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PubMed1991

Direct vasoconstriction evoked by A1-adenosine receptor stimulation in the cutaneous microcirculation.

To determine whether the vasoconstriction evoked by A1-adenosine receptor stimulation in the skin circulation caused the release of other substances or whether A1 stimulation modulated the vasoconstriction evoked by other compounds, a potent A1-selective, synthetic agonist, cyclohexyladenosine (CHA), was topically applied simultaneously with several different vasoconstrictor agonists or antagonists. CHA was chosen instead of adenosine because the parent compound is metabolized quickly and also does not discriminate between A1 or A2 receptors. Blood flow was calculated from measurements of arteriolar diameter (40-60 microns) and red blood cell velocity using intravital videomicroscopy. Responses were recorded only in a steady state. The dose-related vasoconstriction evoked by CHA (ED50, 2.07 +/- 0.80 nM; half-minimal response, 93 +/- 1%) was not attenuated by antagonists to norepinephrine (phentolamine [11 microM] or prazosin [10 microM]), serotonin (methysergide [11 microM]), angiotensin II (saralasin [0.11 microM]), thromboxane (SK&F 88046 [13 microM]), or leukotrienes (SK&F 102922 [2.1 microM]). The vasoconstriction evoked by 2 nM CHA was attenuated by a subthreshold concentration (1 nM) of norepinephrine, whereas the vasoconstriction evoked by 0.1-1 microM norepinephrine was attenuated by a threshold concentration (1 nM) of CHA. Higher concentrations (10-100 nM) of CHA had no additional inhibitory effect. In contrast, CHA had no effect on the vasoconstrictions evoked by angiotensin II (10 nM or 1 microM) or serotonin (100 or 500 nM). Therefore, it is unlikely that A1-receptor stimulation causes the release of norepinephrine, serotonin, angiotensin, thromboxane, or leukotrienes in the skin microcirculation. Because norepinephrine attenuated the vasoconstriction evoked by CHA while CHA attenuated that evoked by norepinephrine, there appears to be a negative interaction between alpha-adrenergic and A1-adenosinergic receptors.

Adenosine↗

PubMed1994

Multiple factors contribute to acetylcholine-induced renal afferent arteriolar vasodilation during myogenic and norepinephrine- and KCl-induced vasoconstriction. Studies in the isolated perfused hydronephrotic kidney.

Acetylcholine (ACh) elicits vasodilation by releasing a number of endothelium-derived relaxing factors (EDRFs). We used the isolated perfused hydronephrotic rat kidney to examine the characteristics of ACh-induced vasodilation of renal afferent arterioles during different types of underlying vasoconstriction. Basal arteriolar tone was increased by either elevating perfusion pressure to 180 mm Hg (myogenic), administering 0.3 mumol/L norepinephrine (NE), or elevating medium potassium concentration to 30 mmol/L (KCl). ACh (10 mumol/L) completely reversed myogenic and NE-induced vasoconstriction and reversed KCl-induced vasoconstriction by 80 +/- 5%. However, whereas ACh produced a sustained vasodilation during KCl- and NE-induced vasoconstriction, only a transient reversal of myogenic vasoconstriction was observed, and myogenic tone recovered within 5 to 10 minutes. ACh-induced vasodilation of arterioles preconstricted with KCl was markedly inhibited by either indomethacin (100 mumol/L) or nitro-L-arginine (100 mumol/L) and was completely abolished by pretreatment with both inhibitors. In contrast, indomethacin and nitro-L-arginine had no effect on the transient response to ACh observed during pressure-induced vasoconstriction. In vessels preconstricted with NE, nitro-L-arginine converted the normally sustained response to ACh to a transient vasodilation, which was refractory to both nitric oxide synthase and cyclooxygenase inhibition. Since this component was not observed during KCl-induced vasoconstriction, it may reflect the actions of an, as yet unidentified, endothelium-derived hyperpolarizing factor (EDHF). Our findings thus suggest that prostanoids, nitric oxide, and EDHF all contribute to ACh-induced renal afferent arteriolar vasodilation and that the relative contributions of these individual EDRFs depends on the nature of the underlying renal vascular tone.

Acetylcholine↗

PubMed2003

Effects of mitochondrial inhibitors and uncouplers on hypoxic vasoconstriction in rabbit lungs.

