RESUMEN

Declines in endothelial function can take place rapidly across the menopause transition, placing women at heightened risk for atherosclerosis. Disturbed patterns of conduit artery shear, characterized by greater oscillatory and retrograde shear, are associated with endothelial dysfunction but have yet to be described across menopause. Healthy women, who were not on hormone therapy or contraceptives, were classified into early perimenopausal, late perimenopausal, and early postmenopausal stage. Resting antegrade, retrograde, and oscillatory shear were calculated from blood velocity and diameter measured in the brachial and common femoral artery using Doppler ultrasound. Serum was collected for measurements of estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone. After adjusting for age, brachial artery oscillatory shear was significantly higher in early postmenopausal women (n = 15, 0.17 ± 0.08 a.u.) than both early (n = 12, 0.08 ± 0.05 a.u., P < 0.05) and late (n = 8, 0.08 ± 0.04 a.u) perimenopausal women, and retrograde shear was significantly greater in early postmenopausal versus early perimenopausal women (-19.47 ± 12.97 vs. -9.62 ± 6.11 sec-1 , both P < 0.05). Femoral artery oscillatory and retrograde shear were greater, respectively, in early postmenopausal women (n = 15, 0.19 ± 0.08 a.u.; -13.57 ± 5.82 sec-1 ) than early perimenopausal women (n = 14, 0.11 ± 0.08 a.u.; -8.13 ± 4.43 sec-1 , P < 0.05). Further, Pearson correlation analyses revealed significant associations between FSH and both retrograde and oscillatory shear, respectively, in the brachial (r = -0.40, P = 0.03; r = 0.43, P = 0.02) and common femoral artery (r = -0.45, P = 0.01; r = 0.56, P = 0.001). These results suggest menopause, and its associated changes in reproductive hormones, adversely influences conduit arterial shear rate patterns to greater oscillatory and retrograde shear rates.

Asunto(s)

RESUMEN

While muscle sympathetic nerve activity (MSNA) is elevated with advancing age, correlational evidence suggests that, in contrast to men, basal MSNA is not related to resting lower limb hemodynamics in women. However, limited data exists in women that have attempted to directly assess the degree of limb sympathetic vasoconstrictor tone, and whether it is altered with age. To address this issue, we measured changes in femoral artery vascular conductance (FVC) during an acute sympatho-inhibitory stimulus (-60 mm Hg neck suction, NS) in groups of healthy younger (n = 8, 23 ± 1 years) and older (n = 7, 66 ± 1 years) women. The percent change in FVC in response to NS was significantly augmented in the older (P = 0.006 vs. young) women. Although NS caused no significant change (3 ± 3%, P = 0.33) in FVC in the young women, there was a robust increase in FVC (21 ± 5%, P = 0.003) in the old women. Collectively, these findings provide evidence that in women, leg sympathetic vasoconstrictor tone emerges with age.

RESUMEN

This study tested the hypothesis that enkephalin increases femoral vascular conductance via the delta-2 phenotype of the opioid receptor (DOR-2) within peripheral sympathetic ganglia. Graded pulses of methionine-enkephalin (ME) were administered (0.03-10 µg/kg) into the terminal aorta of anesthetized dogs proximal to lumbar arteries that perfuse vasomotor ganglia regulating femoral blood flow. Femoral vascular conductance increased sharply (ED50 = 2.6 × 10(-9) mol/kg) accompanied by declines in arterial pressure and femoral vascular resistance. A dose-related increase in arterial pressure preceded each subsequent fall in pressure. The DOR-2 antagonist, naltriben (NTB), abrogated the hyperemic effect of ME (ID50 = 1.4 × 10(-9) mol/kg). DOR-1 blockade (BNTX) was five-fold less effective. The hyperemic effect of ME was also enhanced when sympathetic activity was reflexly increased by bilateral carotid occlusion. The DOR-2 agonist, deltorphin II, produced exaggerated increases in conductance compared with ME that were also reduced by DOR-2 blockade. DOR-1 blockade eliminated the initial pressor responses, exaggerated the subsequent depressor response, increased baseline femoral conductance 10-fold and shifted the ME-mediated hyperemic threshold one dose lower from 0.3 to 0.1 µg/kg, providing indirect support for a competing DOR-1-mediated constriction. Extended exposure to DOR-1 blockade lowered the maximal ME increase in conductance by 30%, suggesting that BNTX reduces the available pool of DOR receptors. In summary, enkephalin mediates a robust hyperemic effect through sympatholytic ganglionic DOR-2 receptors and DOR-1 antagonist studies provide indirect evidence for constituent opposition from a proposed DOR-1-mediated sympathotonic constrictor pathway.

