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PubMed1985

Modification of the vasoconstrictor effects of noradrenaline and serotonin by the selective calcium antagonist PY 108-068 in the peripheral circulation of anesthetized cats.

The effects of a noradrenaline (NA, 1 microgram/kg min) or serotonin (5-HT, 10 micrograms/kg min) infusion on regional blood flow and conductance were assessed with tracer microspheres before and after administration of the calcium-antagonist PY 108-068 (PY; 30 micrograms/kg). Chloralose-urethane-anesthetized cats were pretreated with propranolol 1 mg/kg i.v. or chlorisondamine 1 mg/kg i.v. for the experiments with NA or 5-HT, respectively. PY attenuated the NA-induced increase of blood pressure and the decrease of total peripheral conductance. The NA-induced vasoconstriction, occurring mainly in the kidneys, adrenals, liver, spleen, and arteriovenous shunts, was significantly attenuated by PY. The vessels of heart, stomach, pancreas, and skeletal muscle were not constricted by NA. In contrast, 5-HT dilated or tended to dilate almost all vascular beds examined. Only arteriovenous shunts were constricted. PY did not antagonize this vasoconstrictor effect. Moreover, after but not before PY treatment, a coronary vasoconstrictor effect of 5-HT was seen. Antivasoconstrictor effects of PY were observed both in organs where dihydropyridines normally elicit vasodilatation and in organs where such compounds have no vasodilator effects in the absence of a vasoconstrictor infusion. The regional distribution of the antivasoconstrictor effects was different for each vasoconstrictor tested so far (angiotensin II, 5-HT, and NA). The sites of action of calcium antagonists in peripheral blood vessels appear to depend on the mechanism of activation operating at that site and at the time of the investigation.

Animals↗

PubMed2000

Enhanced vasoconstrictor response to endothelin-B-receptor stimulation in patients with atherosclerosis.

The vascular responses to endothelin-1 [ET-1; nonselective endothelin-A and -B (ET(A) and ET(B) agonist)] and sarafotoxin 6c (S6c; ET(B) agonist) were investigated in patients with atherosclerosis. ET-1 and S6c (3, 10 and 30 pmol/min) were infused into the brachial artery while forearm blood flow (FBF) was measured by venous occlusion plethysmography in seven male patients with atherosclerosis and six age-matched healthy male controls. S6c evoked an initial increase followed by a dose-dependent reduction in FBF. The initial dilator component did not differ between the two groups. The vasoconstrictor component of the two lower doses of S6c was significantly larger in the atherosclerotic patients than in controls. The reduction in FBF induced by 3 and 10 pmol/min S6c was 18 +/- 2% and 27 +/- 6% in the control group compared to 29 +/- 3% (p < 0.02) and 42 +/- 2% (p < 0.05) in patients with atherosclerosis. The vasoconstrictor response to S6c correlated with low-density lipoprotein (LDL) cholesterol levels (r = 0.47, p < 0.05). The vasoconstrictor response to ET-1 was similar in the two groups. It is concluded that the forearm vasoconstrictor response to S6c but not that to ET-1 is enhanced in patients with atherosclerosis as compared with healthy controls. This finding suggests an upregulation of vascular smooth muscle ET(B)-receptors in atherosclerosis.

Aged↗

PubMedDate not supplied

Serotonin enhances sympathetic vasoconstrictor responses in rat isolated perfused tail artery by activation of postjunctional serotonin-2 receptors.

The effects of serotonin and the selective serotonin-2 receptor antagonist ketanserin have been investigated on sympathetic vasoconstrictor responses in rat isolated perfused/superfused proximal tail artery segments. Serotonin (6 nmol/l) markedly enhanced responses to low frequency, short duration electrical stimulation (0.1 ms pulses at 1 Hz for 10 s). Serotonin (6 nmol/l) had a very slight (less than 10 mmHg) direct vasoconstrictor effect. Both the enhancing effect of serotonin on responses to electrical stimulation and the slight direct vasoconstrictor effect were blocked by ketanserin (3 nmol/l). Ketanserin (3 nmol/l) had no significant effect on resting tone or on responses to electrical stimulation. It is concluded that serotonin enhances sympathetic vasoconstrictor responses in rat tail artery by activation of postjunctional serotonin-2 receptors. Blockade of this effect by ketanserin is entirely consistent with its antihypertensive effect in vivo.