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation for optimizing pulmonary gas exchange; however, the underlying mechanism has not yet been fully elucidated. Lung nitric oxide (NO) generation appears to be involved in this process. Recently, mitochondria have been proposed as oxygen sensors, with HPV signaling via a hypoxia-induced increase in the generation of reactive oxygen species derived from mitochondrial complex III and escaping through an anion channel into the cytoplasm. In addition, complex II has been suggested to be specifically involved in hypoxia-dependent generation of reactive oxygen species in the lung. We investigated the effects of several mitochondrial inhibitors and uncouplers on the strength of HPV, and asked for their capacity to mimic HPV during normoxia in isolated buffer-perfused rabbit lungs. Specificity of the agents for HPV was tested by comparison of their effects on non-hypoxia-induced vasoconstriction, elicited by the thromboxane mimetic U46619. Interference with NO metabolism was determined by performing parallel studies with blocked lung NO generation and by measurement of exhaled NO. Rotenone, 3-nitroproprionic acid, and myxothiazol dose-dependently inhibited HPV without being mimics of HPV during normoxia. The inhibitory effect of these agents was only partly specific for HPV by comparison with U46619-induced vasoconstriction. During pre-blocked lung NO synthesis, the selectivity for HPV inhibition was increased for rotenone, but largely lost for myxothiazol. 2-tenoyltrifluoroacetone resulted in an unspecific inhibition of HPV as compared with U46619-induced vasoconstriction. 1-methyl-4-phenylpyridinium iodide and 2-heptyl-4-hydroxyquinoline-N-oxide specifically suppressed HPV and increased normoxic vascular tone. Antimycin A suppressed HPV, an effect being specific in lungs with intact NO synthesis and only partly specific while blocking NO. However, this agent did not mimic HPV during normoxia, as may be expected for interference with the mitochondrial electron transport downstream in complex III. The uncouplers 2,4-dinitrophenol (DNP, 10-200 microM) and carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP, 1-3 microM) induced sustained vasoconstriction during normoxia, with enhancement of HPV by DNP at low and suppression of HPV for both agents at high concentrations. The anion channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid inhibited HPV and U46619-induced vasoconstriction with identical dose-response curves. These findings suggest that mitochondria are in some manner involved in the regulation of HPV in intact rabbit lungs. The hypothesis that enhanced superoxide leak at complex III of mitochondria represents the underlying mechanism of acute HPV is supported by the rotenone and 2-heptyl-4-hydroxyquinoline-N-oxide data, but partly contradicted by the findings with 1-methyl-4-phenylpyridinium iodide, antimycin A, DNP, and FCCP. Further studies are mandatory to clarify the link between mitochondrial respiratory chain and hypoxic pulmonary vasoconstriction.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1991

Endogenous vasoconstrictor prostanoids: role in serotonin and vasopressin-induced coronary vasoconstriction.

A vasoconstrictor-induced prostacyclin (PGI2) production in a perfused rat heart was found, suggesting a mitigating role of PGI2 on coronary vasoconstriction. Treatment of the heart with cyclooxygenase inhibitors (aspirin or indomethacin) decreased PGI2 production by more than 90% and paradoxically reduced the vasoconstriction response. The attenuating effect of cyclooxygenase blockade suggested that endogenous prostanoids contribute to serotonin-, vasopressin- or U46619-induced vasoconstriction. Two prostaglandin (PG) H2/thromboxane A2 (TXA2) receptor antagonists, i.e., 13-azaprostanoic acid (13-APA) and SQ 29,548 were used to investigate putative endogenous vasoconstrictor prostanoids on the exogenously induced vasoconstriction. Retrogradely perfused (5-6 ml/min) rat hearts were rendered guiescent, yet responsive to stimuli, by local injection of lidocaine to the atrioventricular node. Changes in coronary vascular resistance (i.e., perfusion pressure at constant flow) were monitored and the cardiac effluent was collected for analysis of 6-keto PGF1 alpha (the stable metabolite of PGI2) as well as PGF2 alpha by radioimmunoassay. Three vasoconstrictors, i.e., serotonin, vasopressin and the TXA2/PGH2 analog U46619, as well as authentic PGD2, PGE2 and PGF2 alpha were infused. PGD2, PGE2 and PGF2 alpha exerted a dose-related coronary vasoconstriction, as did U46619, serotonin and vasopressin. Treatment with 13-APA (100 microM) or SQ 29,548 (100 nM) almost abolished U46619-induced vasoconstriction. The addition of PGH2/TXA2 receptor antagonists also significantly reduced the pressor effect of exogenously administered PGs, serotonin and vasopressin, with the exception that SQ 29,548 did not significantly antagonize PGE2-induced vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Modulation of sympathetic vasoconstriction by sensory nerves and nitric oxide in rat irideal arterioles.

