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PubMed1998

Moderate exercise increases postexercise thresholds for vasoconstriction and shivering.

The purpose of this study was to evaluate the effect of exercise on the subsequent postexercise thresholds for vasoconstriction and shivering. On two separate days, with six subjects (3 women), a whole body water-perfused suit slowly decreased mean skin temperature (approximately 7.0 degreesC/h) until thresholds for vasoconstriction and shivering were clearly established. Subjects were then rewarmed by increasing water temperature until both esophageal and mean skin temperatures returned to near-baseline values. Subjects either performed 15 min of cycle ergometry (65% maximal O2 consumption) followed by 30 min of recovery (Exercise) or remained seated with no exercise for 45 min (Control). Subjects were then cooled again. We mathematically compensated for changes in skin temperatures by using the established linear cutaneous contribution of skin to the control of vasoconstriction and shivering (20%). The calculated core temperature threshold (at a designated skin temperature of 30.0 degreesC) for vasoconstriction increased significantly from 36.64 +/- 0.20 to 36.89 +/- 0.22 degreesC postexercise (P < 0.01). Similarly, the shivering threshold increased from 35.73 +/- 0.13 to 36.13 +/- 0.12 degreesC postexercise (P < 0.01). In contrast, sequential measurements, without exercise, demonstrate a time-dependent decrease in both the vasoconstriction (0.10 degreesC) and shivering (0.12 degreesC) thresholds. These data indicate that exercise has a prolonged effect by increasing the postexercise thresholds for both cold thermoregulatory responses.

Adult↗
PubMed1999

ET-1-induced pulmonary vasoconstriction shifts from ET(A)- to ET(B)-receptor-mediated reaction after preconstriction.

Endothelin-1 (ET-1) has been reported to induce pulmonary vasoconstriction via either ET(A) or ET(B) receptors, and vasorelaxation after ET-1 injection has been observed. Our study investigated the effects of ET-1 in isolated rabbit lungs, which were studied at basal tone (part I) and after preconstriction (U-46619; part II). Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. In part I, ET-1 (10(-8) M; n = 6; control) was injected after pretreatment with the ET(A)-receptor antagonist BQ-123 (10(-6) M; n = 6) or the ET(B)-receptor antagonist BQ-788 (10(-6) M; n = 6). The same protocol was carried out in part II after elevation of pulmonary vascular tone. ET-1 induced an immediate PAP increase (DeltaPAP 4.3 +/- 0.4 mmHg at 10 min) that was attenuated by pretreatment with BQ-123 (P < 0.05 at 10 min and P < 0.01 thereafter) and that was more pronounced after BQ-788 (P < 0.01 at 10 min and P < 0.001 thereafter). In part II, ET-1 induced an immediate rise in PAP with a maximum after 5 min (DeltaPAP 6.3 +/- 1.4 mmHg), leveling off at DeltaPAP 3.2 +/- 0.2 mmHg after 15 min. Pretreatment with BQ-123 failed to attenuate the increase. BQ-788 significantly reduced the peak pressure at 5 min (0.75 +/- 0.4 mmHg; P < 0.001) as well as the plateau pressure thereafter (P < 0.01). We conclude that ET-1 administration causes pulmonary vasoconstriction independent of basal vascular tone, and, at normal vascular tone, the vasoconstriction seems to be mediated via ET(A) receptors. BQ-788 treatment resulted in even more pronounced vasoconstriction. After pulmonary preconstriction, ET(A) antagonism exerted no effects on PAP, whereas ET(B) antagonism blocked the PAP increase. Therefore, ET-1-induced pulmonary vasoconstriction is shifted from an ET(A)-related to an ET(B)-mediated mechanism after pulmonary vascular preconstriction.

Animals↗
PubMed2006

Assessment of topical corticosteroid activity using the vasoconstriction assay in healthy volunteers.

