Intra-arterial Norepinephrine Research Articles

Efficacy Assessment of Cerebral Perfusion Augmentation through Functional Connectivity in an Acute Canine Stroke Model.

Ischemic stroke disrupts functional connectivity within the brain's resting-state networks (RSNs), impacting recovery. This study evaluates the effects of norepinephrine and hydralazine (NEH), a cerebral perfusion augmentation therapy, on RSN integrity in a hyperacute canine stroke model. Fifteen adult purpose-bred mongrel canines, divided into treatment and control (natural history) groups, underwent endovascular induction of acute middle cerebral artery occlusion (MCAO). Postocclusion, the treatment group received intra-arterial norepinephrine (0.1-1.52 µg/kg/min, adjusted for 25-45 mm Hg above baseline mean arterial pressure) and hydralazine (20 mg). Resting-state fMRI (rs-fMRI) data were acquired with a 3T scanner by using a blood oxygen level dependent-EPI sequence (TR/TE = 1400 ms/20 ms, 2.5 mm slices, 300 temporal positions). Preprocessing included motion correction, spatial smoothing (2.5 mm full width at half maximum), and high-pass filtering (0.01 Hz cutoff). Functional connectivity within RSNs were analyzed through group-level independent component analysis and weighted whole-brain ROI-to-ROI connectome, pre- and post-MCAO. NEH therapy significantly maintained connectivity post-MCAO in the higher-order visual and parietal RSNs, as evidenced by thresholded statistical mapping (threshold-free cluster enhancement P corr > .95). However, this preservation was network-dependent, with no significant (P corr < .95) changes in the primary visual and sensorimotor networks. NEH demonstrates potential as a proof-of-concept therapy for maintaining RSN functional connectivity after ischemic stroke, emphasizing the therapeutic promise of perfusion augmentation. These insights reinforce the role of functional connectivity as a measurable end point for stroke intervention efficacy, suggesting clinical translatability for patients with insufficient collateral circulation.

Hepatic Arterial Blood Flow Modulation in Patients with Hepatocellular Carcinoma: A Pilot Study of the Influence of Intraarterial Norepinephrine Assessed with CT Perfusion

PurposeThis pilot study aims to evaluate the effect of hepatic intraarterial norepinephrine injection in vasculature modulation for hepatocellular carcinoma (HCC) tumors. Materials and MethodsThis is a single-center prospective study of patients with HCC with proven single-lobe tumors > 3 cm. Eight patients were included, with a mean age of 63 y ± 8. All patients had Barcelona Clinic Liver Cancer stage B HCC and an Eastern Cooperative Oncology Group performance status of 0. Mean tumor size was 6.1 cm ± 1.8; all tumors were hypervascular. Patients underwent CT hepatic perfusion before and after injection of 24 μg of norepinephrine intraarterially (4 μg/mL; total 6 mL injected at a rate of 1 mL/s). Color-coded perfusion maps were used to assess the effects of local therapy on hepatic perfusion values. Tumor-to-liver ratio (TLR) was calculated from the ratio of tumor perfusion to background liver perfusion value. ResultsSeven of 8 patents had significant (P = .04) absolute increase in tumor perfusion vs background liver, varying from incremental (–2 mL/min/100 mL) to 290 mL/min/100 mL. There was a nonsignificant increase in TLR from 2.7 ± 1.3 to 2.9 ± 1.4 after norepinephrine injection (P = .8). Mean peak time to maximal increase in tumor perfusion after injection was 6.1 s (range, 4.5–9.1 s). Norepinephrine injection was well tolerated without major adverse events. ConclusionsNorepinephrine causes increased blood flow toward HCC tumors, but with a corresponding smaller increase in blood flow to noncancerous liver tissue, with no observed systemic side effects.

Treatment with a Nitric Oxide-Donating NSAID Alleviates Functional Muscle Ischemia in the Mouse Model of Duchenne Muscular Dystrophy

