Regulation Of Vasomotor Tone Research Articles

Nitric oxide levels in patients with atheromatous carotid plaque

Nitric oxide (NO), an unstable derived of nitrogen, is released by endothelium in response to physiological stimulus. Indeed, the endothelium is not only a barrier between the lumen and the inner side of the vessel wall but also a metabolically active organ with endocrine, paracrine and autocrine functions. Endothelial vascular cells play an important role in the regulating vasomotor tone, local homeostasis and vascular bed proliferation. NO mediates the vasodilation and inhibits platelet aggregation, expression of molecular adhesion of monocyte, neutrophils adhesion and smooth muscle growth. Atherosclerosis risk factors such as hypercholesteremia, high blood pressure, smoking and oxidative stress inhibit NO production, leading paradoxically to vasodilatation, which affects endothelial function and may lead to ischemic manifestations in patients with arterial pathology. Therapies that increase NO production may improve endothelial vasodilatation. To check whether a decrease or lower production of NO terminates with the initial formation of atheromatous plaque or whether it continues, we determined the content of NO in plasma and plaque of subjects undergoing carotid surgery and in plasma of control subjects.

A New Road to Induce Heme Oxygenase-1 Expression by Carbon Monoxide

See related article, pages 919–927 Heme oxygenase (HO)-1 catalyzes the rate-limiting step in the metabolic conversion of heme to bilirubin, iron, and carbon monoxide (CO).1 Ample literature has demonstrated that exogenous or endogenously-produced CO possesses signaling properties affecting numerous critical cellular processes including inflammation, cellular proliferation, and apoptotic cell death.1,2 CO and the bile pigments biliverdin and bilirubin play important physiological roles in the circulation. The production of CO in vascular cells modulates blood flow and blood fluidity by regulating vasomotor tone and inhibiting smooth muscle cell proliferation and platelet aggregation. CO also maintains vessel wall integrity by directly blocking apoptosis and inhibiting the release of proinflammatory cytokines from the vessel wall. These effects of CO are mediated via multiple pathways, including activation of soluble guanylate cyclase, p38 mitogen-activated protein kinase (MAPK), and potassium channels.1,2 Induction of HO-1 gene expression and the subsequent release of CO and bile pigments are observed in numerous vascular disorders providing an adaptive response to preserve homeostasis at sites of vascular injury. Hence, the formation of CO and bile pigments in vascular cells may function as an important vasoprotective system.1,2 Thus far, several transcriptional factors (TF) have been implicated in HO-1 gene expression. Among these TFs, the heat-shock, nuclear factor-κB (NF-κB), nuclear factor–erythroid 2-related factor 2 (Nrf2), and activator protein–1 families are the most important regulators of cellular stress responses. Nrf2 is activated by various xenobiotics and oxidants and regulates genes encoding proteins …

Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats

Nitric oxide (NO) is an important regulator of vasomotor tone in the pulmonary circulation. We tested the hypothesis that the role NO plays in regulating vascular tone changes during early postnatal development. Isolated, perfused lungs from 7- and 14-day-old Sprague-Dawley rats were studied. Baseline total pulmonary vascular resistance (PVR) was not different between age groups. The addition of KCl to the perfusate caused a concentration-dependent increase in PVR that did not differ between age groups. However, the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine augmented the K(+)-induced increase in PVR in both groups, and the effect was greater in lungs from 14-day-old rats vs. 7-day-old rats. Lung levels of total endothelial, inducible, and neuronal NOS proteins were not different between groups; however, the production rate of exhaled NO was greater in lungs from 14-day-old rats compared with those of 7-day-old rats. Vasodilation to 0.1 microM of the NO donor spermine NONOate was greater in 14-day lungs than in 7-day lungs, and lung levels of both soluble guanylyl cyclase and cGMP were greater at 14 days than at 7 days. Vasodilation to 100 microM of the cGMP analog 8-(4-chlorophenylthio)guanosine-3',5'-cyclic monophosphate was greater in 7-day lungs than in 14-day lungs. Our results demonstrate that the pulmonary vascular bed depends more on NO production to modulate vascular tone at 14 days than at 7 days of age. The observed differences in NO sensitivity may be due to maturational increases in soluble guanylyl cyclase protein levels.