OBJECTIVE AND DESIGN: The aim of the study was to evaluate the vasoconstrictive activity of four new galenic preparations of hydrocortisone and to compare it with concentration-equivalent reference preparations. The study comprised two study phases: the pilot study phase and the main study phase. During open, nonrandomized pilot study, the optimal administration period was tested. The main study was performed in a randomized, double-blind intraindividual comparative design. SUBJECTS: Twenty male and female volunteers with healthy skin who responded to topically applied clobetasol-17-propionate before entering the trial participated in this study. TREATMENT: All subjects received the same treatments. The test preparations new galenic formulation (NGF) hydrocortisone 0.25% cream, NGF hydrocortisone acetate 0.25% cream, NGF hydrocortisone 0.5% cream, and NGF hydrocortisone 1.0% cream were compared with the respective reference preparations Soventol hydrocortisone (hydrocortisone acetate 0.25%), Hydroderm HC 0.5% cream (hydrocortisone 0.5%), Hydrogalen cream (hydrocortisone 1.0%) and placebo (vehicle of test preparations). METHOD: The topical preparations were applied occlusively for 2 h (pilot study) or 24 h (main study) on outlined areas (5 x 5 cm with a distance of 3 cm) of both forearms (4 areas for each). Assessment of vasoconstriction was performed before treatment, and 0.5, 4, 6 and 24 h after treatment (observation period) using a subjective rating scale (OLSEN vasoconstriction score) and measuring the colorimetric parameter a* (redness) by use of the Chroma-Meter (Minolta company, Ahrensburg, Germany). RESULTS: A significant vasoconstriction (positive blanching effect) was measured by use of chromametry for test preparations hydrocortisone 0.25% cream, hydrocortisone 0.5% cream, hydrocortisone 1.0% cream and for the reference preparation Hydrogalen cream compared to placebo 30 min after the end of treatment. In contrast, the reference preparations Soventol hydrocortisone and Hydroderm HC 0.5% did not differ significantly from placebo 30 min after treatment. No statistically significant effect of all formulations was observed 4-24 h after treatment in comparison with placebo. CONCLUSIONS: The vasoconstrictive efficacy of test preparations was mostly stronger than the concentration-equivalent reference preparations. This effect was achieved by use of new galenics of test preparations resulting in enhanced skin penetration and improved efficiency. No unwanted side effects were observed during the course of the study despite increased efficacy of the topically applied test preparations.

Administration, Cutaneous↗
PubMed1989

Alpha 2-receptor-mediated vasoconstriction in patients with congestive heart failure.

alpha 2-Adrenoceptors exist postsynaptically to subserve vasoconstriction and presynaptically to modulate norepinephrine release into the synaptic cleft. Because adrenoceptors may down-regulate in response to chronic stimulation, we investigated the activity of alpha 2-receptor-mediated vasoconstriction in patients with congestive heart failure, who had increased levels of plasma norepinephrine. We used the isolated forearm model and intra-arterial infusions of subsystemic doses of yohimbine, a specific alpha 2-blocker, in 11 patients with heart failure and in 15 normal subjects. Yohimbine produced a dose-related increase in forearm blood flow and decrease in forearm vascular resistance. These findings were consistent with a direct vasodilator effect mediated by blockade of the postsynaptic alpha 2-vascular receptor. Furthermore, the vasodilator responses in patients with heart failure were similar to the normal subjects in terms of the percent increase in forearm blood flow, the dose-response relation, and the fractional response to hyperemia and phentolamine; thus, alpha 2-receptor-mediated vasoconstriction is neither enhanced nor down-regulated in heart failure. In addition, in patients with heart failure and in normal subjects, yohimbine produced an increase in the forearm venous norepinephrine concentration, consistent with an inhibition of the presynaptic alpha 2-receptor resulting in an augmented release of norepinephrine into the synaptic cleft. Thus, these data suggest that the postsynaptic alpha 2-receptor is an important mediator of vasoconstriction in patients with heart failure. Despite chronic elevations in plasma norepinephrine in patients with heart failure, alpha 2-receptor mechanisms subserving vasoconstriction and inhibition of norepinephrine release into the synaptic cleft are still functional in heart failure.

Female↗
PubMed1990

Sympathetic nervous system-dependent vasoconstriction in humans. Evidence for mechanistic role of endogenous purine compounds.

