Decrease In Forearm Blood Flow Research Articles

Smooth muscle-derived nitric oxide is elevated in isolated forearm veins in human alcoholic cirrhosis.

1. Cirrhosis is often complicated by disturbances in the systemic circulation. We have previously demonstrated decreased vascular responses to vasoconstrictors in forearm resistance arteries in subjects with alcoholic cirrhosis. In the current study we investigate the role of the potent endogenous vasodilator nitric oxide in the peripheral circulation of these patients. 2. Ten patients with alcoholic cirrhosis (Pugh grade A) and 10 age-matched control subjects were studied. The effect of blockade of nitric oxide synthesis was studied both in vivo in forearm resistance arteries using forearm venous occlusion plethysmography and in vitro in veins isolated from the forearm. The role of endothelium-derived nitric oxide was studied in vivo using the endothelium-dependent vasodilator acetylcholine. 3. Mean arterial pressure and forearm basal flow in vivo were similar in the two groups. The constrictor response (percentage decrease in forearm blood flow) to noradrenaline (100 ng/min) was 26% smaller in patients with cirrhosis (31.65 +/- 2.64%) than in control subjects (42.75 +/- 3.87%, P = 0.037). Constrictor responses to the nitric oxide synthase inhibitor NG-monomethyl-L-arginine were not different in the two groups. Dilator responses to acetylcholine were significantly attenuated in cirrhotic patients compared with control subjects. 4. To investigate the role of smooth muscle-derived nitric oxide in vitro, all veins were stripped of their endothelium. Responses to noradrenaline were significantly diminished in veins isolated from patients with cirrhosis compared with control subjects. Incubation with the nitric oxide synthase inhibitor N omega-nitro-L-arginine had no effect on responses to noradrenaline in veins from control subjects but significantly enhanced the maximal response to noradrenaline by 23.95% (range 3.77-100%, P = 0.043) in veins from patients with cirrhosis. 5. Responses to noradrenaline were attenuated in vivo in forearm resistance arteries in patients with alcoholic cirrhosis. This impairment was also apparent in forearm isolated veins, stripped of the endothelium. Our data exclude a major role for endothelium-derived nitric oxide but highlight a possible role for smooth muscle-derived nitric oxide.

CARDIOVASCULAR RESPONSES TO INSPIRATORY AND EXPIRATORY THRESHOLD LOADED BREATHING 1189

During exercise, ventilatory work is increased. The increase in whole body oxygen uptake is linearly related to the increased ventilatory work. However, because of mechanical events and stimulation of receptors in the thorax, blood flow redistribution to the respiratory muscles may not be adequately reflected by cardiac output changes. These thoracic perturbations may also affect peripheral blood flow. This study evaluated cardiovascular responses to resisted breathing using inspiratory (n=6) or expiratory (n=6) loads of 30 cm H2O. Subjects underwent strain gauge plethysmography for 4 min rest, 4 min of either inspiratory or expiratory loaded breathing, and 4 min recovery. Forearm blood flow (FBF) and heart rate (HR) were recorded continuously, while blood pressure was measured each minute. Results were averaged for rest, load, and recovery, then subjected to a repeated measures ANOVA. During expiratory loading, significant increases were seen in HR(8 bpm, p<.001) and mean arterial pressure (MAP) (9 mmHg, p<.01) along with a nonsignificant decrease in FBF. During inspiratory loading, HR increased significantly (6 bpm, p<.05), MAP showed a nonsignificant increase of 2 mm Hg, and FBF did not change. Differences in the responses to inspiratory and expiratory loading suggest that during resisted breathing the cardiovascular responses may be influenced by the stimulation of various intrathoracic receptors in addition to the increased metabolic cost of the added ventilatory work.

Angiotensin mediates forearm glucose uptake by hemodynamic rather than direct effects.

