Nitric oxide modulates sympathoexcitatory cardiac-cardiovascular reflexes elicited by bradykinin

A number of studies have demonstrated an important role for nitric oxide (NO) in central and peripheral neural modulation of sympathetic activity. To assess the interaction and integrative effects of NO release and sympathetic reflex actions, we investigated the influence of inhibition of NO on cardiac-cardiovascular reflexes. In anesthetized, sinoaortic-denervated and vagotomized cats, transient reflex increases in arterial blood pressure (BP) were induced by application of bradykinin (BK, 0.1-10 microg/ml) to the epicardial surface of the heart. The nonspecific NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA, 10 mg/kg iv) was then administered and stimulation was repeated. L-NMMA increased baseline mean arterial pressure (MAP) from 129 +/- 8 to 152 +/- 9 mmHg and enhanced the change in MAP in response to BK from 32 +/- 3 to 39 +/- 5 mmHg (n = 9, P < 0.05). Pulse pressure was significantly enhanced during the reflex response from 6 +/- 4 to 27 +/- 6 mmHg after L-NMMA injection due to relatively greater potentiation of the rise in systolic BP. Both the increase in baseline BP and the enhanced pressor reflex were reversed by L-arginine (30 mg/kg iv). Because L-NMMA can inhibit both brain and endothelial NOS, the effects of 7-nitroindazole (7-NI, 25 mg/kg ip), a selective brain NOS inhibitor, on the BK-induced cardiac-cardiovascular pressor reflex also were examined. In contrast to L-NMMA, we observed significant reduction of the pressor response to BK from 37 +/- 5 to 18 +/- 3 mmHg 30 min after the administration of 7-NI (n = 9, P < 0.05), an effect that was reversed by L-arginine (300 mg/kg iv, n = 7). In a vehicle control group for 7-NI (10 ml of peanut oil ip), the pressor response to BK remained unchanged (n = 6, P > 0.05). In conclusion, neuronal NOS facilitates, whereas endothelial NOS modulates, the excitatory cardiovascular reflex elicited by chemical stimulation of sympathetic cardiac afferents.     

Central cardiovascular effects of baclofen in spontaneously hypertensive rats

This study was conducted to investigate the effects of centrally administered baclofen on blood pressure and heart rate in conscious spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Administration of baclofen (1.0 microgram/kg) into the lateral cerebral ventricle (icv) produced an increase in mean arterial pressure (MAP) in both SHR and WKY rats. The increase in MAP was significantly lower in SHR (13 +/- 3 mmHg) when compared with WKY (27 +/- 5 mmHg). The changes in heart rate (HR) were variable, from no change to a very small increase and did not differ significantly between SHR and WKY rats. The ability of baclofen to interfere with baroreceptor reflexes was also tested in separate experiments. In SHR, icv injection of baclofen (1.0 microgram/kg) significantly suppressed the pressor response and bradycardia evoked by phenylephrine 3.0 micrograms/kg iv, whereas in WKY, the pressor and HR responses to similar injections of phenylephrine were not affected by icv baclofen. Similarly, baclofen treatment modified hypotensive response and reflex tachycardia induced by nitroprusside (10.0 micrograms/kg) iv in SHR but not in WKY rats. Administration of sympathetic ganglionic blocker hexamethonium (HEX; 25 mg/kg) iv produced an equivalent decrease in MAP between SHR and WKY following icv injection of baclofen (1.0 microgram/kg). These results suggest that the effects of baclofen on the baroreceptor reflexes in SHR may not be mediated by a change in peripheral sympathetic tone.     

