It is generally admitted that endothelial dysfunction is an important factor in both the onset and the development of atherosclerosis, as I demonstrated in earlier papers two decades ago, from the clinical view-point (1-6).
In fact, endothelium plays a pivotal role in the maintenance of vascular tone, taking part to the blood flow regulation in response to changes in tissue and organ perfusion requirements (5,6). When blood flow increases through a vessel, such as vessel dilates: from quantum-biophysical-semeiotic view-point, under such as condition, suddenly the enhancement occurs of both arterial-“in toto” ureteral reflex and arterial-gastric aspecific reflex (Fig.1), the latter easier to be assessed, (See http://www.semeioticabiofisica.it).
Gastric aspecific reflex ( in the stomach both fundus and body are dilated, while antral-pyloric region contracts) caused by digital pressure, applied on brachial artery of a patients in supine position, at rest.
One speaks of the phenomenon called flow-mediated dilatation (FMD). Over the past decade, a clinical quantum-biophysical-semeiotic technique has evolved to evaluate both flow-mediated vasodilation (FMD) and acethylcholine-mediated vasodilation (= Valsalva’s Manoeuvre), an important endothelium-dependent function, assessed, for instance, in the brachial artery (See website http://www.semeioticabiofisica.it/microangiologia).
In health, these stimuli provoke the endothelium to release free radical nitric oxide (NO), probably also by means of PPARS action (22), with subsequent vasodilation that can be assessed and quantified at the bed-side in different ways, as an index of vasomotor function. This technique is attractive because it is non-invasive and allows repeated measurements on very large scale. An increase in flow through the brachial artery can be induced by causing post-ischemic dilation in the downstream vascular bed of the distal forearm, that can be achieved by inflating a cuff placed around the forearm to supra-systolic pressure producing an ischemia in the distal vascular bed.
Really more simple, easier, faster to be performed, and, therefore, preferable in day-to-day practice, is the following bed-side manoeuvre: doctor applies an “intense”, obstructive digital pressure upon brachial artery, and immediately assesses the intensity of gastric aspecific reflex (or “in toto” ureteral reflex): NN = no aspecific gastric reflex happens.
On the contrary, in Arterioscleotic Constitution as well as in overt arteriopathy, of whatever nature the reflex intensity is
After the rapid with-drawl of digital pressure (or of the cuff pressure), a sudden increase of blood flow through the dilated vascular bed occurs, due to flow-mediated vaso-dilation. Firstly, physiologically the reflex disappears rapidly, and soon thereafter, a further reflex occurs spontaneously, showing a three times higher intensity.
In health, the significant increase in shear stress in the down-stream artery causes a NO-dependent dilation of the brachial artery, that can be evaluated clinically also in a different way, i.e., paralleling the basal value of finger pulp-gastric aspecific reflex, evaluated as latency time (in health, 8 sec., if digital pressure upon finger-pulp is “mean intense”) with the second value, which increases to 16 sec., i.e., doubled value.
The arterial dilator response to shear-stress can be almost completely blocked by pre-treatment with nitric oxide synthase inhibitors (7, 8) and therefore it has been suggested that the phenomenon is predominantly due to endothelial release of radical nitric oxide. In fact, the endothelium can no longer be viewed as a static physical barrier that simply separates blood from tissue. It is evident that disturbed endothelial function may be an early marker of an ongoing atherosclerotic process. Thus, inherited endothelial dysfunction has increasingly been recognized to play an important role in a number of conditions associated with a high prevalence of atherosclerotic CVDs (1-6), according to my Microvascular Arteriosclerosis Theory (partly illustrated in above-cited website, URL
A 53-year-long “clinical” experience allows me to state that endothelial function assessed by this method correlates significantly with invasive testing of coronary endothelial function (7, 9) and with the severity and extent of coronary atherosclerosis (10).
