Neutrophil/lymphocyte ratio elevation in renal dysfunction is caused by distortion of leukocyte hematopoiesis in bone marrow.

OBJECTIVE: We investigate the mechanism of neutrophil/lymphocyte ratio (NLR) elevation, a useful prognostic marker in patients with cardiovascular diseases (CVDs). METHODS: In this clinical study, we retrospectively searched for factors associated with NLR elevation in cardiovascular outpatients. In animal experiments using mice with adenine-induced nephropathy, we further examined the hematopoietic process in bone marrow and explored the mechanism of NLR elevation. RESULT: In patients with CVDs or their risk factors, multiple regression analysis revealed that decrease in estimated glemerular filtration rate and increase in white blood cell count were significantly associated with increase in NLR. In mice with adenine-induced nephropathy, NLR and serum indoxyl sulfate (IS) levels were increased. Fluorescence-activated cell sorting revealed the increase in the number of myeloid progenitors and decrease in the number of common lymphoid progenitors, suggesting biased granulocyte side in the hematopoietic process in bone marrow. Treatment with oral charcoal adsorbent AST-120 decreased serum concentration of IS and normalized NLR and bone marrow abnormalities in mice with adenine-induced nephropathy. CONCLUSION: Renal function was a strong determinant of NLR in cardiovascular outpatients. NLR elevation due to renal impairment is caused by distortion of the hematopoietic process in bone marrow. IS plays a significant role in these processes.

Nitric oxide modulation of endothelium-derived hyperpolarizing factor in agonist-induced depressor responses in anesthetized rats.

Vasodilators, such as prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF), released from the vascular endothelium are important in the maintenance of systemic blood pressure. Some studies have shown that NO affects EDHF-induced vasodilator responses in isolated perfused blood vessel segments. However, the effects of NO on EDHF-mediated dilation, and their contribution to systemic blood pressure, have not been clarified. Therefore, in the present study we investigated the mechanisms underlying acetylcholine- and bradykinin-induced depressor responses, as well as the interaction between NO and EDHF, by measuring systemic blood pressure in anesthetized rats. In the presence of indomethacin and N(G)-nitro-l-arginine (l-NA; an NO synthase inhibitor), apamin plus charybdotoxin significantly inhibited depressor responses to acetylcholine and bradykinin, whereas glibenclamide, iberiotoxin, quinacrine, catalase, and combination of ouabain plus BaCl2 failed to inhibit EDHF-induced depressor responses. 4-Aminopyridine significantly inhibited depressor responses to acetylcholine, but not to bradykinin. In the presence of indomethacin and l-NA, carbenoxolone, a gap junction inhibitor, significantly inhibited depressor responses to agonists. l-NA alone significantly potentiated agonist-induced depressor responses. In contrast, infusion of sodium nitroprusside, an NO donor, or 8-br-cGMP significantly inhibited depressor responses to agonist. The findings of the present study raise the possibility that agonist-induced depressor responses are elicited by propagation of endothelial hyperpolarization via apamin- plus charybdotoxin-sensitive K(+) channels to smooth muscle cells through gap junctions, but not by diffusible substance(s). It is suggested that, in anesthetized rats, the EDHF-induced depressor response is attenuated in the presence of endogenous and exogenous NO via an increment in cGMP.

Mechanisms underlying the renoprotective effect of GABA against ischaemia/reperfusion-induced renal injury in rats.