Insulin sensitivity may be improved with the angiotensin-converting enzyme inhibitor captopril, suggesting that inhibition of angiotensin II (Ang II) improves insulin resistance. However, the administration of systemic Ang II has also been associated with an improvement in rather than worsening of glucose utilization. Since both stimulating and antagonizing the renin-angiotensin system improve glucose uptake and both angiotensin-converting enzyme inhibitors and intravenous Ang II elicit skeletal muscle vasodilation, it is conceivable that hemodynamic factors rather than a direct effect of either Ang II or angiotensin-converting enzyme inhibitors on skeletal muscle metabolism modulate the increase in glucose utilization. The direct effects of Ang II on glucose extraction in intact human skeletal muscle have not been previously described. We investigated the effects of local infusion of Ang II on glucose uptake in the forearm of 20 healthy subjects. With the use of the isolated insulin-perfused forearm model, local plasma insulin values were raised to 100 mU/mL over fasting values and maintained there for a 90-minute infusion period. After the first 60 minutes of insulin alone, Ang II was infused into the brachial artery for the last 30 minutes. Intra-arterial Ang II infusion caused a 38% decrease in forearm blood flow (P <.05) and 59% increase in the arteriovenous glucose gradients (P <.05) to maintain a steady glucose utilization (a decrease of 4%, P=NS). Thus, local Ang II infusion does not impair insulin-stimulated glucose utilization. Furthermore, glucose extraction increases to compensate for the decrease in forearm blood flow (as the Fick principle would predict for freely diffusible substances). We conclude that the described increase in glucose utilization from systemic infusion of Ang II and during angiotensin-converting enzyme inhibitor treatment is mediated by hemodynamic factors rather than a direct effect of Ang II on skeletal muscle metabolism.

Effects of arginine vasopressin and 1-desamino-8-D arginine vasopressin on forearm vasculature of healthy subjects and patients with a V2 receptor defect

To assess which vasopressin receptor subtype mediates the vasodilation occurring in response to arginine vasopressin and 1-desamino-8-D (DD)-arginine vasopressin and whether nitric oxide is involved in these effects. Vasoactive effects of arginine vasopressin and DD-arginine vasopressin on forearm vasculature were studied in healthy subjects and in patients with congenital nephrogenic diabetes insipidus with a vasopressin type 2 (V2) receptor gene defect. Venous occlusion plethysmography was used to assess the forearm blood flow responses to the infusion of arginine vasopressin and its analogue into the brachial artery, in the presence and the absence of the nitric oxide synthase inhibitor L-NG-monomethyl-arginine (L-NMMA). In healthy subjects (n =10), DD-arginine vasopressin (0.1, 1 and 10 or 5, 10 and 20 ng/min per dl) induced a dose-related increase in forearm blood flow, but did not affect forearm blood flow in the patients with nephrogenic diabetes insipidus (n = 3). In two healthy subjects, seven increasing doses of arginine vasopressin (0.25-12 ng/min per dl) induced an initial decrease in forearm blood flow and then a gradual increase. In one of the patients, the same arginine vasopressin doses produced a persistent decrease in forearm blood flow. In the healthy subjects, infusion of L-NMMA reduced forearm blood flow significantly (n = 10). Subsequent administration of DD-arginine vasopressin during L-NMMA infusion produced a slight reduction in the forearm blood flow increase compared with DD-arginine vasopressin alone, but this was significant only for the absolute forearm blood flow increase induced by 10 ng/min per dl in all subjects. Infusion of arginine vasopressin in the presence of L-NMMA did not increase forearm blood flow significantly. In human forearm vasculature, extrarenal V2 receptors mediate the vasodilation induced by DD-arginine vasopressin or high doses of arginine vasopressin, whereas these receptors are not necessary for arginine vasopressin-induced vasoconstriction. The DD-arginine vasopressin-induced vasodilation seems to be mediated predominantly by a mechanism other than endothelial nitric oxide release, whereas arginine vasopressin-induced vasodilation seems to involve nitric oxide release only.

Phosphoramidon inhibition of the in vivo conversion of big endothelin-1 to endothelin-1 in the human forearm.