Animals↗

PubMed1991

Endothelin-1 enhances vasoconstrictor responses to sympathetic nerve stimulation and noradrenaline in the rabbit ear artery.

1. In rabbit isolated perfused ear arteries denuded of endothelium, a low concentration of endothelin-1 (0.1 nmol/L) that had no direct vasoconstrictor action produced slowly developing enhancements of vasoconstrictor responses to noradrenaline and sympathetic nerve stimulation. The enhancements reached maximal levels after 60 min of exposure to endothelin-1. 2. A higher concentration of endothelin-1 (1 nmol/L), which produced a slow-developing increase in perfusion pressure of 70 mmHg over the course of 1 h, significantly enhanced vasoconstrictor responses to sympathetic nerve stimulation for the first 30 min, after which there was no significant enhancement. Responses to noradrenaline were not enhanced by 1 nmol/L endothelin-1. 3. The enhancing effect of low concentrations of endothelin-1 on vasoconstrictor responses to sympathetic nerve stimulation and noradrenaline may play a physiological role in modulating vasomotor function.

Animals↗

PubMed1983

Vibration sense and sympathetic vasoconstrictor activity in patients with occlusive arterial disease.

The function of sympathetic vasoconstrictor fibres was studied in 18 patients with occlusive arterial disease of the legs and somatic neuropathy, as evidenced as an increased vibration perception threshold. Nine patients suffered from long-term diabetes mellitus. Sympathetic vasoconstrictor function was studied by the capability of the local sympathetic venoarteriolar reflex (Henriksen 1977) elicited by lowering the leg to induce an arteriolar constriction in subcutaneous tissue at the ankle level. Blood flow was measured by the local isotope washout technique. In only five patients with loss of vibration sense, abnormal vasoconstrictor function was found. In three of these patients, the abnormal response most likely could be ascribed to impaired function of the vascular smooth muscle cells. Neither in diabetics nor in non-diabetics could an abnormal vibration sense be taken as evidence for loss of sympathetic vasoconstrictor function. It is suggested that this is studied by a simple postural test as used in the present study.

Aged↗

PubMed1986

Similarity and dissimilarity of the vasoconstrictor effects of Bay K 8644 on coronary, femoral, mesenteric and renal circulations of dogs.

The effect of the dihydropyridine calcium agonist Bay K 8644 on the coronary, femoral, mesenteric and renal circulations was investigated and compared with that of noradrenaline in pentobarbitone-anaesthetized dogs. The left anterior descending coronary, femoral, cranial mesenteric and renal arteries were cannulated and their arterial beds perfused with autologous blood at a constant pressure slightly higher than the mean systemic arterial blood pressure. Bay K 8644 (0.1-300 nmol) and noradrenaline (0.1-300 nmol) were injected intra-arterially. Bay K 8644 decreased blood flow (vasoconstriction) in all 4 arterial beds. A maximum decrease was attained at 100 nmol and a further increase in dose did not appear to result in a further decrease in blood flow. At maximum effects blood flow decreased to about 35% of the basal value in coronary, 30% in femoral, 20% in renal and 15% in mesenteric circulation. Normalized ED50 values (ED50 divided by basal flow) of Bay K 8644 were 0.07 +/- 0.02 nmol in the femoral, 0.08 +/- 0.01 nmol in the coronary, 0.16 +/- 0.06 nmol in the mesenteric and 0.55 +/- 0.19 nmol in the renal circulation. At 100 nmol, the values for the half-duration of Bay K 8644 vasoconstrictor effects were about 196 s in the renal, 78 s in the mesenteric, 84 s in the femoral and 21 s in the coronary circulation. Noradrenaline produced a dose-dependent decrease in blood flow in femoral, mesenteric and renal circulations, and was about 2 times in femoral, 4 times in mesenteric and 9 times in renal circulation more potent than Bay K 8644. 8. Bay K 8644 produced slight increases in the maximum rate of rise of left ventricular pressure and intraluminal pressure of the ileum. However, the increases did not appear to impede blood flow. 9. Bay K 8644 produced slightly but significantly greater femoral vasoconstriction in normal dogs than in reserpine-pretreated dogs. 10. From these results it was concluded that differences in potency, effectiveness and duration of the vasoconstrictor effects of Bay K 8644 between the 4 arterial beds probably derive from differences in characteristics ofthe smooth muscle ofresistance vessels there. In arterial beds where alpha-adrenoceptors are dominant, potentiation of the vasoconstrictor effect ofendogenous catecholamines by Bay K 8644 seems to contribute to its vasoconstrictor effect.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1988