In patients with Duchenne muscular dystrophy (DMD) and the standard mdx mouse model of DMD, dystrophin deficiency causes loss of neuronal nitric oxide synthase (nNOSμ) from the sarcolemma, producing functional ischemia when the muscles are exercised. We asked if functional muscle ischemia would be eliminated and normal blood flow regulation restored by treatment with an exogenous nitric oxide (NO)-donating drug. Beginning at 8 weeks of age, mdx mice were fed a standard diet supplemented with 1% soybean oil alone or in combination with a low (15 mg/kg) or high (45 mg/kg) dose of HCT 1026, a NO-donating nonsteroidal anti-inflammatory agent which has previously been shown to slow disease progression in the mdx model. After 1 month of treatment, vasoconstrictor responses to intra-arterial norepinephrine (NE) were compared in resting and contracting hindlimbs. In untreated mdx mice, the usual effect of muscle contraction to attenuate NE-mediated vasoconstriction was impaired, resulting in functional ischemia: NE evoked similar decreases in femoral blood flow velocity and femoral vascular conductance (FVC) in the contracting compared to resting hindlimbs (ΔFVC contraction/ΔFVC rest = 0.88±0.03). NE-induced functional ischemia was unaffected by low dose HCT 1026 (ΔFVC ratio = 0.92±0.04; P>0.05 vs untreated), but was alleviated by the high dose of the drug (ΔFVC ratio = 0.22±0.03; P<0.05 vs untreated or low dose). The beneficial effect of high dose HCT 1026 was maintained with treatment up to 3 months. The effect of the NO-donating drug HCT 1026 to normalize blood flow regulation in contracting mdx mouse hindlimb muscles suggests a putative novel treatment for DMD. Further translational research is warranted.

Treatment with a nitric oxide‐donating NSAID counteracts functional muscle ischemia in dystrophin‐deficient mdx mice

The dystrophin‐deficient muscles of boys with Duchenne muscular dystrophy (DMD) and mdx mice, a model of DMD, are susceptible to ischemia during exercise due to loss of neuronal nitric oxide synthase (nNOS) from the sarcolemma. We hypothesized that treatment with a NO‐donating drug would compensate for nNOS deficiency and counteract functional muscle ischemia. We fed mdx mice a standard diet containing 1% soybean oil (vehicle) or a low (15 mg/kg) or high (45 mg/kg) dose of a NO‐releasing derivative of the NSAID flurbiprofen (n = 12/group). After 1 month of treatment, we compared vasoconstrictor responses to intra‐arterial norepinephrine (NE) in resting and contracting hindlimbs. In vehicle‐treated mice, the usual effect of muscle contraction to attenuate NE‐mediated vasoconstriction was impaired as shown by similar decreases in femoral vascular conductance in contracting vs resting hindlimbs (attenuation ratio = 0.88 ± 0.03). NE‐induced ischemia was also seen in the contracting hindlimbs of mice treated with low dose drug (0.92 ± 0.04; P &gt; 0.05 vs vehicle), but was markedly attenuated in mice treated with high dose drug (0.22 ± 0.03; P &lt; 0.05 vs vehicle or low dose). The beneficial effect of the high dose was maintained with treatment up to 3 months. These data demonstrate a robust anti‐ischemic effect of a NO‐donating drug in mdx mice and suggest a potential use in the treatment of DMD patients. Supported by NicOx, 801130.

Restoration of sarcolemmal nNOS is essential to normalize α‐adrenoceptor control of muscle blood flow in transgenic mdx mice

Neuronal nitric oxide synthase (nNOS) is abundantly expressed in skeletal muscle, where it is localized to the sarcolemma via the dystrophin glycoprotein complex (DGC). We previously reported that nNOS‐derived NO blunts α‐adrenergic vasoconstriction in contracting muscle and that this protective effect is absent in boys with muscular dystrophy and in mdx mice in which mutations in the dystrophin gene disrupt the DGC and displace nNOS. We therefore hypothesized that restoration of sarcolemmal nNOS is essential to rescue the normal contraction‐induced attenuation of α‐adrenergic vasoconstriction. In the resting hindlimbs of transgenic mdx mice expressing minidystrophin genes that restore the DGC with (ΔH2‐R15) or without (ΔH2‐R19) restoring nNOS, intraarterial norepinephrine evoked similar decreases in femoral blood flow and vascular conductance. These constrictor responses were markedly attenuated by 81±3% in the contracting hindlimbs of the ΔH2‐R15 transgenics (p&lt;0.05 vs. rest; n=8), but by only 16±4% in the ΔH2‐R19 transgenics (p&gt;0.05 vs. rest; n=6) and by 10±5% in transgene negative littermates (n=3). Minigene expression yielded similar results in mdx4cv mice, which have a different dystrophin mutation and genetic background than mdx mice. These data indicate that recovery of sarcolemmal nNOS is essential to restore normal blood flow regulation in mdx skeletal muscle. Supported by the NIH and MDA.