Coronary vasoconstrictor influence of angiotensin II is reduced in remodeled myocardium after myocardial infarction

The renin-angiotensin system plays an important role in cardiovascular homeostasis by contributing to the regulation of blood volume, blood pressure, and vascular tone. Because AT(1) receptors have been described in the coronary microcirculation, we investigated whether ANG II contributes to the regulation of coronary vascular tone and whether its contribution is altered during exercise. Since the renin-angiotensin system is activated after myocardial infarction, resulting in an increase in circulating ANG II, we also investigated whether the contribution of ANG II to the regulation of vasomotor tone is altered after infarction. Twenty-six chronically instrumented swine were studied at rest and while running on a treadmill at 1-4 km/h. In 13 swine, myocardial infarction was induced by ligation of the left circumflex coronary artery. Blockade of AT(1) receptors (irbesartan, 1 mg/kg iv) had no effect on myocardial O(2) consumption but resulted in an increase in coronary venous O(2) tension and saturation both at rest and during exercise, reflecting coronary vasodilation. Despite increased plasma levels of ANG II after infarction and maintained coronary arteriolar AT(1) receptor levels, the vasodilation evoked by irbesartan was significantly reduced both at rest and during exercise. In conclusion, despite elevated plasma levels, the vasoconstrictor influence of ANG II on the coronary circulation in vivo is reduced after myocardial infarction. This reduction in ANG II-induced coronary vasoconstriction may serve to maintain perfusion of the remodeled myocardium.

Hypoxia, coronary dilation, and the pentose phosphate pathway

hypoxic vasorelaxation of resistance arteries is an important feedback control mechanism to maintain adequate oxygenation of metabolically active tissues and is essential in tissues where oxygen extraction is nearly maximized, as it is in the heart. Although the physiological importance of this

Regional heterogeneity in acetylcholine-induced relaxation in rat vascular bed: role of calcium-activated K+ channels

Ca+ -activated K+ -channels (KCa) regulate vasomotor tone via smooth muscle hyperpolarization and relaxation. The relative contribution of the endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation differs depending on vessel type and size. It is unknown whether these KCa channels are differentially distributed along the same vascular bed and hence have different roles in mediating the EDHF response. We therefore assessed the role of small- (SKCa), intermediate- (IKCa), and large-conductance (BKCa) channels in mediating acetylcholine-induced relaxations in both first- and fourth-order side branches of the rat superior mesenteric artery (MA1 and MA4, respectively). Two-millimeter segments of each MA were mounted in the wire myograph, incubated with Nomega-nitro-L-arginine methyl ester (L-NAME, 100 micromol/l) and indomethacin (10 micromol/l), and precontracted with phenylephrine (10 micromol/l). Cumulative concentration-response curves to ACh (0.001-10 micromol/l) were performed in the absence or presence of selective KCa channel antagonists. Apamin almost completely abolished these relaxations in MA4 but only partially blocked relaxations in MA1. The selective IKCa channel blocker 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) caused a significantly greater inhibition of the ACh-induced relaxation in MA4 compared with MA1. Iberiotoxin had no inhibitory effect in MA4 but blunted relaxation in MA1. Relative mRNA expression levels of SKCa (rSK1, rSK3, and rSK4 = rIK1) were significantly higher in MA4 compared with MA1. BKCa (rBKalpha1 and rBKbeta1) genes were similar in both MA1 and MA4. Our data demonstrate regional heterogeneity in SKCa and IKCa function and gene expression and stress the importance of these channels in smaller resistance-sized arteries, where the role of EDHF is more pronounced.