Studies on the anti-vasoconstrictor activity of BRL 34915 in spontaneously hypertensive rats; a comparison with nifedipine.

1. The blood pressure lowering and anti-vasoconstrictor effects of BRL 34915 and nifedipine were compared in female spontaneously hypertensive rats (SHR). 2. In conscious SHR, intravenous injection of BRL 34915 (0.1, 0.3 mg kg-1) produced rapid, dose-related falls in mean arterial pressure of greater than 3 h duration. Nifedipine, at the same intravenous dose levels, also evoked rapid anti-hypertensive effects, though these responses were of lesser magnitude and duration than those observed for BRL 34915. 3. In anaesthetized, ganglion-blocked SHR, BRL 34915 (0.1, 0.3 mg kg-1 i.v.) dose-dependently antagonized the pressor responses to incremental intravenous infusions of noradrenaline (3.8-28.5 ng min-1) or phenylephrine (120-907 ng min-1) but did not inhibit pressor responses to incremental infusions of methoxamine (0.47-3.63 micrograms min-1), angiotensin II (7.0-52.9 ng min-1) or vasopressin (0.27-2.0 mu min-1). 4. In anaesthetized, ganglion-blocked SHR, nifedipine (0.1, 0.3 mgkg-1 i.v.) antagonized the pressor responses to each of the infused vasoconstrictor agents, being most effective against responses to noradrenaline or angiotensin II. 5. In pithed SHR, both BRL 34915 and nifedipine (each at 0.3 mg kg-1 i.v.) reduced the basal blood pressure level and produced marked inhibition of frequency-dependent pressor responses evoked by electrical stimulation of the spinal cord sympathetic outflow (0.25-4.0 Hz). Restoration of the basal diastolic blood pressure to within the control range, using a continuous intravenous infusion of vasopressin (0.98 mu min-1), prevented the inhibitory effect of BRL 34915. In the case of nifedipine, however, even raising the basal blood pressure to a level exceeding that recorded in control rats (with vasopressin, 2.0 mu min-1), did not reverse the inhibitory effect of the drug on frequency-dependent pressor responses. 6. It is concluded that the anti-hypertensive properties of BRL 34915 in SHR are probably unrelated to an anti-vasoconstrictor action. In contrast, it is suggested that the broadly-based anti-vasoconstrictor properties of nifedipine may contribute substantially to the anti-hypertensive properties of this drug.

Angiotensin II↗

PubMed1996

Effects of short- and long-term sympathectomy on vasoconstrictor responses of the rat mesenteric arterial bed.

