Splanchnic and renal vasoconstrictor and metabolic responses to neuropeptide Y in resting and exercising man.

The local clearance of neuropeptide Y (NPY) and whether NPY influences splanchnic and renal metabolism in man have not been investigated previously. The influence of NPY on splanchnic and renal blood flows at physiologically elevated levels has also not been investigated. The effects of a 40-min constant NPY infusion (3 pmol kg-1 min-1) at rest and during 130 min of exercise (50% of VO2max) were studied in six healthy subjects and compared with resting and exercising subjects receiving no NPY. Blood samples were drawn from arterial, hepatic and renal vein catheters for the determination of blood flows (indicators: cardiogreen and para-aminohippuric acid [PAH]), NPY, catecholamines, glucose, lactate and glycerol. NPY infusion was accompanied by: (1) significant fractional extraction of NPY-like immunoreactivity (NPY-Li) by splanchnic tissues at rest (58 +/- 5%) and during exercise (53 +/- 6%), while no arterial-venous differences could be detected across the kidney; (2) a reduction in splanchnic and renal blood flows of up to 18 and 13% respectively (P less than 0.01-0.001) at rest without any additional changes during exercise; and (3) metabolic changes as reflected in: (a) a more marked fall in arterial glucose during exercise compared to the reference group (P less than 0.05); (b) a 35% lower splanchnic glucose release (P less than 0.01) during exercise due to diminished glycogenolysis (P less than 0.01); and (c) a lower arterial lactate level (18% P less than 0.05) together with unchanged splanchnic lactate uptake during exercise, suggesting reduced lactate production by extrahepatic tissues. The disappearance of plasma NPY-Li after the infusions was biphasic with two similar half-lives at rest (4 and 39 min) and during exercise (3 and 43 min).     

Splanchnic and renal vasoconstrictor and metabolic responses to neuropeptide Y in resting and exercising man

The local clearance of neuropeptide Y (NPY) and whether NPY influences splanchnic and renal metabolism in man have not been investigated previously. The influence of NPY on splanchnic and renal blood flows at physiologically elevated levels has also not been investigated. The effects of a 40-min constant NPY infusion (3 pmol kg^-1 min^-1) at rest and during 130 min of exercise (50% of Vo_2max) were studied in six healthy subjects and compared with resting and exercising subjects receiving no NPY. Blood samples were drawn from arterial, hepatic and renal vein catheters for the determination of blood flows (indicators: cardiogreen and paraaminohippuric acid [PAH]), NPY, catecholamines, glucose, lactate and glycerol. NPY infusion was accompanied by: (1) significant fractional extraction of NPY-like immunoreactivity (NPY-Li) by splanchnic tissues at rest (58±5%) and during exercise (53±6%), while no arterial–venous differences could be detected across the kidney; (2) a reduction in splanchnic and renal blood flows of up to 18 and 13% respectively (P < 0.01–0.001) at rest without any additional changes during exercise; and (3) metabolic changes as reflected in: (a) a more marked fall in arterial glucose during exercise compared to the reference group (P < 0.05); (b) a 35% lower splanchnic glucose release (P < 0.01) during exercise due to diminished glycogenolysis (P < 0.01); and (c) a lower arterial lactate level (18%P < 0.05) together with unchanged splanchnic lactate uptake during exercise, suggesting reduced lactate production by extrahepatic tissues. The disappearance of plasma NPY-Li after the infusions was biphasic with two similar half-lives at rest (4 and 39 min) and during exercise (3 and 43 min).     

Splanchnic release of neuropeptide Y during prolonged exercise with and without beta-adrenoceptor blockade in healthy man.