1. The vasoconstrictor peptide, endothelin-1 (ET-1) and a biologically inactive C-terminal fragment (CTF) are generated from an intermediate big ET-1 by a putative ET converting enzyme, sensitive to phosphoramidon. We have developed a procedure using selective solid-phase extraction and specific radioimmunoassays to measure the levels of immunoreactive (IR) big ET-1 and the products of conversion (ET-1 and CTF) in human plasma. These techniques have been used to determine the levels of the three peptides in venous plasma following local infusions of ET-1 and big ET-1, both alone and together with phosphoramidon. 2. Infusion of ET-1 into the brachial artery (5 pmol min-1) significantly increased (P < 0.05) IR ET levels from a basal level of 2.3 pM to 55.2 pM in plasma from the infused arm after 60 min of infusion. This corresponded with a marked decrease in forearm blood flow from a basal level of 2.6 ml dl-1 min-1 to 1.7 ml dl-1 min-1. The levels of IR big ET-1 and CTF were unchanged. Co-infusion of phosphoramidon (30 nmol min-1) with ET-1 had no significant effect on the plasma IR levels of ET, big ET-1, CTF, or blood flow. 3. Big ET-1 (50 pmol min-1) significantly increased (P < 0.05) venous concentrations of all three IR peptides after 60 min compared to basal (ET: from 2.2 to 7.7 pM, big ET-1; from 0 to 386.0 pM, CTF: from 0.2 to 37.0 pM). Forearm blood flow decreased significantly (P<0.05) from a basal level of 3.0 ml dl-1 min-1 to 1.6 ml dl-1 min-1.4. When phosphoramidon was co-infused with big ET-1, both the rise in IR ET and associated vasoconstriction were abolished. However, IR CTF was still detected, suggesting that either some conversion by phosphoramidon-insensitive enzyme(s) was occurring, and/or that CTF was being protected from further degradation by phosphoramidon.5. These data show that in the human forearm the activity of a phosphoramidon-sensitive ET converting enzyme is at least in part responsible for the vasoconstrictor properties of exogenous big ET-1. Furthermore, because measurable levels of newly synthesized ET-1 are likely to be rapidly reduced in the blood/plasma through receptor binding, assay of IR big ET-1 and CTF may be a more sensitive measure of ET-1 generation in disease.

Systemic hemodynamic, forearm vascular, renal, and humoral responses to sustained cardiopulmonary baroreceptor deactivation in well-compensated cirrhosis

The aim of this study was to assess baroreceptor function in well-compensated cirrhosis by determining the forearm vascular, renal, and humoral responses to sustained baroreceptor deactivation. The effect of sodium status on baroreceptor function was also assessed. Eight cirrhotic patients and 10 age- and sex-matched controls were studied twice after a 20 mmol and 200 mmol of sodium/d diet for 7 days. Systemic and renal hemodynamics, renal sodium handling, forearm blood flow, and neurohurioral factors were assessed before, during, and after the application of lower body negative pressure (LBNP) for 1 hour. Controls and cirrhotic patients had similar baseline mean arterial pressure, heart rate, forearm and renal hemodynamics. High-sodium intake resulted in suppression of sympathetic nervous activity in the controls (plasma norepinephrine, 1.06 ± 0.11 mmol/L on low vs. 0.76 ± 0.08 nmol/L on high sodium; P = 0.01) but not in the cirrhotic patients (1.35 ± 0.22 mmol/L on low vs. 1.26 ± 0.11 mmol/L on high sodium; P > 0.05). Both groups responded to LBNP with significant further increases in plasma norepinephrine, resulting in significant decreases in forearm blood flow on both sodium diets. Controls also responded with a significant worsening of renal hemodynamics on low-sodium diet only, but this was not observed in the cirrhotic patients on either diet. Therefore, in well-compensated cirrhotic patients: (1) sympathetic activation occurs despite an adequate, effective arterial filling, and this may contribute to sodium retention; and (2) baroreceptor function is normal. Apparent end organ unresponsiveness within the renal circulation may account for the lack of renal hemodynamic changes to reflex sympathetic stimulation.

Systemic hemodynamic, forearm vascular, renal, and humoral responses to sustained cardiopulmonary baroreceptor deactivation in well-compensated cirrhosis