1. The effects of short- and long-term sympathectomy were evaluated on vasoconstrictor function of constantly perfused mesenteric arterial beds isolated from rats: the effects of short-term sympathectomy were assessed at 3 and 8 days after 6-hydroxydopamine (6-OHDA) treatment of adult rats; the effects of long-term sympathectomy were assessed in adult rats treated at youth with guanethidine. 2. The relative degree of residual sympathetic innervation of the mesenteric arterial preparations was assessed by responses to electrical field stimulation (EFS; 16 Hz, 1 ms, 90 V, 30 s). Control responses were 95.6 +/- 3.9 mmHg (n = 35). Responses after sympathectomy were: 3 days after 6-OHDA, 2.9 +/- 0.9 mmHg (n = 15) < 8 days after 6-OHDA, 14.1 +/- 2.1 mmHg (n = 14) < guanethidine, 21.1 +/- 4.1 mmHg (n = 16). 3. Three days after 6-OHDA treatment there was an increase in the sensitivities of response to vasopressin and endothelin, producing leftward shifts of the dose-response curves of 0.66 +/- 0.11 and 0.88 +/- 0.13 log units respectively (n = 7-11), and a small increase in sensitivity of responses to noradrenaline (NA) and ATP. The maximal response to 5-hydroxytryptamine (5-HT) was increased. In contrast, there was a decrease in maximal constriction to NA and to the alpha 1-adrenoceptor agonist methoxamine. The alpha 2-adrenoceptor agonist clonidine did not elicit vasoconstriction at basal tone. There was no difference in vasodilator responses to the beta-adrenoceptor agonist isoprenaline in preparations with tone raised with prostaglandin F2 alpha (PGF2 alpha; 0.1-0.3 microM). 4. Eight days after 6-OHDA sympathectomy there was no significant difference in sensitivities or maximal responses to ATP, vasopressin and endothelin, but a small increase in the sensitivity of responses to 5-HT. Maximal responses to NA and methoxamine were significantly lower than the controls, but sensitivities were similar. There was no significant difference in vasodilator responses to isoprenaline in PGF2 alpha-raised tone preparations. 5. After long-term guanethidine sympathectomy maximal responses to 5-HT and NA were significantly reduced. Responses to ATP, vasopressin and endothelin were unchanged. 6. In mesenteric arterial preparations from untreated rats, ouabain (0.1 mM), a blocker of the Na+/K+ pump, significantly augmented the sensitivity and maximal responses to EFS, NA, methoxamine and 5-HT. Responses to ATP, vasopressin and endothelin were unaffected. 7. It is concluded that in the rat mesenteric arterial bed, short-term sympathectomy, where only 3% of the sympathetic nerve-mediated response remained, results in non-uniform changes in sensitivity and maximal responses to different vasoconstrictors, which cannot be entirely explained by changes in the Na+/K+ pump. Most of these changes disappeared at 8 days after 6-OHDA treatment, when nerve-mediated responses had partially returned. After long-term guanethidine sympathectomy, there was little change in responses to vasoconstrictors, and nerve-mediated responses were reduced to 22%. Although the variable factors are complex, it appears that in general, changes in responses of smooth muscle to vasoconstrictor substances after sympathetic denervation only occur if there is near-complete loss of nerve-mediated responses.

Adrenergic alpha-Agonists↗

PubMed1990

Augmented potentiation of renal vasoconstrictor responses by thromboxane A2 receptor stimulation in the alloxan-diabetic rat.

Dose-response curves were obtained to bolus injections of noradrenaline (NA) and 5-hydroxytryptamine (5-HT) in blood and Krebs-perfused kidneys of male Wistar rats. Vasoconstrictor responses to both NA and 5-HT were significantly attenuated in blood-perfused kidneys of alloxan-treated 14 day diabetic rats compared with non-diabetic animals. Responses to low doses of NA were also significantly attenuated in Krebs-perfused kidneys from diabetic rats but responses to 5-HT were augmented. Dose-dependent potentiation of vasoconstrictor responses to NA and 5-HT in Krebs-perfused kidneys of both non-diabetic and diabetic rats occurred during infusion of the thromboxane A2 (TxA2)-mimetic U46619 [15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano) prosta-5Z, 13E-dienoic acid). The potentiation by U46619 (11 ng mL-1) was inhibited in both groups during infusion of the thromboxane receptor antagonist AH23848 [( 1 alpha(Z), 2 beta, 5 alpha]-(+/-)-7-[5[[(1,1'-biphenyl)-4-yl]methoxyl]-2-(4- morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid). Infusion of 5-HT in Krebs-perfused kidneys of non-diabetic rats, causing a rise in perfusion pressure of similar magnitude to that produced by infusion of 111ng mL-1 U46619, did not significantly affect responses to bolus injections of NA. Potentiation of vasoconstrictor responses to low concentrations of 5-HT by U46619 was significantly greater in Krebs-perfused kidneys of diabetic rats than kidneys from non-diabetic animals. Activation of vascular TxA2 receptors augments the vasoconstrictor effects of 5-HT in Krebs-perfused diabetic rat kidneys to a greater extent than in non-diabetic kidneys.

