[Fetal programming of cardiovascular disease: new causes and underlying mechanisms]. / Programmation foetale des maladies cardiovasculaires, nouvelles causes et mecanismes sous-jacents.

There exists an association between pathologic events occurring during early life and the development of cardiovascular disease in adulthood. For example, transient perinatal hypoxemia predisposes to exaggerated hypoxic pulmonary hypertension and preeclampsia predisposes the offspring to pulmonary and systemic endothelial dysfunction later in life. The latter finding offers a scientific basis for observations demonstrating an increased risk for premature cardiovascular morbidity in this population. Very recently, we showed that offspring of assisted reproductive technologies also display generalized vascular dysfunction and early arteriosclerosis. Studies in animal models have provided evidence that oxidative stress and/or epigenetic alterations play an important pathophysiological role in the fetal programming of cardiovascular disease.

In vitro fertilization exacerbates stroke size and neurological disability in wildtype mice.

BACKGROUND AND PURPOSE: Assisted reproductive technologies (ART) induce premature vascular aging in human offspring. The related alterations are well-established risk factors for stroke and predictors of adverse stroke outcome. However, given the young age of the human ART population there is no information on the incidence and outcome of cerebrovascular complications in humans. In mice, ART alters the cardiovascular phenotype similarly to humans, thereby offering the possibility to study this problem. METHODS: We investigated the morphological and clinical outcome after ischemia/reperfusion brain injury induced by transient (45 min) middle cerebral artery occlusion in ART and control mice. RESULTS: We found that stroke volumes were almost 3-fold larger in ART than in control mice (P < 0.001). In line with these morphological differences, neurological performance assessed by the Bederson and RotaRod tests 24 and 48 h after artery occlusion was significantly worse in ART compared with control mice. Plasma levels of TNF-alpha, were also significantly increased in ART vs. control mice after stroke (P < 0.05). As potential underlying mechanisms, we identified increased blood-brain barrier permeability evidenced by increased IgG extravasation associated with decreased tight junctional protein claudin-5 and occludin expression, increased oxidative stress and decreased NO-bioactivity in ART compared with control mice. CONCLUSIONS: In wildtype mice, ART predisposes to significantly worse morphological and functional stroke outcomes, related at least in part to altered blood-brain barrier permeability. These findings demonstrate that ART, by inducing premature vascular aging, not only is a likely risk factor for stroke-occurrence, but also a mediator of adverse stroke-outcome. TRANSLATIONAL PERSPECTIVE: This study highlights that ART not only is a likely risk factor for stroke-occurrence, but also a mediator of adverse stroke-outcome. The findings should raise awareness in the ever-growing human ART population in whom these techniques cause similar alterations of the cardiovascular phenotype and encourage early preventive and diagnostic efforts.

Arterial baroreflex buffering of sympathetic activation during exercise-induced elevations in arterial pressure.

Static muscle contraction activates metabolically sensitive muscle afferents that reflexively increase sympathetic nerve activity and arterial pressure. To determine if this contraction-induced reflex is modulated by the sinoaortic baroreflex, we performed microelectrode recordings of sympathetic nerve activity to resting leg muscle during static handgrip in humans while attempting to clamp the level of baroreflex stimulation by controlling the exercise-induced rise in blood pressure with pharmacologic agents. The principal new finding is that partial pharmacologic suppression of the rise in blood pressure during static handgrip (nitroprusside infusion) augmented the exercise-induced increases in heart rate and sympathetic activity by greater than 300%. Pharmacologic accentuation of the exercise-induced rise in blood pressure (phenylephrine infusion) attenuated these reflex increases by greater than 50%. In contrast, these pharmacologic manipulations in arterial pressure had little or no effect on: (a) forearm muscle cell pH, an index of the metabolic stimulus to skeletal muscle afferents; or (b) central venous pressure, an index of the mechanical stimulus to cardiopulmonary afferents. We conclude that in humans the sinoaortic baroreflex is much more effective than previously thought in buffering the reflex sympathetic activation caused by static muscle contraction.

Nitric oxide release accounts for insulin's vascular effects in humans.