The aim of this study was to assess baroreceptor function in well-compensated cirrhosis by determining the forearm vascular, renal, and humoral responses to sustained baroreceptor deactivation. The effect of sodium status on baroreceptor function was also assessed. Eight cirrhotic patients and 10 age- and sex-matched controls were studied twice after a 20 mmol and 200 mmol of sodium/d diet for 7 days. Systemic and renal hemodynamics, renal sodium handling, forearm blood flow, and neurohumoral factors were assessed before, during, and after the application of lower body negative pressure (LBNP) for 1 hour. Controls and cirrhotic patients had similar baseline mean arterial pressure, heart rate, forearm and renal hemodynamics. High-sodium intake resulted in suppression of sympathetic nervous activity in the controls (plasma norepinephrine, 1.06 +/- 0.11 nmol/L on low vs. 0.76 +/- 0.08 nmol/L on high sodium; P = 0.01) but not in the cirrhotic patients (1.35 +/- 0.22 nmol/L on low vs. 1.26 +/- 0.11 nmol/L on high sodium; P > 0.05). Both groups responded to LBNP with significant further increases in plasma norepinephrine, resulting in significant decreases in forearm blood flow on both sodium diets. Controls also responded with a significant worsening of renal hemodynamics on low-sodium diet only, but this was not observed in the cirrhotic patients on either diet. Therefore, in well-compensated cirrhotic patients: (1) sympathetic activation occurs despite an adequate, effective arterial filling, and this may contribute to sodium retention; and (2) baroreceptor function is normal. Apparent end organ unresponsiveness within the renal circulation may account for the lack of renal hemodynamic changes to reflex sympathetic stimulation.

Measurement of C-Terminal Fragment of Big Endothelin-1

We developed a procedure for individual measurement of big endothelin-1 (big ET-1) and the two products of big ET-1 conversion (ET-1 and C-terminal fragment (CTF) of big ET-1 (big ET-1(22-38)), using selective solid-phase extraction and specific radioimmunoassays. These techniques were used to measure the levels of these peptides in extracts of human plasma after brachial artery infusions of big ET-1. Infusion of big ET-1 (50 pmol/min, n = 6) caused a decrease in forearm blood flow from 3.03 to 1.55 ml/dl/min after 60 min (p < 0.05). In agreement, the levels of plasma immunoreactive (IR) big ET-1, ET, and CTF were significantly increased from basal levels in the infused arm (from undetectable to 386 pM, 2.2-7.5 pM, and 0.17-37 pM, respectively; p < 0.05). In the presence of the metalloprotease inhibitor phosphoramidon (30 nmol/min), the increase in IR-ET and the associated vasoconstriction were abolished. However, IR-CTF was still detected, suggesting that either some conversion by phosphoramidon-insensitive endothelin-converting enzyme (ECE) was occurring and/or that CTF was being preserved from further proteolysis by phosphoramidon. These data confirm that exogenous big ET-1 is locally converted to ET-1 and CTF in the human forearm, at least in part by a phosphoramidon-sensitive ECE. Furthermore, because measurable levels of newly synthesized ET-1 are probably rapidly reduced as a result of receptor binding, the assay of IR-CTF may be a more sensitive measure of the overexpression of ET-1 in disease.

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)

Serotonin-induced vasodilatation in the human forearm is mediated by the "nitric oxide-pathway": no evidence for involvement of the 5-HT3-receptor.

The "nitric oxide (NO)-pathway" is presumed to be involved in acetylcholine (ACh)- and serotonin (5-hydroxytryptamine, 5-HT)-mediated vasodilatation. In addition, both the 5-HT-induced transient and persistent vasodilator responses in the forearm vascular bed are abolished by the 5-HT3/5-HT4-receptor antagonist ICS 205-930 ([1H]-indol-3-carbonic-acid-tropine-ester HCl, tropisetron). We studied 5-HT-mediated vasodilatation in the forearm vascular bed of normotensive volunteers, using venous occlusion plethysmography. Intraarterial (i.a.) infusions of 5-HT, ACh, and sodium nitroprusside (SNP) all caused an increase in forearm blood flow (FBF). Single infusions of ondansetron and granisetron also caused an increase in FBF. Infusion of the NO scavenger and guanylate-cyclase antagonist methylene blue (MB) did not change FBF, whereas the arginine analogue NG-monomethyl-L-arginine (L-NMMA) caused a decrease in FBF, which became less pronounced when infusions were repeated. Unlike ICS 205-930, concomitant infusions of the selective 5-HT3-receptor antagonists ondansetron (OND) and granisetron (GRAN) did not antagonize the transient or persistent vasodilator responses to 5-HT. These findings suggest the involvement of a 5-HT4-receptor. L-NMMA and MB both reduced the persistent vasodilator response to 5-HT, indicating involvement of the NO pathway. Neither MB nor L-NMMA influenced the endothelium-independent vasodilator response to SNP. ACh-induced vasodilatation was markedly potentiated by MB but was not affected by L-NMMA. The mechanism by which MB enhances the vasodilator response to ACh remains unclear.

Effects of oxygen breathing and erythropoietin on hypoxic vasodilation in uremic anemia.

