Endothelial Control Of Vascular Tone Research Articles

Mitochondrial ATP Production is Required for Endothelial Cell Control of Vascular Tone.

Arteries and veins are lined by nonproliferating endothelial cells that play a critical role in regulating blood flow. Endothelial cells also regulate tissue perfusion, metabolite exchange, and thrombosis. It is thought that endothelial cells rely on ATP generated via glycolysis, rather than mitochondrial oxidative phosphorylation, to fuel each of these energy-demanding processes. However, endothelial metabolism has mainly been studied in the context of proliferative cells, and little is known about energy production in endothelial cells within the fully formed vascular wall. Using intact arteries isolated from rats and mice, we show that inhibiting mitochondrial respiration disrupts endothelial control of vascular tone. Basal, mechanically activated, and agonist-evoked calcium activity in intact artery endothelial cells are each prevented by inhibiting mitochondrial ATP synthesis. Agonist-evoked calcium activity was also inhibited by blocking the transport of pyruvate, the master fuel for mitochondrial energy production, through the mitochondrial pyruvate carrier. The role for mitochondria in endothelial cell energy production is independent of species, sex, or vascular bed. These data show that a mitochondrial ATP supply is necessary for calcium-dependent, nitric oxide-mediated endothelial control of vascular tone, and identifies the critical role of endothelial mitochondrial energy production in fueling perfused blood vessel function.

Metabolic syndrome as a factor influencing the course of pregnancy

Background. According to the WHO guidelines, the criteria for metabolic syndrome (MS) include obesity (body mass index (BMI) >30 kg/m2), abdominal obesity (ratio of waist circumference and hips circumference >0.85 for females), blood pressure >160/90 mm Hg, triglyceride level >1.7 mmol/l, impaired glucose tolerance, microalbuminuria >20 μg/min.
 Objective. To assess the impact of MS on pregnancy.
 Materials and methods. Analysis of literature data on this issue and our own study involving 38 obese women. Pregnant women in the study were tested for pregnancy-associated protein A (PAPP-A), placental growth factor (PIGF), arginine, and leptin. They were also prescribed a comprehensive preventive treatment (from 12 weeks of pregnancy – 150 mg of aspirin 1 g per day, from 16 weeks – L-arginine solution (Tivortin aspartate, “Yuria-Pharm”) 5 ml (1 g) 4 times per day for 2 months). The control group consisted of 30 healthy pregnant women, the comparison group – of 30 obese pregnant women who did not receive L-arginine.
 Results and discussion. The pathological consequences of the mother’s MS for the foetus are mediated by the insulin resistance, hyperglycemia, and vascular damage. The negative effects include birth injuries, caesarean section, childhood obesity, and cardiovascular disease. Eclampsia and preeclampsia (PE), which increase the risk of perinatal mortality, are also the important problems of modern obstetrics. The presence of obesity in pregnant women increases the likelihood of PE by 2-3 times. Pre-pregnancy BMI increase by 5-7 kg/m2 also doubles the risk. In addition to PE, obesity also increases the risk of gestational hypertension, premature birth, foetal growth retardation syndrome, macrosomia, gestational diabetes mellitus, sudden foetal death. Endothelial dysfunction (ED) is one of the main pathogenetic links of obstetric complications, primarily PE. Thus, hypertension in PE is a consequence of impaired endothelial control of vascular tone, proteinuria and oedema – of increased vascular permeability, coagulopathy – of overexpression of procoagulants. In obesity, the likelihood of PE increases as chronic inflammation and ED are induced. PE development is also mediated by the increase in the leptin concentration. Nitric oxide donors, namely L-arginine, should be prescribed to correct ED and prevent PE. According to the results of our own study, obese women in the first trimester had significantly higher leptin levels and significantly lower PIGF levels, which is a prerequisite for PE and other gestational complications. In the main group, compared to the comparison group, there was a lower frequency of early moderate PE (5 % vs. 8 %), early severe PE (1 % vs. 5 %), moderate PE after 34 weeks of pregnancy (8 % vs. 12 %), and severe PE after 34 weeks of pregnancy (1 % vs. 4 %).
 Conclusions. 1. Obesity significantly increases the risk of PE and other gestational complications. 2. The main mechanisms of adverse effects of obesity are chronic inflammation and ED. 3. The use of complex prophylaxis with aspirin and L-arginine for 2 months almost 5 times reduced the degree of severe early PE.