Plasma levels of neuropeptide Y- (NPY-) like immunoreactivity (Li) and catecholamines in the brachial artery, femoral vein and hepatic vein were monitored during physical exercise in a total of 19 healthy men to detect any local release from the leg and splanchnic region. In addition, propranolol (0.15 mg kg-1 i.v.) was given during exercise to determine whether beta-adrenoceptor blockade influenced the increase in plasma NPY-Li and catecholamines. Leg and splanchnic blood flows were measured using indicator dilution techniques and indocyanine green dye. Graded arm exercise was associated with elevations of arterial plasma NPY-Li (two-fold) and noradrenaline (12-fold) comparable to those previously found during leg exercise. During prolonged leg exercise a significant vasoconstriction and release of NPY-Li and noradrenaline was observed in the splanchnic region while no net exchange was found in the exercising leg where marked vasodilatation occurred. Administration of propranolol during exercise produced a clear-cut additional increase in plasma NPY-Li as well as in noradrenaline and adrenaline. It is concluded that splanchnic vasoconstriction during exercise is associated with a local release of both NPY-Li and noradrenaline. The additional elevation in plasma NPY-Li and catecholamines after propranolol during exercise is probably due to increased nerve activity and/or decreased disposal.     

Influence of somatostatin on splanchnic haemodynamics in patients with liver cirrhosis

The influence of intravenous somatostatin infusion (7.6 micrograms/min) on systemic and splanchnic haemodynamics was examined in 10 patients with liver cirrhosis and portal hypertension. The hepatic vein catheter technique was employed and indocyanine green dye was injected to evaluate hepatic blood flow. Mean wedged hepatic venous pressure fell from 24.9 +/- 2.8 in the basal state to 21.4 +/- 3.2 mmHg (P less than 0.2) at 60 min of infusion and the mean arterial pressure decreased from 87 +/- 5 to 80 +/- 6 mmHg (P less than 0.05). The rate of indocyanine green dye disappearance decreased from 8.7 +/- 1.9 to 6.6 +/- 1.7%/min (P less than 0.001) during the infusion, indicating decreased hepatic blood flow. Arterial-hepatic venous oxygen differences rose from 69 +/- 11 to 78 +/- 11 ml/l. Blood glucose levels fell from 4.84 +/- 0.31 to 3.79 +/- 0.33 mmol/l at 60 min of infusion (P less than 0.005). It is concluded that a continuous infusion of somatostatin in patients with liver cirrhosis and portal hypertension causes a decreased hepatic blood flow with augmented hepatic oxygen extraction and a modest reduction in mean wedged hepatic venous pressure. In view of the magnitude of the observed haemodynamic changes the findings do not suggest an important role for somatostatin in the treatment of patients with bleeding oesophageal varices.     

Endothelin-1: increased plasma clearance, pulmonary affinity and renal vasoconstriction in young smokers.

Pulmonary and renal haemodynamics and elimination of endothelin-1 (ET-1) were studied in six young smokers in response to 20 min intravenous infusion of ET-1 (4 pmol kg(-1) min(-1)) after smoking. At 20 min of ET-1 infusion fractional ET-1 extractions in the lungs and kidneys were 60 +/- 2 and 60 +/- 7%, respectively. Cardiac output and renal blood flow (RBF) fell by 18 +/- 4% (P<0.05) and 34 +/- 5% (P<0.01). Mean systemic arterial pressure increased (P<0.05) whereas pulmonary pressures were unchanged. Compared with previously published data in non-smokers (Weitzberg et al., 1991, 1993) basal arterial ET-1 and ET-1-values during ET-1 infusion were lower with a more rapid return to basal value. Smokers had higher pulmonary extraction of ET-1 at the same pulmonary arterial concentration (P<0.05). RBF reduction was more pronounced (P<0.05). Systemic vascular resistance increased while pulmonary vascular resistance did not increase as in non-smokers. Increased plasma clearance and more efficient pulmonary elimination of ET-1 lowers the arterial level in young smokers. In addition ET-1 evokes more pronounced renal vasoconstriction in these individuals.     