Gender differences in the relative contribution of NO and EDHF on the regulation of vasomotor tone of rabbit mesenteric arteries

Fruits of Nitraria sibirica Pall. are traditionally used in Uighur medicine to treat hypertension. This study aimed to support that folk use by defining their vasoactive and hypotensive properties.The vasorelaxant activity and the underlying mechanisms of a hydroalcoholic extract from the fruits of Nitraria sibirica Pall. (NSHE) were evaluated on thoracic aortic rings isolated from Wistar rats. In addition, the acute hypotensive effect of NSHE was assessed in anesthetized spontaneously hypertensive rats (SHR) and in their normotensive control Wistar Kyoto (WKY) rats.NSHE (0.1–10 g/l) was clearly more effective to induce vasodilation of phenylephrine- (PE, 1 μM) than high KCl- (60 mM) pre-contracted aortic rings with respective Emax values of 82.9 ± 2.2% and 34.8 ± 3.6%. The removal of endothelium almost abolished the relaxant effect of the extract. In addition, pre-treatment with Nw-nitro-l-arginine-methyl ester (l-NAME, 100 μM), atropine (1 μM) or charybdotoxin (30 nM) plus apamin (30 nM), respective blockers of nitric oxide (NO) synthase, muscarinic receptors and endothelium-derived hyperpolarizing factor (EDHF), significantly reduced the observed effect of NSHE. By contrast, the cyclooxygenase (COX) inhibitor indomethacin (10 μM) or the K+ channels blockers glibenclamide (10 μM), iberiotoxin (30 nM) and 4-amino-pyridine (4-AP, 1 mM) failed to modify the vasodilation. Finally, the acute intravenous injection of NSHE (1, 5, 10, 20 mg/kg) induced an immediate and transient hypotensive effect in anesthetized SHR and in WKY rats.This experimental animal study suggests that hydroalcoholic extract from the fruits of Nitraria sibirica Pall. induces vasorelaxation through an endothelium-dependent pathway involving NO synthase (NOS) activation, EDHF production and muscarinic receptor stimulation. Additionally, our results determine that this vasorelaxant effect is translated by a significant hypotensive effect.

Acute Adaptations of the Coronary Circulation to Exercise

Coronary blood flow is tightly coupled to myocardial oxygen consumption to maintain a consistently high level of myocardial oxygen extraction. This tight coupling has been proposed to depend on periarteriolar oxygen tension, signals released from cardiomyocytes (adenosine acting on K+(ATP) channels), and/or the endothelium (prostanoids, nitric oxide, endothelin [ET]) and autonomic influences (catecholamines), but the contribution of each of these regulatory pathways and their interactions are still incompletely understood. Until recently, experimental studies into the regulation of coronary blood flow during exercise were principally performed in the dog. We have performed several studies on the regulation of vasomotor tone in coronary resistance vessels in chronically instrumented exercising swine. These studies have shown that the coronary resistance vessels in swine lack significant alpha-adrenergic control, but that these vessels are subject to beta-adrenergic feed-forward control during exercise, which is aided by a parasympathetic withdrawal. In addition, withdrawal of an ET-mediated vasoconstrictor influence also contributes to exercise-induced coronary vasodilation. Coronary blood flow regulation by endothelial and metabolic vasodilator pathways contributes to resting vasomotor tone regulation but does not appear to contribute to the exercise-induced coronary vasodilation. Furthermore, blockade of one vasodilator pathway is not compensated by an increased contribution of the other vasodilator mechanisms, suggesting that porcine coronary vasomotor control by endothelial and metabolic factors occurs in a linear additive rather than a nonlinear synergistic fashion.

Contribution of KATP+ channels to coronary vasomotor tone regulation is enhanced in exercising swine with a recent myocardial infarction