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

BackgroundObesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations that give rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that endothelial cells are not a population of uniform cells but are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function. PurposeTo investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contribute to impaired vascular reactivity in obesity. Methods and resultsTo study obesity-related vascular function without complications associated with diabetes, a state of prediabetic obesity was induced in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and population-wide calcium responses. Obesity did not alter the slope of this relationship, but impaired calcium responses in the endothelial cell network. The network comprised structural and functional components. The structural architecture, a hexagonal lattice network of connected cells, was unchanged in obesity. The functional network contained sub-populations of clustered specialized agonist-sensing cells from which signals were communicated through the network. In obesity there were fewer but larger clusters of sensory cells and communication path lengths between clusters increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. ConclusionsThe distribution of cells in the endothelial network is critical in determining overall vascular response. Altered cell heterogeneity and arrangement in obesity decreases endothelial function and provides a novel framework for understanding compromised endothelial function in cardiovascular disease.

Increased Vascular Contractility in Hypertension Results From Impaired Endothelial Calcium Signaling.

Endothelial cells line all blood vessels and are critical regulators of vascular tone. In hypertension, disruption of endothelial function alters the release of endothelial-derived vasoactive factors and results in increased vascular tone. Although the release of endothelial-derived vasodilators occurs in a Ca2+-dependent manner, little is known on how Ca2+ signaling is altered in hypertension. A key element to endothelial control of vascular tone is Ca2+ signals at specialized regions (myoendothelial projections) that connect endothelial cells and smooth muscle cells. This work describes disruption in the operation of this key Ca2+ signaling pathway in hypertension. We show that vascular reactivity to phenylephrine is increased in hypertensive (spontaneously hypertensive rat) when compared with normotensive (Wistar Kyoto) rats. Basal endothelial Ca2+ activity limits vascular contraction, but that Ca2+-dependent control is impaired in hypertension. When changes in endothelial Ca2+ levels are buffered, vascular contraction to phenylephrine increased, resulting in similar responses in normotension and hypertension. Local endothelial IP3(inositol trisphosphate)-mediated Ca2+ signals are smaller in amplitude, shorter in duration, occur less frequently, and arise from fewer sites in hypertension. Spatial control of endothelial Ca2+ signaling is also disrupted in hypertension: local Ca2+ signals occur further from myoendothelial projections in hypertension. The results demonstrate that the organization of local Ca2+ signaling circuits occurring at myoendothelial projections is disrupted in hypertension, giving rise to increased contractile responses.

Mitochondria Modulates Calcium Pulsars Kinetics in Native Endothelial Cells from Mouse Mesenteric Arteries

Endothelial control of vascular tone is modulated by local calcium (Ca2+) signaling events like Ca2+ pulsars, an IP3R‐dependant Ca2+ release restricted to myoendothelial projections (MEP). Aside from the recent report of Ca2+ pulsars being modulated by CaMKII, mechanisms regulating endothelial spontaneous Ca2+ release remain unidentified. Mitochondria are important modulators of intracellular Ca2+ dynamics in various cell types and, we hypothesized mitochondria may control endothelial Ca2+ pulsars. High‐speed confocal microscopy was used to investigate mitochondria's influence on endothelial Ca2+ pulsar in cut‐open mouse mesenteric arteries (en face configuration). Preventing mitochondrial Ca2+ uptake by uncoupling with FCCP uncovered a new Ca2+ pulsar site population that had a lower frequency (≈+30%) but larger diffusional spread (+57%) than controls. Inhibition of mitochondrial Ca2+ uptake via the uniporter using Ru360 increased the spread of Ca2+ pulsars (≈+30%), though kinetics were not significantly altered. Significantly, inhibition of mitochondrial Ca2+ export (CGP37157, CsA) increased the number of active Ca2+ pulsar sites, each with a decreased bursting frequency. In summary, these results suggest that mitochondrial uptake and release of Ca2+ acts as a critical local modulator of Ca2+ pulsar kinetics and may therefore be crucial to endothelial control of vascular tone.Support or Funding InformationFRQS, HSFC, CFI, SQHA and CIHR

Pressure-dependent regulation of Ca2+ signalling in the vascular endothelium.