Insulin exerts effects on the vasculature that (a) may play a role in the regulation of blood pressure; and (b) by boosting its own delivery to target tissues, also have been proposed to play an integral part in its main action, the promotion of glucose disposal. To study the role of nitric oxide (NO) in the mediation of insulin's effects on the peripheral vasculature, NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of the synthesis of endothelium-derived NO, was infused into the brachial arteries of healthy volunteers both before, and at the end of a 2-h hyperinsulinemic (6 pmol/kg per min) euglycemic clamp. L-NMMA (but not norepinephrine, an NO-independent vasoconstrictor) caused larger reductions in forearm blood flow during hyperinsulinemia than at baseline. Moreover, L-NMMA prevented insulin-induced vasodilation throughout the clamp. Prevention of vasodilation by L-NMMA led to significant increases in arterial pressure during insulin/glucose infusion but did not alter glucose uptake. These findings indicate that insulin's vasodilatory effects are mediated by stimulation of NO release, and that they play a role in the regulation of arterial pressure during physiologic hyperinsulinemia. Abnormalities in insulin-induced NO release could contribute to altered vascular function and hypertension in insulin-resistant states.

Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans.

The sympathetic nervous system is an important regulatory mechanism of both metabolic and cardiovascular function, and altered sympathetic activity may play a role in the etiology and/or complications of obesity. In lean subjects, insulin evokes sympathetic activation and vasodilation in skeletal muscle. In obese subjects such vasodilation is impaired and, in turn, may contribute to insulin resistance. To examine the relationship between sympathetic and vasodilatory responses in skeletal muscle to hyperinsulinemia, we simultaneously measured muscle sympathetic nerve activity (MSNA) and calf blood flow at basal and during a 2-h hyperinsulinemic (6 pmol/kg per min) euglycemic clamp in eight lean and eight obese subjects. The major findings of this study are twofold: obese subjects had a 2.2 times higher fasting rate of MSNA, and euglycemic hyperinsulinemia, which more than doubled MSNA and increased calf blood flow by roughly 30% in lean subjects, had only a minor vasodilatory and sympathoexcitatory effect in obese subjects. In contrast, two non-insulin-sympathetic stimuli evoked comparably large increases in MSNA in lean and obese subjects. We conclude that insulin resistance in obese subjects is associated with increased fasting MSNA and a specific impairment of sympathetic neural responsiveness to physiological hyperinsulinemia in skeletal muscle tissue.

Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans.

Euglycemic hyperinsulinemia evokes both sympathetic activation and vasodilation in skeletal muscle, but the mechanism remains unknown. To determine whether insulin per se or insulin-induced stimulation of carbohydrate metabolism is the main excitatory stimulus, we performed, in six healthy lean subjects, simultaneous microneurographic recordings of muscle sympathetic nerve activity, plethysmographic measurements of calf blood flow, and calorimetric determinations of carbohydrate oxidation rate. Measurements were made during 2 h of: (a) insulin/glucose infusion (hyperinsulinemic [6 pmol/kg per min] euglycemic clamp), (b) exogenous glucose infusion at a rate matched to that attained during protocol a, and (c) exogenous fructose infusion at the same rate as for glucose infusion in protocol b. For a comparable rise in carbohydrate oxidation, insulin/glucose infusion that resulted in twofold greater increases in plasma insulin concentrations than did glucose infusion alone, evoked twofold greater increases in both muscle sympathetic nerve activity and calf blood flow. Fructose infusion, which increased carbohydrate oxidation comparably, but had only a minor effect on insulinemia, did not stimulate either muscle sympathetic nerve activity or calf blood flow. These observations suggest that in humans hyperinsulinemia per se, rather than insulin-induced stimulation of carbohydrate metabolism, is the main mechanism that triggers both sympathetic activation and vasodilation in skeletal muscle.

Insulin resistance in mice lacking neuronal nitric oxide synthase is related to an alpha-adrenergic mechanism.

BACKGROUND: nitric oxide (NO) plays an important role in the regulation of cardiovascular and glucose homeostasis. Mice lacking the gene encoding the neuronal isoform of nitric oxide synthase (nNOS) are insulin-resistant, but the underlying mechanism is unknown. nNOS is expressed in skeletal muscle tissue where it may regulate glucose uptake. Alternatively, nNOS driven NO synthesis may facilitate skeletal muscle perfusion and substrate delivery. Finally, nNOS dependent NO in the central nervous system may facilitate glucose disposal by decreasing sympathetic nerve activity. METHODS: in nNOS null and control mice, we studied whole body glucose uptake and skeletal muscle blood flow during hyperinsulinaemic clamp studies in vivo and glucose uptake in skeletal muscle preparations in vitro. We also examined the effects of alpha-adrenergic blockade (phentolamine) on glucose uptake during the clamp studies. RESULTS: as expected, the glucose infusion rate during clamping was roughly 15 percent lower in nNOS null than in control mice (89 (17) vs 101 (12) [-22 to -2]). Insulin stimulation of muscle blood flow in vivo, and intrinsic muscle glucose uptake in vitro, were comparable in the two groups. Phentolamine, which had no effect in the wild-type mice, normalised the insulin sensitivity in the mice lacking the nNOS gene. CONCLUSIONS: insulin resistance in nNOS null mice was not related to defective insulin stimulation of skeletal muscle perfusion and substrate delivery or insulin signaling in the skeletal muscle cell, but to a sympathetic alpha-adrenergic mechanism.