Animals↗

PubMed1998

Influence of nimodipine on vasoconstrictor responses in the hindquarters vascular bed of the cat.

The beneficial effects of the calcium-entry blocking agent, nimodipine, on the cerebral circulation have been extensively studied but less is known about its peripheral vascular effects. In the present study, the effects of nimodipine on vasoconstrictor responses were investigated in the hindquarters vascular bed of the cat under constant-flow conditions. Nimodipine decreased hindquarters vascular resistance and inhibited vasoconstrictor responses to BAY K8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyr idine-5-carboxylate) and noradrenaline, to the alpha1-adrenoceptor agonists phenylephrine and methoxamine, and the alpha2-adrenoceptor agonists BHT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo[5,4-d]azepine dihydrochloride) and UK 14304 (5-bromo-6-(2-imidazoline-2-yl-amino)quinoxaline). In addition to inhibiting alpha-adrenoceptor-mediated responses, nimodipine decreased responses to the vasoactive peptides angiotensin II and endothelin-1. Both the vasodilatory actions and inhibitory effects of nimodipine on vasoconstrictor responses were dose-dependent when the calcium antagonist was infused at rates of 0.1 and 1 microg min(-1). The results of the present study suggest that vasoconstrictor responses to alpha-adrenoceptor agonists and to the vasoactive peptides are dependent, in part, on an extracellular source of calcium. It is concluded that nimodipine and related dihydropyridine calcium-entry blocking agents may be effective in the treatment of peripheral vascular disorders in which adrenergic tone is increased or plasma levels of angiotensin II or endothelin-1 are elevated.

Adrenergic alpha-Agonists↗

PubMed2004

Circulating ATP-induced vasodilatation overrides sympathetic vasoconstrictor activity in human skeletal muscle.

Despite increases in muscle sympathetic vasoconstrictor activity, skeletal muscle blood flow and O2 delivery increase during exercise in humans in proportion to the local metabolic demand, a phenomenon coupled to local reductions in the oxygenation state of haemoglobin and concomitant increases in circulating ATP. We tested the hypothesis that circulating ATP contributes to local blood flow and O2 delivery regulation by both inducing vasodilatation and blunting the augmented sympathetic vasoconstrictor activity. In eight healthy subjects, we first measured leg blood flow (LBF) and mean arterial pressure (MAP) during three hyperaemic conditions: (1) intrafemoral artery adenosine infusion (vasodilator control), (2) intrafemoral artery ATP infusion (vasodilator), and (3) mild knee-extensor exercise (approximately 20 W), and then compared the responses with the combined infusion of the vasoconstrictor drug tyramine, which evokes endogenous release of noradrenaline from sympathetic nerve endings. In all three hyperaemic conditions, LBF equally increased from approximately 0.5 +/- 0.1 l min(-1) at rest to approximately 3.6 +/- 0.3 l min(-1), with no change in MAP. Tyramine caused significant leg vasoconstriction during adenosine infusion (53 +/- 5 and 56 +/- 5% lower LBF and leg vascular conductance, respectively, P < 0.05), which was completely abolished by both ATP infusion and exercise. In six additional subjects resting in the sitting position, intrafemoral artery infusion of ATP increased LBF and leg vascular conductance 27 +/- 3-fold, despite concomitant increases in venous noradrenaline and muscle sympathetic nerve activity of 2.5 +/- 0.2- and 2.4 +/- 0.1-fold, respectively. Maximal ATP-induced vasodilatation at rest accounted for 78% of the peak LBF during maximal bicycling exercise. Our findings in humans demonstrate that circulating ATP is capable of regulating local skeletal muscle blood flow and O2 delivery by causing substantial vasodilatation and negating the effects of increased sympathetic vasoconstrictor activity.