Effect of adrenaline on exchange of glucose in leg tissues and splanchnic area. A comparison with the metabolic response to surgical stress

Surgical trauma is accompanied by increased energy expenditure and raised arterial concentrations of adrenaline and glucose. In order to study the acute effects of an adrenaline infusion on glucose metabolism and oxygen uptake in the leg and splanchnic bed, adrenaline was administered at a rate giving plasma concentrations of adrenaline similar to those in connection with abdominal surgery. Seven healthy males participated in the study. Adrenaline 40 ng/(min X kg body weight) (0.22 nmol/(min X kg body weight] was infused producing a plasma concentration of 2.77 +/- 0.42 nmol/l (mean +/- SEM). Leg and splanchnic blood flows and the femoral and hepatic arterio-venous differences for oxygen, glucose, lactate and other metabolites were determined. Measurements were made before and between 30 and 40 min after the start of the adrenaline infusion. Following the infusion of adrenaline the leg blood flow increased by 140% and hepatic blood flow by 25%. The leg oxygen uptake increased by 30%, but no significant increase in splanchnic oxygen uptake was observed. The arterial glucose concentration rose by 35%. Splanchnic glucose output increased X 2.5, but no significant increase in leg glucose uptake was observed. Leg release of gluconeogenic substrates increased but only lactate and glycerol uptake increased in the splanchnic bed. Leg blood flow increased more than that usually seen after surgery, whereas leg oxygen uptake and splanchnic oxygen uptake was higher in the immediate postoperative period. Splanchnic glucose release increased more during the infusion than in connection with surgery. It is concluded that adrenaline at a plasma concentration similar to that during and immediately after surgery can induce changes in glucose metabolism which are of the same order or more pronounced than those seen in connection with abdominal surgery.     

Reflex activation of renal nerves in humans: differential effects on noradrenaline, dopamine and renin overflow to renal venous plasma

Using a thermodilution technique for renal venous blood flow measurements, renal sympathetic nerve activity was evaluated in 10 healthy volunteers by measurements of noradrenaline (NA) and dopamine (DA) overflow to renal venous plasma. Renin release was measured simultaneously. At rest, arterial adrenaline (ADR) levels were 0.24 +/- 0.03 nmol-1 and NA and DA levels were higher in renal venous than in arterial plasma (1.24 vs. 0.98 and 0.14 vs. 0.09 nmol l-1, respectively, P less than 0.01 for both). The renal extraction of ADR from arterial plasma was 40 +/- 4%. ADR extractions were used to correct for the renal removal of NA or DA from arterial plasma when calculating the renal overflow of NA or DA to renal venous plasma. At rest, the thus corrected renal venous overflows of NA and DA were 228 +/- 34 and 29 +/- 3 pmol min-1, respectively. Isometric handgrip exercise (IHG) increased renal vascular resistance (RVR) by 20% and NA overflow by 123%, without altering renin release or DA overflow. Vasodilatation induced by dihydralazine (HYDR) increased NA overflow by 63% (P less than 0.05) and elevated DA overflow by 107 +/- 59%. The renal DA/NA overflow ratio was reduced from 0.15 to 0.06 (P less than 0.01) during IHG, but was not altered by HYDR. Renin release increased by 377% after HYDR (P less than 0.001) and was correlated to the reduction of mean arterial pressure but not changes in NA overflow. Thus, both IHG and HYDR increased renal sympathetic nerve activity, although differential effects on renin release and DA overflow were observed. The dissociation of renal NA and DA responses suggests that the human kidney may have a subset of dopaminergic nerves.     