Key points Increased pressure suppresses endothelial control of vascular tone but it remains uncertain (1) how pressure is sensed by the endothelium and (2) how the vascular response is inhibited.This study used a novel imaging method to study large numbers of endothelial cells in arteries that were in a physiological configuration and held at normal blood pressures.Increased pressure suppressed endothelial IP3‐mediated Ca2+ signals.Pressure modulated endothelial cell shape.The changes in cell shape may alter endothelial Ca2+ signals by modulating the diffusive environment for Ca2+ near IP3 receptors.Endothelial pressure‐dependent mechanosensing may occur without a requirement for a conventional molecular mechanoreceptor.

Aging of platelet nitric oxide signaling: pathogenesis, clinical implications, and therapeutics.

The nitric oxide (NO)/soluble guanylate cyclase (sGC) system is fundamental to endothelial control of vascular tone, but also plays a major role in the negative modulation of platelet aggregation. The phenomenon of platelet NO resistance, or decreased antiaggregatory response to NO, occurs increasingly with advanced age, as well as in the context of cardiovascular disease states such as heart failure, ischemic heart disease, and aortic valve disease. The central causes of NO resistance are "scavenging" of NO and dysfunction of sGC. In the current review, we discuss the roles of several modulators of NO synthesis and of the NO/sGC cascade on changes in platelet physiology with aging, together with potential therapeutic options to reduce associated thrombotic risk.

TRPV4‐associated alterations of Ca2+ pulsars in a murine model of pulmonary hypertension secondary to heart failure (1090.11)

Heart failure is the most frequent cause of pulmonary hypertension (PH) (group 2). Pathophysiological mechanisms modulating pulmonary vascular tone and leading to group 2‐PH are poorly defined. Since Ca2+ homeostasis is crucial to endothelial control of vascular tone, mechanisms involved, including TRPV4 channels, may be altered. This study aimed to characterize intracellular Ca2+ dynamics in pulmonary endothelium and their alterations in group 2 PH. A mouse model of group 2 PH was developed and 3rd order resistance arteries were isolated to investigate endothelial intracellular Ca2+. TRPV4 involvement was studied using a high‐speed confocal microscope. Characterization of endothelial localized calcium transients, similar to Ca2+ pulsars, was carried out in pulmonary arteries from control mice. Exposure of Sham arteries to GSK1016790A (100 nM), a TRPV4‐agonist, increased the frequency (1.5 fold) of Ca2+ pulsars. However, exposure to GSK1016790A had little if any effect on Ca2+ dynamics in PH arteries. TRPV4 channel expression at both mRNA and protein levels within pulmonary endothelium was confirmed by qPCR, IHC and WB approaches. Our data suggest a potential role for endothelial TRPV4 in vasoregulatory alterations involving local Ca2+ dynamics. This study strengthens our understanding of endothelial Ca2+ dyshomeostasis occurring in a clinically relevant model of PH.Grant Funding Source: FRQS, HSFC, FICM, CIHR

Comparative Effects of Preoperative Angiotensin-converting Enzyme In-hibitor, Statin and Beta-blocker Treatment on Human Internal Mammary Artery Reactivity in Patients with Coronary Artery Disease: A Pilot Study

We investigated the effect of angiotensin-converting enzyme (ACE)- inhibitor, statin, and beta-blocker usage before coronary bypass surgery (CABG) on vascular reactivity of the internal mammary artery (IMA). Patients, who underwent elective CABG were evaluated. Samples of IMA obtained from 22 patients were divided into 4 groups in respect of drugs used by patients before bypass surgery (control group, ACE inhibitor + statin group, ACE inhibitor + statin + beta-blocker group, and ACE inhibitor + beta-blocker group). The discarded, distal end section of IMA was carefully removed, and the vasoreactivity of IMA rings was evaluated in vitro using an organ chamber. Smooth muscle contractile function was tested on artery segments exposed to 10-80 mM KCl and norepinephrine. The endothelial function of IMA rings was assessed with acetylcholine (ACh) and bradykinin, while endothelium-independent vasorelaxation was evaluated by sodium nitroprusside (SNP). Both ACh and bradykinin caused concentration-dependent relaxation in endothelium-intact IMA rings. However, the maximal effect produced by endothelium-dependent agents in all treatment groups was more prominent when compared with the control group. There was no significant difference in the endothelium-dependent relaxation response of IMA between ACE inhibitor + statin, ACE inhibitor + beta-blocker and ACE inhibitor + statin + beta-blocker groups. The vasodilatory potency of SNP was similar in all groups. Similarly, contractile response to KCl or norepinephrine was not significantly different between groups. Use of ACE inhibitors and statins before bypass surgery may influence IMA vasoreactivity by improving endothelial control of vascular tone.