Purine compounds modulate sympathetic neurotransmission; this modulation decreases nervous discharge by stimulating presynaptic inhibitory adenosine receptors, an effect antagonized by theophylline, and causes vasoconstriction through the stimulation of postsynaptic ATP receptors. In humans we evaluated the effect of local theophylline, which was infused into the brachial artery at the rate of 100 micrograms/100 cc/min, on the arteriolar sympathetic vasoconstriction induced by applying a lower-body negative pressure. Forearm blood flow changes were measured by strain-gauge venous plethysmography. Theophylline, which at this dosage blunted the vasodilator effect of adenosine (the physiological agonist for the P1 purinoceptor), significantly increased lower-body negative pressure-mediated vasoconstriction. To evaluate whether neurotransmitters different from norepinephrine participate in the vasoconstrictor effect of theophylline, we repeated the previous experiment in the presence of phenoxybenzamine, which was infused at a dose (60 micrograms/100 cc/min) that abolished the vasoconstrictor effect of norepinephrine. Also, after alpha-adrenoceptor blockade, theophylline continued to increase sympathetic vasoconstriction. Our data confirm that purinergic receptors and neurotransmitters also participate in endogenous sympathetic vasoconstriction in humans.

Adenosine↗
PubMed1991

Endothelin-1-induced vasoconstriction in humans. Reversal by calcium channel blockade but not by nitrovasodilators or endothelium-derived relaxing factor.

The vascular effects of endothelin-1 (ET) in humans were investigated by brachial artery infusions of ET into 25 healthy volunteers. Forearm blood flow increased from a mean +/- SD value of 2.3 +/- 1.5 to 2.5 +/- 1.5 ml/min/100 ml forearm tissue (n = 25, p less than 0.05) in response to low dose (0.5 ng/min/100 ml forearm tissue) ET infusion and decreased to 1.78 +/- 1.3 and 1.1 +/- 0.9 ml/min/100 ml forearm tissue (p less than 0.001) during higher dosages (25 and 50 ng/min/100 ml forearm tissue). Sodium nitroprusside (0.6 micrograms/min/100 ml forearm tissue, n = 6), acetylcholine (16 micrograms/min/100 ml forearm tissue, n = 7), nifedipine (6 micrograms/min/100 ml forearm tissue, n = 6), and verapamil (80 micrograms/min/100 ml forearm tissue, n = 6) were infused alone and in combination with ET to evaluate the interactions between ET-induced vasoconstriction and stimulation of vascular muscle cyclic GMP levels by sodium nitroprusside, release of endothelium-derived relaxing factor by acetylcholine, and blockade of voltage-operated calcium channels by nifedipine and verapamil. Neither the vasodilator nor the vasoconstrictor response to ET was influenced by sodium nitroprusside or acetylcholine. In contrast, both calcium antagonists converted ET-induced vasoconstriction (e.g., delta forearm vascular resistance to ET 50 ng/min/100 ml forearm tissue, 151 +/- 100% and 164 +/- 92% in verapamil and nifedipine groups, respectively) to vasodilation (-35 +/- 12% and -21 +/- 16%, p less than 0.05). Our results demonstrate both ET-induced vasodilation (at low dosages) and vasoconstriction (at high dosages) in resistance vessels of normal humans. Blockade of voltage-operated calcium channels prevented ET-induced vasoconstriction and unmasked the vasodilator effect of high ET dosages. In human resistance vessels, blockade of voltage-operated Ca2+ channels but not cyclic GMP-dependent vasodilation may be an effective tool to inhibit ET-induced vasoconstriction.

Adult↗
PubMed1994

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

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Adult↗
PubMed1994

Physical conditioning decreases norepinephrine-induced vasoconstriction in rabbits. Possible roles of norepinephrine-evoked endothelium-derived relaxing factor.