Interestingly, at this point, coronary artery endothelial function can analogously be easily evaluated by means of Quantum-Biophysical Semeiotics (1, 2, 11). The precise mechanisms for the acute detection of shear forces and subsequent signal transduction to modulate vasomotor tone are not fully understood. The endothelial cell membrane contains specialized ion channels, such as calcium-activated potassium channels, that open in response to shear stress (5). The effect of potassium channel opening is to hyperpolarize the endothelial cell, increasing the driving force for calcium entry (there are no voltage-gated calcium channels in endothelial cells). Calcium activates an enzyme, endothelial nitric oxide synthase (eNOS), and the subsequent generation of NO appears to account for FMD (6).
In humans, the measurement of FMD has been widely adopted to explore endothelial function. However, a number of variations of the method have been described. Cuff placement above or below the scanned part of the artery has been described, and varying duration and pressures for cuff inflation have been used. The brachial artery has been the target artery in most studied, but radial and femoral arteries have also been measured (7). Due to these technical modifications, the normal ranges established in some laboratories differ from normal ranges observed in others (7-8).
In my long clinical experience, Valsalva’s manoeuvre proved to be quiet practical, easy, reliable, and useful, lasting only 5 sec.: in health, manoeuvre-dependent acetylcholine secretion brings about notoriously smooth muscle cells relexation, in the identical way, illustrated above.
In my opinion, based on a large number of clinical quantum-biophysical-semeiotic observations, underlying patho-physiological action mechanism of acetylcholine are more complex, acting favourably also on healthy microcirculation, increasing both vasomotility and vasomotion.
On the contrary, in case of DM, dyslipidaemia, arterial hypertension, a.s.o., doctor mainly either does not observe any change or worsening condition, in relation to the severity of underlying disorder. Diet, ethimologically speaking, and physical exercise (walkig 45 minutes/day, 120 steeps/min), Coniugated Melatonin, improve in general endothelial function rapidly, according to other authors (12).
In addition, melatonin-adenosine, a potent histangioprotective substance (21, 23), in my experience proved to increase vasomotility and vasomotion in the microcirculatory bed of both tissue, and arterial wall.
On contrast, FMD is inversely correlated with age, type 2 diabetes mellitus, dyslipidaemia, hypertension, and tobacco smoking: smokers have decreased FMD (1-6).
In addition, inactivation of endothelium-derived nitric oxide due to increased production of oxygen free radicals in the vessel wall is thought to be an important mechanism for endothelial dysfunction (13, 14-23).
As a result, much interest has focused on antioxidants, such as vitamin E, vitamin C, and other free radical scavengers, like melatonin, as I demonstrated previously, for the first time “clinically” (14-27), since they remove successfully free radicals and, therefore, improve endothelial function.
* Sergio Stagnaro MD
Via Erasmo Piaggio 23/8, CP. 42
16039 Riva Trigoso (
Founder of Quantum Biophysical Semeiotics
Who's Who in the World (and
since 1996 to 2009
1) Stagnaro S., Stagnaro-Neri M., Basi microcircolatorie della semeiotica biofisica. Atti del XVII Cong. Naz. Soc. Ital. Studio Microcircolazione, Firenze ott. 1995, Biblioteca Scient. Scuola Sanità Militare, 1995, 2, 94.
2) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: valutazione della compliance arteriosa e delle resistenze arteriose periferiche. Atti del XVII Cong. Naz. Soc. Ital. Studio Microcircolazione, Firenze Ott. 1995, Biblioteca Scient. Scuola Sanità Militare, 2, 93.
3) Stagnaro-Neri M., Stagnaro S., Auscultatory Percussion Evaluation of Arterio-venous Anastomoses Dysfunction in early Arteriosclerosis. Acta Med. Medit. 5, 141, 1989
4) Stagnaro-Neri M., Stagnaro S. Indagine clinica percusso-ascoltatoria delle unità microvascolotessutali della plica ungueale. Acta Med. Medit. 4, 91, 1988.
5) Il test della Apnea nella Valutazione della Microcircolazione cerebrale Stagnaro S., Stagnaro-Neri M., in Cefalalgici. Atti, Congr. Naz. Soc. Ita. Microangiologia e Microcircolazione. A cura di C. Allegra. Pg. 457, Roma 10-13 Settembre 1987. Monduzzi Ed. Bologna
6) Stagnaro S., Valutazione percusso-ascoltatoria della microcircolazione cerebrale globale e regionale. Atti, XII Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. 13-15 Ottobre, Salerno, e Acta Medit. 145, 163, 1986.