Vasoconstrictor hyporeactivity can be reversed by antioxidants in patients with advanced alcoholic cirrhosis of the liver and ascites

Hyperdynamic circulation and systemic vasodilation complicate cirrhosis of the liver and are related to vasoconstrictor hyporeactivity. We investigated whether impaired vasoconstrictor responsiveness may be overcome by antioxidants in patients with decompensated alcoholic cirrhosis. Controlled clinical study. University setting. Nine patients with liver cirrhosis Child-Pugh grade C and nine healthy age-matched volunteers. Forearm blood flow responses to intra-arterial norepinephrine, angiotensin II, and the nitric oxide synthase inhibitor N-monomethyl-l-arginine were measured by strain-gauge plethysmography and compared between groups of patients. To assess the role of oxidative stress, the antioxidant vitamin C (24 mg/min) was administered locally into the brachial artery, and forearm blood flow responses were reassessed. Plasma concentrations of vitamin C were lower in patients with cirrhosis (p < .05). In patients with cirrhosis, the reactivity to norepinephrine and angiotensin II was markedly reduced (p < .05 vs. controls). Coadministration of vitamin C completely restored the potency of vasoconstrictors to that in controls but had no effect in healthy subjects. No changes were observed in time-control experiments in cirrhosis patients (n = 3) employing vehicle coinfusion. The response to N-monomethyl-L-arginine was comparable between groups and not affected by vitamin C. Oxidative stress with consumption of antioxidants seems to play an important role in the development of vasoconstrictor hyporeactivity in patients with cirrhosis. Antioxidant therapy may be a promising clinical approach to restore vasoconstrictor hyporeactivity in these patients.

Reduced endogenous endothelin-1–mediated vascular tone in chronic renal failure

Endothelin-1 generated by the vascular endothelium contributes to basal vascular tone and blood pressure in healthy humans. Plasma concentrations of endothelin-1, which are elevated in chronic renal failure (CRF), may contribute to increased vascular tone. We investigated the contribution of endogenous and exogenous endothelin-1 to the maintenance of vascular tone in patients with CRF (creatinine > or = 200 mumol/liter) and in age- and sex-matched healthy subjects. In a series of experiments, we measured forearm vascular responses to intra-arterial norepinephrine (30 to 240 pmol/min), endothelin-1 (5 pmol/min), the selective endothelin A (ETA) receptor antagonist BQ-123 (3 mg/hr), the mixed endothelin-converting enzyme and neutral endopeptidase inhibitor phosphoramidon (30 nmol/min), and the selective neutral endopeptidase inhibitor thiorphan (30 nmol/min). The maximum reduction in forearm blood flow (FBF) to norepinephrine in CRF (33 +/- 7%) was similar to that in controls (43 +/- 7%, P = 0.53). Endothelin-1 also produced a similar reduction in FBF in CRF (35 +/- 6%) and controls (36 +/- 5%, P = 0.81). BQ-123 increased FBF in CRF (11 +/- 4%) but significantly less than in controls (44 +/- 10%, P = 0.02). Phosphoramidon increased FBF in CRF (68 +/- 20%), again significantly less than in controls (181 +/- 41%, P = 0.001). Thiorphan reduced FBF similarly in CRF (22 +/- 6%) and controls (14 +/- 6%, P = 0.39). Responses to phosphoramidon were substantially greater than to BQ-123. These studies show that endogenous generation of endothelin-1 contributes to the maintenance of resting vascular tone in patients with CRF, as well as in healthy subjects. Although the contribution of endogenous endothelin-1 to resting vascular tone appears to be reduced in CRF, ETA receptor antagonism, and particularly endothelin-converting enzyme inhibition, should be explored as means by which to reduce vascular tone and blood pressure in patients with CRF.

