/- 7% and 35 +/- 5%, respectively. These effects were reversed by co-infusion of a 3 fold excess of L-arginine (L-Arg). 3. Similarly, intravenous infusion of N omega-nitro-L-arginine methyl ester (NO2Arg) at 30 or 300 micrograms kg-1 min-1 attenuated RCBF by 21 +/- 4% or 53 +/- 4%, respectively, and these effects were reversed by L-Arg (3 or 10 mg kg-1 min-1, i.v.). Most importantly, a low dose of NO2Arg (30 micrograms kg-1 min-1, i.v.), while having no pressor effect, considerably reduced RCBF, indicating that basal release of NO is important for the maintenance of renal cortical blood flow. 4. MeArg (3 mg kg-1 min-1, i.v.) or NO2Arg (300 micrograms kg-1 min-1, i.v.) inhibited endothelium-dependent acetylcholine (ACh, 10 micrograms kg-1 min-1, i.v. for 3 min) increases in RCBF in an L-Arg reversible manner, but did not affect endothelium-independent (dopamine 10 micrograms kg-1 min-1, i.v., for 3 min) increases.(ABSTRACT TRUNCATED AT 250 WORDS)     

大鼠体内硝基精氨酸的手性代谢动力学

目的　应用毛细管电色谱 (CEC)对大鼠体内的硝基精氨酸手性转化和代谢动力学进行研究。方法　采用手性配体交换法检测大鼠血浆中D型硝基精氨酸 (D NNA)和L型硝基精氨酸(L NNA)的浓度,应用非房室模型对所获得的血药浓度-时间数据进行拟合,计算药动学参数。结果　D NNA和L NNA在大鼠体内代谢具有明显的异构体选择性,清除率分别为(0 46±0 02)ml·h-1·kg-1和(0 17±0 03)ml·h-1·kg-1 (P<0 05 );T1 /2分别为 ( 1 44±0 28 )h和(3 48±0 41)h(P<0 05)。D NNA到L NNA的单项手性转化率为(50 03±8 5)%。结论　D NNA和L NNA在大鼠体内的代谢有明显的异构体选择性 (其差异可能主要源于D NNA到L NNA的单向手性转化)。     

Halothane inhibits the pressor effect of diphenyleneiodonium.

1. We have recently found that diphenyleneiodonium (DPI), a novel inhibitor of nitric oxide (NO) synthase, causes pressor and tachycardic responses in pentobarbitone- but not halothane-anaesthetized rats. The present study investigated the mechanism by which halothane suppresses the pressor response of DPI. The effects of halothane on the pressor response of DPI were also compared with those of other anaesthetic agents. 2. In conscious rats, i.v. bolus injections of DPI (0.025- 1.6 mg kg-1) caused dose-dependent increases in mean arterial pressure (MAP), with ED90 of 0.07 +/- 0.01 mg kg-1 and maximal rise of MAP (Emax) of 59 +/- 2 mmHg. While ketamine potentiated Emax without altering the ED50 and pentobarbitone increased the ED50 without changing Emax of the pressor response to DPI, chloralose, urethane and ethanol displaced the curve to the right and potentiated Emax. In contrast, halothane (0.5-1.25%) dose-dependently and non-competitively reduced the pressor responses to DPI. 3. Intravenous bolus injection of a single dose of DPI (1.6 mg kg-1) caused immediate and large increases in plasma noradrenaline and adrenaline, as well as MAP in conscious rats. Halothane (1.25%) almost completely inhibited these increases. 4. The results suggest that DPI causes a pressor response in conscious rats by activating the sympathetic nervous system and halothane abolishes this pressor response by inhibiting activities of the sympathetic nervous system. The results also show that influences of anaesthetics must be taken into consideration when evaluating pressor response of vasoactive agents.     

A comparison of the inhibitory effects of sodium nitroprusside, pinacidil and nifedipine on pressor response to NG-nitro-L-arginine.

1. The inhibitory effects of sodium nitroprusside (SNP), a nitric oxide (NO) donor, on mean arterial pressure (MAP) responses to NG-nitro-L-arginine (L-NNA) (NO synthase inhibitor), angiotensin II (AII) and noradrenaline (NA) were compared with those of pinacidil (KATP channel opener) and nifedipine (L-type calcium antagonist) in conscious, unrestrained rats. 2. Intravenous bolus injections of L-NNA (1-64 mg kg-1), AII (0.02-1.28 micrograms kg-1) and NA (0.25-16 micrograms kg-1) dose-dependently increased MAP to similar maxima. Intravenous infusions of SNP (1, 4 and 16 micrograms kg-1 min-1) dose-dependently increased ED20S of L-NNA, AII and NA. However, the maximum response evoked by L-NNA, but not by AII nor NA, was dose-dependently reduced by SNP. Moreover, the inhibitory effect of SNP on the pressor response to L-NNA ceased when the infusion of SNP was terminated. 3. Pinacidil (80 micrograms kg-1 min-1 for 30 min followed by 5 micrograms kg-1 min-1) increased ED50S of L-NNA, AII and NA but did not decrease the maximum responses to any of these agents. 4. Nifedipine (1 mg kg-1 min-1) non-selectively reduced maximum responses to L-NNA, AII and NA to similar levels and increased ED50S of AII and NA but not L-NNA. 5. The results show that SNP causes a selective, non-competitive and reversible inhibition of the pressor response to L-NNA. This inhibition by SNP is unlikely to be related to hypotension, the opening of ATP-sensitive potassium channels or blockade of L-type calcium channels.     