Transmural nerve stimulation of arterioles in the rat iris produces a vasoconstriction mediated via alpha-1B adrenoceptors and the mobilization of intracellular calcium. This study has investigated the role of sensory nerves in modulating this vasoconstriction using isolated preparations of iris perfused with Krebs' solution. Repeated stimulation of the transmural nerves for 1 sec (10 Hz), at intervals less than 2 min, produced a rapid and long-lasting loss of the vasoconstriction. This inhibition was not seen in arterioles taken from rats treated neonatally with capsaicin (50 mg/kg) nor after application of capsaicin (10(-5) M) to control preparations. In arterioles from control rats, both the substance P analog Sar9 and calcitonin gene-related peptide (CGRP) were effective in inhibiting nerve-mediated vasoconstriction. L-NG-nitroarginine methyl ester (10(-5) M), but not D-NG-nitroarginine methyl ester (10(-5) M), prevented the loss of vasoconstriction during repetitive stimulation, which suggested the involvement of nitric oxide. Antagonists to the NK1 and NK2 neurokinin receptor subtypes, RP 67580 and L-659877, respectively, were without effect, whereas the antagonist to the CGRP1 receptor, CGRP8-37, prevented the loss of vasoconstriction during repetitive nerve stimulation. The effects of both Sar9 and CGRP (10(-8) M) in inhibiting the nerve-mediated vasoconstriction were prevented by preincubation in L-NG-nitroarginine methyl ester (10(-5) M), which suggested that the mechanism of action of both peptides involved the release of nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Role of thromboxane and angiotensin in cyclosporine-induced renal vasoconstriction in the dog.

Cyclosporine is associated with renal insufficiency characterized by a reduction in glomerular filtration rate that may result from renal vasoconstriction. Injection of cyclosporine in the isolated renal artery perfused at a constant flow induces a potent dose-dependent vasoconstriction of renal arterial vessels in the dog. The present study was designed to investigate the role of thromboxane A2, angiotensin, and endothelial-dependent vasodilation in the cyclosporine-induced renal vasoconstriction. A specific thromboxane A2-receptor antagonist (pinane-thromboxane A2), administered at a dose of 150 micrograms, significantly decreased the renal vasoconstriction response to cyclosporine from 103 +/- 26 mm Hg to 45 +/- 11 mm Hg (p < 0.05), with cyclosporine serum levels at the end of injection averaging 382 +/- 105 and 421 +/- 150 nmol/L before and after injection of the antagonist. In contrast, pharmacologic blockade of angiotensin receptors by saralasin had no effect on the cyclosporine arterial vasoconstriction in the kidney. The endothelium-dependent vasodilation to acetylcholine was not modified during cyclosporine injection. Thus cyclosporine renal vasoconstriction appears independent of the renin-angiotensin system and of endothelium-dependent vasodilation. It is at least partly mediated by thromboxane A2. Prevention of cyclosporine vasoconstriction by thromboxane A2-receptor antagonist may likely be possible, with more potent agents having more affinity to thromboxane A2 renal receptors.

Acetylcholine↗

PubMed1996

[Sevoflurane comparably decreases the threshold for thermoregulatory vasoconstriction as isoflurane].

The core temperature triggering thermoregulatory arteriovenous shunt constriction is defined as the threshold for vasoconstriction. Vasoconstriction helps prevent further core hypothermia by decreasing cutaneous heat loss and constraining metabolic heat to the core thermal compartment. A previous study showed isoflurane inhibited thermoregulatory threshold. However there is no study to confirm whether sevoflurane perturb thermoregulatory vasoconstriction or not. Consequently we tested the hypothesis that 1.0 minimum alveolar concentration (MAC) sevoflurane and 1.0 MAC isoflurane would reduce the vasoconstriction threshold comparably. With institutional review board approval, we studied 20 patients, aged 20-60 yr, undergoing open abdominal surgery. No premedication was given. Ten patients each were anesthetized with 1.0 MAC sevoflurane (2.0%) alone or 1.0 MAC isoflurane (1.2%) alone. A forearm minus fingertip, skin temperature gradient 0 degree C was considered to demonstrate significant vasoconstriction; the esophageal temperature triggering vasoconstriction identified the threshold. Morphometric characteristics were comparable in each group. The threshold for vasoconstriction was 35.1 +/- 0.4 degrees C in the patients given 1.0 MAC sevoflurane, which was comparable that in those given 1.0 MAC isoflurane: 35.3 +/- 0.7 degrees C. We thus conclude that sevoflurane impairs thermoregulation comparably with isoflurane.

Adult↗

PubMed1998

Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography.

