Remote Limb Ischemic Preconditioning Attenuates Cerebrovascular Depression During Sinusoidal Galvanic Vestibular Stimulation via α1-Adrenoceptor-Protein Kinase Cε-Endothelial NO Synthase Pathway in Rats.

BACKGROUND: Vasovagal syncope (VVS) is characterized by hypotension and bradycardia followed by lowering of cerebral blood flow. Remote limb ischemic preconditioning (RIPC) is well documented to provide cardio- and neuroprotection as well as to improve cerebral blood flow. We hypothesized that RIPC will provide protection against VVS-induced hypotension, bradycardia, and cerebral hypoperfusion. Second, because endothelial nitric oxide synthase has been reported as a mediator of cerebral blood flow control, we hypothesized that the mechanism by which RIPC primes the vasculature against VVS is via the α1-adrenoceptor-protein kinase Cε-endothelial nitric oxide synthase pathway. METHODS AND RESULTS: We utilized sinusoidal galvanic vestibular stimulation in rats as a model of VVS. RIPC attenuated the lowerings of mean arterial pressure, heart rate, and cerebral blood flow caused by sinusoidal galvanic vestibular stimulation, as well as improving behavior during, and recovery after, stimulation. RIPC induced elevated serum norepinephrine, increased expression of brain α1-adrenoceptors, and reduced brain expression of norepinephrine transporter 1. Antagonizing adrenoceptors and norepinephrine transporter 1 prevented RIPC protection of cerebral perfusion during sinusoidal galvanic vestibular stimulation. CONCLUSIONS: Taken together, this study indicates that RIPC may be a potential therapy that can prevent VVS pathophysiology, decrease syncopal episodes, and reduce the injuries associated with syncopal falls. Furthermore, the α1-adrenoceptor-protein kinase Cε-endothelial nitric oxide synthase pathway may be a therapeutic target for regulating changes in cerebral blood flow.

Nitric oxide synthase inhibition restores orthostatic tolerance in young vasovagal syncope patients.

OBJECTIVE: Syncope is sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). We previously demonstrated impaired post-synaptic adrenergic responsiveness in young VVS patients was reversed by blocking nitric oxide synthase (NOS). We hypothesised that nitric oxide may account for reduced orthostatic tolerance in young recurrent VVS patients. METHODS: We recorded haemodynamics in supine VVS and healthy volunteers (aged 15-27 years), challenged with graded lower body negative pressure (LBNP) (-15, -30, -45 mm Hg each for 5 min, then -60 mm Hg for a maximum of 50 min) with and without NOS inhibitor NG-monomethyl-L-arginine acetate (L-NMMA). Saline plus phenylephrine (Saline+PE) was used as volume and pressor control for L-NMMA. RESULTS: Controls endured 25.9±4.0 min of LBNP during Saline+PE compared with 11.6±1.4 min for fainters (p<0.001). After L-NMMA, control subjects endured 24.8±3.2 min compared with 22.6±1.6 min for fainters. Mean arterial pressure decreased more in VVS patients during LBNP with Saline+PE (p<0.001) which was reversed by L-NMMA; cardiac output decreased similarly in controls and VVS patients and was unaffected by L-NMMA. Total peripheral resistance increased for controls but decreased for VVS during Saline+PE (p<0.001) but was similar following L-NMMA. Splanchnic vascular resistance increased during LBNP in controls, but decreased in VVS patients following Saline+PE which L-NMMA restored. CONCLUSIONS: We conclude that arterial vasoconstriction is impaired in young VVS patients, which is corrected by NOS inhibition. The data suggest that both pre- and post-synaptic arterial vasoconstriction may be affected by nitric oxide.

Postsynaptic α1-Adrenergic Vasoconstriction Is Impaired in Young Patients With Vasovagal Syncope and Is Corrected by Nitric Oxide Synthase Inhibition.