Comparative Effects of Preoperative Angiotensin-converting Enzyme In-hibitor, Statin and Beta-blocker Treatment on Human Internal Mammary Artery Reactivity in Patients with Coronary Artery Disease: A Pilot Study

Purpose: We investigated the effect of angiotensin-converting enzyme (ACE)- inhibitor, statin, and beta-blocker usage before coronary bypass surgery (CABG) on vascular reactivity of the internal mammary artery (IMA). Methods: Patients, who underwent elective CABG were evaluated. Samples of IMA obtained from 22 patients were divided into 4 groups in respect of drugs used by patients before bypass surgery (control group, ACE inhibitor + statin group, ACE inhibitor + statin + beta-blocker group, and ACE inhibitor + beta-blocker group). The discarded, distal end section of IMA was carefully removed, and the vasoreactivity of IMA rings was evaluated in vitro using an organ chamber. Smooth muscle contractile function was tested on artery segments exposed to 10-80 mM KCl and norepinephrine. The endothelial function of IMA rings was assessed with acetylcholine (ACh) and bradykinin, while endothelium-independent vasorelaxation was evaluated by sodium nitroprusside (SNP). Results: Both ACh and bradykinin caused concentration-dependent relaxation in endothelium-intact IMA rings. However, the maximal effect produced by endothelium-dependent agents in all treatment groups was more prominent when compared with the control group. There was no significant difference in the endothelium-dependent relaxation response of IMA between ACE inhibitor + statin, ACE inhibitor + beta-blocker and ACE inhibitor + statin + beta-blocker groups. The vasodilatory potency of SNP was similar in all groups. Similarly, contractile response to KCl or norepinephrine was not significantly different between groups. Conclusion: Use of ACE inhibitors and statins before bypass surgery may influence IMA vasoreactivity by improving endothelial control of vascular tone.

Nutritional improvement of the endothelial control of vascular tone by polyphenols: role of NO and EDHF

Numerous studies indicate that regular intake of polyphenol-rich beverages (red wine and tea) and foods (chocolate, fruit, and vegetables) is associated with a protective effect on the cardiovascular system in humans and animals. Beyond the well-known antioxidant properties of polyphenols, several other mechanisms have been shown to contribute to their beneficial cardiovascular effects. Indeed, both experimental and clinical studies indicate that polyphenols improve the ability of endothelial cells to control vascular tone. Experiments with isolated arteries have shown that polyphenols cause nitric oxide (NO)-mediated endothelium-dependent relaxations and increase the endothelial formation of NO. The polyphenol-induced NO formation is due to the redox-sensitive activation of the phosphatidylinositol3-kinase/Akt pathway leading to endothelial NO synthase (eNOS) activation subsequent to its phosphorylation on Ser 1177. Besides the phosphatidylinositol3-kinase/Akt pathway, polyphenols have also been shown to activate eNOS by increasing the intracellular free calcium concentration and by activating estrogen receptors in endothelial cells. In addition to causing a rapid and sustained activation of eNOS by phosphorylation, polyphenols can increase the expression level of eNOS in endothelial cells leading to an increased formation of NO. Moreover, the polyphenol-induced endothelium-dependent relaxation also involves endothelium-derived hyperpolarizing factor, besides NO, in several types of arteries. Altogether, polyphenols have the capacity to improve the endothelial control of vascular tone not only in several experimental models of cardiovascular diseases such as hypertension but also in healthy and diseased humans. Thus, these experimental and clinical studies highlight the potential of polyphenol-rich sources to provide vascular protection in health and disease.

Chronic treatment with progesterone but not medroxyprogesterone acetate restores the endothelial control of vascular tone in the mesenteric artery of ovariectomized rats.