Ammonia metabolism during exercise in man

Physical exercise is accompanied by increased plasma levels of ammonia but it is not known whether this rise primarily reflects accelerated formation in muscle or decreased removal by the liver. Consequently, leg and splanchnic exchange of ammonia was examined, using the catheter technique, in 11 healthy subjects at rest, during three consecutive 15 min periods of bicycle exercise at gradually increasing work loads (35%, 55% and 80% of maximum oxygen uptake) and for 60 min during post-exercise recovery. The basal arterial ammonia level was 22 +/- 2 mumol/l, the concentration rose curvilinearly in response to increasing work loads (peak value 84 +/- 12 mumol/l), and fell rapidly after exercise, reaching basal levels after 30-60 min. A linear regression was found for ammonia levels in relation to lactate concentrations at rest and during exercise (r = 0.85, P less than 0.001). A significant relationship was also observed between arterial ammonia and alanine levels (r = 0.75, P less than 0.001). Leg tissues showed a net uptake of ammonia in the basal state (2.4 +/- 0.5 mumol/min). During exercise this changed to a net production, which increased curvilinearly with rising work intensity (peak value 46 +/- 15 mumol/min) but reverted to a net ammonia uptake at 30-60 min after exercise. Splanchnic ammonia uptake (basal 12 +/- 2 mumol/min) did not change in response to exercise but increased transiently during the early post-exercise period. From the above observations we conclude that the hyperammonaemia of exercise comes primarily from muscle release, while the splanchnic removal of ammonia is essentially unaltered. Part of the ammonia formed in contracting muscle is most likely used in the synthesis of amino acids, mainly glutamine and probably alanine.     

Mechanisms involved in colonic vasoconstriction and inhibition of motility induced by neuropeptide Y

Neuropeptide Y (NPY) and noradrenaline are suggested to coexist as neurotransmitters in sympathetic neurons. The present study investigated the mechanisms involved in the colonic vasoconstriction and inhibition of motility induced by infusion of NPY and noradrenaline close i.a. Colonic blood flow was monitored using a drop recorder, and motility was registered by a volume recording device, both operating an ordinate writer. Colonic motility was stimulated either by electrical stimulation of the pelvic nerves (PNS; 4 Hz, 5 ms, 8 V) acting via enteric ganglia or by i.v. infusion of bethanechol (10 nmol kg-1 min-1) acting directly on muscarinic receptors on smooth muscle. With both types of motility stimulation, an immediate colonic vasodilatation was registered. Electrical stimulation of the lumbar colonic nerves (4 Hz, 5 ms, 8 V) induced colonic smooth muscle relaxation and vasoconstriction during continuous PNS (P less than 0.05). Colonic contraction induced by PNS (P less than 0.01) was dose-dependently reduced by NPY (50-400 pmol min-1; P less than 0.05-0.01) and noradrenaline (1000-6000 pmol min-1; P less than 0.05-0.01). Simultaneously, vasoconstriction was induced by both NPY and noradrenaline (P less than 0.01). Colonic contraction induced by infusion of bethanechol (P less than 0.01) was not inhibited by NPY (50-200 pmol min-1). However, at the highest dose (400 pmol min-1) the motility response was reduced (P less than 0.05). Similarly, noradrenaline only at the highest dose (6000 pmol min-1) reduced the contractile response (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Direct neural inhibition of insulin secretion in response to systemic hypoglycemia.

The innervated pancreas of an anesthetized small "pancreas" dog was cross-perfused with blood from a large "support" dog in order to separate neural from blood-borne influences on the immunoreactive insulin secretion rate (ISR). The arterial plasma reducing sugar (sugar) concentration could be varied independently in the pancreas dog systemic circulation and in its pancreas. After tying of the hepatic arteries and portal vein in the pancreas dog, its systemic arterial plasma sugar concentration was allowed to fall in 10 experiments. This was prevented in five control experiments by intravenous glucose infusion (7 mg/kg-min). In all experiments, pancreatic arterial plasma sugar concentration was sustained, and at 40 min it was elevated 50 mg/100 ml by glucose infusion into the pancreatic blood supply. Bilateral splanchnic nerve section at 120 min caused an increase of the ISR in all experiments, but a greater rise occurred from the pancreases of the 10 dogs allowed to become hypoglycemic (P less than .02). In two further experiments, the splanchnic nerves were not cut, and no rise in ISR occurred. In conclusion, systemic hypoglycemia can inhibit insulin secretion by means of the splanchnic nerves.     