Loss of hypoxic vasodilation has been proposed as a causative factor in the development of hypertension in dialysis patients treated with recombinant human erythropoietin (rHuEPO). Venous occlusion plethysmography was therefore performed on 22 dialysis patients (aged 23 to 71 years, dialysis duration 6 to 260 months, 8 males) before and after correction of anemia with rHuEPO, 50 U/kg 3x/week (Hb: 7.4 +/- 0.3 vs. 10.8 +2- 0.3 g/dl, P less than 0.0001). Hypertension (greater than 15 mm Hg rise in mean BP) occurred in 11 patients. The study was performed while breathing room air and repeated after breathing 60% O2 for 10 to 12 minutes. Before rHuEPO therapy, total blood O2 content increased from 10.01 +/- 0.39 to 10.32 +/- 0.29 ml O2/100 ml blood with breathing 60% O2 (P less than 0.01). After correction of anemia it was 14.65 +/- 0.40 ml O2/100 ml blood on room air (P less than 0.001). There was a significant decrease in forearm blood flow (7.9 +/- 0.5 vs. 6.5 +/- 0.6 ml/min/100 ml tissue, P less than 0.05) and increase in forearm vascular resistance (12.8 +/- 0.1 vs. 16.8 +/- 0.2 mm Hg/ml/min/100 ml tissue, P less than 0.05) with O2 breathing prior to rHuEPO therapy in the blood pressure responders, but no change in these parameters in the group in which blood pressure remained unchanged. When all patients were studied on room air, forearm vascular resistance rose significantly after correction of anemia (13.0 +/- 0.8 vs. 16.3 +/- 0.8 mm Hg/ml/min/100 ml tissue, P less than 0.05), compared with that prior to rHuEPO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

EFFECT OF PETHIDINE PREMEDICATION AND HALOTHANE ANAESTHESIA ON UPPER LIMB BLOOD FLOW

Forearm blood flow (FBF), hand blood flow (HBF) and arterial pressure were measured in 12 patients, before and after premedication with pethidine and during halothane anaesthesia. After pethidine there was a significant (P less than 0.01) increase in HBF (180%) and decreased hand vascular resistance; heart rate also increased significantly (P less than 0.05), whilst mean arterial pressure (MAP) did not change. The large increase in HBF without hypotension suggests a local effect. With halothane, there was a significant (P less than 0.05) decrease in MAP, increase in HBF and decrease in hand vascular resistance compared with either control or effects produced by pethidine; there was a significant decrease in FBF and reversal of the action of pethidine on forearm vascular resistance.

Acute Hemodynamic Effects of Pinacidil in Hypertensive Patients with and without Propranolol Pretreatment

To study the systemic and regional hemodynamic effects of the new antihypertensive agent pinacidil, the authors administered intravenously two doses of pinacidil (0.1 mg/kg) to patients with hypertension after 3 days of randomized, double-blind pretreatment with either propranolol or placebo. Pinacidil administration decreased systemic arterial pressure and total peripheral vascular resistance in both groups of patients. It also decreased pulmonary artery wedge pressure, and increased cardiac output, heart rate, and plasma norepinephrine levels; the changes in cardiac output and heart rate were attenuated by propranolol pretreatment. In addition, propranolol-pretreated patients responded to pinacidil with a decrease in forearm blood flow. In contrast, pinacidil administration exerted no significant effects on right atrial pressure, stroke volume, or mean pulmonary arterial pressure alone or in combination with propranolol. The results show that pinacidil is a potent arterial dilator but has little effect on the venomotor tone in patients with hypertension.

Effects of 5-Hydroxytryptamine on Capillary and Arteriovenous Anastomotic Blood Flow in the Human Hand and Forearm and in the Pig Hind Leg