Asunto(s)

RESUMEN

Brief interruptions in coronary blood flow precondition the heart, engage delta-opioid receptor (DOR) mechanisms and reduce the damage that typically accompanies subsequent longer coronary occlusions. Repeated short occlusions of the sinoatrial (SA) node artery progressively raised nodal methionine-enkephalin-arginine-phenylalanine (MEAP) and improved vagal transmission during subsequent long occlusions in anesthetized dogs. The DOR type-1 (DOR-1) antagonist, BNTX reversed the vagotonic effect. Higher doses of enkephalin interrupted vagal transmission through a DOR-2 mechanism. The current study tested whether the preconditioning (PC) protocol, the later occlusion or a combination of both was required for the vagotonic effect. The study also tested whether evolving vagotonic effects included withdrawal of competing DOR-2 vagolytic influences. Vagal transmission progressively improved during successive SA nodal artery occlusions. The vagotonic effect was absent in sham animals and after DOR-1 blockade. After completing the PC protocol, exogenously applied vagolytic doses of MEAP reduced vagal transmission under both normal and occluded conditions. The magnitude of these DOR-2 vagolytic effects was small compared to controls and repeated MEAP challenges rapidly eroded vagolytic responses further. Prior DOR-1 blockade did not alter the PC mediated, progressive loss of DOR-2 vagolytic responses. In conclusion, DOR-1 vagotonic responses evolved from signals earlier in the PC protocol and erosion of competing DOR-2 vagolytic responses may have contributed to an unmasking of vagotonic responses. The data support the hypothesis that PC and DOR-2 stimulation promote DOR trafficking, and down regulation of the vagolytic DOR-2 phenotype in favor of the vagotonic DOR-1 phenotype. DOR-1 blockade may accelerate the process by sequestering newly emerging receptors.

Asunto(s)

RESUMEN

PURPOSE: Cerebral oxidative stress and metabolic dysfunction impede neurological recovery from cardiac arrest-resuscitation. Pyruvate, a potent antioxidant and energy-yielding fuel, has been shown to protect against oxidant- and ischemia-induced neuronal damage. This study tested whether acute pyruvate treatment during cardiopulmonary resuscitation can prevent neurological dysfunction and cerebral injury following cardiac arrest. METHODS: Anesthetized, open-chest mongrel dogs underwent 5 min cardiac arrest, 5 min open-chest cardiac compression (OCCC), defibrillation and 3-day recovery. Pyruvate (n=9) or NaCl volume control (n=8) were given (0.125 mmol kg(-1) min(-1) i.v.) throughout OCCC and the first 55 min recovery. Sham dogs (n=6) underwent surgery and recovery without cardiac arrest-resuscitation. RESULTS: Neurological deficit score (NDS), evaluated at 2-day recovery, was sharply increased in NaCl-treated dogs (10.3+/-3.5) versus shams (1.2+/-0.4), but pyruvate treatment mitigated neurological deficit (NDS=3.3+/-1.2; P<0.05 versus NaCl). Brain samples were taken for histological examination and evaluation of inflammation and cell death at 3-day recovery. Loss of pyramidal neurons in the hippocampal CA1 subregion was greater in the NaCl controls than in pyruvate-treated dogs (11.7+/-2.3% versus 4.3+/-1.2%; P<0.05). Cardiac arrest increased caspase-3 activity, matrix metalloproteinase activity, and DNA fragmentation in the CA1 subregion; pyruvate prevented caspase-3 activation and DNA fragmentation, and suppressed matrix metalloproteinase activity. CONCLUSION: Intravenous pyruvate therapy during cardiopulmonary resuscitation prevents initial oxidative stress and neuronal injury and enhances neurological recovery from cardiac arrest.