硝基左旋精氨酸对睡眠抑制作用的机制研究

本文观察了硝基左旋精氨酸（Ｌ－ＮＮＡ,５０ｍｇ／ｋｇ,ｉｐ）和Ｌ－精氨酸（Ｌ－ａｒｇ,１１０ｍｇ／ｋｇ,ｉｐ）对慢性植入电极的大鼠睡眠－觉醒周期的影响及中缝核５－羟色胺（５－ＨＴ）神经元免疫阳性反应的变化。结果表明：Ｌ－ＮＮＡ显著抑制慢波睡眠和快眼动睡眠,使平均动脉压（ＭＡＰ）升高。Ｌ－ａｒｇ则使ＭＡＰ显著降低,对睡眠无明显影响。预先给予Ｌ－ａｒｇ可逆转Ｌ－ＮＮＡ的效应。腹腔给予Ｌ－ＮＮＡ后２ｈ,     

Involvement of the nitric oxide/L-arginine and sympathetic nervous systems on the vasodepressor action of human urotensin II in anesthetized rats

This study examined if the nitric oxide (NO)/L-arginine pathway participates in and if the sympathetic nervous system attenuates the depressor action of human urotensin II. I.V. bolus injections of human urotensin II (0.1-30 nmol/kg) caused dose-dependent decreases in mean arterial pressure (MAP, EC(50) = 2.09 +/- 0.8 nmol/kg; Emax = -18 +/- 3 mmHg ) and increases in heart rate. The depressor response to human urotensin II (3 nmol/kg) was attenuated by approximately 50% in rats with MAP elevated through pretreatment with N(G)-nitro-L-arginine methyl ester (inhibitor of NO synthase), relative to that in rats with MAP elevated to a similar level through a continuous infusion of noradrenaline. Autonomic blockade with i.v. injections of mecamylamine (ganglion blocker) and propranolol (beta-adrenoceptor antagonist) markedly augmented the depressor response to human urotensin II, but almost completely attenuated the tachycardia. The results suggest that the depressor response to human urotensin II is partially mediated via the NO/L-arginine pathway, and is suppressed by activity of the sympathetic nervous system. Furthermore, tachycardic response to human urotensin II is primarily mediated indirectly via baroreflex mechanisms.     

Nitric oxide-independent effects of tempol on sympathetic nerve activity and blood pressure in DOCA-salt rats

The role of sympathetic nerves and nitric oxide (NO) in tempol-induced cardiovascular responses was evaluated in urethane-anesthetized sham and deoxycorticosterone acetate (DOCA)-salt-treated (DOCA-salt) rats. Tempol (30-300 micromol/kg iv), a superoxide (O) scavenger, decreased renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) in DOCA-salt and sham rats. The antioxidants tiron and ascorbate did not alter MAP, HR, or RSNA in any rat. Tempol responses were unaffected after sham rats were treated with N(G)-nitro-L-arginine (L-NNA, 13 mg/kg). In DOCA-salt rats, L-NNA reduced tempol-induced depressor responses but not the inhibition of HR or RSNA. Tempol did not significantly decrease MAP, HR, or RSNA after hexamethonium (30 mg/kg iv) treatment in any rat. Dihydroethidine histochemistry revealed increased O levels in arteries and veins from DOCA-salt rats. Tempol treatment in vitro reduced O levels in arteries and veins from DOCA-salt rats. In conclusion, tempol-induced depressor responses are mediated largely by NO-independent sympathoinhibition in sham and DOCA-salt rats. There is an additional interaction between NO and tempol that contributes to depressor responses in DOCA-salt rats.     

NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo?

Nitric oxide is a major endothelium-derived vascular smooth muscle relaxing factor; its synthesis from L-arginine is selectively inhibited by L-NG-methylarginine. To assess whether basal nitric oxide release contributes to blood pressure regulation in vivo, we have investigated the cardiovascular effects of L-NG-methylarginine in the anesthetized guinea pig. L-NG-methylarginine (0.1-10 mg/kg, i.v. bolus) elicited a sustained, dose-dependent, increase in arterial pressure and a moderate bradycardia. L-arginine (30 mg/kg i.v.) prevented or reversed the pressor effect of L-NG-methylarginine, while atropine (2 mg/kg) abolished the associated bradycardia. In contrast, L-arginine did not attenuate the pressor effect of norepinephrine or angiotensin. Our findings suggest that basal nitric oxide production is sufficient to modulate peripheral vascular resistance; hence nitric oxide may play a role in arterial pressure homeostasis.     