CONTEXT: Clinical observations and case reports suggest that there are important cerebrovascular complications of cocaine use, but no studies have documented a direct link. OBJECTIVE: To determine whether low-dose cocaine administration induces cerebral vasoconstriction in healthy cocaine users. DESIGN: Randomized controlled trial. SUBJECTS: Twenty-four healthy and neurologically normal men (mean age, 29 years) reporting median cocaine use of 8 lifetime exposures (range, 3 to >40). INTERVENTION: Double-blind intravenous administration of cocaine (0.4 or 0.2 mg/kg) or placebo, with cerebral magnetic resonance angiography performed at baseline and 20 minutes following infusion. MAIN OUTCOME MEASURE: Cocaine-induced angiographic change indicative of vasoconstriction, as independently and concordantly rated by 2 reviewers blind to treatment condition. RESULTS: Cocaine-induced cerebral vasoconstriction in a dose-related fashion (P=.03), with angiograms indicative of vasoconstriction found in 5 of 8 and 3 of 9 subjects receiving 0.4- and 0.2-mg/kg cocaine, respectively, compared with 1 of 7 subjects administered placebo. Outcome stratification by frequency of self-reported lifetime cocaine use (3-10 times, 11-40 times, or >40 times) revealed a statistically stronger dose-related effect (P<.001), suggesting that greater lifetime cocaine use was associated with a greater likelihood of vasoconstriction. CONCLUSIONS: Cocaine administration induced dose-related cerebral vasoconstriction on magnetic resonance angiograms. These changes occurred at low cocaine doses and in the absence of other risk factors, including polydrug abuse, hypertension, or cerebrovascular disease. Outcome stratification by prior cocaine use statistically strengthened the relationship between cocaine administration and vasoconstriction, suggesting that cocaine may have a cumulative residual effect in promoting cerebrovascular dysfunction.

Adult↗

PubMed1998

Modulation of vasoconstriction by insulin.

OBJECTIVE: To test the hypothesis that insulin differently modifies vasoconstriction and recovery from vasoconstriction induced by endogenously released versus circulating norepinephrine, and to investigate the time-dependency of its effect METHODS: Healthy male subjects were studied. Norepinephrine was infused for 10 min into the brachial artery with 40 min pauses in between, three times with vehicle and three times during concurrent intra-arterial infusion of 0.1 mU/kg per min insulin, inducing locally high, above physiologic, concentrations of insulin. We infused tyramine, to release endogenous norepinephrine from sympathetic nerve endings, similarly into six other subjects. Ratios of infused: control arm forearm blood flow (FBFi: FBFc) were determined during the infusions of agonists and for 10 min after their cessation. Because of insulin's vasodilator effect, responses to norepinephrine after vasodilatation by isoproterenol or sodium nitroprusside were also determined for six other subjects. RESULTS: Exogenous norepinephrine induced a transient peak vasoconstriction and then a partial recovery from vasoconstriction that remained stable throughout the infusion. Administration of norepinephrine decreased the FBFi: FBFc ratio by 29+/-7% (mean +/- SEM) before and 45+/-4% during infusion of insulin (P < 0.01). After cessation of the norepinephrine infusions blood flow rapidly recovered, which even resulted in an overshoot vasodilatation during infusion of insulin. Administration of tyramine induced only a plateau vasoconstrictor phase; the FBFi: FBFc ratio decreased by 49+/-6% before and 63+/-5% during infusion of insulin (P < 0.01). After cessation of the tyramine infusions, vasoconstriction slowly and only partially recovered, which was not affected by infusion of insulin. No time-dependency was observed for the repeated infusions of agonist. Infusion of insulin significantly reduced the apparent concentrations of norepinephrine and tyramine at which half maximal effect occurs (EC50). Dilatation with isoproterenol or sodium nitroprusside beforehand dose-dependently also reduced the EC50 of norepinephrine, with a correlation coefficient of 0.613 (P < 0.001) for relationship between individual EC50 values and baseline flows. CONCLUSIONS: Vasoconstriction induced by exogenous or endogenous norepinephrine is augmented by a high concentration of insulin. This augmentation is not time-dependent This augmentation is, however, an unspecific effect insofar as other vasodilators also enhance norepinephrine-induced vasoconstriction. The finding that hyperinsulinemia stimulates norepinephrine's vasoconstrictor effect implies that these two growth-stimulating and vascular hypertrophy-stimulating factors may act synergistically on vascular remodeling in patients with hypertension and hyperinsulinemia.

Adult↗

PubMed1997

Pyridoxalated hemoglobin polyoxyethylene conjugate does not restore hypoxic pulmonary vasoconstriction in ovine sepsis.