Asunto(s)

RESUMEN

Delta-opioid receptors (DORs) are associated with ischemic preconditioning and vagal transmission in the sinoatrial (SA) node and atria. Although functional studies suggested that DORs are prejunctional on parasympathetic nerve terminals, their precise location remains unconfirmed. DORs were colocalized in tissue slices and synaptosomes from the canine right atrium and SA node along with cholinergic and adrenergic markers, vesicular acetylcholine transporter (VAChT), and tyrosine hydroxylase (TH). Synapsin I immunofluorescence verified the neural character of tissue structures and isolated synaptosomes. Acetylcholine and norepinephrine measurements suggested the presence of both cholinergic and adrenergic synaptosomes. Fluorescent analysis of VAChT and TH signals indicated that >80% of the synapsin-positive synaptosomes were of cholinergic origin and <8% were adrenergic. DORs colocalized 75-85% with synapsin in tissue slices from both atria and SA node. The colocalization was equally strong (85%) for nodal synaptosomes but less so for atrial synaptosomes (57%). Colocalization between DOR and VAChT was 75-85% regardless of the source. Overlap between DOR and TH was uniformly low, ranging from 8% to 17%. Western blots with synaptosomal extracts confirmed two DOR-positive bands at molecular masses corresponding to those reported for DOR monomers and dimers. The abundance of DOR was greater in nodal synaptosomes than in atrial synaptosomes, largely attributable to a greater abundance of monomers in the SA node. The abundant nodal and atrial DORs predominantly associated with cholinergic nerve terminals support the hypothesis that prejunctional DORs regulate vagal transmission locally within the heart.

Asunto(s)

RESUMEN

This study examined the hypothesis that vagotonic and sympatholytic effects of cardiac enkephalins are independently mediated by different receptors. A dose-response was constructed by administering the delta-receptor opioid methionine-enkephalin-arginine-phenylalanine (MEAP) by microdialysis into the interstitium of the canine sinoatrial node during vagal and sympathetic stimulation. The right cardiac sympathetic nerves were stimulated as they exited the stellate ganglion at frequencies selected to increase heart rate approximately 35 bpm. The right cervical vagus was stimulated at frequencies selected to produce a two-step decline in heart rate of 25 and 50 bpm. A six-step dose-response was constructed by recording heart rates during nerve stimulation as the dose of MEAP was increased between 0.05 pmol/min and 1.5 nmol/min. Vagal transmission improved during MEAP at 0.5 pmol/min. However, sympathetically mediated tachycardia was unaltered with any dose of MEAP. In Study 2, a similar dose-response was constructed with the kappa-opioid receptor agonist trans(+/-)-3-4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide-HCl (U-50488H) to illustrate an independent sympatholytic effect and to verify its kappa-receptor character. U-50488H gradually suppressed the sympathetic tachycardia, with a significant effect obtained only at the highest dose (1.5 nmol/min). U-50488H had no effect on vagally mediated bradycardia. Surprisingly, the sympatholytic effect was not reversed by withdrawing U-50488H or by the subsequent addition of the kappa-antagonist 17,17'-(dichloropropylmethyl)-6,6',7,7'-6,6'-imino-7,7'-binorphinan-3,4',14,14'-tetroldi-hydrochloride (norBNI). Study 3 was conducted to determine whether the sympatholytic effect of U-50488H could be prevented by norBNI. NorBNI blocked the sympatholytic effect of the U50488H for 90 mins. When norBNI was discontinued afterward and U-50488H was continued alone, a sympatholytic effect emerged within 30 mins. Collectively these observations support the hypothesis that the vagotonic influence of MEAP is not dependent on a sympatholytic influence. Furthermore, the sympatholytic effect is mediated independently by kappa-receptors. The sympatholytic effect of sustained kappa-receptor stimulation appears to evolve gradually into a functional state not easily reversed.

Asunto(s)