Excitation of the renal sympathetic nervous system is important for the development of ischaemic acute kidney injury (AKI) in rats. We reported that intravenous treatment with GABA has preventive effects against ischaemia/reperfusion (I/R)-induced renal dysfunction with histological damage in rats; however, the mechanisms underlying these effects on renal injury remain unknown. Thus, the aim of the present study was to clarify how GABA mechanistically affects ischaemic AKI in rats. Ischaemic AKI was induced in rats by clamping the left renal artery and vein for 45 min and then reperfusing the kidney to produce I/R-induced injury. Treatment with the GABAB receptor antagonist CGP52432 (100 nmol/kg, i.v., or 1 nmol/kg, i.c.v.) abolished the suppressive effects of 50 µmol/kg, i.v., GABA on enhanced renal sympathetic nerve activity (RSNA) during ischaemia, leading to elimination of the renoprotective effects of GABA. Intracerebroventricular treatment with 0.5 µmol/kg GABA or i.v. treatment with 1 µmol/kg baclofen, a selective GABAB receptor agonist, prevented the I/R-induced renal injury equivalent to i.v. treatment with GABA. Conversely, i.v. treatment with 10 µmol/kg bicuculline, a GABAA receptor antagonist, failed to affect the preventive effects of GABA against ischaemic AKI. We therefore concluded that GABAB receptor stimulation in the central nervous system, rather than peripheral GABAB receptor stimulation, mediates the preventive effect of GABA against ischaemic AKI by suppressing the enhanced RSNA induced by renal ischaemia.

Obesity-induced cerebral hypoperfusion derived from endothelial dysfunction: one of the risk factors for Alzheimer's disease.

Increasing evidence supports the idea that chronic hypoperfusion in the brain is responsible for the pathogenesis underling Alzheimer's disease (AD). Obesity at midlife is associated with the risk of cognitive loss and AD at later life. Obesity decreases cerebral blood flow that is associated with decreased synthesis and actions of nitric oxide (NO) derived from the endothelium and also increases the production of oxidative stress. Increased plasma levels of asymmetric dimethylarginine decreases the production of NO by inhibiting NO synthase activity, leading to cerebral hypoperfusion and cognitive and neurodegenerative changes in AD. Adiponectin has a cerebroprotective action through an eNOSdependent mechanism. Obesity-induced endothelial dysfunction and cerebral hypoperfusion enhance the production of ß-amyloid that in turn impairs endothelial function; this vicious cycle promotes the pathogenic changes leading to AD. Interrupting this cycle by enhancement of NO-mediated cerebral blood flow is expected to promote prophylaxis against AD pathogenesis. This review summarizes recent advances in prophylactic or therapeutic measures, including physical exercise, nutritionally adequate dietary intake, pharmacological treatments such as acetylcholinesterase inhibitors and antioxidants, and bariatric surgery that are efficient in protecting and retarding the progress of cognitive failure and neurodegeneration.

Involvement of renal sympathetic nerve overactivation in the progression of chronic kidney disease in rats.

Time-dependent changes in the renal sympathetic nerve activity (RSNA) in the progression of chronic kidney disease (CKD) have not been investigated, despite the fact that renal sympathetic nervous system is augmented in the condition of CKD. In the present study, we examined time-dependent changes in RSNA and renal venous norepinephrine concentrations for 12 weeks using 5 of 6 nephrectomized CKD rats. Both RSNA and norepinephrine concentrations were increased during the early phase in the progression of CKD. Urinary protein excretion and systolic blood pressure (SBP) were gradually increased during 12 weeks after 5 of 6 nephrectomy. Treatment with γ-aminobutyric acid or the combination of prazosin and propranolol in the early phase (0-4 weeks) after 5 of 6 nephrectomy significantly attenuated the increases in urinary protein excretion and SBP in 5 of 6 nephrectomized rats. On the other hand, the same treatment in the late phase (8-12 weeks) after 5 of 6 nephrectomy failed to suppress the proteinuria and increase in SBP. Treatment with hydralazine at hypotensive dose for 12 weeks also failed to affect the proteinuria in 5 of 6 nephrectomized CKD rats. In conclusion, the augmentation of renal sympathetic nervous system in early phase after 5 of 6 nephrectomy is closely related to the development of partial ablation-induced CKD in rats.

Neurogenic and endothelial nitric oxide regulates blood circulation in lingual and other oral tissues.