Previous studies demonstrated a decreased flow reserve in the hypertrophied myocardium early after myocardial infarction (MI). Previously, we reported that exacerbation of hemodynamic abnormalities and neurohumoral activation during exercise caused slight impairment of myocardial O(2) supply in swine with a recent MI. We hypothesized that increased metabolic coronary vasodilation [via ATP-sensitive K(+) (K(ATP)(+)) channels and adenosine] may have partially compensated for the increased extravascular compressive forces and increased vasoconstrictor neurohormones, thereby preventing a more severe impairment of myocardial O(2) balance. Chronically instrumented swine were exercised on a treadmill up to 85% of maximum heart rate. Under resting conditions, adenosine receptor blockade [8-phenyltheophylline (8-PT), 5 mg/kg i.v.] and K(ATP)(+) channel blockade (glibenclamide, 3 mg/kg i.v.) produced similar decreases in myocardial O(2) supply in normal and MI swine. However, while glibenclamide's effect waned in normal swine during exercise (P < 0.05), it was maintained in MI swine. 8-PT's effect was maintained during exercise and was not different between normal and MI swine. Finally, in normal swine combined treatment with 8-PT and glibenclamide produced a vasoconstrictor response that equaled the sum of the responses to blockade of the individual pathways. In contrast, in MI swine the vasoconstrictor response to 8-PT and glibenclamide was similar to that produced by glibenclamide alone. In conclusion, despite significant hemodynamic abnormalities in swine with a recent MI, myocardial O(2) supply and O(2) consumption in remodeled myocardium are still closely matched during exercise. This close matching is supported by increased K(ATP)(+) channel-mediated coronary vasodilation. Although the net vasodilator influence of adenosine was unchanged in remodeled myocardium, it became exclusively dependent on K(ATP)(+) channel opening.

Arginine and Endothelial and Vascular Health

The vascular endothelium is a crucial regulator of vascular function and homeostasis. Nitric oxide (NO) is an important paracrine substance released by the endothelium to regulate vasomotor tone. Risk factors for atherosclerosis, as well as atherosclerosis per se, are associated with endothelial dysfunction and decreased bioavailablilty of NO. Indeed, endothelial dysfunction is integral to the pathogenesis of atherosclerosis and other cardiovascular diseases. Moreover, endothelial dysfunction relates to an increased risk of adverse cardiovascular outcomes. L-Arginine is an essential amino acid required by the constitutive enzyme, endothelial NO oxide synthase (eNOS), to produce NO. Administration of L-arginine improves endothelial function in animal models and in humans with hypercholesterolemia and with atherosclerosis. Clinical trials to date support potential clinical applications of L-arginine in the treatment of coronary artery disease and peripheral arterial disease, as well as in the prevention of in-stent restenosis. The mechanism of benefit of L-arginine on endothelial function is unclear, because intracellular concentrations of L-arginine far exceed that required by eNOS. One potential explanation of this "arginine paradox" is that L-arginine restores endothelial function in atherosclerotic patients, in whom there are elevated levels of asymmetric dimethylarginine, an endogenous inhibitor of eNOS. Given the promising findings of early studies of L-arginine as a potential therapy for cardiovascular disorders, large-scale clinical trials are warranted.

Inhaled nitric oxide in neonatology: state of the art

In the late 1970 s it was demonstrated that nitric oxide (NO) was involved in the regulation of vasomotor tone. In Europe inhaled NO (iNO) was approved as a therapy option for the treatment of pulmonary hypertension in term and slightly preterm (> 34 weeks of gestation) neonates. Therapy by iNO mainly reduces the necessity for treatment by extracorporeal membrane oxygenation. However, the mortality of the underlying disease is not affected. According to our current knowledge iNO therapy for term and slightly preterm (> 34 weeks of gestation) neonates does not represent an additional risk factor for the neurological development. Today, iNO therapy constitutes the gold standard for pulmonary hypertension in new-born babies. However, the 30 % non-responders warrant a continued search for alternative treatment concepts. Prophylactic therapy according to a risk profile has not yet proved to be meaningful. An indication for the treatment of preterm neonates of less than 34 weeks of gestation has not yet been confirmed.

Pathophysiology of stroke in sickle cell disease.

Stroke affects both motor and cognitive function in patients with sickle cell disease (SCD). Symptomatic stroke is associated with intimal disease of the large cerebral arteries. Silent stroke, defined as cerebral infarction in the absence of overt clinical neurologic symptoms, is often due to microinfarcts suggestive of microvascular disease. While the natural history of stroke in SCD is well described, the pathophysiology remains poorly understood and probably varies with the site of vascular injury. Increased red cell adhesion, oxidative injury of the vessel wall, inflammation, abnormal vasomotor tone regulation, and increased activity of the coagulation system all may contribute to cerebral vasopathology in SCD.