Effects of pancreatic noradrenaline infusion on basal and stimulated islet hormone secretion in the dog

We investigated the direct pancreatic effects of noradrenaline in vivo on the secretion of insulin, glucagon, and somatostatin from the in situ pancreas in halothane-anaesthetized dogs. Noradrenaline was infused into the superior pancreatic artery at 12 ng min-1, a rate that did not alter systemic glucose or noradrenaline levels nor heart rate or blood pressure. This pancreatic infusion of noradrenaline did not affect the basal pancreatic output of insulin, yet did markedly inhibit arginine-stimulated insulin secretion. The acute insulin response (AIR) to an intravenous injection of arginine (2.5 g), which was 4293 +/- 1260 microM min-1 under control conditions, was reduced to 1054 +/- 396 microU min-1 by noradrenaline (P less than 0.01). Noradrenaline increased basal pancreatic glucagon output from 321 +/- 130 pg min-1 to 876 +/- 309 pg min-1 after 20 min of infusion (P less than 0.05) and the acute glucagon response (AGR) to arginine, being 1033 +/- 203 pg min-1 under control conditions and 1746 +/- 249 pg min-1 during noradrenaline infusion (P less than 0.05). The basal output of somatostatin did not change during noradrenaline infusion, but arginine-stimulated somatostatin secretion was impaired. The acute somatostatin response (ASLIR) to arginine was 473 +/- 124 fmol min-1 under control conditions and was decreased to 140 +/- 80 fmol min-1 by noradrenaline (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Release of endothelin-like immunoreactivity in relation to neuropeptide Y and catecholamines during endotoxin shock and asphyxia in the pig

The changes in endothelin-like immunoreactivity in plasma during various provocations in the pig were investigated and related to those of neuropeptide Y, noradrenaline and adrenaline. Release as revealed by overflow was determined in the spleen, kidney and femoral vascular bed (skeletal muscle) simultaneously by collecting local venous and arterial blood samples. Under basal conditions there was no net release of endothelin-like immunoreactivity from any region but a net removal (negative overflow) over the kidney. Endotoxin administration (20 micrograms kg-1 h-1 for 4 h) increased arterial endothelin-like immunoreactivity, neuropeptide Y-like immunoreactivity, noradrenaline and adrenaline seven-, 27-, 100- and 166-fold respectively, as well as splenic and renal vascular resistance. An increased overflow of endothelin-like immunoreactivity, neuropeptide Y-like immunoreactivity and noradrenaline, indicating local release, was observed in the spleen during endotoxin administration. The arterial plasma endothelin-like immunoreactivity during endotoxaemia correlated significantly with the splenic and renal vasoconstriction (r = 0.75 and 0.68 respectively). Chromatographic characterization revealed that the main portions of arterial plasma endothelin-like immunoreactivity collected during endotoxaemia corresponded to synthetic endothelin-1 and big endothelin. A similar uptake (50-90%) and plasma half-life (1-2 min) of exogenous endothelin-1-like immunoreactivity was observed both under control conditions and after endotoxin, suggesting that elevated plasma endothelin-like immunoreactivity after endotoxin was the result not of reduced clearance but rather of enhanced release. Asphyxia for 2 min did not increase arterial endothelin-like immunoreactivity but evoked an increased overflow of endothelin-like immunoreactivity, neuropeptide Y-like immunoreactivity and noradrenaline as well as vasoconstriction in the spleen. Capsaicin induced a release of neuropeptide Y-like immunoreactivity and noradrenaline from both the spleen and the kidney and of adrenaline from the adrenal, but no detectable overflow of endothelin-like immunoreactivity from any of the vascular regions. Renal nerve stimulation, renal artery occlusion for 30 min, haemorrhagic shock, hypotension induced by nitroprusside infusion or serotonin did not cause any detectable increase in arterial plasma levels or local overflow of endothelin-like immunoreactivity. It is concluded that plasma levels of endothelin-like immunoreactivity are increased, suggesting release in the pig in response to endotoxin administration and asphyxia. The possible involvement of endothelin as a mediator of the peripheral vasoconstrictor responses during these situations remains to be further established.     