Blood flow in oral tissues, including the tongue, salivary glands, gingiva, dental pulp, and lip, plays an important role in modulating the complex oral functions involved in food intake. Oral tissue circulation is regulated by nitric oxide (NO) synthesized by neuronal NO synthase mainly present in parasympathetic vasodilator neurons and also by endothelial NO sythase. Electrical stimulation of parasympathetic nerves causes vasodilatation and blood flow increase in the tongue, submandibular gland, and lip in various mammals in vitro and in vivo. Lingual arteries isolated from Japanese monkeys respond to perivascular nerve stimulation by electrical pulses and nicotine with relaxations that are mediated via neurogenic NO. There is evidence supporting the hypothesis that the superior salivatory nucleus delivers central information through the geniculate ganglion and greater petrosal nerve to the pterygopalatine ganglion, which sends off impulses through nitrergic nerves to oral tissues. Endothelial NO also plays an important role in improving oral blood circulation not only in resting conditions but also under conditions activated by chemical and physical stimuli in the tongue, submandibular and parotid glands, dental pulp/gingiva, and cheek pouch. Maintenance of health in oral circulation by minimizing factors responsible for impairment of endothelial and neurogenic NO bioavailability would be important for the prophylaxis of life-style related diseases.

Nitrergic nerves derived from the pterygopalatine ganglion innervate arteries irrigating the cerebrum but not the cerebellum and brain stem in monkeys.

The functional roles of the nitrergic nerves innervating the monkey cerebral artery were evaluated in a tension-response study examining isolated arteries in vitro and cerebral angiography in vivo. Nicotine produced relaxation of arteries by stimulation of nerve terminals innervating isolated monkey arteries irrigating the cerebrum, cerebellum and brain stem. Relaxation of arteries induced by nicotine was abolished by treatment with N(G)-nitro-L-arginine, a nitric oxide synthase inhibitor, and was restored by addition of L-arginine. Cerebral angiography showed that electrical stimulation of the unilateral greater petrosal nerve, which connects to the pterygopalatine ganglion via the parasympathetic ganglion synapse, produced vasodilatation of the anterior, middle and posterior cerebral arteries in the stimulated side. However, stimulation failed to produce vasodilatation of the superior and anterior-inferior cerebellar arteries and the basilar artery in anesthetized monkeys. Therefore, nitrergic nerves derived from the pterygopalatine ganglion appear to regulate cerebral vasomotor function. In contrast, circulation in the cerebellum and brain stem might be regulated by nitrergic nerves originating not from the pterygopalatine ganglion, but rather from an unknown ganglion (or ganglia).

Mechanisms underlying the renoprotective effect of GABA against ischemia/reperfusion-induced renal injury in rats.

The excitation of the renal sympathetic nervous system plays an important role in the development of ischemic acute kidney injury (AKI) in rats. We have reported that intravenous treatment with GABA has preventive effects on ischemia/reperfusion (I/R)-induced renal dysfunction with histological damage in rats. However, detailed mechanisms of the action of GABA on the renal injury were still unknown. Therefore, in the present study, we aimed to clarify the detailed mechanisms of GABA in ischemic AKI in rats. Ischemic AKI was induced by clamping the left renal artery and vein for 45 min. Thereafter, the kidney was reperfused to produce I/R-induced injury. Intravenous or intracerebroventricular treatment with 3-[[[(3,4-dichlorophenyl)methyl]amino]propyl] diethoxymethyl) phosphinic acid (CGP52432), a GABA(B) receptor antagonist, abolished the suppressive effects of intravenously applied GABA on enhanced renal sympathetic nerve activity during ischemia, leading to the elimination of the renoprotective effects of GABA. Intracerebroventricular treatment with GABA or intravenous treatment with baclofen, a selective GABA(B) receptor agonist, prevented I/R-induced renal injury equivalent to intravenous treatment with GABA. However, intravenous treatment with bicuculline, a GABA(A) receptor antagonist, failed to affect the preventive effects of GABA on ischemic AKI. Therefore, we demonstrated the novel finding that the preventive effect of GABA on ischemic AKI through the suppression of enhanced renal sympathetic nerve activity induced by renal ischemia is presumably mediated via GABA(B) receptor stimulation in the central nervous system rather than peripheral GABA(B) receptor.