BACKGROUND: Physical activity can reduce sympathetic tone and may be beneficial to human health. Whether the vascular responses to norepinephrine (NE), an adrenergic vasoconstrictor, could be altered by chronic exercise was unclear. We therefore conducted this study to investigate the effects of endurance exercise training on NE-induced vasoconstrictive response in healthy rabbits. Possible mechanisms were also studied. METHODS AND RESULTS: Twenty-four male New Zealand White rabbits were used for this study. They were divided into two groups: control and training. The training group was trained on a treadmill with running speed of 0.88 km/h at a 0 degree grade for 10 to 60 minutes per day, for 5 days a week for a total of 8 weeks. At the end of the experiments, thoracic aortae (3 mm long) were isolated. The vascular tension was measured with a force transducer. The dose-response relation of NE-induced vasoconstriction was determined and compared for control (n = 5) and trained (n = 6) groups. To verify the possible involvement of endothelium-derived relaxing factor (EDRF) in the alteration of NE-induced vasoconstriction after exercise training, we compared the vascular responses to NE in endothelium-intact, N omega-nitro-L-arginine (L-NNA, 10(-4) mol/L)-pretreated, or denuded vessel segments (n = 4 for each experiment of each group). EDRF release in the presence or absence of NE was also evaluated by the increased tension induced by hemoglobin (10(-5) mol/L), an EDRF scavenger (n = 6 for the control group and n = 8 for the trained group). In addition, vascular responses to some specific adrenergic agonists (ie, phenylephrine, an alpha 1-agonist, and clonidine, an alpha 2-agonist) were also studied to see if a specific adrenergic receptor was involved (n = 4 for each experiment of each group). Our results indicated that (1) [NE]ED50 of the thoracic aorta was elevated by exercise training; (2) in the presence of NE, EDRF release from the thoracic aorta, assessed by addition of hemoglobin or L-NNA, was higher in the trained group than in the control group; (3) both phenylephrine (10(-8) mol/L) and clonidine (10(-6) mol/L) could evoke vasorelaxation that would be inhibited by L-NNA; and (4) in addition to causing vasoconstriction, NE could stimulate EDRF release, possibly via alpha 1- and alpha 2-receptors of endothelial cells. CONCLUSIONS: Our data suggest that exercise training may decrease NE-induced vasoconstrictive response and may increase NE-stimulated EDRF release.

Animals↗
PubMed1995

Endothelin at pathophysiological concentrations mediates coronary vasoconstriction via the endothelin-A receptor.

BACKGROUND: Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor peptide. Controversy persists regarding the predominant ET receptor that mediates coronary vasoconstriction at pathophysiological concentrations. The aim of the present study was to test the hypothesis that ET mediates local coronary vasoconstriction via the ET-A receptor at low concentrations of exogenous ET-1 designed to mimic pathophysiological states compared with pharmacological concentrations. METHODS AND RESULTS: ET-1 (group 1, n = 5) or sarafotoxin, a specific ET-B receptor agonist (group 3, n = 6) (each at 2 ng/kg per minute), was infused into the left circumflex coronary artery in the anesthetized dog. In group 2 dogs (n = 5), the same dose of ET-1 was infused with 4 micrograms/kg per minute of the specific ET-A receptor antagonist FR-139317. In group 4 (n = 5), the same dose of sarafotoxin was infused with 50 micrograms/kg per minute of the specific inhibitor of nitric oxide formation, NG-monomethyl-L-arginine (L-NMMA). No difference in hemodynamics, coronary blood flow (CBF), coronary vascular resistance (CVR), or coronary artery diameter (CAD) was observed at baseline between the groups. In group 1, intracoronary ET-1 significantly decreased CBF and CAD in association with an increase in CVR. The percentage decrease in CBF and CAD in the group that received ET-1 and the ET-A receptor antagonist (group 2) was significantly less than that in the group that received ET-1 alone (group 1) (-12 +/- 3% versus -48 +/- 6% [P < .001] and -4.6 +/- 0.8 versus 1.0 +/- 0.3 [P < .05], respectively). The administration of the ET-A receptor antagonist (group 2) abolished the ET-mediated increase in CVR (7 +/- 5% versus 105 +/- 21%, P < .005). There was no significant effect on CBF, CVR, or CAD in the group receiving sarafotoxin alone (group 3). The administration of L-NMMA and sarafotoxin (group 3). The administration of L-NMMA and sarafotoxin (group 4) resulted in a significant percentage decrease in CBF compared with the group that received sarafotoxin alone (-28 +/- 7% versus -8 +/- 2% [P < .05]). CONCLUSIONS: The present study demonstrates that low concentrations of exogenous ET-1, which may mimic pathophysiological concentrations, result in coronary vasoconstriction mediated predominantly via the ET-A receptor because such vasoconstriction is significantly attenuated by blockade with FR-139317. The ET-B receptor may have a dual vasoconstrictive and vasodilatory effect.