Effects of Concentrated Fine Ambient Particles on Rat Plasma Levels of Asymmetric Dimethylarginine

The health effects of ambient fine particulate matter (PM2.5) and its potential impact on vascular endothelial function have not been thoroughly investigated. As endothelial dysfunction plays an important role in the pathogenesis of atherosclerosis and its complications, we examined the effects of concentrated fine ambient particles (CAPs) on the plasma level of asymmetric dimethylarginine (ADMA) in a pilot study. ADMA is a circulating endogenous inhibitor of nitric oxide synthase (NOS) that is associated with impaired vascular function and increased risk for cardiovascular events. A mobile air research laboratory (AirCARE 1) was used to provide “real-world” CAPs exposures for this study conducted in Detroit, MI. Fourteen Brown Norway rats were exposed to filtered air (FA) (n = 7) or CAPs (0.1–2.5 μm) (n = 7) for 3 consecutive days (8 h/day) in July 2002. Rats were exposed during these periods to average particle mass concentrations of 354 μg/m3. Rat plasma samples were collected 24 h postexposure. Plasma concentrations of ADMA were significantly elevated in rats exposed to CAPs versus those exposed to FA (mean ± standard deviation = 1.49 ± 0.18 vs. 1.29 ± 0.26 μM, p = .05 by one-tailed t-test). Analyses of meteorological data and CAPs trace element composition suggest thatlocal particle emission sources contributed largely to overall mass of CAPs. Results of this pilot study suggest that exposure to PM2.5 at high concentrations may trigger an acute increase in circulating ADMA level. This finding has implications for the regulation of vasomotor tone by particulate pollutants and the propensity for adverse cardiovascular events.

Pathophysiology of Stroke in Sickle Cell Disease

Stroke affects both motor and cognitive function in patients with sickle cell disease (SCD). Symptomatic stroke is associated with intimal disease of the large cerebral arteries. Silent stroke, defined as cerebral infarction in the absence of overt clinical neurologic symptoms, is often due to microinfarcts suggestive of microvascular disease. While the natural history of stroke in SCD is well described, the pathophysiology remains poorly understood and probably varies with the site of vascular injury. Increased red cell adhesion, oxidative injury of the vessel wall, inflammation, abnormal vasomotor tone regulation, and increased activity of the coagulation system all may contribute to cerebral vasopathology in SCD.

Adenosine

Adenosine has been recognized as a potentially important signaling molecule in the heart for nearly a half century. The original adenosine hypothesis proposed that production of adenosine by cardiac myocytes reflects the metabolic state of the myocardium and serves to regulate vasomotor tone in the coronary resistance vessels, thereby coupling blood flow to the energetic needs of the heart.1 There are two major pathways for adenosine production in the cardiac myocyte. The transmethylation pathway involves the hydrolysis of S -adenosylhomocysteine (SAH) by SAH hydrolase to l-homocysteine and adenosine. A second pathway, the hydrolysis of AMP by 5′-nucleotidase, predominates during ischemic or hypoxic conditions.2 According to the adenosine hypothesis, when the energy requirements of the heart increase, the increased rate of ATP hydrolysis would cause cytosolic free ADP levels to rise. In this situation, the myokinase reaction can utilize two molecules of ADP to produce one molecule each of ATP and AMP, the later being the substrate for 5′-nucleotidase to produce adenosine, which can enter the interstitial space to cause coronary vasodilation. Although this hypothesis for preserving the oxygen supply/demand relationship is attractive, it does not appear to operate during physiological conditions in the normal heart, since adenosine receptor inhibition does not decrease coronary blood flow or impair the increase of coronary flow during exercise.3 Implicit in the adenosine hypothesis is the assumption that during increased cardiac work, increases of cytosolic free [ADP] would be required to drive mitochondrial respiration and would serve to increase adenosine production. In fact, over a wide range of workloads, cytosolic free [ADP] remains at a stable low level; only at extreme workloads does ADP rise significantly in the normal heart.4 Although it has been difficult to demonstrate adenosine effects during normal physiological conditions, adenosine is clearly able to exert important effects …