Adenosine↗

PubMed1988

Vasoconstriction is amplified by autoregulation during vasoconstrictor-induced hypertension.

This study investigated the degree to which autoregulation of blood flow interacts with vasoconstrictors to determine vascular resistance. Anesthetized rats were instrumented with a Doppler flow probe on the superior mesenteric artery (SMA) to measure blood flow and for calculation of vascular resistance. An adjustable occluder was placed on the SMA to set local perfusion pressure at values independent of mean arterial pressure (MAP) even when MAP was increased by the vasoconstrictors. Infusion of angiotensin II (ANG II, 50-1,247 ng.kg-1.min-1) produced a dose-dependent rightward shift in the intestinal pressure-flow relationship and elevated MAP from 85 to 127 mmHg. Low doses of phenylephrine (PE, 2.5-12.4 micrograms.kg-1.min-1) failed to shift the pressure-flow curve but did increase arterial pressure from 83 to 102 mmHg. At higher doses (25-62 micrograms.kg-1.min-1), PE also shifted the pressure-flow curve to the right. Maintaining local perfusion pressure at different values during the infusion of ANG II or PE produced a family of dose-response curves, with each exhibiting a different maximum change in resistance. When local pressure was permitted to increase with MAP, the composite dose-response curve for resistance that was obtained reflected the influence of the rise in local pressure (i.e., auto-regulation) and vasoconstrictor dose. At low doses of PE the increase in vascular resistance was attributable solely to an autoregulatory response related to the rise in MAP and not due to the constrictor effects of PE. Thus these data indicate that the rise in MAP accompanying systemic infusion of a vasoconstrictor stimulates autoregulation to amplify the local increase in vascular resistance.

Angiotensin II↗

PubMed2002

Role of CO in attenuated vasoconstrictor reactivity of mesenteric resistance arteries after chronic hypoxia.

Chronic hypoxia (CH) is associated with a persistent reduction in systemic vasoconstrictor reactivity. Experiments on aortic ring segments isolated from CH rats suggest that enhanced vascular expression of heme oxygenase (HO) and resultant production of the vasodilator carbon monoxide (CO) may underlie this attenuated vasoreactivity after hypoxia. Similar to the aorta, small arteries from CH rats exhibit blunted reactivity; however, the regulatory role of CO in the resistance vasculature has not been established. Therefore, we examined the significance of HO activity on responsiveness to phenylephrine (PE) in the mesenteric circulation of control and CH rats. To document that the mesenteric bed demonstrates reduced reactivity after CH, we determined the vasoconstrictor responses of conscious, chronically instrumented male Sprague-Dawley rats to PE under control conditions and then immediately after exposure to 48 h CH (0.5 atm). All rats showed reduced mesenteric vasoconstriction to PE after CH. To examine the role of CO in reduced reactivity, small mesenteric arteries (100-200 microm intraluminal diameter) from control and 48-h CH rats were isolated and mounted on glass cannulas, pressurized to 60 mmHg and superfused with increasing concentrations of PE under normoxic conditions. Similar to the intact circulation, vessels from CH rats exhibited reduced vasoconstrictor sensitivity to PE compared with controls that persisted in the presence of nitric oxide synthase inhibition. The HO inhibitor, zinc protoporphyrin IX (5 microM) enhanced reactivity only in CH vessels. Additionally, a range of concentrations of the HO substrate heme-L-lysinate caused vasodilation in CH vessels but not in controls. Thus we conclude that CO contributes a significant vasodilator influence in resistance vessels after CH that may account for diminished vasoconstrictor responsiveness under these conditions.