To examine whether chronic administration of the natural hormone progesterone or a synthetic progestogen, medroxyprogesterone acetate, to ovariectomized rats affects the endothelial control of arterial tone in the isolated mesenteric artery. Sham-operated rats received a daily subcutaneous injection of solvent (sesame oil), whereas ovariectomized rats received either sesame oil, progesterone (22 mg kg/day), or medroxyprogesterone acetate (22 mg kg/day) for 4 weeks, according to their respective group. Phenylephrine-induced contractions were significantly increased (about 200% at 10 microM) by N-nitro-L-arginine, a nitric oxide synthase inhibitor, in intact mesenteric arterial rings from the sham-operated but not from the ovariectomized group. The progesterone but not the medroxyprogesterone treatment restored the potentiating effect of N-nitro-L-arginine on phenylephrine-induced contraction (about 180% at 10 microM). Contractions to phenylephrine were not affected by the combination of charybdotoxin plus apamin, two inhibitors of endothelium-derived hyperpolarizing factor-mediated responses, in all groups. Acetylcholine induced endothelium-dependent relaxations, which were partially inhibited by N-nitro-L-arginine and abolished by the combination of N-nitro-L-arginine plus charybdotoxin and apamin, in all groups. Acetylcholine induced similar charybdotoxin and apamin-sensitive hyperpolarizations in intact mesenteric artery segments from all groups. Chronic administration of progesterone, but not medroxyprogesterone, to ovarictomized rats restores the endothelium-dependent attenuation of contractile responses to phenylephrine in mesenteric arterial rings through the endothelial formation of nitric oxide. Thus, an enhancement of the protective effect of endothelial cells on the arterial wall might contribute to the beneficial effect of certain progestogen-containing preparations during hormonal treatment.

Endothelins: a Possible Mechanism of Cytostatics-induced Cardiomyopathy

Endothelium responds to physical and chemical stimuli by synthesis and release of a variety of vasoactive and signal molecules. Cardiac performance is regulated by cardiac endothelial cells in a paracrine manner, analogous to vascular endothelial control of vascular tone. Endothelin-1 (ET-1), one of the most potent vasoconstrictor peptides, which is synthetized and released by endothelial cells. The role of ET-1 in some special pathological state is still unclear. Authors have investigated the effect of anthracyclines (maximal dose: 450 mg/bodysurface m2) on left ventricular systolic and diastolic function and on the level of plasma ET-1, in 31 (13 male, aged 19 – 70 years, mean: 38.9) patients suffered from Hodgkin (24) and Non-Hodgkin (7) lymphomas. They have also studied the association between plasma ET-1 concentration and echocardiographic parameters. Serum ET-1 was measured by ELISA method. Left ventricular function analyzed by echocardiography: ejection fraction (EF), time velocity integral (VTI), E and A waves, E/A ratio, deceleration time (DT), Doppler index were assessed. Statistical analysis was made by the Wilcoxon rank test. ET-1 plasma level decreased significantly after therapy (5.6 ± 3.5 vs. 3.1 ± 0.9 pg/ml, P < 0.0006). EF (56.4 ± 5.0% vs. 48.7 ± 5.1%, P < 0.0001) decreased, and DT (168.1 ± 36.8 ms vs. 206.5 ± 58.8 ms, P < 0.0073) increased significantly after administration of anthracycline, showing that both systolic and diastolic left ventricular performance was deteriorated. There was no difference in other echocardiographic parameters before and after therapy. In conclusion, decrease of serum ET-1 concentration might be a result of anthracyclin's direct cytotoxic effect and the decreasing level of ET-1 may play a role in the reduction of the EF. More studies are needed to evaluate the presence and severity of endothelial damage, and long-term follow-up may reveal the importance of low ET-1 level and may show the time is needed for the restoration of the ET-1 concentration to the basic level after cessation of cytostatic therapy.