OBJECTIVES: Hypoxic pulmonary vasoconstriction, a protective mechanism, minimizes perfusion of underventilated lung areas to reduce ventilation-perfusion mismatching. We studied the effects of sepsis on hypoxic pulmonary vasoconstriction and attempted to determine whether hypoxic pulmonary vasoconstriction is influenced by pyridoxalated hemoglobin polyoxyethylene conjugate, a nitric oxide scavenger. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational intensive care unit at a university medical center. SUBJECTS: Nineteen female merino sheep, divided into three groups: group 1, controls (n = 5); group 2, sheep with sepsis (n = 6); and group 3, septic sheep treated with pyridoxalated hemoglobin polyoxyethylene conjugate (n = 8). INTERVENTIONS: All sheep were instrumented for chronic study. An ultrasonic flow probe was placed around the left pulmonary artery. After a 5-day recovery, a tracheostomy was performed and a double-lumen endotracheal tube was placed. Animals in groups 2 and 3 received a 48-hr infusion of live Pseudomonas aeruginosa (6 x 10(4) colony-forming units/kg/hr). After 24 hrs, sheep in group 3 received pyridoxalated hemoglobin polyoxyethylene conjugate (20 mg/kg/hr) for 16 hrs; sheep in groups 1 and 2 received only the vehicle. Hypoxic pulmonary vasoconstriction was repeatedly tested by unilateral hypoxia of the left lung with 100% nitrogen. Hypoxic pulmonary vasoconstriction was assessed as the change in left pulmonary blood flow. MEASUREMENTS AND MAIN RESULTS: In the animals in group 1, left pulmonary blood flow decreased by 62 +/- 8 (SEM)% during left lung hypoxia and remained stable during repeated hypoxic challenges throughout the study period. After 24 hrs of sepsis, left pulmonary blood flow decreased from 56 +/- 10% to 26 +/- 2% (group 2) and from 50 +/- 8% to 23 +/- 6% (group 3). In the sheep in group 2, there was no adaptation over time. Pulmonary shunt fraction increased. Pyridoxalated hemoglobin polyoxyethylene conjugate had no effect on hypoxic pulmonary vasoconstriction or pulmonary shunt. The animals receiving the bacterial infusion developed a hyperdynamic circulatory state with hypotension, decreased systemic vascular resistance, and increased cardiac output. Pyridoxalated hemoglobin polyoxyethylene conjugate increased mean arterial pressure and systemic vascular resistance but did not influence cardiac index. Pulmonary arterial pressure was increased during sepsis and increased even further after pyridoxalated hemoglobin polyoxyethylene conjugate administration. Oxygenation and oxygen delivery and uptake were not affected by pyridoxalated hemoglobin polyoxyethylene conjugate. CONCLUSIONS: Hypoxic pulmonary vasoconstriction is blunted during sepsis and there is no adaptation over time. It is not influenced by pyridoxalated hemoglobin polyoxyethylene conjugate. Pyridoxalated hemoglobin polyoxyethylene conjugate reversed hypotension and, with the exception of an increase in pulmonary arterial pressure, had no adverse effects on hemodynamics or oxygenation.

Animals↗

PubMed2000

Novel angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induced vasoconstriction in canine coronary arteries and human platelet aggregation.

This study was conducted to investigate whether the novel orally active nonpeptide angiotensin II (Ang II) AT(1) receptor antagonist irbesartan interacts with the thromboxane A(2)/prostaglandin endoperoxide H(2) (TxA(2)/PGH(2)) receptor in canine coronary arteries and human platelets. Coronary artery rings were isolated from male dog hearts (n = 18) and isometric tension of vascular rings was measured continuously at optimal basal tension in organ chambers. Autoradiographic binding of [(3)H]SQ29,548, a TxA(2) receptor antagonist, in canine coronary sections was determined. Blood for platelet aggregation studies was collected by venous puncture from healthy human volunteers (n = 6) who were free of aspirin-like agents for at least 2 weeks. Vascular reactivity and platelet aggregation in response to the TxA(2) analogs U46619 and autoradioagraphic receptor binding to the TxA(2) receptor antagonist [(3)H]SQ29,548 were studied with and without irbesartan. The TxA(2) analog U46619 produced dose-dependent vasoconstriction in coronary rings (EC(50) = 11.6 +/- 1.5 nM). Pretreatment with irbesartan inhibited U46619-induced vasoconstriction, and the dose-response curve was shifted to the right in a dose-dependent manner. The EC(50) of U46619 was increased 6- and 35-fold in the presence of 1 and 10 microM of irbesartan without a change of maximal contraction. At 1 microM, irbesartan is 2-fold more potent than the AT(1) receptor antagonist losartan in the inhibition of U46619-induced vasoconstriction in canine coronary arteries. In contrast, neither AT(1) receptor antagonists (CV11974 and valsartan), the AT(2) receptor antagonist PD123319, nor the angiotensin converting enzyme inhibitor lisinopril had any effect on U46619-induced coronary vasoconstriction. Irbesartan did not change potassium chloride-induced vasoconstriction; however, irbesartan did inhibit the vasoconstriction mediated by another TxA(2)/PGH(2) receptor agonist prostaglandin F(2alpha) (PGF(2alpha)). Neither the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester nor the cyclooxygenase inhibitor indomethacin had any effect on irbesartan's attenuation of U46619-induced vasoconstriction. Irbesartan specifically reversed U46619-preconstricted coronary artery rings with and without endothelium in a dose-dependent manner. Irbesartan at high concentrations significantly competed for [(3)H]SQ29,548 binding in canine coronary sections. U46619 stimulated dose-dependent human platelet aggregation of platelet-rich plasma. Preincubation with irbesartan significantly inhibited platelet aggregation in a concentration-dependent manner. In conclusion, the dual antagonistic actions of irbesartan by acting at both the AT(1) and TxA(2) receptors in blood vessels and platelets may overall enhance its therapeutic profile in the treatment of hypertension, atherosclerosis, and arterial thrombosis.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1993