Animals↗

PubMed1991

Selective inhibition of vasoconstrictor responses by platelet-activating factor in rat kidney.

We examined the effect of platelet-activating factor (PAF) on renal vascular reactivity in the pentobarbital sodium-anesthetized male Wistar rat. Intrarenal infusion of C16-PAF at hypotensive (2.5 ng.min-1.kg-1) or nonhypotensive (0.5 ng.min-1.kg-1) doses caused renal vasodilation and dose dependently antagonized the renal vasoconstrictor responses of intrarenal boluses of angiotensin II (ANG II) greater than norepinephrine (NE) greater than vasopressin (AVP). PAF infusion at the high dose did not alter non-receptor-mediated renal vasoconstriction induced by intrarenal KCl injection. The inhibitory effect of PAF on agonist-induced renal vasoconstriction was accentuated by eicosanoid synthesis inhibition (indomethacin or dexamethasone), unaffected by dopamine-receptor blockade (haloperidol) but was totally abolished by PAF receptor antagonism (L-659,989). In contrast, intrarenal infusion of a calcium channel antagonist (nimodipine) or an intracellular calcium channel antagonist (TMB-8) equally inhibited the renal vasoconstrictor responses of ANG II, NE, and AVP. Thus PAF can cause renal vasodilation in the rat kidney and dose-dependently antagonizes the renal vasoconstrictor responses of ANG II greater than NE greater than AVP. The inhibitory effect of PAF on renal vasoconstrictor responses is mediated by PAF receptors and does not appear to be due to a nonspecific membrane effect, reduction in calcium mobilization, or the release of vasodilatory eicosanoids or dopamine.

Animals↗

PubMed1977

beta-Receptor influence on lung vasoconstrictor responses to hypoxia and humoral agents.

The role of the adrenergic receptor in mediating pulmonary vascular responses to gaseous and humoral agents was investigated by use of epinephrine injections in the perfused feline pulmonary circulation. Alteration of the balance between alpha- and beta-adrenergic activity was quantified by measurement of decreasing vasoconstrictor activity to epinephrine and rising lobar tissue 3',5'-adenosine cyclic monophosphate (cAMP) levels. The increased beta-adrenergic activity thus generated was associated with marked reductions in the pulmonary vasoconstrictor responses to hypoxia, hypercapnic acidosis, and histamine, but not to serotonin. Repeated pulmonary vasodilations or increases in blood, but not pulmonary tissue, levels of cAMP induced by theophylline doses, which would not necessarily affect the beta-adrenergic activity, did not alter the pulmonary vasoconstrictor responses to hypoxia, hypercapnia, or histamine. These data support the significant role which the adrenergic system plays in mediating pulmonary vasoconstrictor responses to certain specific gaseous and humoral agents, and the specificity with which this mediation occurs serves to link hypoxia and histamine together so that the latter could serve as a mediator of the former.

Acidosis↗

PubMed2001

Multiple firing of single muscle vasoconstrictor neurons during cardiac dysrhythmias in human heart failure.

Single vasoconstrictor nerve fibers in humans normally fire only once but have the capacity to fire as many as eight times, per cardiac interval. Our laboratory recently demonstrated that the mean firing frequency of individual vasoconstrictor fibers is more than doubled in the sympathoexcitation associated with congestive heart failure (Macefield VG, Rundqvist B, Sverrisdottir YB, Wallin BG, and Elam M. Circulation 100: 1708--1713, 1999). However, the propensity to fire only once per cardiac interval was retained. In the present retrospective study, we tested the hypothesis that vasoconstrictor fibers fire more than once per cardiac interval in response to transient sympathoexcitatory stimuli, providing one mechanism for further increase of an already augmented sympathetic discharge. Six patients with congestive heart failure (New York Heart Association functional class II--IV; left ventricular ejection range 13--37%, average 22%) were studied at rest and during premature ectopic heartbeats. Analyzed for a total of 60 premature beats, the average firing probability of 10 vasoconstrictor fibers increased from 61 to 80% in the prolonged cardiac interval (i.e., reduced diastolic pressure) after premature beats. The incidence of multiple within-burst firing increased markedly, with two spikes being more common than one. Our results illustrate two different mechanisms (increases in firing probability and multiple within-burst firing), and indirectly indicate a third mechanism (recruitment of previously silent fibers), for acute sympathoexcitatory responses.