Animals↗
PubMed1997

Nifedipine attenuates systemic and renal vasoconstriction during nitric oxide inhibition in humans.

Clinical states associated with nitric oxide deficiency are often accompanied by vasoconstriction. We studied the effects of prolonged infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on systemic and renal hemodynamics in humans and the reversibility of the established vasoconstriction by calcium channel blockade with nifedipine. Seven healthy men underwent three 7-hour clearance studies. During one study, L-NMMA (3 mg/kg priming dose plus 3 mg.kg-1.h-1) was infused during hours 2 through 5, and during another study, nifedipine (0.015 mg/kg priming dose plus 0.015 mg.kg-1.h-1) was coinfused during hours 4 and 5. A third study served as time control. L-NMMA elicited reproducible systemic and renal vasoconstriction that was stable during the 4 hours of infusion. Systemic vascular resistance index, calculated from bioimpedance-derived cardiac index, increased from 22 +/- 1 to 29 +/- 2 mm Hg.min.m2.L-1 (P < .05). Mean arterial pressure rose by 4 +/- 1 mm Hg (P < .05), and heart rate, stroke index, and cardiac index decreased. Renal blood flow, calculated from renal plasma flow, decreased from 1182 +/- 101 to 785 +/- 53 mL/min, and renal vascular resistance increased from 73 +/- 5 to 115 +/- 6 mm Hg.min.L-1 (P < .05). Glomerular filtration rate decreased from 114 +/- 6 to 104 +/- 6 mL/min (P < .05), and filtration fraction increased. Sodium excretion fell from 89 +/- 9 to 32 +/- 7 mumol/min (P < .05). Nifedipine completely reversed systemic vasoconstriction. Nifedipine caused partial restoration of renal vascular resistance and complete normalization of glomerular filtration rate and sodium excretion but left the elevated filtration fraction unaltered. We conclude that sustained nitric oxide deficiency in humans is accompanied by strong systemic and renal vasoconstriction, decreased glomerular filtration rate, and sodium retention. Nifedipine can reverse most of these effects, suggesting a role for calcium channel blockade in pathological states of impaired nitric oxide activity.

Adult↗
PubMedDate not supplied

Sympathetic vasoconstriction sensitive to alpha 2-adrenergic receptor blockade. No evidence for preferential innervation of alpha 1-adrenergic receptors in the canine femoral bed.

In the canine femoral bed, we studied the involvement of vascular alpha 2-adrenergic receptors in vasoconstriction by stimulating the sympathetic nerve during different degrees of activation of metabolic counterregulation (constant pressure and constant flow perfusion). In chloralose-anesthetized, despinalized dogs under beta-blockade (2 mg/kg nadolol) and under a constant femoral perfusion pressure, cumulative doses of rauwolscine (0.03, 0.3, and 3.0 mg/kg i.v., n = 8) or of prazosin (0.012, 0.12, and 1.2 mg/kg i.v., n = 8) caused dose-dependent shifts to the right of the dose-response curve of intraarterial norepinephrine (NE) infusions. These cumulative doses also caused attenuations of the vasoconstriction initiated by lumbar sympathetic stimulation (0.1, 0.3, 1.0, and 3.0 Hz). Sham treatment (n = 8) had no such results. In experiments with constant flow perfusion (n = 6 for each antagonist), rauwolscine shifted the NE dose-response curve significantly more compared to the experiments with constant pressure perfusion, while prazosin was similarly effective under both conditions. Under constant flow perfusion, both antagonists dose-dependently attenuated the vasoconstrictions caused by sympathetic stimulation. While prazosin and sham treatment did not modify the overflow of NE from the femoral bed during stimulation, this overflow was augmented by rauwolscine during stimulation at 3 Hz, which indicated presynaptic modulation of NE release. Under both experimental conditions, no significant difference could be observed in the attenuation of low-frequency sympathetic vasoconstriction by the two antagonists, when dosages were compared on the basis of their action against infused NE. It is concluded that both a rauwolscine-sensitive component and a prazosin-sensitive component are involved in the competition between sympathetic vasoconstriction and metabolic dilation. The vascular alpha-adrenergic receptors activated by these two components have a similar postsynaptic localization relative to the nerve endings.