Impairment by hypoxia or hypoxia/reoxygenation of nitric oxide-mediated relaxation in isolated monkey coronary artery: the role of intracellular superoxide.

To investigate the effect of hypoxia or hypoxia/reoxygenation on vascular smooth muscle function, mechanical response of monkey coronary artery without endothelium was studied under normoxia, hypoxia, and hypoxia/reoxygenation. Hypoxia or hypoxia/reoxygenation impaired the relaxation by nitroglycerin or isosorbide dinitrate but not that by 8-bromoguanosine-3',5'-cyclic monophosphate or isoproterenol. Tempol restored the impaired relaxation by nitroglycerin or isosorbide dinitrate, but superoxide dismutase had no effect. Apocynin, an NADPH oxidase inhibitor, improved the nitroglycerin-induced relaxation under hypoxia, but not under reoxygenation. Under combined treatment of apocynin with oxypurinol (xanthine oxidase inhibitor), rotenone (mitochondria electron transport inhibitor), or both, hypoxic impairment of vasorelaxation was restored more effectively. Similarly, impairment of the nitroglycerin-induced vasorelaxation under hypoxia/reoxygenation was restored by combined treatment with three inhibitors, apocynin, oxypurinol, and rotenone. Increase in superoxide production under hypoxia tended to be inhibited by apocynin and that under hypoxia/reoxygenation was abolished by combined treatment with three inhibitors. These findings suggest that increased intracellular superoxide production under hypoxia or hypoxia/reoxygenation attenuates vasodilation mediated with a nitric oxide/soluble guanylyl cyclase, but not adenylyl cyclase, signaling pathway. The main source of superoxide production under hypoxia seems to be different from that under reoxygenation: superoxide is produced by NADPH oxidase during hypoxia, whereas it is produced by xanthine oxidase, mitochondria, or both during reoxygenation.[Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.11031FP].

Contribution of nitric oxide in big endothelin-1-induced cardioprotective effects on ischemia/reperfusion injury in rat hearts.

We have recently shown that an appropriate amount of exogenous big endothelin-1 (ET-1) has beneficial effects on ischemia-/reperfusion-induced norepinephrine overflow and cardiac dysfunction in rat hearts and that these effects occur through a conversion to ET-1 by endothelin-converting enzyme and following stimulation of ETB receptor. In this study, we examined the possible involvement of nitric oxide (NO) in the big ET-1-induced cardioprotective effects. According to the Langendorff technique, isolated rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. Exogenous big ET-1 (0.3 nM) significantly increased NOx (NO2/NO3) level in the coronary effluent after onset of reperfusion. This effect was markedly attenuated by treatment with SM-19712 (selective endothelin-converting enzyme inhibitor), A-192621 (selective ETB receptor antagonist), or NG-nitro-l-arginine (nonselective NO synthase inhibitor), respectively. In addition, N-nitro-l-arginine blunted big ET-1-induced suppression of norepinephrine overflow and improvement of cardiac dysfunction after ischemia/reperfusion. These findings suggest that NO produced by ETB receptor activation plays an important role in exogenous big ET-1-induced actions.

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts.