Acute Hypertension Impairs Endothelium-Dependent Vasodilatation

1. Previous investigations have demonstrated an impaired endothelium-dependent vasodilatation (EDV) in patients with hypertension. The present study aimed to investigate if an acute rise in blood pressure to hypertensive levels impairs EDV in otherwise normotensive subjects. 2. Twenty-seven young, healthy, normotensive subjects were studied. Eight of these underwent evaluation of EDV and endothelium-independent vasodilatation (EIDV) by means of forearm blood flow measurements during local intra-arterial infusions of methacholine (2 and 4 micrograms/min) and sodium nitroprusside (5 and 10 micrograms/min), before and after 1 h of sustained hypertension, induced by noradrenaline given intravenously. Identical measurements were made in 11 subjects before and during concomitant local intra-arterial infusion of noradrenaline without change in blood pressure and eight subjects were studied during saline infusions. 3. One hour of sustained hypertension (diastolic blood pressure > 95 mmHg) significantly attenuated both forearm blood flow (17.4 +/- 6.8 versus 27.4 +/- 6.8 ml.min-1.100 ml-1 tissue at baseline, P < 0.05) and forearm vascular resistance decrease (3.2 +/- 0.87 versus 7.4 +/- 2.5 units at baseline, P < 0.05) during methacholine infusion. These attenuations were significantly more pronounced for methacholine than for sodium nitroprusside (P < 0.05). In contrast, local intra-arterial noradrenaline infusions impaired vasodilatation induced by methacholine and sodium nitroprusside to a similar extent. Saline infusions did not change either EDV or EIDV. 4. Thus, an acute rise in blood pressure to hypertensive levels induced by noradrenaline impaired EDV more than EIDV in otherwise normotensive subjects, while no such selective effect of local noradrenaline was seen, suggesting that a high blood pressure impairs endothelial vasodilator function.

Contribution of collagen, elastin, and smooth muscle to in vivo human brachial artery wall stress and elastic modulus.

The contributions of collagen, elastin, and smooth muscle to arterial mechanical properties in the in vivo human artery are not known. We used a recently developed intravascular ultrasound technique to measure total brachial artery wall stress and incremental elastic modulus (Einc) in seven normal human subjects at baseline and after intra-arterial norepinephrine (1.2 micrograms) and nitroglycerin (100 micrograms). Then we applied a modified Maxwell model to estimate the elastic modulus of elastin (EE); the recruitment of collagen fibers supporting wall stress; and the differential contributions of collagen, elastin, and smooth muscle to wall stress and Einc over a wide range of pressure and smooth muscle tone. With this model, EE was 3 x 10(6) dynes/cm2. Collagen fibers were recruited increasingly as transmural arterial pressure increased and reached a value of approximately 5% to 6% at 100 mm Hg under each of the conditions studied. Isobaric smooth muscle contraction resulted in a small decrease in total wall stress and no significant change in total Einc while shifting the predominant element contributing to these mechanical parameters from collagen in parallel with the smooth muscle to collagen in series with the smooth muscle. In contrast, isometric smooth muscle contraction produced large increases in total wall stress (from 0.11 x 10(6) dynes/cm2 after nitroglycerin administration to 1.35 x 10(6) dynes/cm2 after norepinephrine administration) and Einc (from 3.84 x 10(6) dynes/cm2 after nitroglycerin administration to 57.8 x 10(6) dynes/cm2 after norepinephrine administration) entirely as a result of the additional contribution of the smooth muscle and its associated series collagen. This study describes a technique for determining arterial elastic properties and a model that can be used to estimate a number of mechanical parameters of the human brachial artery in vivo. This technique may be useful in studies of the arterial elastic properties of arteries in patients with vascular pathology.

Erythropoietin enhances vascular responsiveness to norepinephrine in renal failure

The mechanism of hypertension induced by recombinant human erythropoietin (rHuEPO) is unclear but may include an increase in peripheral vascular resistance. We studied changes of arterial pressure and plasma endothelin in nine consecutive hemodialysis patients before, and 6 and 12 weeks after, starting rHuEPO. In six patients, changes in cardiac index (CI), stroke index (SI) and total peripheral resistance index (TPRI) were measured by bioimpedance, and forearm vascular responsiveness to intra-arterial norepinephrine (30 to 240 pmol/min) and endothelin-1 (5 pmol/min) were assessed. Six healthy age and sex matched subjects also underwent assessment of forearm vascular responsiveness to norepinephrine and endothelin-1. Treatment with rHuEPO significantly increased hemoglobin and mean arterial pressure (MAP). TPRI also increased by 35 +/- 11%. Plasma endothelin, although elevated basally, remained unchanged. Intra-arterial infusion of norepinephrine caused a maximal increase in forearm vascular resistance (FVR) of 17 +/- 9% before rHuEPO, significantly less than the 32 +/- 5% increase in healthy control subjects (P = 0.04). The response increased to 65 +/- 15% (P = 0.03) after 12 weeks rHuEPO treatment (P = 0.51 vs. controls). Endothelin-1 caused a maximal increase of FVR at 60 minutes of 45 +/- 24% before rHuEPO, which was not significantly different from controls, and tended to decrease with rHuEPO therapy. The response to endothelin-1, but not norepinephrine, correlated inversely with MAP (r = -0.52; P = 0.03) and TPRI (r = -0.51; P = 0.04). In conclusion, these studies show that anemia in chronic renal failure is associated with depressed vascular responsiveness to norepinephrine which is restored by rHuEPO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasoconstriction with norepinephrine causes less forearm insulin resistance than a reflex sympathetic vasoconstriction.