Endothelium, Inflammation, and Diabetes

The normal endothelium produces a number of vasodilator substances such as nitric oxide (NO) and prostacyclin (PGI2) that regulate vasomotor tone, reduce platelet aggregation, and inhibit the recruitment and activity of inflammatory cells. The functions of vascular endothelial cells are disturbed in diabetic patients. The major cause for mortality and a great percent of morbidity in patients with diabetes mellitus is atherosclerosis. Insulin has recently been shown to stimulate NO release and the expression of NO synthase by the endothelium. Insulin is thus a vasodilator, has anti-platelet activity, and now has been shown to be anti-inflammatory and thus, potentially anti-atherogenic. Similar anti-inflammatory effects of thiazolidenediones (TZDs), troglitazone, and rosiglitazone suggest that they too may have potential anti-atherogenic effects. These effects of insulin and TZDs are of importance since the two major states of insulin resistance, obesity and type 2 diabetes, are associated with a marked increase in atherosclerosis, coronary heart disease, and stroke. These recent observations have extremely important implications for the understanding of the pathogenesis of atherosclerosis in insulin-resistant states and for a rational approach to their comprehensive treatment, including the prevention of atherosclerosis and its complications. This review challenges the previously proposed hypothesis that hyperinsulinemia represents a common pathophysiological pathway of diabetic complications and advances our hypothesis that insulin, through its effect on the endothelium, leucocytes, and platelets, has anti-inflammatory and thus potentially anti-atherogenic properties. Furthermore, through its anti-inflammatory effects, its use improves clinical outcomes in at least two clinical states characterized by profound inflammation-acute myocardial infarction and sepsis.

Diabetes mellitus impairs vasodilation to hypoxia in human coronary arterioles: reduced activity of ATP-sensitive potassium channels.

ATP-sensitive K+ channels (K(ATP)) contribute to vasomotor regulation in some species. It is not fully understood the extent to which K(ATP) participate in regulating vasomotor tone under physiological and pathophysiological conditions in the human heart. Arterioles dissected from right atrial appendage were studied with video microscopy, membrane potential recordings, reverse transcription-polymerase chain reaction, and immunohistochemistry. Hypoxia produced endothelium-independent vasodilation and membrane hyperpolarization of vascular smooth muscle cells, both of which were attenuated by glibenclamide. Aprikalim, a selective K(ATP) opener, also induced a potent endothelium-independent and glibenclamide-sensitive vasodilation with membrane hyperpolarization. Reverse transcription-polymerase chain reaction detected mRNA expression for K(ATP) subunits, and immunohistochemistry confirmed the localization of the inwardly rectifying Kir6.1 protein in the vasculature. In patients with type 1 or type 2 diabetes mellitus (DM), vasodilation was reduced to both aprikalim (maximum dilation, DM(+) 90+/-2% versus DM(-) 96+/-1%, P<0.05) and hypoxia (maximum dilation, DM(+) 56+/-8% versus DM(-) 85+/-5%, P<0.01) but was not altered to sodium nitroprusside or bradykinin. Baseline myogenic tone and resting membrane potential were not affected by DM. We conclude that DM impairs human coronary arteriolar dilation to K(ATP) opening, leading to reduced dilation to hypoxia. This reduction in K(ATP) function could contribute to the greater cardiovascular mortality and morbidity in DM.

Involvement of adrenomedullin induced by hypoxia in angiogenesis in human renal cell carcinoma.