110 Anthracyclines induced cardiomyopathy and endothelins

Endothelium responds to physical and chemical stimuli by synthesis and release of a variety of vasoactive and signal molecules. Cardiac performance is regulated by cardiac endothelial cells in a paracrin manner, analogous to vascular endothelial control of vascular tone. Endothelin-1 (ET-1) one of the most potent vasoconstrictor peptides, which is synthetized and released by endothelial cells. The role of ET-1 in some special pathological state is still unclear. Authors have investigated the effect of anthracyclines (maximal dose: 450 mg/bodysurface m2) on left ventricular systolic and diastolic function and on the level of plasma ET-1, in 31 (13 male, aged 19-70 years, mean:38,9) patients suffered from Hodgkin (24) and Non-Hodgkin (7) lymphomas. They have also studied the association between plasma ET-1 concentration and echocardiographic parameters. Methods: Serum ET-1 was measured by ELISA method. Left ventricular function analysed by echocardiography: ejection fraction (EF), time velocity integral (VTI), E and A waves, E/A ratio, deceleration time (DT), Doppler index were assessed. Statistical analysis was made by the Wilcoxon rank test. Results: ET-1 plasma level decreased significantly after therapy (5,6± 3,5 vs. 3,1±0,9 pg/ml, p<0,0006). EF (56,4±5,0% vs. 48,7±5,1%, p<0,0001) decreased, and DT (168,1±36,8ms vs. 206,5±58,8ms p<0,0073) increased significantly after administration of anthracycline, showing that both systolic and diastolic left ventricular performance was deteriorated. There was no difference in other echocardiographic parameters before and after therapy. Conclusion: Decrease of serum ET-1 concentration might be a result of anthracyclin’s direct cytotoxic effect and the decreasing level of ET-1 can play a role in the reduction of the EF. More studies are needed to evaluate the presence and severity of endothelial damage and long term follow up may reveal the importance of low ET-1 level and may show the time needed for the restoration of the ET-1 concentration to the basic level after cessation of cytostatic therapy.

Cigarette smoking and renal function impairment.

Cigarette smoking and renal function impairment.

Regulation of tone in penile cavernous smooth muscle. Established concepts and new findings.

Since Benson, in 1983, reported on a potent nonadrenergic, noncholinergic (NANC) transmitter postulated to relax penile vessels and the corpus cavernosum, much new information on the mechanisms of contraction and relaxation of corporeal smooth muscle and penile vasculature has been obtained. The information currently available suggests that NANC transmitters may be involved in both contractile and relaxant responses of penile erectile tissues. There is good experimental evidence to allow the assumption that neurogenic nitric oxide (NO) is a mediator of penile erection, but even if NO probably is the most important factor for relaxation of penile vessels and the corpus cavernosum, this does not exclude the possibility that other agents released from nerves may have a modulatory function in this process. However, the roles of, for example, vasoactive intestinal polypeptide and related peptides as neurotransmitters and/or neuromodulators in the nervous control of penile erection have yet to be established. The restricted availability of human penile erectile tissues has led to the use of cavernous tissue and penile vessels from animals, both for screening and for detailed analysis of mechanisms previously demonstrated to exist also in human tissues. When interpreting the results obtained, it is important to stress that there may be important differences between human and animal tissues, that each of the tissues only gives a piece of information on the complex process of penile erection, and that the physiological and clinical importance of results from such experiments may be limited. The differing responses in different parts of the vasculature within the penis and the multiplicity of putative transmitters present in the corpus cavernosum and in perivascular nerves make further investigations necessary, as do the interactions between transmitters and neuromodulators at the neuromuscular junction, and between the neural and endothelial control of vascular tone.

Diminished vascular response to inhibition of endothelium-derived nitric oxide and enhanced vasoconstriction to exogenously administered endothelin-1 in clinically healthy smokers.

Smoking is a major risk factor for the development of atherosclerosis. Because endothelial dysfunction may be a marker for future atherosclerosis, we investigated the effects of smoking on endothelium-dependent control of vascular tone. The effects of brachial arterial infusions of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthesis inhibitor; sodium nitroprusside; endothelin-1; and norepinephrine on forearm blood flow (strain-gauge plethysmography) were compared in 29 long-term smokers and 16 nonsmokers. The acute effects of smoking on systemic hemodynamics, plasma catecholamines, and forearm vascular responses to these compounds were investigated in smokers only. Smokers did not differ from nonsmokers (n = 16) regarding the vascular effects of sodium nitroprusside (n = 13) or vasoconstriction due to norepinephrine and endothelin-1 (n = 16). Low-dose endothelin-1-induced vasodilation, believed to reflect endothelial prostacyclin or nitric oxide release, was absent in smokers (n = 16), and their increase of forearm vascular resistance (FVR) after L-NMMA (n = 13) was impaired (35.6 +/- 27.9% versus 118.8 +/- 43.2%, P < .001). Short-term smoking (n = 11) increased blood pressure, heart rate, and plasma epinephrine concentrations (P < .05 or less); enhanced endothelin-1-induced vasoconstriction (delta FVR, 457 +/- 192% versus 254 +/- 143%, P < .01); and decreased norepinephrine-induced vasoconstriction (P < .05), but had no effect on the other interventions. Long-term smoking is associated with a diminished nitric oxide-dependent component of basal vascular tone and an impaired endothelium-dependent vasodilator response to low-dose endothelin-1 and short-term smoking enhances endothelin-1-induced vasoconstriction. Impaired endothelial control of vascular tone might reflect impairment of normal antiatherosclerotic endothelial functions in smokers, but the relevance of smoking-induced enhancement of endothelin-1 vasoconstriction remains to be determined.