We used the insulin-perfused human forearm model to assess the effects of vasoconstriction induced with norepinephrine on the extraction of glucose in the forearm in two groups of healthy young volunteers. The norepinephrine findings were compared with a previously studied group in which vasoconstriction has been caused by reflex activation of the sympathetic nervous system. The aim of the study was to determine the relative importance of hemodynamic and receptor-mediated mechanisms of insulin resistance. Plasma insulin, arterial and venous glucose samples, and forearm blood flow were measured at 10-minute intervals during a 30-minute baseline, a 60-minute intra-arterial insulin infusion, and during 30 minutes of insulin infusion plus vasoconstriction. Group 1 (n = 14) had physiological vasoconstriction induced by inflation of bilateral thigh cuffs to 40 mm Hg to cause pooling of blood in the lower extremities and reflex vasoconstriction in the forearm; group 2 (n = 8) had intra-arterial infusion of norepinephrine to achieve the same degree of vasoconstriction as seen with inflation of thigh cuffs in group 1. Subjects in group 3 (n = 7) had infusion of intra-arterial norepinephrine to achieve a twofold increase in physiological vasoconstriction. With a physiological decrease in forearm blood flow (group 1), there was a 19% decrease in forearm blood flow resulting in a 23% reduction in glucose uptake in the forearm (P < .03). The same degree of reduction in forearm blood flow with a predominantly alpha-adrenergic agonist, norepinephrine (group 2), causes much less insulin resistance (a decrease in utilization of 13%) (P < .04).(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide‐mediated changes in vascular reactivity in pregnancy in spontaneously hypertensive rats

1. To examine the mechanisms which may account for pregnancy-induced vasodilatation in spontaneously hypertensive rats (SHR), we have investigated the changes in vascular reactivity and the effects of endothelial nitric oxide (NO) inhibition in the in situ blood-perfused, mesenteric resistance vessels of 18-20 day pregnant SHR. The effects of NG-nitro-L-arginine (L-NOARG) were compared in pregnant and nonpregnant SHR and gestation matched normotensive Wistar-Kyoto (WKY) rats. 2. Intra-arterial mean blood pressures (MBP) were similar in pregnant and nonpregnant SHR. Basal perfusion pressures (BPP) were decreased in pregnant compared with nonpregnant SHR. Pregnant WKY had lower MBP and BPP than either pregnant or nonpregnant SHR. 3. Vasoconstrictor responses to electrical stimulation (ES) and intra-arterial noradrenaline (NA) were decreased in pregnant compared with nonpregnant SHR. These responses were still greater in pregnant SHR when compared with pregnant WKY. Vascular reactivity to angiotensin II (AII) in pregnant SHR was reduced to a similar level to that in pregnant WKY. 4. L-NOARG (5 mg kg-1, i.v.), an inhibitor of nitric oxide synthase, increased MBP and BPP in all groups. After L-NOARG, BPP were equalized between pregnant and nonpregnant SHR. Pregnant WKY still showed lower MBP and BPP than SHR groups. 5. L-NOARG potentiated vascular responses to ES, NA and AII in all groups. The blunted vascular responses to NA and ES were normalized and the reactivity to AII was only partially reversed in pregnant SHR compared with nonpregnant SHR. Pregnant WKY still had much lower vascular responses to ES and NA than either pregnant or nonpregnant SHR. L-NOARG enhanced vascular responses to All to a greater extent in pregnant SHR than in pregnant WKY.6. These results demonstrate that blunted responses to NA and ES were NO-dependent, while diminished reactivity to AII was only partially dependent on NO in the in situ blood perfused mesenteric resistance vessels of pregnant SHR.7. The present results in pregnant SHR differ from our previous finding with pregnant normotensive WKY, in which blunted responses to NA, but not to ES, were equalized by L-NOARG. Pregnancy induced vasodilatation in hypertensive rats appears to be more dependent on endothelial NO than in normotensive WKY. A defect of the endothelial NO generating pathway which promotes vasodilatation in pregnancy may contribute to the predisposition of women with essential hypertension to develop pre-eclampsia.