Independent modification of baroreceptor and exercise pressor reflex function by nitric oxide in nucleus tractus solitarius

It has been suggested that nitric oxide (NO) is a key modulator of both baroreceptor and exercise pressor reflex afferent signals processed within the nucleus tractus solitarius (NTS). However, studies investigating the independent effects of NO within the NTS on the function of each reflex have produced inconsistent results. To address these concerns, the effects of microdialyzing 10 mM L-arginine, an NO precursor, and 20 mM N(G)-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, into the NTS on baroreceptor and exercise pressor reflex function were examined in 17 anesthetized cats. Arterial baroreflex regulation of heart rate was quantified using vasoactive drugs to induce acute changes in mean arterial pressure (MAP). To activate the exercise pressor reflex, static hindlimb contractions were induced by electrical stimulation of spinal ventral roots. To isolate the exercise pressor reflex, contractions were repeated after barodenervation. The gain coefficient of the arterial cardiac baroreflex was significantly different from control (-0.24 +/- 0.04 beats.min(-1).mmHg(-1)) after the dialysis of L-arginine (-0.18 +/- 0.02 beats.min(-1).mmHg(-1)) and L-NAME (-0.29 +/- 0.02 beats.min(-1).mmHg(-1)). In barodenervated animals, the peak MAP response to activation of the exercise pressor reflex (change in MAP from baseline, 39 +/- 7 mmHg) was significantly attenuated by the dialysis of L-arginine (change in MAP from baseline, 29 +/- 6 mmHg). The results demonstrate that NO within the NTS can independently modulate both the arterial cardiac baroreflex and the exercise pressor reflex. Collectively, these findings provide a neuroanatomical and chemical basis for the regulation of baroreflex and exercise pressor reflex function within the central nervous system.     

Studies on gastroprotection induced by capsaicin and papaverine.

Capsaicin and papaverine are potent vasorelaxants with strong gastroprotective activity against damage induced by absolute ethanol. This protection was originally attributed to the increase in gastric mucosal blood flow (GBF) but the possibility that NO mediates the protective and hyperemic effects of capsaicin and papaverine has been little studied. Using N-nitro-L-arginine (L-NNA), a selective blocker of NO synthase, and L-arginine as a substrate for NO, we investigated the role of NO in protective action of capsaicin and papaverine against ethanol-induced gastric damage and in GBF. Pretreatment with capsaicin (0.1-0.5 mg/kg i.g.) or papaverine (0.1-2 mg/kg i.g.) reduced dose-dependently the area of ethanol-induced lesions, the LD50 being 0.3 and 1 mg/kg, respectively. This protection was accompanied by a gradual increase in the GBF. Intravenous (i.v.) injection of L-NNA (1.2-5 mg/kg), which by itself caused only a small increase in ethanol lesions, reversed dose-dependently the protective and hyperemic effects of capsaicin and papaverine against ethanol-induced damage and attenuated the increase in GBF induced by each of these agents alone. This deleterious effect of L-NNA on the gastric mucosa and the GBF was fully antagonized by L-arginine (200 mg/kg i.v.) but not by D-arginine. L-arginine partly restored the decrease in GBF induced by L-NNA. Pretreatment with indomethacin (5 mg/kg i.p.), which suppressed the generation of PG by 85%, slightly enhanced the mucosal lesions induced by ethanol but failed to affect the fall in GBF induced by this irritant. Gastroprotective and hyperemic effects of capsaicin and papaverine were partly reversed by indomethacin suggesting that endogenous PG are also implicated in these effects. Addition of L-NNA to indomethacin completely eliminated both the protective and hyperemic effects of capsaicin and papaverine. We conclude that both NO and PG contribute to the gastroprotective and hyperemic effects of capsaicin and papaverine on the gastric mucosa.     