7) Joannides R, Haefeli WE, Linder L, et al. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation 1995;91:1314-19.
8) Agewall S, Hulthe J, Fagerberg B, et al. Post-occlusion brachial artery vasodilatation after ischaemic handgrip exercise is nitric oxide mediated. Clin Physiol Funct Imaging 2002;22:18-23.
9) Takase B, Uehata A, Akima T, et al. Endothelium-dependent flow-mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease. Am J Cardiol 1998;82:1535-39.
10) Neunteufl T, Katzenschlager R, Hassan A, et al. Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 1997;129:111-18.
11) Stagnaro S. A clinical efficacious maneouvre, reliable in bed-side diagnosing coronary artery disease, even initial or silent, as well as "heart coronary risk". 3rd Virtual International Congress of Cardiology, FAC, 2003, http://www.fac.org.ar/tcvc/marcoesp/marcos.htm
12) Sowers JR, Lester MA. Diabetes and cardiovascular disease. Diabetes Care. 1999;22(suppl 3):C14-C20.
13) Ohara Y, Peterson TE, Zheng B, Kuo JF,
14) Stagnaro-Neri M., Stagnaro S., Amlodipina: Calcio-Antagonista e Scavenger dei Radicali Liberi. Tec. 4, 43, 1993.
15) Stagnaro-Neri M., Stagnaro S., Ketanserina: antagonista dei recettori 5Ht2-serotoninergici e scavenger dei radicali liberi. Clin. Ter. 141, 465, 1992 [MEDLINE]
16) Stagnaro-Neri M., Stagnaro S., Radicali liberi e alterazioni del microcircolo nelle flebopatie ipotoniche costituzionali. Min. Angiol. 18, Suppl. 2 al N. 4, 105, 1993.
17) Stagnaro Stagnaro-Neri M., Stagnaro S., Silimarina: un potente scavenger dei radicali liberi. Studio clinico percusso-ascoltatorio. Epat. 38, 3, 1992.
18) Stagnaro S., Stagnaro-Neri M. Il danno da radicali liberi sul microcircolo. Congr. Naz. SISM., Milano,10 giugno,1991, Comun. Atti, Min. Angiologica, Suppl. 1, N°1 16,398,1991
19) Stagnaro-Neri M., Stagnaro S., Acidi grassi w-3, scavengers dei radicali liberi e attivatori del ciclo Q e della sintesi del Co Q10. Gazz. Med. It. – Arch. Sc. Med. 151, 341, 1992 (Infotrieve)
20) Stagnaro Sergio, Stagnaro-Neri Marina. Introduzione alla Semeiotica Biofisica. Il Terreno oncologico”. Travel Factory SRL., Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm
21) Stagnaro S., Stagnaro-Neri M.,
22) John A. Polikandriotis; Louis J. Mazzella; Heidi L. Rupnow; C. Michael Hart
Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25: 1810.
23) Stagnaro Sergio Endothelial cell function can ameliorate under safer drugs, such as Melatonin-Adenosine. BMC Cardiovascular disorders. 2004. http://www.biomedcentral.com/1471-2261/4/4/comments
24) Stagnaro Sergio. Role of Coronary Endoarterial Blocking Devices in Myocardial Preconditioning - c007i. Lecture, V Virtual International Congress of Cardiology, 2007. http://www.fac.org.ar/qcvc/llave/c007i/stagnaros.php
26) Stagnaro Sergio. CAD Inherited Real Risk, Based on Newborn-Pathological, Type I, Subtype B, Aspecific, Coronary Endoarteriolar Blocking Devices. Diagnostic Role of Myocardial Oxygenation and Biophysical-Semeiotic Preconditioning. www.athero.org, 29 April, 2009 http://www.athero.org/commentaries/comm907.asp
27) Stagnaro Sergio. Epidemiological evidence for the non-random clustering of the components of the metabolic syndrome: multicentre study of the Mediterranean Group for the Study of Diabetes. Eur J Clin Nutr. 2007 Feb 7; [MEDLINE]