Mechanisms of vasodilatation in pregnancy: studies of the role of prostaglandins and nitric‐oxide in changes of vascular reactivity in the in situ blood perfused mesentery of pregnant rats

1. To examine the possible mechanisms of the vasodilatation and blunted pressor responses in late pregnancy, we have studied vascular reactivity of the in situ blood perfused mesenteric resistance vessels of 18-20 day pregnant Wistar-Kyoto rats (WKY). 2. Intra-arterial mean blood pressure (MBP) was lower in pregnant rats than in nonpregnant controls. There was no significant difference in basal mesenteric perfusion pressure (BPP) between groups. 3. Vascular reactivity to electrical stimulation (ES) or intra-arterial noradrenaline (NA), angiotensin II (AII) and arginine vasopressin (AVP) was decreased in the preparations from pregnant rats compared to that from nonpregnant controls. Noradrenaline spillover into mesenteric venous blood following ES was similar in pregnant and nonpregnant animals. 4. Indomethacin (5 mg kg-1, i.v.), an inhibitor of cyclo-oxygenase, induced significant increases in reactivity to ES in both pregnant and nonpregnant groups while potentiating the responses to NA and AII in nonpregnant animals only and having no effect on AVP-induced contractions in the preparations from either pregnant or nonpregnant animals. 5. NG-nitro-L-arginine (L-NOARG) (5 mg kg-1, i.v.), an inhibitor of nitric-oxide synthase, increased MBP and BPP in both pregnant and nonpregnant animals, but the difference in MBP between groups was still evident. 6. L-NOARG enhanced mesenteric vascular responses to ES, NA and AII in both pregnant and nonpregnant groups. Only the difference in NA responses between groups was abolished after pretreatment with L-NOARG. 7. These data show that vasoconstrictor responses to a variety of agonists are decreased in the in situ blood-perfused mesenteric resistance vessels of pregnant rats. Increase in endothelial-dependent nitric oxide generation could contribute to the vasodilatation seen in pregnancy but other mechanisms might also be involved. Cyclo-oxygenase products are not responsible for any decreased contractile responses in this preparation.

Effects of norepinephrine on endothelium-dependent vasodilation of forearm resistance vessels.

Endothelium-dependent dilatation of forearm resistance vessels is attenuated in patients with heart failure. Activation of the sympathetic nervous system could cause this abnormality by way of vasoconstriction and chemical inactivation of nitric oxide. The effects of concurrent intra-arterial norepinephrine infusions (25, 50 and 100 ng/min) on forearm blood flow responses to equipotent doses of an endothelium-dependent vasodilator, methacholine (0.3 and 1.5 micrograms/min), and an endothelium-independent vasodilator, nitroprusside (1 and 5 micrograms/min), were studied in 12 normal subjects. Norepinephrine infusions increased the mean plasma norepinephrine from 255 pg/ml at baseline to 460, 629, and 1089 pg/ml, respectively. Basal forearm blood flow was reduced from 2.9 to 1.6 ml/min/100 ml of forearm volume at the highest dose (p < 0.01). The average response to the lowest dose of methacholine (4.5 ml/min/100 ml) was not significantly reduced by concurrent infusion of norepinephrine (4.4, 4.2, and 4.3 ml/min/100 ml, respectively), whereas the response to the higher dose of methacholine (8.9 ml/min/100 ml) tended to be lower (7.2, 6.7, and 7.4 ml/min/100 ml, respectively) but did not attain statistical significance. Methacholine induced vasodilation was not more sensitive to norepinephrine than nitroprusside responses. Lower body negative pressure (-20 mm Hg) also significantly reduced baseline forearm flow and increased plasma norepinephrine but did not effect either methacholine or nitroprusside induced vasodilation. Sympathetic stimulation induced by infusion of norepinephrine or lower body negative pressure is not a potent antagonist to endothelium-dependent vasodilation of the forearm vasculature. These data suggest that sympathetic activation does not completely explain the abnormal endothelium-dependent vasodilation seen in patients with heart failure.

Pressor responsiveness in corticosteroid-induced hypertension in humans.