延髓腹外侧区微量注射L－NNA和SNP对大鼠血压、心率和肾交感神经活动的影响

在麻醉大鼠观察了向延髓腹外侧区微量注射ＮＯ合成酶抑制剂Ｎ－硝基左旋精氨酸（ＬＮＮＡ）和硝普钢（ＳＮＰ）对血压、心率和肾交感神经活动的影响,旨在探讨中枢左旋精氨酸－ＮＯ通路在动脉血压调节中的作用及其机制。实验结果如下：（１）向延髓腹外侧头端区（ＲＶＬＭ）注射Ｌ－ＮＮＡ后,平均动脉压（ＭＡＰ）升高,肾交感神经活动（ＲＳＮＡ）增强;心率（ＨＲ）减慢,但无统计学意义。ＭＡＰ和ＲＳＮＡ的变化持续３０ｍｉｎ以上;此效应可被预先静注左旋精氨酸所逆转。（２）向ＲＶＬＭ微量注射ＳＮＰ,ＭＡＰ降低,ＲＳＮＡ减弱;但ＨＲ的变化无统计学意义。（３）向延髓腹外侧尾端区（ＣＶＬＭ）注射Ｌ－ＮＮＡ,ＭＡＰ降低,ＨＲ减慢,ＲＳＮＡ减弱。（４）向ＣＶＬＭ微量注射ＳＮＰ,ＭＡＰ升高,ＲＳＮＡ增强,而心率无明显变化。以上结果表明,中枢左旋精氨酸－ＮＯ通路对延髓腹外侧部的神经元活动有调变作用。     

Participation of the components of L-arginine/nitric oxide/cGMP cascade by chemically-induced abdominal constriction in the mouse

The purpose of this study was to investigate the role of the L-arginine/nitric oxide (NO)/cGMP pathway in p-benzoquinone-induced writhing model in mouse. L-arginine, a NO precursor, displayed antinociceptive effects at the doses of 0.125-1.0 mg/kg. When the doses of L-arginine were increased gradually to 10-100 mg/kg, a dose-dependent triphasic pattern of nociception-antinociception-nociception was obtained. The NO synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) (18.7515 mg/kg), possessed antinociceptive activity. Methylene blue (MB), a guanylyl cyclase and/or NOS inhibitor, (5-160 mg/kg) also produced a dose-dependent triphasic response. When L-arginine (50 mg/ kg) was combined with L-NAME (75 mg/kg). L-arginine-induced antinociception did not change significantly. Cotreatment of L-arginine with 5 mg/kg MB significantly decreased MB-induced antinociception and reversed the nociception induced by 40 mg/kg MB to antinociception. It is concluded that the components of L-arginine/nitric oxide/cGMP cascade may participate in nociceptive processes both peripherally and centrally by a direct effect on nociceptors or by the involvement of other related pathways of nociceptive processes induced by NO.     

Nitric oxide modulates the cardiovascular effects elicited by acetylcholine in the NTS of awake rats

Microinjection of acetylcholine chloride (ACh) in the nucleus of the solitary tract (NTS) of awake rats caused a transient and dose-dependent hypotension and bradycardia. Because it is known that cardiovascular reflexes are affected by nitric oxide (NO) produced in the NTS, we investigated whether these ACh-induced responses depend on NO in the NTS. Responses to ACh (500 pmol in 100 nl) were strongly reduced by ipsilateral microinjection of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 nmol in 100 nl) in the NTS: mean arterial pressure (MAP) fell by 50 +/- 5 mmHg before L-NAME to 9 +/- 4 mmHg, 10 min after L-NAME, and HR fell by 100 +/- 26 bpm before L-NAME to 20 +/- 10 bpm, 10 min after L-NAME (both P < 0.05). Microinjection of the selective inhibitor of neuronal nitric oxide synthase (nNOS), 1-(2-trifluoromethylphenyl) imidazole (TRIM; 13.3 nmol in 100 nl), in the NTS also reduced responses to ACh: MAP fell from 42 +/- 3 mmHg before TRIM to 27 +/- 6 mmHg, 10 min after TRIM (P < 0.05). TRIM also tended to reduce ACh-induced bradycardia, but this effect was not statistically significant. ACh-induced hypotension and bradycardia returned to control levels 30-45 min after NOS inhibition. Control injections with D-NAME and saline did not affect resting values or the response to ACh. In conclusion, injection of ACh into the NTS of conscious rats induces hypotension and bradycardia, and these effects may be mediated at least partly by NO produced in NTS neurons.     

Role of nitric oxide in the nicotine-induced pituitary-adrenocortical response.