[High-altitude related illness]. / Maladies de haute altitude.

Development of modern tourist industry facilitates access to high altitude for a growing population of non-acclimatized individuals who frequently are unaware of the hazards related to this environment, which is characterized by low ambient oxygen due to low atmospheric pressure. High-altitude related illnesses therefore represent an emerging medical issue, which may become of concern for every practitioner. Three clinical entities are classically described: acute mountain sickness (AMS), high altitude cerebral edema (HACE) and high altitude pulmonary edema (HAPE), the two latter representing vital emergencies. The present paper presents the current recommendations for their diagnostic, prophylactic and therapeutic management.

[Fetal programming: an underestimated risk factor for cardiovascular and metabolic diseases]. / Programmation foetale: un facteur de risque méconnu des maladies cardiovasculaires et métaboliques.

Many epidemiological studies have shown a link between adverse events occuring during pregnancy and the development of cardiovascular and metabolic diseases later in life, a phenomenon called "fetal programming". The aim of this article is to summarize the knowledge in this field, and to present the main underlying mechanisms, among which epigenetics seems to play a determining role. This new knowledge might become particularly important for the practitioner and should prompt him to include an assessment of his patient's perinatal events in his daily practice, especially, in the light of the forthcoming availability of new drugs able to counteract the detrimental long term effects of such events.

Exaggerated endothelin release in high-altitude pulmonary edema.

BACKGROUND: Exaggerated pulmonary hypertension is thought to play an important part in the pathogenesis of high-altitude pulmonary edema (HAPE). Endothelin-1 is a potent pulmonary vasoconstrictor peptide that also augments microvascular permeability. METHODS AND RESULTS: We measured endothelin-1 plasma levels and pulmonary artery pressure in 16 mountaineers prone to HAPE and in 16 mountaineers resistant to this condition at low (580 m) and high (4559 m) altitudes. At high altitude, in mountaineers prone to HAPE, mean (+/-SE) endothelin-1 plasma levels were approximately 33% higher than in HAPE-resistant mountaineers (22.2+/-1.1 versus 16.8+/-1.1 pg/mL, P<0.01). There was a direct relationship between the changes from low to high altitude in endothelin-1 plasma levels and systolic pulmonary artery pressure (r=0.82, P<0.01) and between endothelin-1 plasma levels and pulmonary artery pressure measured at high altitude (r=0.35, P=0.05). CONCLUSIONS: These findings suggest that in HAPE-susceptible mountaineers, an augmented release of the potent pulmonary vasoconstrictor peptide endothelin-1 and/or its reduced pulmonary clearance could represent one of the mechanisms contributing to exaggerated pulmonary hypertension at high altitude.

Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase.

BACKGROUND: Insulin resistance and arterial hypertension are related, but the underlying mechanism is unknown. Endothelial nitric oxide synthase (eNOS) is expressed in skeletal muscle, where it may govern metabolic processes, and in the vascular endothelium, where it regulates arterial pressure. METHODS AND RESULTS: To study the role of eNOS in the control of the metabolic action of insulin, we assessed insulin sensitivity in conscious mice with disruption of the gene encoding for eNOS. eNOS(-/-) mice were hypertensive and had fasting hyperinsulinemia, hyperlipidemia, and a 40% lower insulin-stimulated glucose uptake than control mice. Insulin resistance in eNOS(-/-) mice was related specifically to impaired NO synthesis, because in equally hypertensive 1-kidney/1-clip mice (a model of renovascular hypertension), insulin-stimulated glucose uptake was normal. CONCLUSIONS: These results indicate that eNOS is important for the control not only of arterial pressure but also of glucose and lipid homeostasis. A single gene defect, eNOS deficiency, may represent the link between metabolic and cardiovascular disease.

Insulin-induced sympathetic activation and vasodilation in skeletal muscle. Effects of insulin resistance in lean subjects.