Characterization of pulsed-dye laser-mediated vasodilatation in a rabbit femoral artery model of vasoconstriction.

Vasoconstriction is a clinical problem associated with invasive vascular procedures, microvascular reconstruction and subarachnoid hemorrhage. We sought to characterize the ability of pulsed-dye laser irradiation to reverse and prevent vasoconstriction in an anesthetized rabbit model of surgically and pharmacologically induced vasoconstriction. Five groups of experiments were performed to study the effect of pulsed-dye laser irradiation delivered through a 320 microns core ball-tip fiber into the femoral artery. The studies demonstrated that pulsed-dye irradiation can reproducibly cause vascular dilatation. The zone of vasodilatation propagated equally proximal and distal to the site of irradiation within the vessel. When saline was infused into the vessel to replace flowing blood during delivery of laser irradiation, no significant vasodilatation occurred. After laser irradiation reversed surgical and pharmacologic vasoconstriction, the vessel was resistant to further pharmacologic vasoconstriction. This resistance to pharmacologic vasoconstriction did not occur if the vessel was pharmacologically predilated before delivery of laser irradiation. Pathologic analysis of the vessels revealed endothelial damage and mild to moderate medial necrosis, most significant at the site of energy delivery. These studies provide characterization of pulsed-dye laser-mediated vasodilatation in an in vivo model. Delivery of pulsed-dye laser energy has potential clinical application and warrants further investigation.

Absorption↗

PubMed1988

Dibutyryl cyclic adenosine monophosphate inhibits pulmonary vasoconstriction.

The effects of the cell-permeable dibutyryl derivative of cyclic AMP on the vascular reactivity of isolated perfused rat lungs were examined. In lungs perfused with homologous blood, pulmonary arterial infusion of db-cAMP (30 micrograms/min) inhibited hypoxia-induced vasoconstriction (IC50 = 6.3 X 10(-5) M) and vasoconstriction due to bolus injection of angiotensin II (IC50 = 8.2 X 10(-5) M). Cyclic AMP phosphodiesterase inhibition by aminophylline acted synergistically with db-cAMP in the reduction of hypoxia-induced vasoconstriction. Somatostatin, an inhibitor of adenylate cyclase, prevented the decay of hypoxic vasoconstriction typically observed in isolated lungs, suggesting that a rise in intracellular cAMP may occur during hypoxic vasoconstriction as a consequence of activation of the adenylate cyclase. In lungs perfused with cell and protein-free salt solution, db-cAMP inhibited both initial and prolonged vasoconstriction following bolus injection of 2 microgram leukotriene C4. Thus, db-cAMP inhibited pulmonary vascular reactivity nonspecifically.

Aminophylline↗

PubMed1989

Antagonism of leukotriene receptors and administration of a 5-lipoxygenase inhibitor do not affect hypoxic vasoconstriction.