Nitric oxide (NO) is a major signaling molecule and biological mediator of the hypothalamic-pituitary-adrenal (HPA) axis. We investigated the role of NO formed by endothelial (e), neuronal (n) and inducible (i) nitric oxide synthase (NOS) in the stimulatory effect of nicotine on the HPA axis in rats under basal conditions. Also possible interaction of NOS systems with endogenous prostaglandins (PG) in that stimulation was assessed. NOS and cyclooxygenase inhibitors were administered i.p. 15 min prior to nicotine (2, 5 mg/kg i.p.). Plasma ACTH and serum corticosterone levels were measured 1 h after nicotine injection. NOS blockers given alone did not markedly affect the resting ACTH and corticosterone levels. L-NAME (2-10 mg/kg), a broad spectrum NOS inhibitor considerably and dose dependently enhanced the nicotine-induced ACTH and corticosterone secretion. L-NNA (2 mg/kg) and 7-nitroindazole (7-NI 20 mg/kg), neuronal NOS inhibitors in vivo also significantly augmented the nicotine-induced ACTH and corticosterone levels. L-arginine greatly impaired the nicotine-induced hormone responses and reversed the L-NNA elicited enhancement of the nicotine-evoked ACTH and corticosterone response. In contrast to the constitutive eNOS and nNOS antagonists, an inducible NOS antagonist guanethidine (50-100 mg/kg i.p.) did not substantially affect the nicotine-elicited pituitary-adrenocortical responses. Indomethacin (2 mg/kg i.p.), a non-selective cyclooxygenase blocker abolished the L-NAME and L-NNA-induced enhancement of the nicotine-evoked ACTH and corticosterone response. These results indicate that NO is an inhibitory mediator in the HPA axis activity. Inhibition of its generation by eNOS and nNOS significantly enhances the nicotine-induced HPA response. Under basal conditions iNOS is not involved in the nicotine-induced ACTH and corticosterone secretion. Prostaglandins play an obligatory role in the response of HPA axis to systemic nicotine administration.     

Cardiovascular effects of the essential oil of Croton zehntneri leaves and its main constituents, anethole and estragole, in normotensive conscious rats

Cardiovascular effects of the essential oil of Croton zehntneri (EOCZ) were investigated in conscious rats. In these preparations, intravenous (i.v.) injections of EOCZ (1-20 mg kg(-1)) and its main constituents anethole and estragole (both at 1-10 mg kg(-1)) elicited brief and dose-dependent hypotension and bradycardia (phase I) that were followed by a significant pressor effect associated with a delayed bradycardia (phase II). The initial hypotension and bradycardia (phase I) of EOCZ were unchanged by atenolol (1.5 mg kg(-1), i.v.) or L-NAME (20 mg kg(-1), i.v.) pretreatment, but were respectively reversed into pressor and tachycardic effects by methylatropine (1 mg kg(-1), i.v.) pretreatment. The subsequent pressor effect and the delayed bradycardia (phase II) remained unaffected by atenolol, but were abolished by L-NAME and methylatropine pretreatment, respectively. In rat endothelium-containing aorta preparations, the vasoconstrictor responses to phenylephrine were enhanced and reduced, respectively, by the lower (1-30 microg mL(-1)) and higher (300-1000 microg mL(-1)) concentrations of EOCZ. Only the enhancement of phenylephrine-induced contraction was abolished by either the incubation with L-NAME (50 microM) or in the absence of the endothelium. These data show, for the first time, that i.v. administration EOCZ induces an initial hypotension followed by a pressor response, two effects that appear mainly attributed to the actions of anethole and estragole. The EOCZ-induced hypotension (phase I) is mediated by a cholinergic mechanism and seems to result mainly from the concomitant bradycardia. The pressor response of EOCZ (phase II) seems to be caused by an indirect vasoconstrictive action of EOCZ most likely through inhibition of endothelial nitric oxide production.     

Influence of nitric oxide synthase inhibitors on the vasopressin-induced pituitary-adrenocortical activity and hypothalamic catecholamine levels.

