Nitric Oxide
Demography of Syncope
Alpha Agonists in Syncope
Aging and Alpha-Adrenoreceptors
Genetics of Baroreflex Function
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To review the original abstract of these articles, click on the references below
Focus on nitric oxide
Nitric oxide (NO) is
arguably the most important local endogenous vasodilator. Its evanescent nature
suggests that its effects are confined to the site of production. It has been
argued that hemoglobin can act as a carrier, transporting NO to distal sites
where it can be delivered and act as a distant vasodilator. Rassaf et al.
report that NO can interact with plasma proteins to form S-nitrosothiols (RSNOs)
which can also act as NO carriers. They infused pharmacological doses of
aqueous NO solutions into a hand vein and showed increases in antecubital vein
RNSO levels, and forearm vasodilation in the contralateral arm. Intravenous NO
also lowered blood pressure without much change in heart rate. These results
support the notion that NO can be transported to induce distal vasodilation. To
what degree this occurs under physiological conditions is not clear.
It is known that the exercising muscle elicits systemic sympathetic
activation but is locally protected from the resultant vasoconstriction by a
process coined “functional sympatholysis”. To test the potential role of NO on
this phenomenon, Chavoshan et al. induced sympathetic activation using lower
body negative pressure (LBNP) while monitoring forearm muscle microcirculation
with near-infrared spectroscopy. LBNP decreased muscle oxygenation by 20% in
resting forearm, but only by 2% in exercising forearm. This functional
sympatholysis was not observed after suppression of NO synthesis by L-NAME,
suggesting a role of NO in this process (for more on functional sympatholysis,
see Autonomic News, Clin Auton Res (2002) volume 12, number 4).
Despite its beneficial effects, NO may have a dark side. NO reacts
with superoxide anion to form peroxynitrate which is damaging to the endothelium
and the perinerium. This biochemical reaction can be estimated by measuring the
nitrotyrosine component of protein. Hoedltke et al. followed 37 patients with
type I diabetes for three years and measured peripheral nerve function and
nitrosative stress annually. Levels of nitrite/nitrate (NO metabolites),
nitrotyrosine (nitrosative oxidation) and isoprostanes (oxidative stress) were
higher in diabetic patients, particularly those poorly controlled. These
measurements correlated with impaired peripheral nerve function. Although a
causal relationship was not established in this study, these results raise the
possibility that nitrosative stress contributes to the pathophysiology of
diabetes.
Rassaf T, Kleinbongard P, Preik M et al.
(2002) Plasma Nitrosothiols Contribute
to the Systemic Vasodilator Effects of Intravenously Applied NO:
Experimental and Clinical Study on the Fate of NO in Human Blood.
Circ Res
91:470-477.
Chavoshan B, Sander M, Sybert TE et
al.
(2002) Nitric oxide-dependent
modulation of sympathetic neural control of oxygenation in exercising human
skeletal muscle. J Physiol 540:377-386.
Hoeldtke RD, Bryner KD,
McNeill DR et al. (2002)
Nitrosative stress, uric Acid, and peripheral nerve function in early type 1
diabetes. Diabetes 51:2817-2825.
Incidence
and prognosis of syncope in the general population. Confirming our suspicions.
Several studies have
described the prognosis of the different causes of syncope, but virtually all
have been based in referral centers and very little information is available in
the general population. Soteriades et al. report that 822 out of 7814
participants in the Framingham study had syncope during an average follow-up of
17 years, an incidence of 6.2 per 1000 person-years. Assuming this figure can
be applied to the US population (~288M), this would mean that 1.79M people will
have syncope every year. The incidence of syncope increased significantly after
age 70. The cause of syncope was assigned by review of medical records as
vasovagal (21%), cardiac (10%), orthostatic (10%) and unknown (37%). Mortality
was increased 2-fold in patients with cardiac syncope. Patients with vasovagal
syncope had identical survival as subjects without syncope. Subjects with
unknown causes of syncope were at intermediate risk. Subjects with neurological
causes of syncope (stroke, transient ischemic attacks or seizure) had worse
prognosis compare to vasovagal syncope, but this was mostly due to a higher
incidence of stroke. This study confirms the widely held view that cardiogenic
syncope carries a bad prognosis, whereas neurogenic (vasovagal) syncope is a
benign condition. It also provides important incidence information in a general
population.
Soteriades
ES, Evans JC, Larson MG et al. (2002)
Incidence and prognosis of syncope. N Engl J Med 347:878-885.
