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)。     

毛细管电色谱手性配体交换法检测生物样品中的硝基精氨酸异构体研究

目的：建立毛细管电色谱（CEC）分离检测生物样品中硝基精氨酸异构体的方法。方法：采用CEC手性配体交换模式检测血浆样品中D-硝基精氨酸（D—NNA）和L-硝基精氨酸（L—NNA），流动相为50mmol／L醋酸缓冲液[pH5．0，含2mmol／Laspartame，1mmol／L Cu^2＋和5％（v／v）甲醇]；流速为0．02mL／min；操作压为1000psi；检测波长为UV280nm。结果：L—NNA和D—NNA在0．025～0．75mmol／L的浓度范围内峰面积／浓度的相关系数均可达0．99以上，日内变异系数均小于3．0％，日间变异系数分别为3．1％和3．4％。结论：本研究方法具有快速、高分辨、检测样品量和流动相用量少等优点。     

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     

Pressor effects of L and D enantiomers of NG-nitro-arginine in conscious rats are antagonized by L- but not D-arginine.

The effects of NG-nitro-L-arginine (L-NNA) and NG-nitro-D-arginine (D-NNA) on mean arterial pressure (MAP) were studied in conscious, unrestrained rats. I.v. bolus of either L-NNA (1-64 mg/kg) or D-NNA (2-64 mg/kg) dose dependently increased MAP to similar maximum values of 55 +/- 7 and 52 +/- 4 mm Hg and with ED50 values of 4.0 +/- 0.9 and 8.9 +/- 1.2 mg/kg (P less than 0.05), respectively. The time course of the MAP response to a single dose (32 mg/kg i.v. bolus) of L-NNA and D-NNA were also obtained. The pressor effects of L-NNA and D-NNA each lasted greater than 2 h with the rise phase t 1/2 of 5 and 27 min (P less than 0.05), respectively. I.v. infusions (10 mg/kg per min) of L-arginine (L-Arg) and D-arginine (D-Arg) did not alter the pressor response to noradrenaline nor angiotensin II. L-Arg but not D-Arg attenuated the pressor responses to both L-NNA and D-NNA. Therefore, both L-NNA and D-NNA are efficacious and long-lasting pressor agents; the pressor effects of both can be antagonized by L-Arg but not D-Arg. Our results suggest that the pressor effects of both L-NNA and D-NNA involve the L-Arg/nitric oxide pathway.     

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.     

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     

D-硝基精氨酸对小鼠肾损伤及氧化应激作用

目的研究D-硝基精氨酸(D-NNA)对小鼠的肾损伤及其氧化应激机制。方法 ICR小鼠ig给予D-NNA150,50和15 mg·kg-1,连续30 d。测定并计算肾系数;血液生化分析仪检测血清中肌酐(Crea)和尿素氮(BUN);分光光度法测定肾组织一氧化氮(NO),硫代巴比妥酸法测丙二醛(MDA)含量,比色法测定谷胱甘肽过氧化酶(GSH-Px)和超氧化物歧化酶(SOD)活性;观察肾病理组织学变化。结果与5%葡萄糖对照组相比,D-NNA 150,50和15 mg·kg-1组血清中BUN分别明显升高了83.6%,36.2%和27.4%(P<0.05),D-NNA150和50 mg·kg-1组血清中Crea分别明显升高了281.6%和10.6%(P<0.05);D-NNA150 mg·kg-1组肾系数和NO水平分别明显降低了5.6%和25.5%(P<0.05);D-NNA150和50 mg·kg-1组肾组织中MDA水平分别明显升高了69.0%和36.9%(P<0.01),SOD活性和GSH-Px活性分别明显下降了17.4%和17.7%,7.3%和13.7%(P<0.05);D-NNA150 mg·kg-1组病理检查可见肾小管损伤,嗜碱性变,萎缩或囊性扩张和间质炎性浸润,D-NNA50和15 mg·kg-1组出现炎症细胞浸润。结论 D-NNA对小鼠肾有一定的损伤作用,其作用机制可能与D-NNA的手性转化产物L-NNA导致NO合成减少,产生ROS有关。     

The effect of L-NG-nitro arginine on non-adrenergic, non-cholinergic (NANC) relaxations in the longitudinal muscle of the guinea pig proximal colon]