In previous studies short-term cortisol increased cold pressor responses and the rise in forearm vascular resistance accompanying intra-arterial norepinephrine without an increase in overall resting sympathetic nervous activity. The present study examined whether these alterations in pressor response are glucocorticoid or mineralocorticoid effects, or both. Normal male subjects (n = 12) received either fludrocortisone, 0.3 mg daily (n = 6), or dexamethasone, 3 mg daily (n = 6), for 7 days. Hemodynamic studies were performed before and on day 7 of treatment. Fludrocortisone increased body weight from 69.3 +/- 1.8 to 71.1 +/- 2 kg (p less than 0.001), cardiac output from 5.0 to 6.0 l/min (+/- 0.1, p less than 0.01), mean arterial pressure from 82 +/- 1 to 91 +/- 1 mm Hg (p less than 0.001), cold pressor responsiveness from 13.0 to 39.0 mm Hg/ml per 100 ml per minute (R units) (+/- 4.3, p less than 0.01), and forearm vascular response to intra-arterial norepinephrine (F = 59.4, p less than 0.01) and angiotensin II (F = 30.8, p less than 0.01) infusions. Total peripheral resistance fell from 22.0 to 20.1 mm Hg/l per minute (+/- 0.3, p less than 0.05). Dexamethasone did not increase cardiac output, 5.1 to 5.2 l/min (+/- 0.1), or body weight but did increase mean arterial pressure from 82 +/- 3 to 91 +/- 3 mm Hg (p less than 0.001), cold pressor responsiveness from 8.6 to 17.1 R units (+/- 2.8, p less than 0.05), and forearm vascular response to intra-arterial norepinephrine (F = 33.0, p less than 0.01) and angiotensin II (F = 54.9, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence from lack of decentralization‐induced supersensitivity that β2‐ adrenoceptors of the cat nictitating membrane are non‐innervated

The right superior of cervical sympathetic trunk of cats was sectioned preganglionically under anaesthesia. Six days later the blood pressure, heart rate and contractions of the left (control) and right (decentralized) nictitating membranes were recorded under chloralose anaesthesia (80 mg kg-1). The alpha-adrenoceptor-mediated contractile responses of the nictitating membrane to intravenous adrenaline were greater on the decentralized side than the control side, with a significant shift of the dose-response curve to the left. After phentolamine (8 mg kg-1 i.v.), adrenaline administered intra-arterially exerted beta-adrenoceptor-mediated relaxation of the nictitating membranes. However, there was no difference in the sensitivity or magnitude of responses between decentralized and control sides. In a separate series of experiments, the alpha-adrenoceptor-mediated contractile responses of the nictitating membrane to intra-arterial noradrenaline displayed supersensitivity on the decentralized side, the dose-response curve being significantly shifted to the left. In the same animals, the beta-adrenoceptor-mediated relaxation responses to intra-arterial isoprenaline were non-significantly greater on the decentralized side, presumably because of raised tone. However, when expressed as a percentage of the maximum relaxation, there was no difference in sensitivity. This study shows that the alpha-adrenoceptor-mediated contractile response of the nictitating membrane displays supersensitivity after preganglionic section of the sympathetic innervation. This is presumably because of an up-regulation arising from loss of sympathetic traffic onto the receptor. The relaxation response is mediated via adrenoceptors of the beta 2-subtype and shows no supersensitivity. This suggests that these receptors are not under the influence of the sympathetic innervation.

Pulse Oximeter Failure Thresholds in Hypotension and Vasoconstriction

The degree of systolic hypotension causing failure and recovery were tested simultaneously with three oximeters (CSI 504US, Nellcor N-200, and Ohmeda 3740) in nine normal male volunteers. Perfusion of the right hand was slowly reduced and restored by 1) elevation of the hand plus systemic hypotension with nitroprusside if needed (EL); 2) clamp compression of the brachial artery (CL); 3) brachial cuff inflation (CU); and 4) intraarterial norepinephrine (NE). With EL, pulse pressure was normal whereas right radial arterial systolic pressure (SP) was 25.3 +/- 12.4 mmHg at failure and 34.1 +/- 13.3 at recovery (mean of three oximeters, n = 189). With CL, pulse pressure fell more than did mean pressure, and failure occurred at 37.3 +/- 9.8 and recovery at 46.8 +/- 17.6 mmHg, n = 84. With CL, threshold of function, defined as the average of failure SP and recovery SP, was 47.1 +/- 13.5, n = 41 for Nellcor, higher than for either CSI (38.7 +/- 14.5, n = 17) or Ohmeda (36.0 +/- 3.4, n = 26) (P less than 0.05). With EL, no difference among instruments was found (mean 29.7 +/- 12.8, n = 189). Threshold was 58.2 +/- 8.4, n = 17 with CU if cuff inflation was slow (filling veins), but recovery was similar to EL after rapid cuff occlusion. With NE, SP threshold was increased to 58.3 +/- 21.0 with CL but only to 41.0 +/- 13.8 with EL.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenaline facilitates neurogenic vasoconstriction in borderline hypertensive subjects