In the present study the role of endogenous nitric oxide (NO) in the vasopressin-induced ACTH and corticosterone secretion was investigated in conscious rats. Vasopressin (AVP 5 microg/kg i.p.) considerably augmented ACTH and corticosterone secretion. L-arginine (120 and 300 mg/kg i.p.) did not significantly alter the AVP-induced secretion of those hormones. Nitric oxide synthase (NOS) blockers N(omega)-nitro-L-arginine (L-NNA) and its methyl ester (L-NAME) given i.p. 15 min before AVP markedly increased the AVP-induced ACTH secretion. L-NNA (2 mg/kg) more potently and significantly increased the AVP-induced ACTH secretion, whereas L-NAME elicited a weaker and not significant effect. Both those NOS antagonists intensified significantly and to a similar extent the AVP-induced corticosterone secretion. L-arginine (120 mg/kg i.p.) reversed the L-NNA-induced rise in the AVP-stimulated ACTH secretion and substantially diminished the accompanying corticosterone secretion. Neither vasopressin alone nor in combination with L-arginine and L-NAME evoked any significant alterations in the hypothalamic noradrenaline and dopamine levels. L-NNA (2 and 10 mg/kg i.p.) elicited a dose dependent and significant decrease in the hypothalamic noradrenaline level. The hypothalamic dopamine level was not significantly altered by any treatment. These results indicate that in conscious rats endogenous NO has an inhibitory influence on the AVP-induced increase in ACTH and corticosterone secretion. L-NNA is significantly more potent than L-NAME in increasing the AVP-induced ACTH secretion. This may be connected with a considerable increase by L-NNA of hypothalamic noradrenergic system activation which stimulates the pituitary-adrenal axis in addition to specific inhibition of NOS.     

Stimulatory effects of endogenous and exogenous nitric oxide on gastric acid secretion in anesthetized rats

We previously reported the stimulatory effect of endogenous nitric oxide (NO) on gastric acid secretion in the isolated mouse whole stomach and histamine release from gastric histamine-containing cells. In the present study, we investigated the effects of endogenous and exogenous NO on gastric acid secretion in urethane-anesthetized rats. Acid secretion was studied in gastric-cannulated rats stimulated with several secretagogues under urethane anesthesia. The acid secretory response to the muscarinic receptor agonist bethanechol (2 mg/kg, s.c.), the cholecystokinin(2) receptor agonist pentagastrin (20 microg/kg, s.c.) or the centrally acting secretagogue 2-deoxy-D-glucose (200 mg/kg, i.v.) was dose-dependently inhibited by the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA, 10 or 50 mg/kg, i.v.). This inhibitory effect of L-NNA was reversed by a substrate of NO synthase, L-arginine (200 mg/kg, i.v.), but not by D-arginine. The histamine H(2) receptor antagonist famotidine (1 mg/kg, i.v.) completely inhibited the acid secretory response to bethanechol, pentagastrin or 2-deoxy-D-glucose, showing that all of these secretagogues induced gastric acid secretion mainly through histamine release from gastric enterochromaffin-like cells (ECL cells). On the other hand, histamine (10 mg/kg, s.c.)-induced gastric acid secretion was not inhibited by pretreatment with L-NNA. The NO donor sodium nitroprusside (0.3-3 mg/kg, i.v.) also dose-dependently induced an increase in acid secretion. The sodium nitroprusside-induced gastric acid secretion was significantly inhibited by famotidine or by the soluble guanylate cyclase inhibitor methylene blue (50 mg/kg, i.v.). These results suggest that NO is involved in the gastric acid secretion mediated by histamine release from gastric ECL cells.     