Influence of glucose and fructose ingestion on the capacity for long-term exercise in well-trained men

The aim of the present study was to examine the influence of glucose and fructose ingestion on the capacity to perform prolonged heavy exercise. Eight well-trained healthy volunteers exercised on a bicycle ergometer at 68 +/- 3% of their VO2 max until exhaustion, on three occasions, with 8-day intervals. During the exercise they ingested either glucose (250 ml, 7%), fructose (250 ml, 7%) or water (250 ml) every 20 min in a double-blind randomized study design. Arterial blood samples were collected at rest and during exercise for the determination of substrates and hormones. Muscle glycogen content (m. quadriceps femoris) was measured before and after exercise. The duration of exercise lengthened with repeated exercise (3rd test: 136 +/- 13 min v. 1st test: 110 +/- 12 min, P less than 0.01). Corrected for the sequence effect, total work time until exhaustion was significantly longer with glucose (137 +/- 13 min) than with either fructose (114 +/- 12 min) or water (116 +/- 13 min) (both P less than 0.01). When glucose or fructose was ingested, the arterial plasma glucose concentration was maintained at the normoglycaemic level; with water ingestion, plasma glucose values fell during exercise in seven subjects and remained at the resting level in the eighth subject. The muscle glycogen concentration was 467 +/- 29 mmol kg d.w.-1 at rest and fell to approximately half the initial value at exhaustion. In the subgroup of seven subjects in whom glucose values decreased with water intake, the mean rate of glycogen degradation was significantly lower (P less than 0.05) with the ingestion of glucose (1.3 +/- 0.4 mmol kg d.w.-1 min-1) as compared to fructose (2.1 +/- 0.5 mmol kg d.w.-1 min-1) or water (2.3 +/- 0.5 mmol kg d.w.-1 min-1). Intermittent glucose ingestion (3 X 17.5 g h-1) during prolonged, heavy bicycle exercise postpones exhaustion and exerts a glycogen-conserving effect in the working muscles. In contrast, fructose ingestion during exercise maintains the glucose concentration at the basal level but fails to influence either muscle glycogen degradation or endurance performance.     

Possible involvement of neuropeptide Y in sympathetic vascular control of canine skeletal muscle

Sympathetic nerve stimulation (2 min, 2 and 10 Hz) increased perfusion pressure in the blood perfused canine gracilis muscle in situ after pretreatment with atropine, desipramine and beta-adrenoceptor antagonists. This vasoconstriction was accompanied by clear-cut increases in the overflow of endogenous noradrenaline (NA) at both frequencies and, at 10 Hz but not at 2 Hz, also of neuropeptide Y-like immunoreactivity (NPY-LI). The irreversible alpha-adrenoceptor antagonist phenoxybenzamine enhanced the nerve stimulation induced overflows of NA and NPY-LI five- to eightfold and threefold, respectively. The fractional overflows of NA and NPY-LI per nerve impulse were similar in response to the high-frequency stimulation, indicating equimolar release in relation to the tissue contents of the respective neurotransmitter. The maximal vasoconstrictor response elicited by 10 Hz was reduced by about 50% following a dose of phenoxybenzamine which abolished the effect of exogenous NA and the remaining response was more long-lasting. Local i.a. infusion of NPY evoked long-lasting vasoconstriction in the presence of phenoxybenzamine, while the stable adenosine 5(1)-triphosphate (ATP) analogue alpha-beta-methylene ATP was without vascular effects. Locally infused NPY reduced the nerve stimulation evoked NA overflow by 31% (P less than 0.01) at 1 microM in arterial plasma, suggesting prejunctional inhibition of NA release. In conclusion, NPY-LI is released from the canine gracilis muscle upon sympathetic nerve stimulation at high frequencies. There is nerve stimulation evoked vasoconstriction, which is resistant to alpha-adrenoceptor blockade. This may in part be mediated by NPY released together with NA from the sympathetic vascular nerves.     