The effects of intraarterially infused serotonin (5-HT) on capillary and arteriovenous anastomotic (AVA) blood flow were investigated in the hand and forearm of 19 healthy volunteers, and in the hind leg of six anesthetized pigs using radioactive microspheres with a diameter of 15 microns. The 5-HT2-receptor antagonist ketan-serin was used in an attempt to identify the receptors involved. None of the drugs in the doses used induced systemic hemodynamic effects. Low doses of 5-HT significantly increased forearm blood flow with a maximum response at the dose of 1 ng/kg/min (68 +/- 14%, p less than 0.05), whereas only at the highest dose of 80 ng/kg/min was a net decrease in forearm blood flow measured (-28 +/- 6%, p less than 0.05). Conversely, finger blood flow was not influenced by the lower doses of 5-HT, whereas a major reduction was observed at the highest dose (-90 +/- 3%). Ketanserin increased both total forearm blood flow and AVA blood flow. The drug blunted the constrictor response to 5-HT in the forearm but only slightly attenuated this response in the finger. The percentage AVA blood flow in the human hand and forearm was not influenced by an infusion of 5-HT at 80 ng/kg/min alone. However, after pretreatment with ketanserin, which itself increased the AVA component, this dose of 5-HT significantly reduced AVA flow. In the pig, total femoral blood flow was not influenced by 5-HT, but AVA blood flow was significantly reduced and capillary skin blood flow increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Arterial and Venous Effects of Serotonin in the Forearm of Healthy Subjects Are Not Age-Related

The influence of age on the regional arterial and venous effects of serotonin (5-HT) was investigated in 13 young (aged 22-31 years) and seven older (aged 50-69 years) healthy volunteers. Single-dose infusions of 5-HT (1, 10, and 80 ng/kg/min) and of the 5-HT2 receptor antagonist ritanserin (50, 150, and 500 ng/kg/min) were administered into the brachial artery. Subsequently, the relative arterial and venous effects of the highest dose of 5-HT were investigated. Forearm blood flow (FBF) and maximum venous outflow (MVO) were measured by venous occlusion plethysmography. Heart rate (HR) and intraarterial (i.a.) blood pressure were recorded semicontinuously. In both age groups, 5-HT induced an initial transient arterial dilation, followed by a persistent increase in FBF for the doses of 1 and 10 ng/kg/min and a relative small decrease in FBF for the highest dose. In both age groups, the highest dose of 5-HT induced a similar large reduction in MVO (p less than 0.05 for both). The reduction in MVO was attenuated by ritanserin (500 ng/kg/min, p less than 0.05 for both groups). In the younger subjects, this dose of ritanserin also unmasked an arterial dilator effect of the highest dose of 5-HT (p less than 0.05). The single infusions of ritanserin did not influence FBF significantly in either study group. No significant differences were observed between the age groups. These results show that in the forearm of healthy subjects arterial and venous vascular responses to 5-HT were not age-related. In the arterial vascular bed, 5-HT acted predominantly as a vasodilator; at high doses, mainly venous vasoconstriction was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of oral administration of nifedipine on neuropeptide Y- and noradrenaline-induced vasoconstriction in the human forearm.

Neuropeptide Y (NPY) has recently been shown be co-released with noradrenaline (NA) from sympathetic nerves and to cause arterial vasoconstriction in experimental animals and man. The effect of a single oral dose (10 mg capsule) of nifedipine on NPY- and NA-induced reductions of forearm blood flow (FBF) was studied in seven healthy volunteers. Intra-arterial infusions of NPY and NA into the brachial artery before nifedipine caused dose-dependent reductions in FBF with threshold doses of 0.2 and 0.03 nmol x min-1, respectively. The response to NPY was slower in onset and more long lasting than that to NA. Forty-five min after administration of nifedipine, FBF and heart rate had increased significantly (by 49% and seven beats x min-1, respectively, P less than 0.001), while no significant change was observed in systemic blood pressure. The NPY-induced decrease in FBF was slightly but significantly attenuated after compared to before nifedipine (19 +/- 6 vs. 28 +/- 5% at 1.0 nmol NPY x min-1; P less than 0.01). The response to NA was, however, not significantly altered by nifedipine. In conclusion, the NPY-induced reduction in FBF in man was only slightly prevented and the NA response not significantly affected by oral nifedipine administration in a clinically used dose. This suggests that this calcium antagonist, in the present dosage, does not, to any major extent, inhibit the vasoconstrictor effect of NPY or NA in man in vivo.