We have investigated the effect of the NO synthesis inhibitor L-NG-nitro arginine (L-NNA) on the NANC relaxation induced by electrical field stimulation (FS) or the 5-HT1-like receptor agonist 5-carboxamidotryptamine (5-CT) in the longitudinal muscle of the guinea pig proximal colon. In the presence of atropine (0.2 microM) and guanethidine (5.0 microM), NANC relaxations induced by FS (0.1-10 Hz, 160 mA, 0.3 ms) or 5-CT (1.0-30 microM) were completely abolished by tetrodotoxin (0.3 microM). L-NNA (10-100 microM) produced concentration-dependent inhibition of NANC relaxations, but D-NNA had no effect. This inhibitory effect of L-NNA on NANC relaxations was prevented by L-arginine (1 mM) or L-citrulline (1 mM), but was not affected by D-arginine (1 mM). Like L-NNA, L-NMMA (100-300 microM) also inhibited the NANC relaxation induced by FS and 5-CT. These results suggest that nitric oxide (NO) or a substance releasing NO may contribute to NANC relaxations of guinea pig proximal colon induced by FS and the stimulation of 5-HT1-like receptors.     

A possible role of the L-arginine-nitric oxide pathway in the modulation of cholinergic transmission in the guinea-pig taenia coli.

1. The role of the L-arginine-nitric oxide (NO) pathway for non-adrenergic, non-cholinergic (NANC) relaxation of the guinea-pig taenia coli was studied by recording isometric tension in response to transmural field stimulation (TMS). 2. In preparations precontracted with prostaglandin F2 alpha (PGF2 alpha, 10(-6) M), TMS induced frequency-dependent responses of the muscle strips which could be abolished by tetrodotoxin (10(-6) M). NG-nitro-L-arginine (L-NNA, 10(-4) M), an L-arginine analogue, and potent inhibitor of NO synthesis, stereospecifically inhibited maximum relaxations, but did not shift the frequency-response curve. Pre-incubation with NG-nitro-D-arginine (D-NNA, 10(-4) M), atropine (10(-6) M) plus L-NNA (10(-4) M), or atropine (10(-6) M) alone, had no influence on the frequency-response characteristics. 3. L-NNA (10(-7)-10(-4) M) concentration-dependently inhibited relaxations in PGF2 alpha (10(-6) M) precontracted strips in response to TMS, but did not abolish relaxations. Preincubation with L-arginine (10(-4) M) inhibited these effects of L-NNA. L-NNA (10(-4) M) had no effect on the inhibitory response during TMS in strips preincubated with atropine (10(-6) M). 4. The relaxation induced by sodium nitroprusside and forskolin (10(-9)-10(-4) M) was not influenced by L-NNA (10(-4) M) preincubation as expressed by identical pD2 and Emax values. 5. Contractions induced by PGF2 alpha (10(-9)-10(-4) M) and carbachol (10(-9)-10(-4) M) were not affected by pretreatment with L-NNA (10(-4) M), was expressed by identical pD2 and Emax values.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

硝基精氨酸—赖氨酸三肽合成及其对一氧化氮合酶的抑制作用

液相合成法合成了由左旋精氨酸、左旋赖氨酸组成的硝基精氨酸-赖氨酸三肽HCl．Arg(NO     

The role of the L-arginine-nitric oxide pathway in relaxation of the opossum lower oesophageal sphincter.

1. The role of the L-arginine-nitric oxide pathway in lower oesophageal sphincter (LOS) relaxation and oesophageal peristalsis was investigated. 2. Twenty four adult opossums were anaesthetized and the right vagus nerve was isolated in the neck and sectioned. Electrical stimulation, applied to the peripheral end of the nerve, resulted in a frequency-dependent relaxation of the LOS, and peristaltic and non-peristaltic contractions in the oesophageal body. 3. N omega-nitro-L-arginine (L-NNA, 10(-8)-10(-5) mol kg-1), an inhibitor of the L-arginine-nitric oxide pathway, inhibited LOS relaxation in a dose-dependent manner, but did not affect resting LOS pressure. At the highest dose of L-NNA no relaxation of the LOS was elicited in response to vagal stimulation. The effect of L-NNA, (10(-5) mol kg-1) was fully reversed by infusion of 10(-4) mol kg-1 L-arginine. Peristaltic velocity and amplitude of contractions in the oesophageal body were unaffected by L-NNA. 4. Infusion of sodium nitroprusside reduced LOS pressure to zero, and the drug was equally potent in control animals (-log ED50:8.1 +/- 0.2 mol kg-1) and in animals pretreated with L-NNA (-log ED50:8.2 +/- 0.3 mol kg-1). This suggests that the effect of L-NNA was not directly on guanylate cyclase. 5. A significant elevation of blood pressure was recorded after administration of L-NNA (10(-5) mol kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

N-nitro L-arginine causes coronary vasoconstriction and inhibits endothelium-dependent vasodilatation in anaesthetized greyhounds.