Increased vasoconstriction to noradrenaline by 1400W, inhibitor of iNOS, in rats with streptozotocin-induced diabetes

There is evidence that inducible nitric oxide synthase (iNOS) is activated at the acute phase of diabetes. We examined if selective inhibition of iNOS by 1400W (N-3-aminomethyl-benzyl-acetamidine) increases vascular response to noradrenaline in rats with streptozotocin (60 mg/kg i.v.)-induced diabetes for a duration of 3 weeks. The effects of noradrenaline on mean arterial pressure (MAP; 6, 16, 45 and 122x10(-9) mol/kg/min) and mean circulatory filling pressure (MCFP; 16 and 45x10(-9) mol/kg/min) were obtained in conscious and unrestrained diabetic rats and control rats before as well as after treatment with 1400W (3 mg/kg followed by 3 mg/kg/h, i.v.). Rats with early streptozotocin-induced diabetes had decreased mean arterial pressure and mean circulatory filling pressure responses to noradrenaline. Treatment with 1400W did not affect responses in the control rats but increased maximum pressor response to noradrenaline (from 46+/-3 to 63+/-5) and mean circulatory filling pressure response to the high dose (45 nmol/kg/min) of noradrenaline (from 1.0+/-0.2 to 3.8+/-0.3 mmHg) in the diabetic rats. Thus, selective inhibition of iNOS by 1400W increases arterial and venous constriction to noradrenaline in conscious rats with streptozotocin-induced diabetes.     

Equal potency of nifedipine to inhibit alpha 1-(dobutamine and BDF 6143) and alpha 2-adrenoceptor (B-HT 920) induced pressor responses in pithed rats; lack of effect of phenoxybenzamine

Intravenous (i.v.) dobutamine and BDF 6143 were partial agonists in increasing diastolic pressure in beta-adrenoceptor-blocked pithed rats. The log dose-pressor effect curves were not influenced by yohimbine (1 mg/kg i.v., -15 min) but were markedly shifted to the right by prazosin (0.1 mg/kg i.v., -15 min) indicating the exclusive involvement of alpha 1-adrenoceptors. Nifedipine (0.1-1 mg/kg i.a., -15 min) non-competitively inhibited the pressor effects of dobutamine and BDF 6143 as well as of the alpha 2-adrenoceptor agent B-HT 920 with equal potency. The -log ED50 values calculated for nifedipine amounted to 6.25 +/- 0.12, 6.16 +/- 0.14 and 6.20 +/- 0.10, respectively. Phenoxybenzamine (3 or 10 micrograms/kg i.v., -60 min) did not affect the effectiveness of nifedipine (0.1 mg/kg) to inhibit the pressor effects of dobutamine and BDF 6143. Following treatment with Bay k 8644 (1 mg/kg i.a., -15 min), the log dose-pressor effect curves for dobutamine and BDF 6143 were shifted to the left and the maximum responses were elevated. Our findings suggest that the alpha 1-adrenoceptor-induced pressor effects of dobutamine and BDF 6143 rely heavily on the influx of Ca2+, and are indistinguishable in this respect from the effects initiated by alpha 2-adrenoceptor stimulation. The data further support the view that the sensitivity of alpha-adrenoceptor-mediated pressor effects to inhibition by Ca2+ entry blockers depends on the extent to which Ca2+ influx contributes to the overall response and is not determined by the intrinsic activity or by the receptor reserve of the alpha-adrenoceptor agonist.     

N omega-nitro-L-arginine attenuates the accumulation of aortic cyclic GMP and the hypotension produced by zaprinast.

To determine if N omega-nitro-L-arginine (NNA), an inhibitor of the synthesis and/or release of endothelium-derived relaxing factor (EDRF), alters the response to zaprinast, a selective inhibitor of cyclic GMP (cGMP) phosphodiesterase, zaprinast (3-30 mg/kg) or vehicle (1 ml/kg) was given to conscious, spontaneously hypertensive rats (SHR) in a cumulative i.v. dose-response manner 30 min after pretreatment with NNA (1 or 3 mg/kg) or saline (1 ml/kg). Mean arterial pressure (MAP) was measured 5 min after each dose of zaprinast. Five minutes after the last dose of zaprinast (30 mg/kg), the rats were anesthetized with pentobarbital (25 mg i.v.). A segment of the abdominal aorta was freeze-clamped in situ and removed for the determination of cGMP levels. NNA (3 mg/kg) decreased basal aortic cGMP levels by 54% and increased MAP by 37 +/- 2 mm Hg. Zaprinast (30 mg/kg) increased aortic cGMP by 187% and decreased MAP by 49 +/- 4 mm Hg. NNA (3 mg/kg) reduced the accumulation of cGMP in aortic tissue (from 4.1 +/- 0.4 to 1.3 +/- 0.1 fmol/microgram protein) and attenuated the depressor response (from -49 +/- 4 to -31 +/- 4 mm Hg) produced by zaprinast. These data are consistent with the hypothesis that NNA inhibits the tonic release of EDRF and that the depressor effects of zaprinast are due, at least in part, to the potentiation of the vasodilator effects of EDRF in vivo. Moreover, since the changes in MAP produced by NNA and zaprinast were significantly correlated with cGMP levels in aortic tissue, the concentration of cGMP in vascular tissue may be a determinant of blood pressure in SHR.