TRPV1-mediated protection against endotoxin-induced hypotension and mortality in rats

This study was designed to test the hypothesis that the transient receptor potential vanilloid type 1 (TRPV1) channel, expressed primarily in sensory nerves, and substance P (SP), released by sensory nerves, play a protective role against lipopolysaccharide (LPS)-induced hypotension. LPS (10 mg/kg iv) elicited tachycardia and hypotension in anesthetized male Wistar rats, which peaked at 10 min and gradually recovered 1 h after the injection. Blockade of TRPV1 with its selective antagonist capsazepine (CAPZ, 3 mg/kg iv) impaired recovery given that the fall in mean arterial pressure (MAP) was greater 1 h after CAPZ plus LPS injections compared with LPS injection alone (45 +/- 5 vs. 25 +/- 4 mmHg, P < 0.05). Blockade of the neurokinin 1 (NK1) receptor with its selective antagonists RP-67580 (5 mg/kg iv) or L-733,060 (4 mg/kg iv) prevented recovery, considering that falls in MAP were not different 1 h after injections of NK1 antagonists plus LPS from their peak decreases (66 +/- 9 vs. 74 +/- 5 mmHg or 60 +/- 7 vs. 69 +/- 3 mmHg, respectively, P > 0.05). LPS increased plasma SP, norepinephrine (NE), and epinephrine (Epi) levels compared with vehicles, and the increases in plasma SP, NE, and Epi were significantly inhibited by CAPZ or RP-67580. The survival rate at 24 or 48 h after LPS injection (20 mg/kg ip) was lower in conscious rats pretreated with CAPZ or RP-67580 compared with rats treated with LPS alone (P < 0.05). Thus our results show that the TRPV1, possibly via triggering release of SP which activates the NK1 and stimulates the sympathetic axis, plays a protective role against endotoxin-induced hypotension and mortality, suggesting that TRPV1 receptors are essential in protecting vital organ perfusion and survival during the endotoxic condition.     

Tachykinin-stimulated small bowel myoelectric pattern: sensitization by NO inhibition, reversal by neurokinin receptor blockade

Tachykinins stimulate motility whereas NO inhibits motility in the gastrointestinal tract. AIM: To investigate if inhibition of NO production sensitizes myoelectric activity to subthreshold doses of tachykinins in the small intestine of awake rats. METHODS: Rats were supplied with a venous catheter and bipolar electrodes at 5, 15 and 25 cm distal to pylorus for electromyography of small intestine. The motor responses were evaluated using pattern recognition. Substance P and neurokinin A dose-dependently stimulated gut motility, with neurokinin A being more potent than substance P. Therefore, neurokinin A was chosen and administered under baseline conditions and 45-60 min after N(omega)-nitro-L-arginine (L-NNA) 1 mg kg(-1), with or without pretreatment with L-arginine 300 mg kg(-1). In addition, myoelectric activity effects of neurokinin A in conjunction with L-NNA were studied before and after administration of the tachykinin receptor antagonists, SR140333 (NK1), SR48968 (NK2) and SR142801 (NK3), each at 2.5 mg kg(-1). RESULTS: Dose-finding studies verified 10 pmol kg(-1) min(-1) to be the threshold dose at which NKA caused phase II-like activity in a low percentage of experiments (12%, n=41). This dose was therefore used in combination with L-NNA for sensitization experiments of gut myoelectric activity. In experiments where NKA-induced no response, pretreatment with L-NNA led to phase II-like activity in 9 of 18 (50%, p<0.05) experiments. Co-administration of SR140333 and SR48968 abolished this effect. CONCLUSION: NO counteracts the stimulatory effect of tachykinins on small bowel myoelectric activity in the rat. Inhibition of the L-arginine/NO pathway sensitizes the gut to tachykinin-stimulated motor activity.     

NO-dependent mechanisms of adaptation to hypoxia.

In studying NO-dependent mechanisms of resistance to hypoxia, it was shown that (1) acute hypoxia induces NO overproduction in brain and leaves unaffected NO production in liver of rats; (2) adaptation to hypoxia decreases NO production in liver and brain; and (3) adaptation to hypoxia prevents NO overproduction in brain and potentiates NO synthesis in liver in acute hypoxia. Dinitrosyl iron complex (DNIC, 200 microg/kg, single dose, iv), a NO donor, decreases the resistance of animals to acute hypoxia by 30%. Nomega-nitro-L-arginine (L-NNA, 50 mg/kg, single dose, ip), a NO synthase inhibitor, and diethyl dithiocarbamate (DETC, 200 mg/kg, single dose, iv), a NO trap, increases this parameter 1.3 and 2 times, respectively. Adaptation to hypoxia developed against a background of accumulation of heat shock protein HSP70 in liver and brain. A course of DNIC reproduced the antihypoxic effect of adaptation. A course of L-NNA during adaptation hampered both accumulation of HSP70 and development of the antihypoxic effect. Therefore, NO and the NO-dependent activation of HSP70 synthesis play important roles in adaptation to hypoxia.     