The role of leukotrienes in hypoxic vasoconstriction remains controversial. Our previous study using the lipoxygenase inhibitor BW 755C in dogs failed to show a substantive role for leukotrienes in hypoxic vasoconstriction. To clarify further the role of leukotrienes, we designed 3 protocols. In the first protocol, we examined the effects of LTD4 boluses on the pulmonary circulation in 6 anesthetized dogs. LTD4, 1 microgram/kg, (a large dose relative to other species) produced no detectable constriction of the pulmonary artery, while systemic vascular resistance increased 41 +/- 17% (SD), left atrial pressure rose 3.5 +/- 1.5 mmHg, and cardiac output fell 18 +/- 8%. Two leukotriene receptor antagonists, LY171883 and L-648051, decreased these effects by more than 50%. In the second protocol, we tested these antagonists in 7 anesthetized, paralyzed, closed-chest dogs with acute left lower lobe atelectasis. Two manifestations of hypoxic vasoconstriction were examined: shunt fraction (as an inverse indicator of regional constriction in response to local hypoxia) and the pulmonary pressor response to global alveolar hypoxia (as an index of general hypoxic vasoconstriction). During normoxia before administration of the inhibitor, shunt fraction, measured using an SF6 infusion, was 25 +/- 7%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient (PDG) produced by 10% O2 inhalation, averaged +10.5 +/- 3.6 mmHg. The increase in pulmonary vascular resistance (PVR) with hypoxia was +2.4 +/- 1.7 mmHg/L/min. Then, during normoxia, 1 of the 2 antagonists was administered. Shunt fraction was unchanged (26 +/- 4%; p = 0.5). The pressor response to hypoxia was slightly less but remained substantial (the increase in PDG with hypoxia was +7.9 +/- 2.8 mmHg; p less than 0.05; the increase in PVR was +1.8 +/- 1.2 mmHg/L/min, p less than 0.10). In the third protocol we gave RG 5901, a relatively specific 5-lipoxygenase inhibitor, to 5 dogs with lobar atelectasis. The indices of hypoxic vasoconstriction were not affected by RG 5901. Shunt fraction was 29.5 +/- 8.1% before and 27.0 +/- 7.4% after RG 5901 (p greater than 0.05). The pressor response to hypoxia was +8.9 +/- 2.1 mmHg before and +8.7 +/- 3.7 mmHg after RG 5901 (p greater than 0.05). We conclude that in dogs, hypoxic vasoconstriction does not appear to be mediated by leukotrienes.

Acetophenones↗

PubMed1990

Effect of cyclic guanosine monophosphate on hypoxic and angiotensin-II-induced pulmonary vasoconstriction.

We examined, in isolated blood perfused rat lungs, the effect of the cell permeable 8-bromo derivative of cGMP on pulmonary vasoconstriction induced by either alveolar hypoxia or angiotensin II. 8-Bromo cGMP dose-dependently reduced both hypoxia-(IC50 = 2.2 X 10(-5) M) and angiotensin-II-induced pulmonary vasoconstriction (IC50 = 5.0 X 10(-5) M). This effect of 8-bromo cGMP on pulmonary vasoconstriction was not affected by cyclooxygenase blockade. M & B 22948 (0.1 mM), an inhibitor of cGMP-phosphodiesterase, reduced synergistically with 8-bromo cGMP the hypoxia or angiotensin-II-induced vasoconstriction. The cGMP-phosphodiesterase inhibitor M & B 22948, by itself, selectively reduced hypoxia-induced vasoconstriction, suggesting a modulating effect of endogenous cGMP during hypoxic vasoconstriction.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2002

Shear stress modulates vasopressin-induced renal vasoconstriction in rats.

Vasopressin is a potent renal vasoconstrictor in vitro which elicits relatively minor renal vascular effects in vivo. Efficient modulation might occur through shear stress-elicited release of vasodilator compounds from endothelial cells. The aim of this study was to evaluate in vitro, in the isolated perfused kidney, the influence of shear stress and related nitric oxide (NO) release on basal renal vascular tone and on vasopressin-induced renal vasoconstriction. Rat kidneys were perfused at a constant flow rate of 8 ml/min with Tyrode's solution (relative viscosity eta=1) or, in order to increase shear stress, with Tyrode's solution supplemented with 4.7% Ficoll 400 (Ficoll 400; eta=2.3), which is representative of the relative viscosity found in small vessels. Renal shear stress was further elevated during vasoconstriction elicited by vasopressin. Basal renal true vascular conductance, which reflects mean blood vessel radius, was 2.5-fold higher and overall wall shear stress doubled in Ficoll 400 - as compared to Tyrode-perfused kidneys. The decrease in vascular conductance elicited by NO synthase inhibition with N(omega)-nitro-L-arginine (L-NNA) increased with the viscosity of the perfusate. Shear stress was elevated during vasopressin-induced renal vasoconstriction, all the more kidneys were Ficoll 400-perfused. In these kidneys, the concentration-response curve to vasopressin was shifted to the right, giving evidence of hyporeactivity to the peptide. L-NNA potentiated vasoconstriction to vasopressin particularly in Ficoll 400-perfused kidneys, although additional inhibition of cyclooxygenase and/or cytochrome P(450) was without effect. These results provide in vitro evidence that shear stress enhanced by perfusate viscosity increases basal renal vascular conductance by an NO-dependent mechanism. Together with shear stress enhanced during vasoconstriction, it blunts vasopressin-induced renal vasoconstriction.