Insulin-induced stimulation of blood flow and sympathetic nerve activity in skeletal muscle tissue is impaired in obesity, but the underlying mechanism is unknown. To determine whether insulin resistance alters sympathetic and vasodilatory responses to euglycemic hyperinsulinemia, in eight healthy subjects we measured calf blood flow and muscle sympathetic nerve activity (MSNA) (n = 5) during insulin/glucose infusion (euglycemic hyperinsulinemic [6 pmol.kg-1.min-1] clamp) performed alone and performed during concomitant fat emulsion infusion, a maneuver designed to induce insulin resistance. The major new finding is that fat emulsion infusion, which attenuated insulin-induced stimulation of carbohydrate oxidation by 39 +/- 7% (P < 0.01), did not have any detectable effect on insulin-induced vasodilatory and sympathetic responses: at the end of the 2-h clamp, blood flow and MSNA had increased by 35 +/- 6% (P < 0.01) and 152 +/- 58% (P < 0.01), respectively, during insulin infusion alone and by 35 +/- 7% (P < 0.01) and 244 +/- 90% (P < 0.01), respectively, during insulin infusion superimposed on free fatty acid infusion. These observations in lean healthy subjects indicate that induction of resistance to the stimulatory effects of insulin on carbohydrate metabolism does not attenuate muscle blood flow and MSNA responses evoked by acute euglycemic hyperinsulinemia. These findings provide further evidence that hyperinsulinemia per se is the primary stimulus that triggers stimulation of muscle blood flow and MSNA during insulin/glucose infusion in humans and suggest that the impaired insulin-induced vasodilation in obese subjects is not related primarily to impaired stimulation of muscle carbohydrate metabolism.

Sympathectomy potentiates the vasoconstrictor response to nitric oxide synthase inhibition in humans.

OBJECTIVE: Nitric oxide exerts its cardiovascular actions at least in part by modulation of the sympathetic vasoconstrictor tone. There is increasing evidence that nitric oxide inhibits central neural sympathetic outflow, and preliminary evidence suggests that it may also modulate peripheral sympathetic vasoconstrictor tone. METHODS: To test this latter concept, in six subjects having undergone thoracic sympathectomy for hyperhydrosis, we compared the vascular responses to systemic L-NMMA infusion (1 mg/kg/min over 10 min) in the innervated and the denervated limb. We also studied vascular responses to the infusion of the non-nitric-oxide-dependent vasoconstrictor phenylephrine. RESULTS: L-NMMA infusion evoked a roughly 3-fold larger increase in vascular resistance in the denervated forearm than in the innervated calf. In the denervated forearm, vascular resistance increased by 58 +/- 10 percent (mean +/- SE), whereas in the innervated calf it increased only by 21 +/- 6 percent (P < 0.01, forearm vs. calf). This augmented vasoconstrictor response was specific for L-NMMA, and not related to augmented non-specific vasoconstrictor responsiveness secondary to sympathectomy, because phenylephrine infusion increased vascular resistance similarly in the denervated forearm and the innervated calf (by 24 +/- 7, and 29 +/- 8 percent, respectively). The augmented vasoconstrictor response was related specifically to denervation, because in control subjects, the vasoconstrictor responses to L-NMMA were comparable in the forearm and the calf. CONCLUSIONS: These findings indicate that in the absence of sympathetic innervation, the vasoconstrictor responses to nitric oxide synthase inhibition are augmented.

Interaction between cholinergic and nitrergic vasodilation: a novel mechanism of blood pressure control.

OBJECTIVE: Cholinergic vasodilation has been thought to play little if any role in the regulation of blood pressure in humans. Autonomic denervation potentiates the vasoconstriction evoked by nitric oxide synthase inhibition in humans, but the mechanism is unclear. We hypothesized that this may be related to loss of neuronal, non-nitric-oxide-dependent vasodilation. METHODS: To test this hypothesis, we examined effects of cholinergic blockade on blood pressure, heart rate and peripheral vascular responses to systemic infusion of the nitric-oxide-dependent vasoconstrictor L-NMMA (0.5 mg/kg/min over 15 min) in eight normal subjects. RESULTS: The L-NMMA-induced increase in mean (+/-S.E.) arterial pressure was roughly three times larger (P=0.002) in the presence than in the absence of cholinergic blockade (38+/-6 vs. 13+/-2 mmHg). Similarly, the increase in systemic and calf vascular resistance was more than twofold larger during L-NMMA-atropine. This potentiation was specific for nitric-oxide-dependent vasoconstriction, because atropine did not alter the responses to phenylephrine infusion. Cholinergic blockade also altered (P=0.004) the heart rate response to nitric oxide synthase inhibition; during L-NMMA alone heart rate decreased by 10+/-2 beats/min, whereas during L-NMMA-atropine infusion it increased by 14+/-4 beats/min. CONCLUSION: Cholinergic mechanisms play an important hitherto unrecognized role in offsetting the hypertension and cardiac sympathetic activation caused by nitric oxide synthase inhibition in humans. Decreased parasympathetic activity and impaired nitric oxide synthesis characterize several cardiovascular disease states, as well as normal aging. The conjunction of these two defects could trigger sudden death and contribute to the hypertension of the elderly.