Pressor responses in rats following intravenous dynorphin A(1-13) administration are blocked by AVP-V1 receptor antagonism

Hemodynamic (blood pressure and heart rate) experiments were conducted in conscious and/or anesthetized male Sprague-Dawley (S.D.), heterozygous and homozygous Brattleboro rats given intravenous (iv) dynorphin A(1-13), arginine vasopressin (AVP), norepinephrine (HCl, (NE) or sterile saline before and 10 min after an iv bolus injection of a specific receptor antagonist. These receptor blockers (kappa receptor antagonist Mr2266, alpha adrenoceptor antagonist phentolamine HCl or the AVP-V1 receptor antagonist d(CH2)5Tyr-(Me)AVP were given in equimolar concentrations (15 nmol/kg iv). In all conscious S.D. groups, iv injection of AVP (60 pmol/kg), NE (12.5 nmol/kg) and dynorphin A(1-13) (60 nmol/kg) evoked significant increases in mean arterial pressure (MAP) associated with concomitant bradycardia. The hemodynamic responses to 'both' AVP and dynorphin A(1-13) were blocked if given subsequent to AVP-V1 administration but not following phentolamine or Mr2266 pretreatment. The pressor and bradycardic responses of conscious heterozygous and homozygous Brattleboro rats after iv AVP or dynorphin again were only blocked by the AVP-V1 receptor antagonist. Anesthetized heterozygous and homozygous Brattleboro rats again showed pressor responses following iv AVP, NE or dynorphin A(1-13) but with slight or no associated bradycardia. The rise in blood pressure with AVP 'and' dynorphin A(1-13) in these groups also was only blocked by the d(CH2)5Tyr(Me)AVP antagonist. The results indicate that the pressor responses of rats given intravenous dynorphin A(1-13) involve the interaction of AVP-V1 receptors and suggest a functional interaction of these two neuropeptides in the modulation of vascular tone.     

Central integration of muscle reflex and arterial baroreflex in midbrain periaqueductal gray: roles of GABA and NO

It has been suggested that the midbrain periaqueductal gray (PAG) is a neural integrating site for the interaction between the muscle pressor reflex and the arterial baroreceptor reflex. The underlying mechanisms are poorly understood. The purpose of this study was to examine the roles of GABA and nitric oxide (NO) in modulating the PAG integration of both reflexes. To activate muscle afferents, static contraction of the triceps surae muscle was evoked by electrical stimulation of the L7 and S1 ventral roots of 18 anesthetized cats. In the first group of experiments (n = 6), the pressor response to muscle contraction was attenuated by bilateral microinjection of muscimol (a GABA receptor agonist) into the lateral PAG [change in mean arterial pressure (DeltaMAP) = 24 +/- 5 vs. 46 +/- 8 mmHg in control]. Conversely, the pressor response was significantly augmented by 0.1 mM bicuculline, a GABAA receptor antagonist (DeltaMAP = 65 +/- 10 mmHg). In addition, the effect of GABAA receptor blockade on the reflex response was significantly blunted after sinoaortic denervation and vagotomy (n = 4). In the second group of experiments (n = 8), the pressor response to contraction was significantly attenuated by microinjection of L-arginine into the lateral PAG (DeltaMAP = 26 +/- 4 mmHg after L-arginine injection vs. 45 +/- 7 mmHg in control). The effect of NO attenuation was antagonized by bicuculline and was reduced after denervation. These data demonstrate that GABA and NO within the PAG modulate the pressor response to muscle contraction and that NO attenuation of the muscle pressor reflex is mediated via arterial baroreflex-engaged GABA increase. The results suggest that the PAG plays an important role in modulating cardiovascular responses when muscle afferents are activated.