Role of gluconeogenesis in epinephrine-stimulated hepatic glucose production in humans

To evaluate the contribution of gluconeogenesis to epinephrine-stimulated glucose production, we infused epinephrine (0.06 micrograms X kg-1 X min-1) for 90 min into normal humans during combined hepatic vein catheterization and [U-14C]alanine infusion. Epinephrine infusion produced a rise in blood glucose (50-60%) and plasma insulin (30-40%), whereas glucagon levels increased only at 30 min (19%, P less than 0.05). Net splanchnic glucose output transiently increased by 150% and then returned to base line by 60 min. In contrast, the conversion of labeled alanine and lactate into glucose increased fourfold and remained elevated throughout the epinephrine infusion. Similarly, epinephrine produced a sustained increase in the net splanchnic uptake of cold lactate (four- to fivefold) and alanine (50-80%) although the fractional extraction of both substrates by splanchnic tissues was unchanged. We conclude that a) epinephrine is a potent stimulator of gluconeogenesis in humans, and b) this effect is primarily mediated by mobilization of lactate and alanine from extrasplanchnic tissues. Our data suggest that the initial epinephrine-induced rise in glucose production is largely due to activation of glycogenolysis. Thereafter, the effect of epinephrine on glycogenolysis (but not gluconeogenesis) wanes, and epinephrine-stimulated gluconeogenesis becomes the major factor maintaining hepatic glucose production.     

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.     

Noradrenaline as a possible mediator in the renal response to vascular expansion with blood in the cat

In chloralose anaesthetized cats with renal arterial pressure kept constant at 100 mmHg, vascular expansion with precirculated blood, 20 ml kg b.w.-1, caused significant increments in arterial inflow rates of blood to the deep (ARBFD) and superficial (ARBFS) renal venous drainage area of 35 +/- (SE)10 and 19 +/- 6%, respectively, and in the excretion rates of water and sodium of 73 +/- 24 and 75 +/- 28%, respectively, while GFR remained essentially unchanged. In acutely denervated kidneys the responses to expansion were not significantly different from those of innervated kidneys, which indicated largely humoral mediation. Arterial plasma concentrations of noradrenaline, adrenalin, and vasopressin fell significantly to values of a half to one-third of pre-expansion values, while plasma dopamine was not significantly changed by expansion. The response to expansion could be (1) reversed by a 'substituting' intraaortic infusion of noradrenaline, and (2) imitated, without volume expansion, by an infusion of an alpha-adrenergic blocking agent (phentolamine). It is concluded that the renal response (excretory and vascular) to volume expansion with blood is largely humorally mediated and that circulating noradrenaline may play a causal role in the response.     

Co-release of neuropeptide Y and catecholamines upon adrenal activation in the cat