Animals↗
PubMed2003

Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor-receptor pathway.

Matrix metalloproteinase (MMP)-dependent shedding of heparin-binding epidermal growth factor (HB-EGF) and subsequent activation of the EGF receptor (EGFR) in the cardiovasculature is emerging as a unique mechanism signaling growth effects of diverse G protein-coupled receptors (GPCRs). Among these GPCRs are adrenoceptors and angiotensin receptors that contribute to the pathogenesis of hypertension through their vasoconstrictive and growth effects. Focusing on alpha(1b)-adrenoceptors, we suggest here that MMP-dependent activation of the EGFR promotes vasoconstriction as well as growth. We identified MMP-7 as a major HB-EGF sheddase in rat mesenteric arteries and alpha(1b)-adrenoceptors, angiotensin receptors, and hypertension-stimulated MMP-7 activity. Adrenoceptors stimulated EGFR autophosphorylation in arteries, and this transactivation was opposed by the MMP-7 inhibitor GM6001 as well as MMP-7-specific antibodies. In isolated microperfused arteries, blockade of EGFR transactivation with inhibitors of the EGFR (AG1478 and PD153035), HB-EGF (CRM197 and neutralizing antibodies), or MMPs (doxycycline) inhibited adrenergic vasoconstriction. In spontaneously hypertensive rats but not in normotensive rats, the inhibition of MMPs with doxycycline (19.2 mg/d from week 7 until week 12) reduced systolic blood pressure and attenuated HB-EGF shedding in the mesenteric arteries. These findings suggest a previously unknown mechanism of vasoregulation whereby agonists of certain GPCRs (such as adrenoceptors and angiotensin receptors) activate MMPs (such as MMP-7) that shed EGFR ligands (such as HB-EGF), which then activate the EGFR, thereby promoting vasoconstriction as well as growth. Because this mechanism is triggered by agonists typically overexpressed in hypertension, its blockade may have therapeutic potential for simultaneously inhibiting pathological vasoconstriction and growth in hypertensive disorders.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1983

Influence of perfusate PO2 on hypoxic pulmonary vasoconstriction in rats.

The purpose of these studies was to evaluate the influence of perfusate oxygen tension on hypoxic pulmonary vasoconstriction and to identify the site at which both alveolar and perfusate gas tensions stimulate hypoxic pulmonary vasoconstriction. Lungs from adult rats were ventilated and perfused in vitro at constant temperature, PCO2, and pH, with a perfusion circuit incorporating a membrane oxygenator that allowed independent control of the alveolar and perfusate gas tensions. Blood flow to the lung was constant (0.06 ml per g body weight per min), and pulmonary vascular resistance was therefore proportional to pulmonary artery pressure. In study 1, the pulmonary artery pressor response to zero or 22 mm Hg alveolar oxygen was measured when the perfusate oxygen tensions were approximately 8, 26, 41, 64, or 128 mm Hg. The pressor response as a percent of the maximum pressure change was progressively reduced as perfusate oxygen tension increased. For alveolar oxygen tension of zero; the pressor response = 128 -39 (Log PPO2) and r = 0.8 (P less than 0.01), the effect of perfusate gas tension on the response to alveolar gas tension of 22 mm Hg was similar. These results demonstrate that the stimulus for hypoxic pulmonary vasoconstriction is a function of both alveolar and perfusate oxygen tension. In study 2, the response to alveolar oxygen tension of 42 mm Hg was measured with mean perfusate oxygen tensions of 130, 52, and 17 mm Hg. In six animals with forward perfusion, the responses decreased with increasing perfusate oxygen tension, as in study 1. In another six animals, with retrograde perfusion, the responses to alveolar hypoxia were not altered when perfusate oxygen tension was increased. These results demonstrate that the sensor region for hypoxic pulmonary vasoconstriction is precapillary. These studies confirm and extend previous hypotheses that alveolar and perfusate oxygen tensions together, determine the PO2 at a precapillary site to stimulate hypoxic pulmonary vasoconstriction.