Modulation of Noradrenaline Release by Peripheral Presynaptic α2-Adrenoceptors in Humans

The existence of a functional presynaptic alpha 2-adrenoceptor that modulates noradrenaline release was studied in 15 volunteers. Noradrenaline spillover was measured in the forearm under basal conditions, during single intraarterial infusions of the alpha-adrenoceptor antagonists yohimbine (alpha 2, 1.0 micrograms/kg/min) and doxazosin (alpha 1, 0.1 microgram/kg/min), and during intraarterial infusion of tyramine (1.25 microgram/kg/min) alone and in combination with either and both alpha-adrenoceptor antagonists. Forearm blood flow (FBF) was measured by plethysmography. Noradrenaline spillover was calculated as the product of FBF and the difference in arterial and venous plasma noradrenaline. The various infusions did not induce systemic hemodynamic effects. Tyramine induced a dose-dependent decrease in FBF (p less than 0.001) which was reduced by yohimbine (p less than 0.01), as well as by doxazosin (p less than 0.01), and abolished by the combination of both alpha-adrenoceptor antagonists (p less than 0.001). During basal conditions noradrenaline spillover was virtually zero, and this was not changed by yohimbine or doxazosin. Local infusion of tyramine increased noradrenaline spillover (p less than 0.05). This tyramine-induced noradrenaline spillover was further increased by yohimbine (p less than 0.01) and by the combination of yohimbine and doxazosin (p less than 0.001). The single infusion of doxazosin only enhanced the tyramine-induced noradrenaline spillover significantly when it was preceded by yohimbine. The present investigation supports the concept of a presynaptic alpha 2-adrenoceptor modulating noradrenaline release from sympathetic nerve endings via a negative feedback mechanism in humans. Stimulation of noradrenaline release might help to reveal this mechanism.

Vasoconstrictor effects in vivo and plasma disappearance rate of neuropeptide Y in man

Vascular effects of neuropeptide Y (NPY) and noradrenaline (NA) were studied in six human volunteers. Systemic infusion of human NPY for 40 min (5 pmol × kg − × min −1) increased arterial plasma NPY-like immunoreactivity (NPY-LI) from 12±2 to 356±30 pM. This concentration caused no systemic cardiovascular effects. The disappearance curve for NPY-LI was biphasic; the slopes of the two phases corresponding to half lifes of 4.1±0.4 and 20±2 min respectively. Close i.a. infusion of human NPY in the forearm caused a slowly developing and dose dependent decrease in forearm blood flow (FBF) and increase in venous tone with maximal values of 44±6 and 235±81 % of control respectively at 5 nmol × min −1. The corresponding values for NA (5 nmol × min −1) were 21±9 and 489±78 % of control. A threshold concentration for a decrease in FBF was obtained at a plasma NPY-LI of 3.7±0.6 nM. The decrease in FBF caused by NPY was maintained for a much longer period compared to that of NA.

Effects of digitalis on cardiopulmonary baroreflex in man.

We examined whether digitalis augments cardiopulmonary baroreflex control of forearm vascular resistance in normal young men. Cardiopulmonary baroreceptor input was reduced with lower body negative pressure (LBNP) at 10 and 20 mmHg which decreased central venous pressure (CVP) but did not alter blood pressure (BP) or heart rate (HR). Decreases in forearm blood flow and increases in forearm vascular resistance with LBNP were greater after cedilanid than before and the slope of the regression line relating changes in central venous pressure and those in forearm vascular resistance was steeper after cedilanid. Vasoconstrictor responses to a cold pressor test did not differ before and after cedilanid, which suggested that augmented responses to LBNP after cedilanid were not due to a generalized change in reflex control. These results suggest that cedilaniid augments the tonic inhibitory influence of cardiopulmonary baroreceptors in normal men.

Digitalis-induced augmentation of cardiopulmonary baroreflex control of forearm vascular resistance.

We sought to determine whether digitalis augments cardiopulmonary baroreflex control of forearm vascular resistance in normal young men. Cardiopulmonary baroreceptor input was reduced with lower body negative pressure (LBNP) at 10 and 20 mm Hg, which decreased central venous pressure but did not alter blood pressure or heart rate. Decreases in forearm blood flow and increases in forearm vascular resistance with LBNP were greater after administration of lanatoside C (Cedilanid) than before, and the slope of the regression line relating changes in central venous pressure and those in forearm vascular resistance was steeper after lanatoside C. Vasoconstrictor responses to the cold pressor test did not differ before and after lanatoside C, which suggested that augmented responses to LBNP after the drug were not caused by a generalized change in reflex control. These results suggest that lanatoside C augments the tonic inhibitory influence of cardiopulmonary baroreceptors in normal men.