The release of neuropeptide Y (NPY)-like immunoreactivity (-LI) in relation to catecholamines from the cat adrenal was studied in anaesthetized animals. Abdominal surgery increased plasma levels of NPY-LI from 65 +/- 6 to 149 +/- 26 pmol l-1. A positive veno-arterial concentration gradient over the adrenal gland was found for both NPY-LI, adrenaline (Adr) and noradrenaline (NA) during basal conditions. Asphyxia for 2 min increased the output of both NPY-LI and catecholamines from the adrenal. Electrical stimulation of the splanchnic nerve caused a marked increase in adrenal output of NPY-LI and catecholamines. The adrenal content of NPY-LI, as well as the release of NPY-LI from the adrenal, was at least 1000-fold lower on a molar basis than that of catecholamines. The concentration of NPY-LI in the adrenal vein upon splanchnic nerve stimulation was in the nM range. Reversed-phase HPLC characterization revealed that NPY-LI in the adrenal, and in the adrenal venous plasma collected during splanchnic nerve stimulation, was closely related to synthetic porcine NPY. Stimulation with bursts of 20 Hz for 1 S with 10 s intervals for 2 min caused a four-fold higher output of NPY-LI and Adr compared to a continuous stimulation with 2 Hz, giving the same number of impulses. The NA output, however, was only slightly increased by burst stimulation. Guanethidine did not reduce the adrenal output of NPY-LI or catecholamines induced by splanchnic nerve stimulation, while the release was abolished by chlorisondamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of alpha-adrenergic receptor stimulation on splanchnic intravascular volume in conscious humans.

The influence of selective alpha-adrenergic receptor stimulation on total splanchnic intravascular volume and blood volume in individual splanchnic organs in humans has not been previously examined. The present study employed a previously validated quantitative radionuclide imaging technique, involving a gamma camera and Tc-99m labeled erythrocytes, to measure changes in total splanchnic, hepatic, splenic, and extrahepatosplenic volume during a 20-minute phenylephrine infusion (30-120 micrograms min-1 iv). Changes in total splanchnic volume were estimated from changes in total splanchnic radioactivity, blood radioactivity, and estimated in vivo tissue attenuation. Radionuclide-estimated total splanchnic volume increased 477 +/- 96 ml (P less than 0.0003) at the end of phenylephrine infusion. Hepatic volume increased 25 +/- 5% (P less than 0.0003), splenic volume decreased 46 +/- 7% (P less than 0.0003), and extrahepatosplenic volume decreased 15 +/- 2% (P less than 0.0003). Systolic and diastolic arterial pressures increased from 119 +/- 4 to 138 +/- 5 mmHg (P less than 0.0003) and from 83 +/- 1 to 96 +/- 2 mmHg (P less than 0.0003), respectively. Heart rate decreased from 62 +/- 2 to 51 +/- 3 bpm (P less than 0.0003). Thus, in man, selective alpha-adrenergic receptor stimulation is associated with an increase in splanchnic intravascular volume that is due to an increase in hepatic volume and occurs despite decreases in splenic and extrahepatosplenic volumes. This increase in total splanchnic volume would be associated with a decrease in venous return from the splanchnic vasculature to the right heart which would act to decrease cardiac output.     

Endogenous hyperglycemia restores insulin release impaired by somatostatin analogue

These studies assessed the ability of des-Asn5-[D-Trp8-D-Ser13]-somatostatin (d-ATS-SS) to selectively inhibit insulin release and produce a hyperglycemia sufficient to compensate for the original impairment. d-ATS-SS at 0.017 micrograms/min inhibited basal insulin output (delta = -38 +/- 6%, P less than 0.005) and increased basal pancreatic glucagon output (delta - +21 +/- 6%, P less than 0.05, n = 5). d-ATS-SS at 0.17 micrograms/min markedly inhibited insulin output (delta = -84 +/- 4%, P less than 0.0005) and slightly inhibited glucagon output (delta = -14 +/- 6%, P less than 0.05, n = 5). d-ATS-SS at 0.055 micrograms/min decreased basal and stimulated insulin release but not basal nor stimulated glucagon release. By 3.5 of analogue infusion, plasma glucose had risen by 116 +/- 13 mg/dl, and base-line insulin levels and the insulin responses to both isoproterenol and arginine, but not glucose, increased toward control values. We conclude that d-ATS-SS produces selective insulinopenia resulting in hyperglycemia which in turn compensates for the original impairment. Thus, the hyperglycemia observed in other states of selective insulin deficiency (e.g., noninsulin-dependent diabetes mellitus) may compensate for defects in beta-cell function.