Animals↗
PubMed1983

Evidence that serotonin receptors mediate the cutaneous vasoconstriction produced by 5-hydroxytryptamine in canine forelimbs.

The effects of local intra-arterial infusions of serotonin (5 or 25 micrograms base/min) or norepinephrine (1 or 5 micrograms base/min) on cutaneous (skin) and skeletal muscle vasculatures were investigated in canine forelimbs perfused at constant flow in dogs anesthetized with pentobarbital. Norepinephrine produced dose-related constriction of the skin and skeletal muscle vasculatures. In the cutaneous vascular circuit, norepinephrine produced large artery, small vessel, and large vein constriction. The increase in cutaneous vascular resistance was primarily due to an increase in small vessel resistance. Serotonin did not increase skeletal muscle vascular resistance but produced marked cutaneous vasoconstriction subsequent to large artery and large vein constriction. The small vessels, if anything, tended to dilate. The skin and skeletal muscle vascular responses to serotonin and norepinephrine were similar in innervated and acutely denervated forelimbs. Phentolamine pretreatment completely blocked all vascular actions of norepinephrine, and largely inhibited the cutaneous vasoconstriction produced by the infusion of the low dose of serotonin. However, the cutaneous large artery and large vein constriction produced by the infusion of the high dose of serotonin was not affected by phentolamine pretreatment. Cyproheptadine pretreatment blocked or largely inhibited the cutaneous vasoconstriction produced by serotonin only in doses which also inhibited norepinephrine and vasopressin cutaneous vasoconstriction. Pretreatment with methysergide blocked or largely inhibited the cutaneous large artery and large vein constriction produced by infusions of serotonin. Norepinephrine and vasopressin produced significant vasoconstriction in the presence of methysergide. These data suggest that the cutaneous large artery and large vein constriction produced by serotonin is not due to the activation of postjunctional alpha-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Inhibition of adrenergic vasoconstriction by endothelial cell shear stress.

Isolated perfused rabbit carotid arteries were used to determine the effects of endothelial cell shear stress on the response to adrenergic nerve stimulation. Arterial segments with and without endothelium were cannulated and perfused with physiological salt solution. Adrenergic nerves were activated by transmural electrical field stimulation. Neurogenic vasoconstriction was significantly greater in segments without endothelium when compared with that of segments with endothelium. In segments with endothelium only, vasoconstriction was depressed when shear stress was increased by increasing the viscosity of the perfusate with dextran. Perfusion with methylene blue (2 X 10(-6) M), a guanylate cyclase inhibitor, increased vasoconstriction in segments with endothelium only. In the presence of methylene blue, vasoconstriction was no longer different between segments with and without endothelium, and perfusion with dextran had no effect. In a perfusion-cascade system, perfusion with dextran of donor segments with but not without endothelium caused further relaxation of a contracted bioassay ring. These results suggest that shear stress on endothelial cells modulates adrenergic vasoconstriction by augmenting release of endothelial cell-derived vasodilators.

Animals↗
PubMed1989

Contribution of the baroreflex afferent nerves to the production of vasoconstricted hypertension in volume-expanded dogs.

Dextran in lactated Ringer's solution (20 ml/kg) was infused for 1 hour into anesthetized dogs with sinoaortic denervation and vagotomy (deafferentation; n = 10) and dogs treated with hexamethonium (de-efferentation; n = 13) to compare with our previous observation in dogs with an intact autonomic nervous system (control, n = 34). During the infusion, increase in blood pressure associated with increase in cardiac output was observed in all three groups. The increases in blood pressure were larger in the two groups with an impaired autonomic nervous system. In the recovery period, the control dogs and the hexamethonium-treated dogs showed gradual increases in total peripheral resistance and in vasoconstricted hypertension 3 hours after stopping the infusion. In contrast, the dogs with sinoaortic denervation and vagotomy did not show any increase in total peripheral resistance. The vasoconstricted groups showed peaks of natriuresis soon after the infusion, not 3 hours after the infusion when vasoconstriction was observed, although the dogs with deafferentation did not show a significant increase in natriuresis. Norepinephrine (0.5 micrograms/kg) was administered intravenously before and after volume expansion, and the pressor responses in the three groups after volume expansion were enhanced similarly (143%, 128%, and 136%, respectively). These results indicate that the afferent signals from peripheral vessels to the brain contribute to the production of vasoconstricted hypertension after acute volume expansion and that the vasoconstriction is independent of pressor hypersensitivity and is dissociated in time from the natriuresis.