1. The effect of N-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide biosynthesis, on large coronary artery diameter and coronary blood flow was examined in anaesthetized greyhounds. The effects of L-NNA on the coronary vascular responses to acetylcholine (ACh), glyceryl trinitrate (GTN) and 5-hydroxytryptamine (5-HT) were also assessed. 2. L-NNA (5 mg kg-1), infused into the left circumflex coronary artery, increased systemic mean arterial pressure and decreased the external diameter of the artery. Infusion of L-NNA decreased coronary blood flow in 5 of the 7 dogs tested and increased mean coronary resistance but neither of these effects was statistically significant. There was no change in heart rate. 3. Intra-arterial injection of both ACh (0.01-0.05 micrograms kg-1) and GTN (0.1-0.5 micrograms kg-1) increased large coronary artery diameter and coronary blood flow. Coronary vascular responses to the endothelium-dependent vasodilator ACh were significantly reduced by L-NNA, whereas the responses to the endothelium-independent vasodilator GTN were not significantly affected. 4. 5-HT (0.1 microgram kg-1, injected into the left circumflex coronary artery) decreased coronary artery diameter but increased coronary blood flow. After the administration of L-NNA the 5-HT-induced dilatation of the coronary resistance vessels was significantly attenuated whereas the constriction of the circumflex coronary artery was increased in 3 out of 3 dogs in which diameter could be measured, although the latter effect was not statistically significant. 5. These data indicate that L-NNA causes coronary and systemic vasoconstriction and selectively inhibits endothelium-dependent vasodilatation in the coronary circulation of the anaesthetized greyhound.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Influence of NG-nitro-L-arginine on non-adrenergic non-cholinergic relaxation in the guinea-pig gastric fundus.

1. The influence of NG-nitro-L-Arginine (L-NNA) on non-adrenergic non-cholinergic (NANC) relaxations induced by electrical field stimulation was investigated in circular muscle strips of the guinea-pig gastric fundus. 2. In the presence of 10(-6) M atropine and 4 x 10(-6) M guanethidine, electrical field stimulation (40 V, 1 ms, 0.125-16 Hz) with 10 s trains at 5 min intervals induced short-lasting, frequency-dependent relaxations. Continuous stimulation, with cumulative increase of the stimulation frequency, induced sustained frequency-dependent relaxations. Both types of response were abolished by 3 x 10(-6) M tetrodotoxin. 3. L-NNA (10(-5) M and 10(-4) M) concentration-dependently reduced both types of NANC response. Pre-incubation with 2 x 10(-3) M L-arginine prevented the inhibitory action of 10(-5) M L-NNA and partially antagonized that of 10(-4) M L-NNA. D-arginine (2 x 10(-3) M) did not protect against the inhibitory effect of L-NNA. 4. L-NNA did not consistently influence the basal tone of the tissues. L-Arginine and D-arginine likewise did not influence basal tone; they also had no influence on the electrically-induced NANC relaxations. 5. NO (10(-6)-10(-4) M) induced short-lasting concentration-dependent relaxations, while vasoactive intestinal polypeptide (VIP, (10(-9)-10(-7) M) induced more sustained relaxations, that developed at a slower rate. The NO- and VIP-induced relaxations were not influenced by 10(-4) M L-NNA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Unchanged cardiac angiotensin II levels accompany losartan-sensitive cardiac injury due to nitric oxide synthase inhibition

Chronic nitric oxide synthase (NOS) inhibition results in hypertension and myocardial injury. In a rapid and severe model of chronic NOS inhibition, we determined the role of angiotensin II in these effects by using angiotensin II receptor blockade and by measuring cardiac angiotensin II concentrations before and during development of cardiac damage. Rats received either no treatment, the NOS inhibitor Nomega-nitro-L-arginine (L-NNA; 500 mg/l), the angiotensin AT(1) receptor antagonist losartan (400 mg/kg chow), or L-NNA plus losartan for 21 days. In the second protocol, five groups of rats received L-NNA (500 mg/l) for 0, 4, 7, 14 and 21 days, respectively. L-NNA increased systolic blood pressure (SBP) (227+/-8 versus 143+/-6 mm Hg; P<0.01), heart weight index (0.44+/-0.02 versus 0.32+/-0.01; P<0.01) and induced coronary vasculitis and myocardial necrosis. Co-treatment with losartan prevented all changes. L-NNA during 4 days decreased cardiac angiotensin II (23+/-4 versus 61+/-15 fmol/g; P<0.05). Although after 7 days, fresh infarcts and after 14 days organized infarcts were present, cardiac angiotensin II was only slightly increased after 21 days (100+/-10 fmol/g; P<0.05). In conclusion, losartan-sensitive cardiac damage due to chronic NOS inhibition is not associated with primary increase of cardiac angiotensin II, suggesting that chronic NOS inhibition increases cardiac sensitivity for angiotensin II.     