Animals↗

PubMed2004

Clozapine and olanzapine, but not haloperidol, reverse cold-induced and lipopolysaccharide-induced cutaneous vasoconstriction.

RATIONALE: Reduction of body temperature is used as predictor of psychotropic drug action. The cutaneous circulation functions as a heat-loss component of temperature regulation. Clozapine and olanzapine reverse hyperthermia and sympathetically-mediated cutaneous vasoconstriction induced by MDMA (3,4-methylenedioxymethamphetamine, ecstasy), suggesting that these drugs might reverse other forms of sympathetically mediated cutaneous vasoconstriction. OBJECTIVES: Clozapine and olanzapine were compared with haloperidol with respect to their ability to reverse cold-induced and LPS (lipopolysaccharide)-induced cutaneous vasoconstriction in rabbits. METHODS: Cutaneous blood flow was measured in conscious rabbits by Doppler ultrasonic flow probe implanted around the central ear artery, and body temperature was measured telemetrically. After control observations, animals were transferred from 26 to 10 degrees C, or LPS (0.5 microLg/kg IV) was administered. After 30 min, clozapine, olanzapine or haloperidol was administered and ear pinna blood flow and body temperature were measured for another 30 min. RESULTS: Clozapine, in a dose responsive manner (1, 2.5 and 5 mg/kg IV), substantially reversed cold-induced ear pinna vasoconstriction and reduced body temperature. Clozapine (1 mg/kg IV) reversed LPS-induced cutaneous vasoconstriction and reduced the LPS-induced rise in body temperature. Olanzapine had generally similar effects. Haloperidol (1 mg/kg IV in cold experiments and 0.2 mg/kg IV in LPS experiments) did not reverse ear pinna vasoconstriction, or affect body temperature. CONCLUSIONS: Both clozapine and olanzapine, but not haloperidol, reverse physiologically induced cutaneous sympathetic vasomotor discharge. Because of the close link between psychological function and sympathetic regulation of cutaneous blood flow, similar neuropharmacological mechanisms might underly the cutaneous vasodilating action and the psychotropic actions of atypical antipsychotic drugs.

Animals↗

PubMed1996

SR 120107A antagonizes neuropeptide Y Y1 receptor mediated sympathetic vasoconstriction in pigs in vivo.

The effects of the neuropeptide Y Y1 receptor antagonist SR 120107A (1-[2-[2-(2-naphtylsulfamoyl)-3-phenylpropionamido]-3-[4-[N- [4- (dimethylaminomethyl)-cis-cyclohexylmethyl]amidino]phenyl]propiony l] pyrrolidine, (S,R) stereoisomer) on sympathetic non-adrenergic vasoconstriction in a variety, of vascular beds were studied in reserpinized anesthetized pigs in vivo. The rapid vasoconstrictor response evoked by single impulse stimulation, in hind limb and nasal mucosa, was not affected by SR 120107A (1.5 mg kg-1 i.v.). In contrast, SR 120107A potently inhibited the long-lasting phase of vasoconstriction evoked by high frequency (60 impulses at 20 Hz) sympathetic nerve stimulation, in the main and deep femoral, the saphenous and the internal maxillary arteries, leaving merely the initial rapid peak of vasoconstriction in these vessels. Furthermore, the vasoconstrictor response was nearly abolished in the kidney and was attenuated in the spleen and main femoral artery, despite maintained neuropeptide Y overflow. The vasoconstrictor response evoked in the kidney by peptide YY, a neuropeptide Y Y1 and Y2 receptor agonist, was also nearly abolished in the presence of SR 120107A. This inhibitory effect on the response to exogenous agonist correlated well with the long-lasting inhibition of the response to nerve stimulation in the same tissue. The peptide YY-evoked vasoconstriction in the spleen was not altered by SR 120107A, in accordance with the view that the neuropeptide Y receptor population in this organ consists mainly of neuropeptide Y Y2 receptors. SR 120107A did not influence the vasoconstrictor effects of alpha, beta-methylene ATP (mATP) or phenylephrine in any of the tissues studied. We conclude that SR 120107A is a potent neuropeptide Y Y1 receptor antagonist with long duration of action in vivo. Endogenous neuropeptide Y acting on the neuropeptide Y Y1 receptor is likely to account for the long-lasting component of the reserpine-resistant sympathetic vasoconstriction upon high frequency stimulation in hind limb and nasal mucosa. Furthermore, the peak vasoconstriction in kidney, and to some extent in spleen, is also neuropeptide Y Y1 receptor mediated.

Adenosine Triphosphate↗