Afferent Pathways↗
PubMed1999

Effects of S-nitrosoglutathione on acute vasoconstriction and glutamate release after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) causes acute vasoconstriction that contributes to ischemic brain injury shortly after the initial bleed. It has been theorized that decreased availability of nitric oxide (NO) may contribute to acute vasoconstriction. Therefore we examined the effect of the NO donor N-nitroso glutathione (GSNO) on acute vasoconstriction and early ischemic glutamate release after experimental SAH. METHODS: SAH was induced by the endovascular suture method in anesthetized rats. GSNO (1 micromol/L/kg, n=31) or saline (n=21) was injected 5 minutes after SAH. Sham-operated rats received GSNO (1 micromol/L/kg, n=5) 5 minutes after sham surgery. Arterial and intracranial pressures, cerebral blood flow (CBF), and extracellular glutamate release were measured serially for 60 minutes after SAH. SAH size was determined, and vascular measurements were made histologically. RESULTS: GSNO had no effect on resting blood pressure, intracranial pressure, cerebral perfusion pressure, or CBF in sham-operated animals. However, administration of GSNO after SAH was associated with significantly increased CBF (161.6+/-26.6% versus saline 37.1+/-5.5%, 60 minutes after SAH, P<0.05), increased blood vessel diameter (internal carotid artery [ICA] 285.0+/-16.5 microm versus saline 149.2+/-14.1 microm, P<0.01), decreased vessel wall thickness (ICA12.9+/-0.7 microm versus saline 25.1+/-1.6 microm, P<0.01), and decreased extracellular glutamate levels (3315.6+/-1048.3% versus saline469. 7+/-134.3%, P<0.05). Blood pressure decreased transiently, whereas intracranial pressure, cerebral perfusion pressure, and SAH size were not affected. CONCLUSIONS: These results suggest that GSNO can reverse acute vasoconstriction and prevent ischemic brain injury after SAH. This further implies that acute vasoconstriction contributes significantly to ischemic brain injury after SAH and is mediated in part by decreased availability of NO.

Animals↗
PubMed2001

Cerebral vasoconstriction in vasovagal syncope: any link with symptoms? A transcranial Doppler study.

BACKGROUND: Cerebral vasoconstriction has been described previously in vasovagal syncope (VVS). This phenomenon appears paradoxical in view of the well-known decrease of systemic vascular resistances taking places during VVS. We aimed to assess (1) whether cerebral vasoconstriction in VVS is an independent paradoxical phenomenon and (2) whether cerebral vasoconstriction has any link with symptoms and/or VVS onsets. METHODS AND RESULTS: Seven young patients with recurrent VVS participated in the study. Each patient underwent monitoring of heart rate, blood pressure, cerebral blood flow velocity (by means of transcranial Doppler), end-tidal PCO(2), peripheral oximetry, respiratory rate, and tidal volumes both at rest and during head-up tilt. All the subjects experienced tilt-induced VVS. A significant increase of respiratory tidal volumes was observed in each subject >/=160 seconds before VVS. This deep breathing induced a PCO(2) decrease and, consequently, also a decrease in cerebral blood flow velocity and increase in cerebrovascular resistance (expressed by the increase of the pulsatility index). Within 40 seconds, 5 subjects started complaining of discomfort, in the absence of any significant blood pressure drop. CONCLUSIONS: Cerebral vasoconstriction is not a paradoxical phenomenon when it occurs before tilt-induced VVS but rather is only the physiological consequence of the hyperventilation-induced hypocapnia that occurs in habitual fainters. The large lag between the onset of syncope and cerebral vasoconstriction excludes the hypothesis that VVS is dependent on abnormal behavior of cerebral hemodynamics.

Adolescent↗