Endothelial control of vascular and myocardial function in heart failure.

The effect of vascular endothelium, endocardium, and coronary endothelium on vascular tone and myocardial contraction-relaxation sequence in heart failure is discussed. Vascular endothelium affects underlying vascular smooth muscle through paracrine secretion of relaxing and constricting factors. In heart failure, systemic vasoconstriction results not only from neuroendocrine activation, but also from disturbed local endothelial control of vascular tone because of impaired endothelial-dependent vasodilation and because of increased plasma concentration of endothelin. Experimental evidence obtained in isolated cardiac muscle strips established the influence of endocardial endothelium on the duration of myocardial contraction and on the onset of myocardial relaxation. By analogy to vascular endothelium, both diffusible agents that abbreviate (endothelial-derived relaxation factor-like substance) and those that prolong (endocardin) myocardial contraction have been shown to be released from the endocardium. Similar agents are released from the coronary endothelium and, because of the close proximity of capillaries and myocytes, could exert a major effect on myocardial performance. Endothelial dysfunction and concomitant lack of release of myocardial relaxant factors could explain left ventricular relaxation abnormalities observed in the cardiac allograft or in arterial hypertension. Since endothelial-derived relaxation factor or nitric oxide mediates the coronary reactive hyperemic response, a negative inotropic action of nitric oxide could contribute to left ventricular failure when left ventricular wall stress is elevated, as occurs after myocardial infarction in the noninfarcted zone and during left ventricular volume or pressure overload in the absence of adequate hypertrophy.

Ethanol affects sympathetic cotransmission and endothelium-dependent relaxation in the rat

The influence of ethanol on sympathetic nerve-mediated contractions of rat tail arteries and on endothelium-dependent relaxation of rat mesentric arteries by acetylcholine was examined using the method of in vitro pharmacology. Ethanol potentiated sympathetic nerve-mediated contractions. Ethanol had no effect on the neurogenic contractions that remained after α-adrenoceptor blockade by prazosin. However, after P 2x-purinoceptor desensitisation, the residual nerve-mediated contractions were significantly enhanced by ethanol. Contractions to exogenous noradrenaline and α,β-methylene ATP were unaffected by ethanol. It is concluded that ethanol selectively potentiates the noradrenergic component of sympathetic neurotransmission. Ethanol depressed the relaxation by acetylcholine but not that induced by sodium nitroprusside. These results indicate that ethanol can affect both the neural and endothelial control of vascular tone. The potentiated noradrenergic vasoconstrictor response to sympathetic nerve stimulation and the compromised capacity of the endothelium to cause relaxation after ethanol treatment may contribute to the development of vascular diseases associated with alcohol consumption.

Endothelial control of vascular tone in large and small coronary arteries

The endothelium modulates coronary vascular tone by the release of endothelium-derived relaxing or contracting substances. The endothelium-derived relaxing factor has been identified as nitric oxide synthesized in endothelial cells from l-arginine. The endothelium can release other relaxing substances such as prostacyclin and a hyperpolarizing factor. Endothelin-1 is a potent vasoconstrictor peptide formed by endothelial cells, and is likely to be the physiologic antagonist of endothelium-derived relaxing factor. Other putative contracting factors include superoxide anions and products of arachidonic acid metabolism.Endothelium-derived relaxing factor is released spontaneously and in response to flow, platelet-derived products (that is, serotonin, thrombin and adenosine diphosphate) and certain autacoids (that is, acetylcholine, bradykinin, histamine, substance P, vasopressin, alpha-adrenergic agonists). A considerable heterogeneity of responses exists among vessels of different size from different anatomic origin and different species. Hypercholesterolemia, atherosclerosis, hypertension and myocardial ischemia or reperfusion, or both, impair endothelium-dependent relaxation.Under normal conditions, endothelium-derived relaxing factor appears to dominate the control of vascular tone of large and small coronary vessels, whereas in disease states, endothelium-derived contracting factors are released. Impairments of endothelial function may be important in the development of various forms of cardiovascular disease.