α-agonists
in the treatment of syncope and hypotension
Despite the high incidence
of neurogenic syncope and the medical costs associated with it, treatment
remains a challenge. Kaufmann reports a double-blind, randomized, crossover
study showing that the selective
α1-adrenergic agonist midodrine (5 mg) prevented head-up tilt induced
syncope in 10/12 patients with a history of recurrent syncope, compared to 4/12
while on placebo. These results indicate that midodrine significantly improves
orthostatic tolerance during head-up tilt in patients with recurrent
neurally-mediated syncope. It is still not clear if normalization of tilt
responses predicts response to therapy. However, a similar study by Takata et
al. using lower body negative pressure to simulate orthostatic stress found that
the serotonin reuptake inhibitor Paxil, another drug commonly used to treat
neurocardiogenic syncope, did not improve orthostatic tolerance. Hoeben et al.
found that midodrine also prevents hypotension in end-stage renal disease
patients during dialysis. Of interest, this was associated with preservation of
central blood volume and cardiac output, rather than by elevating peripheral
vascular resistance. Such a hemodynamic profile, if documented during upright
tilt, would be ideal in the management of orthostatic hypotension.
Kaufmann
H, Saadia D, and Voustianiouk A (2002) Midodrine in neurally
mediated syncope: a double-blind, randomized, crossover study. Ann Neurol
52:342-345.
Takata TS, Wasmund SL, Smith ML et al.
(2002)
Serotonin reuptake inhibitor (Paxil) does not prevent the vasovagal reaction
associated with carotid sinus massage and/or lower body negative pressure in
healthy volunteers. Circulation 106:1500-1504.
Hoeben
H, Abu-Alfa AK, Mahnensmith R et al.
(2002) Hemodynamics in
patients with intradialytic hypotension treated with cool dialysate or midodrine.
American Journal of Kidney Diseases 39:102-107.
Impaired
α-adrenergic
vasoconstriction with aging
Sympathetic nerve activity
(measured in the muscle, MSNA) and plasma norepinephrine increase with age.
However, there is evidence that sympathetically-mediated vasoconstriction is
decreased in the elderly. To determine if this paradoxical response is due to a
reduction in postjunctional α-adrenergic
responsiveness to norepinephrine, Dinenno et al. examined the forearm
vasoconstrictor response to α-agonists
(phenylephrine for α1 and clonidine for α2)
and endogenously released norepinephrine (induced by tyramine) in 10 young (mean
age 26 years) and 10 older (65 years) healthy men. Studies were done in the
presence of β-blockade
with propranolol and all drugs were infused into the brachial artery. Tyramine
produced less forearm vasoconstriction in the older group, despite inducing a
greater increase in venous norepinephrine. The vasoconstrictive response to
phenylephrine was also impaired, but that of clonidine was not. These results
indicate that aging is associated with a reduction in vasoconstrictive
α-adrenergic
responsiveness. A similar conclusion was reached by Seals and Jones in a
preliminary study presented to the Society (Clin Auton Res (2002) 12:306).
These investigators found a decrease in the pressor effect of intravenous
phenylephrine in the elderly during ganglionic blockade with trimethaphan (to
eliminate baroreflex mechanisms). It is possible that this defect may lead to
impair orthostatic tolerance in the elderly.
Dinenno
FA, Dietz NM, and Joyner MJ (2002) Aging and forearm
postjunctional alpha-adrenergic vasoconstriction in healthy men.
Circulation 106:1349-1354.
Genetics of baroreflex
function
There is substantial
evidence that resting blood pressure and baroreflex regulation of blood pressure
are strongly influenced by genetic variance. Recently, a mice with disrupted
expression of the calcium-sensitive potassium channel (BK) was found to have
increased blood pressure. Gollasch et al. used the twin model to determine if
this gene (KCNMB1) would play a role in blood pressure regulation in humans.
The sequenced the KCNMB1 gene in 30 individuals and found two known and four new
single-nucleotide polymorphisms (SNPs). Four of them track with heart rate
variability. In particular exon 4b SNP AA individuals had higher high frequency
heart rate variability, compared to CA or CC persons. Homozygous AA persons had
greater baroreflex slopes than CA or CC persons. These results support the
notion that heart rate variability and baroreflex gain are under genetic
modulation. It is possible that such variation may also play a role in the
development of hypertension.
Gollasch
M, Tank J, Luft FC et al.
(2002) The BK channel beta1 subunit gene is associated with human
baroreflex and blood pressure regulation. Journal of Hypertension 20:927-933.