BACKGROUND: Syncope is a sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). During VVS, gravitational pooling excessively reduces central blood volume and cardiac output. In VVS, as in hemorrhage, impaired adrenergic vasoconstriction and venoconstriction result in hypotension. We hypothesized that impaired adrenergic responsiveness because of excess nitric oxide can be reversed by reducing nitric oxide. METHODS AND RESULTS: We recorded cardiopulmonary dynamics in supine syncope patients and healthy volunteers (aged 15-27 years) challenged with a dose-response using the α1-agonist phenylephrine (PE), with and without the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine, monoacetate salt (L-NMMA). Systolic and diastolic pressures among control and VVS were the same, although they increased after L-NMMA and saline+PE (volume and pressor control for L-NMMA). Heart rate was significantly reduced by L-NMMA (P<0.05) for control and VVS compared with baseline, but there was no significant difference in heart rate between L-NMMA and saline+PE. Cardiac output and splanchnic blood flow were reduced by L-NMMA for control and VVS (P<0.05) compared with baseline, while total peripheral resistance increased (P<0.05). PE dose-response for splanchnic flow and resistance were blunted for VVS compared with control after saline+PE, but enhanced after L-NMMA (P<0.001). Postsynaptic α1-adrenergic vasoconstrictive impairment was greatest in the splanchnic vasculature, and splanchnic blood flow was unaffected by PE. Forearm and calf α1-adrenergic vasoconstriction were unimpaired in VVS and unaffected by L-NMMA. CONCLUSIONS: Impaired postsynaptic α1-adrenergic vasoconstriction in young adults with VVS can be corrected by nitric oxide synthase inhibition, demonstrated with our use of L-NMMA.

Sequential serum creatine kinase determination differentiates vaso-vagal syncope from generalized tonic-clonic seizures.

MATERIALS AND METHODS: In a prospective study we evaluated patients with first generalized tonic-clonic seizure (GTCS) (n = 16, age: 31 +/- 11 years, 8 women) and patients with vaso-vagal syncope (VVS) (n = 17, age: 32 +/- 13 years, 8 women), diagnosed on the basis of past history and clinical presentation who had serum creatine kinase (CK) levels assessed at admission to the emergency room and 24-26 h later. Patients with physical injuries were excluded. RESULTS: On admission, CK levels were > 130 mU/ml (2.16 microkat/l) in 25% (4/16) GTCS vs 6% (1/17) VVS patients; 24 h later, the figures were 56% (9/16) vs 12% (2/17) respectively. For GTCSD patients CK level > 200 mU/ml (3.33 microkat/l) had a sensitivity and specificity of 0.12 and 0.94 on the first day, and 0.25 and 1.0 respectively on the second day. The change in the CK level from the first to the second day was 155 +/- 266 mU/ml (2.58 +/- 4.43 microkat/l) for GTCS group and -2 +/- 37 mU/ml (-0.03 +/- 0.61 microkat/l) in VVS. An increase of more than 15 mU/ml (0.25 microkat/l) was observed in 11/16 GTCS patients and only in 1/17 VVS patients. Taking an increase of > 15 mU/ml (0.25 microkat/l) as a cut-off value, the sensitivity of this figure is 0.69 and specificity 0.94. An increase of > 15 mU/ml (0.25 microkat/l) in CK level among the patients with normal CK on both days was seen in 50% of GTCS but in none with VVS. Using the criteria of CK levels > 200 mU/ml (3.33 microkat/l) (on either day) and/or elevation from the first to the second day of > 15 mU/ml (0.25 microkat/l), there were only 12% false negatives and 12% false positives. CONCLUSIONS: We conclude that a higher increase in CK levels from the first to the second day occurs in GTCS as compared to VVS, and even when both sequential tests are within the normal range, an increase of at least 15 mU/ml (0.25 microkat/l) is highly indicative of an epileptic event. CK levels above 200 mU/ml (3.33 microkat/l) are unlikely to be the result of VVS.