Adult↗

PubMed1999

Firing properties of single muscle vasoconstrictor neurons in the sympathoexcitation associated with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) in humans is associated with a marked sympathoexcitation, including an augmented muscle sympathetic nerve activity (MSNA) in intraneural multiunit recordings. In the present study, single-unit recording was used to evaluate whether the firing properties of individual muscle vasoconstrictor neurons can reveal underlying mechanisms for this increase in MSNA. METHODS AND RESULTS: Eight patients with CHF (NYHA class II to IV; left ventricular ejection fraction, 29+/-5%, mean+/-SEM) were studied. In standard multiunit recordings, MSNA burst incidence (bursts/100 heartbeats) ranged from 65% to 100% (88+/-5%). Using selective tungsten microelectrodes, we made recordings from 16 single muscle vasoconstrictor axons. Mean unit firing probability (ie, the percentage of cardiac intervals in which a single axon fired) was 54.5+/-5.2% (range, 21 to 89%), and mean firing frequency was 0.98+/-0.22 Hz (0.14 to 3.86 Hz), both of which were higher than seen previously in healthy subjects (P<0.001). Although single neurons occasionally generated multiple spikes per sympathetic burst, such multiple firing was rare and was not different from that seen in healthy subjects. CONCLUSIONS: An increased firing frequency of individual vasoconstrictor neurons is one mechanism for the increased number of multiunit MSNA bursts at rest in CHF. The neurons discharge in more diastoles than in healthy subjects (ie, firing probability is increased), but the likelihood of discharging >1 impulse per sympathetic burst is not increased. Despite the intense multiunit activity at rest, the firing characteristics of individual vasoconstrictor axons indicate a remaining capacity for transient increases of MSNA in CHF.

Adult↗

PubMed1990

Involvement of endothelin in the regulation of human vascular tonus. Potent vasoconstrictor effect and existence in endothelial cells.

Endothelin, a recently discovered endothelium-derived peptide, has been reported to produce potent vasoconstriction in various vessels of experimental animals. To study the involvement of endothelin in the regulation of vascular tonus in humans, isolated human mesenteric arteries were investigated by both pharmacological and immunohistochemical methods. The vasoconstrictor action of endothelin-1 was examined on ring segments of human mesenteric arteries. Endothelin-1 induced a slowly developing and sustained contraction, with an EC50 value (half-maximal effective concentration) of 2.9 x 10(-9) M, two orders of magnitude smaller than that of norepinephrine (EC50 of 3.9 x 10(-7) M), indicating that the vasoconstrictor action of endothelin-1 is about 100 times more potent than that of norepinephrine. The contractile effect of endothelin-1 was affected neither by adrenergic, cholinergic, histaminergic, nor serotonergic antagonists, nor by inhibitors of arachidonic acid metabolism. The vasoconstrictor response to endothelin-1 was effectively antagonized by nicardipine, a dihydropyridine Ca2+ channel blocker. Endothelin-1 profoundly augmented contractile response to Ca2+ in partially depolarized tissues. Immunohistochemical studies revealed for the first time that endothelin-like immunoreactivity was localized in endothelial cells of human mesenteric artery. The results of the present study indicate that endothelin-1 is one of the most potent vasoconstrictors in the human mesenteric artery and that it induces vasoconstriction via an ultimately accelerating Ca2+ influx through voltage-dependent Ca2+ channels. Since endothelin-1 can be located in human endothelial cells, it may play an important physiological or pathophysiological role.

Adult↗