Endothelin-1 (ET-1) is involved in norepinephrine (NE) overflow and cardiac dysfunction after myocardial ischemia/reperfusion via the activation of ET(A) receptors. As ET-1 is generated from big ET-1 via endothelin-converting enzyme (ECE), ischemia/reperfusion-induced cardiac injury may be exacerbated by exogenous big ET-1. The aim of this study was to investigate the influence of exogenously applied big ET-1 on ischemia/reperfusion-induced NE overflow and cardiac dysfunction. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Exogenous big ET-1 (0.1, 0.3 and 1 nM) was perfused, beginning 15 min before ischemia. Unexpectedly, higher doses (0.3 and 1 nM) of big ET-1 significantly improved indices of left ventricular function after ischemia/reperfusion, such as left ventricular developed pressure (LVDP), the maximum value of the first derivative of left ventricular pressure (dP/dt(max)) and left ventricular end diastolic pressure (LVEDP). In addition, big ET-1 significantly suppressed excessive NE overflow in the coronary effluent from the postischemic heart. These effects of big ET-1 were markedly attenuated by treatment with SM-19712 (selective ECE inhibitor) or A-192621 (selective ET(B) receptor antagonist). On the other hand, those were not potentiated even though combined with ABT-627 (selective ET(A) receptor antagonist). From these findings, we suggest that exogenous big ET-1 has beneficial effects on ischemia/reperfusion-induced cardiac injury. It seems likely that big ET-1 is converted to ET-1, locally in the heart, and this ET-1 preferentially binds to ET(B) receptors to exert its related beneficial actions.

Effect of nitric oxide synthase inhibitor on increase in nasal mucosal blood flow induced by sensory and parasympathetic nerve stimulation in rats.

OBJECTIVES: Neural control of nasal blood flow (NBF) has not been systematically investigated. The aim of the present study was to evaluate the effect of electrical stimulation of both sensory and parasympathetic nerves innervating the nasal mucosal arteries on NBF in rats. METHODS: In anesthetized rats, nasociliary (sensory) nerves and postganglionic (parasympathetic) nerves derived from the right sphenopalatine ganglion were electrically stimulated. We measured NBF with a laser-Doppler flowmeter. RESULTS: The nerve stimulation increased NBF on both sides and increased the mean arterial blood pressure. The increase in NBF was larger on the ipsilateral side than on the contralateral side. Hexamethonium bromide, a ganglion blocker, abolished the stimulation-induced pressure effect and the increase in NBF on the contralateral side, but did not abolish the increase in NBF on the ipsilateral side. The remaining increase in NBF was abolished by N(G)-nitro-L-arginine, a nitric oxide synthase inhibitor. Histochemical analysis with nicotinamide adenine dinucleotide phosphate-diaphorase showed neuronal nitric oxide synthase-containing nerves that innervate nasal mucosal arteries. CONCLUSIONS: Nitric oxide released from parasympathetic nitrergic nerves may contribute to an increase in NBF in rats. The afferent impulses induced by sensory nerve stimulation may lead to an increase in mean arterial blood pressure that is partly responsible for the increase in NBF.

Vascular actions of nitric oxide as affected by exposure to alcohol.

Vasodilator substances liberated from endothelial cells, mainly nitric oxide (NO), play important roles in physiologically regulating blood flow and blood pressure and preventing pathological vascular damage. Impairment of these actions promotes the genesis of cardiovascular diseases such as hypertension, cerebral and cardiac hypoperfusion, impaired vasodilatation and atherosclerosis. Low concentrations of alcohol induce increased release of NO from the endothelium due to activation and expression of NO synthase (NOS). In contrast, administration of high concentrations of alcohol or its chronic ingestion impairs endothelial functions in association with reduced NO bioavailability. The endogenous NOS inhibitor asymmetric dimethylarginine may participate in decreased synthesis of NO. Chronic alcohol intake also impairs penile erectile function possibly by interfering with endothelial, but not nitrergic nerve, function. This review article summarizes the vascular actions of NO derived from endothelial and neuronal NOS as affected by alcohol, other than wine, and acetaldehyde in healthy individuals, human materials and various experimental animals.

Postconditioning improves postischemic cardiac dysfunction independently of norepinephrine overflow after reperfusion in rat hearts: comparison with preconditioning.