Adrenomedullin (AM) has pluripotent activities and is involved in the regulation of vasomotor tone, cell differentiation and embryogenesis. However, the expression and pathophysiological role of AM has not been determined in human renal cell carcinoma (RCC). Twenty-six RCC specimens and three cultured human RCC cell lines (A498, SN12C and KPK-13) were analyzed. Expression of AM was determined by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis. The correlation between AM expression and microvessel count (MVC) in RCC specimens was examined to determine if AM plays a role in tumor angiogenesis. The correlation between the expression of AM and vascular endothelial growth factor (VEGF) was also investigated. Lastly, the effect of hypoxia upon the mRNA expression of AM, VEGF and hypoxia inducible factor-1 (HIF-1) by RCC cell lines was determined. Immunohistochemistry indicated that AM and VEGF were primarily localized in the cytosol of RCC cells. AM and VEGF mRNA were detected in all RCC specimens and cultured RCC cell lines analyzed by RT-PCR. There was a positive correlation between AM mRNA expression and MVC (r = 0.516, P = 0.0062), and between VEGF mRNA expression and MVC (r = 0.485, P = 0.0111). We also observed a positive correlation between AM mRNA expression and VEGF mRNA expression (r = 0.552, P = 0.0029). Hypoxia significantly induced AM and VEGF mRNA expression, although the increase of the AM mRNA level (10.6-26.7 fold) was markedly greater than that of the VEGF mRNA level (1.5-1.9 fold). These results suggest that hypoxia-induced AM plays a part in tumor angiogenesis in conjunction with VEGF and facilitates human RCC growth under hypoxic conditions.

Does it make sense to develop new centrally acting cardiovascular drugs?

1. The autonomic nervous system plays a pivotal role in modulating all the components of the cardiovascular regulation. Therefore, one can assume that drugs targeting this system may be useful in the management of several cardiovascular diseases. 2. Drugs acting on central nervous system centres seem to be modulators rather than blockers; as such, they are expected to preserve the contraregulatory processes and to generate only a few side effects. 3. Because the sympathetic nervous system is largely involved in the regulation of vasomotor tone, centrally acting antihypertensive drugs were developed first. 4. Recently, new leader compounds selective for non- adrenergic imidazoline recepetors have been synthetized. Although such drugs have no capacity to activate alpha2-adrenoceptors, they have been proven to be hypotensive. These drugs are expected to be even better tolerated than the currently available centrally active drugs. They may also have additional beneficial effects. 5. Here, the experimental evidence suggesting that such drugs may be useful in the management of some cardiac arrhythmias and/or left ventricular dysfunction will be reviewed.

I 1 receptors, cardiovascular function, and metabolism

When injected into the medullary site of the hypotensive action of clonidine, imidazolines and related compounds decrease blood pressure (BP), whereas no phenylethylamine compounds were capable of producing such an effect at the same site. There is much biochemical and pharmacologic evidence to support the involvement of imidazoline receptors in the regulation of vasomotor tone as well as in the mechanism of action of some centrally acting antihypertensive drugs. Imidazoline-specific binding sites, which do not recognize catecholamines, have been described in various tissues. Functional studies using selective antagonists have confirmed that the hypotensive effects of clonidine-like drugs are mediated, at least in part, by nonadrenergic imidazoline-specific receptors, whereas their sedative action clearly involves α 2-adrenergic receptors located in the locus coeruleus. Compared with clonidine, newer centrally acting antihypertensive drugs such as rilmenidine are more selective for imidazoline receptors than for α 2-adrenergic receptors. This selectivity may explain the reduced incidence of side effects of these drugs at therapeutic doses. Very recently, imidazoline-like compounds with no affinity and no activity at α 2-adrenergic receptors have become available. Some of these compounds lowered the BP when injected centrally, indicating that an action on imidazoline I 1 receptors alone is sufficient to cause hypotension. Nevertheless, imidazoline receptors and α 2-adrenoceptors cooperate in the control of the vasomotor tone and in the hypotensive action of centrally acting hybrid drugs (ie, drugs that bind to both types of receptor). Additional noncardiovascular effects of imidazoline-like drugs have also been described, such as insulin secretion stimulation and renal sodium reabsorption inhibition. These effects may account for the long-term benefits of imidazoline selective drugs, such as rilmenidine.