Effects of sympathectomy and nitric oxide synthase inhibition on vascular actions of insulin in humans.

Insulin exerts cardiovascular actions by stimulating nitric oxide (NO) release and sympathetic neural outflow. It is unclear, however, whether insulin stimulates muscle blood flow (and NO release) by a direct action at the vasculature and/or by stimulating neural vasodilator mechanisms. In these studies we used patients with regional sympathectomy to examine the vascular actions of insulin in the presence and absence of sympathetic vasoconstrictor and vasodilator innervation. A 2-hour insulin (6 pmol/kg per minute)/glucose clamp increased muscle blood flow in both innervated and denervated limbs by roughly 40% (P<0.01 versus baseline for both limbs). The vasodilation reached its maximum within the first 30 to 45 minutes of insulin/glucose infusion in sympathetically denervated limbs, but only at the end of the infusion in innervated limbs (P<0. 01, denervated versus innervated limb). Infusion of a NO synthase inhibitor (N(G)-monomethyl-L-arginine [L-NMMA]) increased baseline arterial pressure, abolished the vasodilation in the denervated limb, and led to a significant additional increase in arterial pressure during the clamp, but did not alter whole body glucose uptake. Our data indicate that insulin stimulates blood flow in sympathectomized limbs by a direct action at the vasculature. This effect is mediated by stimulation of NO release and appears to be masked by the sympathetic vasoconstrictor tone in innervated limbs.

Cyclosporine causes sympathetically mediated elevations in arterial pressure in rats.

Cyclosporine-induced immunosuppression has emerged as a new cause of hypertension, but the underlying mechanisms are poorly understood. In patients, this hypertension is accompanied by sympathetic neural activation. We therefore hypothesized that increased sympathetic nerve discharge is an important mechanism by which cyclosporine raises blood pressure. To test this hypothesis, we examined effects of acute administration of cyclosporine (5 mg/kg i.v.) or vehicle on renal and lumbar sympathetic nerve activity, renal and femoral blood flow velocity (pulsed Doppler flowmetry), and arterial pressure in chloralose-anesthetized rats. Vehicle had no effect on sympathetic nerve activity, whereas cyclosporine caused renal and lumbar sympathetic nerve activity to increase progressively over 60 minutes to levels that were 362 +/- 46% and 388 +/- 70%, respectively, of the baseline values (p less than 0.05). These increases in sympathetic nerve activity were accompanied by proportional increases in renal and femoral vascular resistance and sustained increases in mean arterial pressure (+19 +/- 3 mm Hg, p less than 0.05 versus baseline). The cyclosporine-induced increases in regional vascular resistance and arterial pressure were greatly attenuated, or abolished, by ganglionic blockade or by clonidine (central sympatholysis) but were unaffected by angiotensin converting enzyme inhibition. These findings demonstrate that in an anesthetized animal preparation, the vasoconstrictor and blood pressure-raising effects of cyclosporine are caused by sympathetic neural activation.

Mechanisms of dexamethasone-induced insulin resistance in healthy humans.