We investigated whether the cardioprotective effect of ischemic postconditioning (postC) against ischemia/reperfusion (I/R)-induced cardiac dysfunction is associated with the negative control of I/R-enhanced norepinephrine (NE) overflow, an aggravating factor of I/R injury, in comparison with the effects induced by ischemic preconditioning (preC). According to the Langendorff technique, isolated rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. PostC, consisting of three cycles of 30-second reperfusion followed by 30-second ischemia at the end of the 40-minute ischemia, improved I/R-induced cardiac dysfunction. However, the potency of this postC-induced improvement was somewhat weaker than that produced by preC, consisting of three cycles of 5-minute ischemia followed by 5-minute reperfusion before 40-minute ischemia. The preC treatment markedly suppressed I/R-enhanced NE overflow, whereas postC had no apparent effect. A nonselective nitric oxide synthase inhibitor, N-nitro-L-arginine, almost completely abolished postC-induced cardiac protection without affecting NE overflow, whereas the effect of preC on I/R-induced cardiac dysfunction and NE overflow was only partially inhibited by N-nitro-L-arginine. These findings indicate that the beneficial effect of postC on I/R-induced cardiac dysfunction depends on nitric oxide and is irrelevant to NE overflow after reperfusion in contrast to the preC effect.

Renoprotective effects of gamma-aminobutyric acid on ischemia/reperfusion-induced renal injury in rats.

Enhanced renal sympathetic nerve activity during ischemic period and the renal venous norepinephrine overflow after reperfusion play important roles in the development of ischemic acute kidney injury. We investigated the effect of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter mainly in the central nervous system, on ischemia/reperfusion-induced acute kidney injury in anesthetized rats. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45min followed by reperfusion 2weeks after the contralateral nephrectomy. Intravenous injection of GABA (10 and 50micromol/kg) to ischemic acute kidney injury rats dose-dependently suppressed the enhanced renal sympathetic nerve activity during the renal ischemia, the renal venous norepinephrine overflow after reperfusion and attenuated the ischemia/reperfusion-induced renal dysfunction with histological damage. Intravenous injection of CGP52432 (0.1micromol/kg), a selective GABA(B) receptor antagonist, eliminated the preventive effect by GABA (50micromol/kg) on ischemic acute kidney injury. In contrast, intravenous injection of baclofen (1micromol/kg), a selective GABA(B) receptor agonist, attenuated the ischemia/reperfusion-induced renal injury equivalent to GABA (50micromol/kg). These results indicate that GABA prevents the development of ischemia/reperfusion-induced acute kidney injury presumably via GABA(B) receptor, by suppressing the enhanced renal sympathetic nerve activity during ischemia and the increased norepinephrine overflow from renal sympathetic nerve ending.

Cerebral blood flow regulation by nitric oxide in neurological disorders.

There has been a rapid increase in the amount of information on the physiological and pathophysiological roles of nitric oxide (NO) in the brain. This molecule, which is formed by the constitutive isoforms of NO synthase, endothelial (eNOS) and neuronal (nNOS), plays an obligatory role in the regulation of cerebral blood flow and cell viability and in the protection of nerve cells or fibres against pathogenic factors associated with Alzheimer's disease, Huntington's disease, seizures, and migraine. Cerebral blood flow is impaired by decreased formation of NO from endothelial cells, autonomic nitrergic nerves, or brain neurons and also by increased production of reactive oxygen species (ROS). The NO-ROS interaction is an important topic in discussing blood flow and cell viability in the brain. Excessive production of NO by inducible NOS (iNOS) and nNOS in the brain participates in neurotoxicity. Recent studies on brain circulation have provided useful information about the involvement of impaired NO availability or uncontrolled NO production in cerebral pathogenesis, including Alzheimer's disease, seizures, vascular headaches, and inflammatory disorders. Insight into the role of NO in the brain will contribute to our better understanding of cerebral hemodynamic dysfunction and will aid in developing novel therapeutic measures in diseases of the central nervous system.

Control of systemic and pulmonary blood pressure by nitric oxide formed through neuronal nitric oxide synthase.