Adrenaline facilitates the neural release of endogenous noradrenaline by stimulating prejunctional beta-receptors on adrenergic nerve endings. Recently, we demonstrated the functional significance of this action in the control of vascular resistance in young subjects with normal blood pressure. In the present study, we tested the hypothesis that the effects of adrenaline on neurogenic vasoconstriction are exaggerated in humans with borderline hypertension. Forearm blood flow was measured simultaneously in the experimental and contralateral arms of seven young men with borderline hypertension. We compared forearm vasoconstrictor responses to a reflex stimulus to noradrenaline release (lower-body negative pressure, LBNP) and to intra-arterial infusion of noradrenaline before and 30 min after brachial artery infusion of adrenaline (50 ng/min). These doses had no systemic effects. In the experimental arm, the vasoconstrictor response to LBNP was 65% greater 30 min after the adrenaline infusion (P = 0.075), whereas the response to intra-arterial noradrenaline decreased by 36% (P greater than 0.1). Forearm vascular responses to LBNP in the contralateral control arm that did not receive adrenaline were similar before and after the adrenaline infusion. The ratio of forearm vasoconstrictor responses (i.e. the increase in forearm vascular resistance) with LBNP to the forearm vasoconstrictor response to noradrenaline in the experimental arm was used as an index of neural release of the neurotransmitter noradrenaline. This ratio increased from 0.8 to 2.1 (P less than 0.05) after the adrenaline infusion. These facilitatory neural after-effects of adrenaline were similar in magnitude to our previous observation in young normotensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal reserpine exposure alters cardiovascular parameters in rat offspring

Electrocardiograms (ECGs) and blood pressures (BPs) were recorded and evaluated in postnatal rats that had been exposed in utero to 0.375 or 0.75 mg reserpine/kg/day sc on Gestational Days (GD) 12–15. These doses caused reduced maternal weight gain during pregnancy and decreased pup body weight at birth, as well as reduced heart weight during the preweaning period. There were no changes in other maternal parameters or in litter size. During the postweaning period, pup body weight was reduced only at the highest dose at Postnatal Days (PND) 30 and 60. By PND 342, the weight reduction was no longer significant when compared to controls. Lead II ECGs were recorded in conscious animals on PND 30, 60, and 342; BPs were recorded in anesthetized animals on PND 346. Several ECG parameters were attenuated by prenatal reserpine exposure: R wave and S wave amplitudes and the QRS interval in males, and the PR interval in females. The BP recordings showed that low-dose males had significantly higher pulse pressures than did high-dose males, but neither group was significantly different from controls. Following an intraarterial norepinephrine challenge, resultant peak pulse pressure was greater in high-dose females than in controls. These results indicate that subtle, long-term, sex-specific alterations in cardiovascular parameters were produced by prenatal reserpine treatment at doses that altered body weight in young animals at PNDs 30 and 60, but this change was no longer apparent at PND 342.

Atrial natriuretic factor attenuates sympathetic neuroeffector responses in hindlimb vasculature of rabbits

To determine whether atrial natriuretic factor (ANF) affects vasoconstrictor responses to electrical stimulation of sympathetic nerves or intra-arterial norepinephrine (NE), changes in perfusion pressure were measured during lumbar sympathetic nerve stimulation (LSNS, 1-8 Hz), or administration of NE (50-200 ng), in an isolated constant flow-perfused hindlimb of chloralose-anesthetized rabbit before and after intra-arterial infusion of ANF (0.5 ng.mL-1.min-1). ANF significantly attenuated responses to LSNS (relative potency, RP = 0.65) and to NE (RP = 0.47). We conclude that ANF attenuates vasoconstrictor responses to both LSNS and NE. Thus ANF alters sympathetic nervous system mediated changes in vascular resistance possibly at the neuroeffector site.