Insulin resistance may result from decreased muscle blood flow, impaired cellular glucose transport, or intracellular deficits of glucose metabolism. The mechanisms responsible for dexamethasone-induced insulin resistance were investigated in healthy human subjects. During a 2-h hyperinsulinemic clamp, dexamethasone decreased glucose uptake, oxidation, and nonoxidative glucose disposal during the first hour. During the second hour, glucose uptake was normalized by means of hyperglycemia; glucose oxidation, however, remained suppressed by dexamethasone. Dexamethasone also abolished the insulin-mediated increase in calf blood flow. When acipimox was administered during the clamps to correct glucocorticoid-induced inhibition of glucose oxidation, dexamethasone decreased whole body glucose uptake and nonoxidative glucose disposal in the same proportion as when no acipimox was administered. However, glucose oxidation and insulin-mediated calf blood flow were normalized after acipimox. During the second hour, exogenous glucose infusion was matched to that used in the control clamp and normalized whole body glucose uptake. However, hyperglycemia developed, indicating insulin resistance. It is concluded that dexamethasone 1) decreases glucose oxidation independently of glucose transport; this inhibition is reversed by acipimox; and 2) decreases whole body glucose uptake independently of increased lipolysis, decreased glucose oxidation, or an altered muscle blood flow.

Insulin, nitric oxide and the sympathetic nervous system: at the crossroads of metabolic and cardiovascular regulation.

Epidemiological studies demonstrate an association between insulin resistance, hypertension and cardiovascular morbidity. Over the past decade, evidence has accumulated indicating that short-term insulin administration, in addition to its metabolic effects, also has important cardiovascular actions. The sympathetic nervous system and the L-arginine-nitric oxide pathway have emerged as central players in the mediation of insulin's cardiovascular actions. The underlying mechanisms and the factors that may govern the interaction between insulin and these two major cardiovascular regulatory systems have been studied extensively in healthy people and insulin-resistant subjects. Here we summarize the current understanding and gaps in knowledge on insulin's cardiovascular actions in humans, and discuss possible pathophysiological consequences of their alteration. Based on recent new insight, we propose that a genetic and/or acquired defect of nitric oxide synthesis could represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states, all of which may predispose to cardiovascular disease.

Haemodynamic and sympathetic effects of inhibition of nitric oxide synthase by systemic infusion of N(G)-monomethyl-L-arginine into humans are dose dependent.

BACKGROUND: In several animal species, nitric oxide (NO) buffers central neural sympathetic outflow, but data concerning humans are sparse and conflicting. We hypothesized that these conflicting results could be related to large differences in the dose of N(G)-monomethyl-L-arginine, a stereospecific inhibitor of NO synthase, infused in these human studies. OBJECTIVE: To investigate the haemodynamic and sympathetic effects of systemic inhibition of NO synthase by intravenous infusion of two different doses of N(G)-monomethyl-L-arginine into healthy humans and compare these effects with those of an equipressor dose of the non-endothelium-dependent vasoconstrictor phenylephrine. METHODS: Muscle sympathetic nerve activity was measured by microneurography and blood flow by venous occlusion plethysmography. N(G)-monomethyl-L-arginine was infused over 15 min at a rate of 50 microg/kg per min into members of one group (n = 8) and at a rate of 450 microg/kg per min into members of another group (n = 7). An equipressor dose of phenylephrine was infused into four subjects from each group. RESULTS: Infusions of N(G)-monomethyl-L-arginine and of phenylephrine at the higher dose similarly suppressed sympathetic activity. In contrast, infusions of N(G)-monomethyl-L-arginine and of an equipressor dose of phenylephrine at the lower dose had different sympathetic effects. Burst frequency of muscle sympathetic nerve activity remained unchanged during infusion of N(G)-monomethyl-L-arginine but decreased by roughly 50% during infusion of phenylephrine. Infusion of N(G)-monomethyl-L-arginine at both doses did not alter forearm blood flow. Only infusion of N(G)-monomethyl-L-arginine at the higher dose increased forearm vascular resistance. CONCLUSIONS: Haemodynamic and sympathetic effects of inhibition of NO synthase by infusion of N(G)-monomethyl-L-arginine into humans are dose dependent. At higher doses, N(G)-monomethyl-L-arginine exerts sympathoinhibitory effects that are comparable to those evoked by a non-specific vasoconstrictor drug, whereas at lower doses, it exerts sympatho-excitatory effects.

Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity.

Epidemiological studies demonstrate an association between insulin resistance, hypertension and cardiovascular morbidity. In addition to its metabolic effects, insulin also has important cardiovascular actions. The sympathetic nervous system and the nitric oxide-l-arginine pathway have emerged as central players in the mediation of these actions. Over the past decade, the underlying mechanisms and the factors that may govern the interaction between insulin and these two major cardiovascular regulatory systems have been studied extensively in healthy people and insulin-resistant individuals. Here we summarize the current understanding and gaps in knowledge on these interactions. We propose that a genetic and/or acquired defect of nitric oxide synthesis could represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states, all of which may predispose to cardiovascular disease.