Nitric oxide formed by neuronal nitric oxide synthase (nNOS) in the brain, autonomic inhibitory (nitrergic) nerves, and heart plays important roles in the control of blood pressure. Activation of nitrergic nerves innervating the systemic vasculature elicits vasodilatation, decreases peripheral resistance, and lowers blood pressure. Impairment of nitrergic nerve function, as well as endothelial dysfunction, results in systemic and pulmonary hypertension and decreased regional blood flow. Blockade of nNOS activity in the brain, particularly the medulla and hypothalamus, causes systemic hypertension. Under hypertensive states, such as those in spontaneously hypertensive and Dahl salt-sensitive rats, the expression of the nNOS gene in the brain is increased; this appears to counteract the activated sympathetic function in the vasomotor center. The present article summarizes information concerning the modulation of systemic and pulmonary hypertension through nNOS-derived nitric oxide produced in the brain and periphery.

Characterization of nitrergic function in monkey penile erection in vivo and in vitro.

The nitrergic nerve appears to have a major role in the neuronal regulation of penile erection. Cholinergic innervation has been shown histochemically in penile cavernous tissues, but its functional role is not well understood. This study was aimed at examining the functional properties of the nitrergic nerve and the possible involvement of cholinergic function in the regulation of monkey penile erection in vivo and in vitro. In anesthetized Japanese monkeys, electrical stimulation of the cavernous nerve caused a frequency-dependent increase in intracavernous pressure and penile erection, and atropine enhanced the pressure response. Intravenous injections of N(G)-nitro-L-arginine (L-NA) markedly inhibited the stimulation-induced pressure increase and the erectile response, and L-arginine partially restored the pressure response. In some monkeys, the intracavernous pressure increase caused by nerve stimulation was reversed by treatment with L-NA; however, L-arginine restored the pressor response. In addition, hexamethonium suppressed the pressure increase that resulted from the nerve stimulation. In corpus cavernosum isolated from monkeys, transmural electrical stimulation elicited frequency-dependent relaxation. The relaxation was attenuated by physostigmine, and was potentiated by atropine. Relaxation was markedly inhibited by treatment with L-NA. It appears that nitric oxide (NO) released from inhibitory nerves, even at low frequencies, has a pivotal role in the initiation and maintenance of intracavernous pressure increase and penile erection in monkeys. Prejunctional muscarinic receptors in nitrergic nerves are expected to participate in the impairment of NO release. Nitrergic nerves responsible for penile erection may originate from ganglia close to the corpus cavernosum.

Cerebral blood flow regulation by nitric oxide: recent advances.

Nitric oxide (NO) is undoubtedly quite an important intercellular messenger in cerebral and peripheral hemodynamics. This molecule, formed by constitutive isomers of NO synthase, endothelial nitric-oxide synthase, and neuronal nitric-oxide synthase, plays pivotal roles in the regulation of cerebral blood flow and cell viability and in the protection of nerve cells or fibers against pathogenic factors associated with cerebral ischemia, trauma, and hemorrhage. Cerebral blood flow is increased and cerebral vascular resistance is decreased by NO derived from endothelial cells, autonomic nitrergic nerves, or brain neurons under resting and stimulated conditions. Somatosensory stimulation also evokes cerebral vasodilatation mediated by neurogenic NO. Oxygen and carbon dioxide alter cerebral blood flow and vascular tone mainly via constitutively formed NO. Endothelial dysfunction impairs cerebral hemodynamics by reducing the bioavailability of NO and increasing the production of reactive oxygen species (ROS). The NO-ROS interaction is an important issue in discussing blood flow and cell viability in the brain. Recent studies on brain circulation provide quite useful information concerning the physiological roles of NO produced by constitutive isoforms of nitric-oxide synthase and how NO may promote cerebral pathogenesis under certain conditions, including cerebral ischemia/stroke, cerebral vasospasm after subarachnoid hemorrhage, and brain injury. This information would contribute to better understanding of cerebral hemodynamic regulation and its dysfunction and to development of novel therapeutic measures to treat diseases of the central nervous system.