Involvement of α-adrenoceptors in the endothelium-dependent depression of noradrenaline-induced contraction in rat aorta

The involvement of endothelium-derived nitric oxide (NO) in the depressant action of the endothelium on noradrenaline-induced contractions and characterization of the receptor involved in the release of NO were studied using rat aorta. The noradrenaline-induced contraction was significantly potentiated by endothelium removal and in the presence of N^G-nitro-L-arginine (L-NNA) or N^G-monomethyl-L-arginine (L-NMMA). The contraction induced by phenylephrine was also potentiated in the presence of L-NNA. Clonidine could induce contraction only in endothelium-denuded preparations or in the presence of L-NNA. The potentiating action of L-NNA on noradrenaline-induced contractions could also be observed in the presence of yohimbine or rauwolscine, although dose-response curves were shifted to the right. The depression of noradrenaline-induced contractions observed in the presence of the endothelium was increased by repeated stimulation. The depression was prevented by L-NNA and this effect was reversed by L-arginine. These results indicate the possibility that NO can be released through stimulation of α₁- and α₂-adrenoceptors on the endothelium and depresses noradrenaline-induced contractions of smooth muscle, although the contribution of the respective adrenoceptors remains to be investigated. The release of NO was increased when the stimulation was applied repeatedly.     

NITRIC OXIDE DEFICIENCY INDUCES MYOCARDIAL INFARCTION IN HYPERCHOLESTEROLAEMIC STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. To observe the effect of nitric oxide (NO) on the myocardium, the NO synthesis inhibitor N^G-nitro-L-arginine (L-NNA) was administered to hypercholesterolaemic stroke-prone spontaneously hypertensive (SHRSP) rats. 2. Hypercholesterolaemic SHRSP were produced by feeding SHRSP a high fat and high cholesterol diet (HFC) for 2 weeks. The rats were then divided into three groups: (i) the N group, which were fed the HFC diet containing 0.023% L-NNA and 1% NaCl in their drinking water (n = 10); (ii) the NH group, which were fed the HFC diet containing 0.023% L-NNA and 1% NaCl in their drinking water which also contained 80 mg/L hydralazine (n = 10); and (iii) the C group, which were fed the HFC diet and 1% NaCl in their drinking water (n = 10). 3. All rats in the N and NH groups died within 35 days of the initiation of L-NNA administration. Rats in the N and NH groups had significantly increased serum creatine phosphokinase, lactate dehydrogenase, glutamic oxaloacetic transaminase and serum total cholesterol levels compared with rats in the C group. 4. Fibrosis in response to necrosis was histopathologically observed in the hearts of all rats in the N and NH groups without exception. Occlusion or intimal thickening in the arteries adjacent to the necrotic regions was also observed. 5. These results suggest that nitric oxide deficiency induces myocardial infarction in hypercholesterolaemic SHRSP. These NO-deficient hypercholesterolaemic SHRSP offer a new model of myocardial infarction in rats.     

Enhancement of noradrenergic constriction of large coronary arteries by inhibition of nitric oxide synthesis in anaesthetized dogs.

1. Coronary vascular responses to bilateral carotid occlusion (BCO) and the intravenous infusion of tyramine (Tyr, 20 micrograms kg-1 min-1) and noradrenaline (NA, 0.5 microgram kg-1 min-1) were examined after bilateral vagotomy and antagonism of beta-adrenoceptors. BCO, Tyr and NA decreased large coronary artery diameter and increased mean coronary resistance and systemic arterial pressure without affecting heart rate. 2. Inhibition of nitric oxide (NO) synthase with NG-nitro-L-arginine (L-NNA, 5 and 15 mg kg-1) significantly increased mean arterial pressure and decreased heart rate and large coronary artery diameter. Mean coronary resistance was unaffected by either dose of L-NNA. L-NNA significantly reduced depressor and coronary vasodilator responses to the endothelium-dependent vasodilator acetylcholine (ACh, 10 micrograms kg-1, i.v.). Systemic and coronary vasodilator responses to sodium nitroprusside (SNP, 5 micrograms kg-1) were unaffected by L-NNA with the exception that the dilatation of the large coronary artery was significantly enhanced by the higher dose. 3. L-NNA significantly enhanced constriction of the large coronary arteries caused by BCO, Tyr and NA but did not affect the increases in mean coronary resistance or systemic arterial pressure. 4. Inhibition of NO synthesis enhances adrenergic constriction of large coronary arteries caused by both neuronally released and exogenous noradrenaline. In contrast, L-NNA did not affect adrenergic constriction of coronary or systemic resistance vessels. Endothelium-derived NO may play an important role in the modulation of noradrenergic vasoconstriction in coronary conductance arteries.