Hepatic alpha- and beta-adrenergic receptors are not essential for the increase in R(a) during exercise in diabetes

The purpose of this study was to determine the role of direct hepatic adrenergic stimulation in the control of endogenous glucose production (R(a)) during moderate exercise in poorly controlled alloxan-diabetic dogs. Chronically catheterized and instrumented (flow probes on hepatic artery and portal vein) dogs were made diabetic by administration of alloxan. Each study consisted of a 120-min equilibration, 30-min basal, 150-min moderate exercise, 30-min recovery, and 30-min blockade test period. Either vehicle (control; n = 6) or alpha (phentolamine)- and beta (propranolol)-adrenergic blockers (HAB; n = 6) were infused in the portal vein. In both groups, epinephrine (Epi) and norepinephrine (NE) were infused in the portal vein during the blockade test period to create suprapharmacological levels at the liver. Isotopic ([3-(3)H]glucose, [U-(14)C]alanine) and arteriovenous difference methods were used to assess hepatic function. Arterial plasma glucose was similar in controls (345 +/- 24 mg/dl) and HAB (336 +/- 23 mg/dl) and was unchanged by exercise. Basal arterial insulin was 5 +/- 1 mU/ml in controls and 4 +/- 1 mU/ml in HAB and fell by approximately 50% during exercise in both groups. Basal arterial glucagon was similar in controls (56 +/- 10 pg/ml) and HAB (55 +/- 7 pg/ml) and rose similarly, by approximately 1.4-fold, with exercise in both groups. Despite greater arterial Epi and NE levels in HAB compared with controls during the basal and exercise periods, exercise-induced increases in catecholamines from basal were similar in both groups. Gluconeogenic conversion from alanine and lactate and the intrahepatic efficiency of this process were increased by twofold during exercise in both groups. R(a) rose similarly by 2.9 +/- 0.7 and 2.7 +/- 1.0 mg. kg(-1). min(-1) at time = 150 min during exercise in controls and HAB. During the blockade test period, arterial plasma glucose and R(a) rose to 454 +/- 43 mg/dl and 11.3 mg. kg(-1). min(-1) in controls, respectively, but were essentially unchanged in HAB. The attenuated response to the blockade test in HAB substantiates the effectiveness of the hepatic adrenergic blockade. In conclusion, these results demonstrate that direct hepatic adrenergic stimulation does not play a role in the stimulation of R(a) during exercise in poorly controlled diabetes.     

Effect of alpha adrenergic blockade on brain blood flow and ventilation during hypoxia in newborn piglets.

The influence of cardiovascular changes on ventilation has been demonstrated in adult animals and humans (Jones, French, Weissman & Wasserman, 1981; Wasserman, Whipp & Castagna 1974). It has been suggested that neonatal hypoxic ventilatory depression may be related to some of the hemodynamic changes that occur during hypoxia (Brown & Lawson, 1988; Darnall, 1985; Suguihara, Bancalari, Bancalari, Hehre & Gerhardt, 1986). To test the possible relationship between the cardiovascular and ventilatory response to hypoxia in the newborn, eleven sedated spontaneously breathing piglets (age: 5.9 +/- 1.6 days; weight: 1795 +/- 317 g; SD) were studied before and after alpha adrenergic blockade with phenoxybenzamine. Minute ventilation (VE) was measured with a pneumotachograph, cardiac output (CO) by thermodilution and total and regional brain blood flow (BBF) with radiolabeled microspheres. Measurements were performed while the animals were breathing room air and after 10 min of hypoxia induced by breathing 10% O2. Hypoxia was again induced one hour after infusion of phenoxybenzamine (6 mg/kg over 30 min). After 10 min of hypoxia, in the absence of phenoxybenzamine, the animals responded with marked increases in VE (P less than 0.001), CO (P less than 0.001), BBF, and brain stem blood flow (BSBF) (P less than 0.02). However, the normal hemodynamic response to hypoxia was eliminated after alpha adrenergic blockade. There were significant decreases in systemic arterial blood pressure, CO, and BBF during hypoxia after phenoxybenzamine infusion; nevertheless, VE increased significantly (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Possible sensory receptor of nonadrenergic inhibitory nervous system

To determine the sensory receptor of the nonadrenergic inhibitory nervous system (NAIS), 22 cats were anesthetized and serotonin was continuously administered (50-250 micrograms.kg-1.min-1 iv) to increase pulmonary resistance (RL) to 377 +/- 57% (SE) of the control value. We then 1) mechanically irritated the trachea, 2) intravenously administered capsaicin (5 micrograms/kg), or 3) induced hypoxia (arterial PO2 30-40 Torr) to stimulate irritant and bronchial C-fiber receptors, pulmonary C-fiber receptors, or the carotid body (chemoreceptors), respectively. After treatment with atropine (3 mg/kg iv) and propranolol (2 mg/kg iv), the serotonin-induced change in RL was reduced by 58.6 +/- 14.3% by mechanical irritation and 63.3 +/- 12.1% by intravenous capsaicin. However, hypoxia produced no dilatation of the airways. In further experiments, we employed capsaicin inhalation to stimulate bronchial C-fiber receptors. Inhaled capsaicin (0.1%, for 5 breaths) also reduced RL by 79.2 +/- 9.2% of the elevated value, after atropine and propranolol. Treatment with a ganglionic blocking agent, hexamethonium (2 mg/kg iv), abolished bronchodilator responses, implying that a reflex pathway through vagal nerves is involved in this phenomenon. These results suggest that pulmonary and bronchial C-fiber receptors may be involved as sensory receptors in NAIS reflex bronchodilatation.     

Effect of theophylline treatment on the functional hyperaemic and hypoxic responses of cerebrocortical microcirculation

The purpose of the present study was to elucidate the importance of extracellular adenosine (ADO) in the regulation of cerebrocortical microcirculation during rest, hypoxia, and brain activation. Cerebrocortical microcirculation and fluorescence of reduced nicotinamide adenine dinucleotide (NADH) were measured by surface fluororeflectometry through a cranial window. Arterial hypoxia and brain activation were produced by respirating the animals with a gas mixture containing 6-7% O2 and by injecting 4-6 mg/kg metrazol into the lingual artery, respectively. These reactions were used as test before and after theophylline (THEO) treatment. In some of the experiments only the cortical area beneath the cranial window was treated with THEO (10(-4) M), in others 2 X 10(-4) mol/kg THEO was injected intraperitoneally. Potency of THEO in antagonizing the cerebral blood flow (CBF) increasing effect of topically applied ADO was also tested. It was found that superfusion of the brain cortex with artificial cerebrospinal fluid (mock CSF) containing 10(-4) M THEO does not alter resting CBF, but inhibits the CBF increasing effect of 10(-6) M and 10(-5) M ADO by approximately 70% and 40%, respectively. Intraperitoneally injected THEO increased CBF by approximately 60%, which has been attributed mostly to its action on the systemic circulation. Under control conditions, arterial hypoxia and epileptic seizures increased CBF by approximately 150% and 300%, respectively. Since neither topical nor systemic THEO treatment altered the vasodilatory and CBF increasing potency of arterial hypoxia and attenuated these effects of epilepsy slightly, it was concluded that extracellular ADO is not a critical factor in the regulation of cerebrocortical microcirculation.     

Reversal of propranolol blockade of adrenergic receptors and related toxicity with drugs that increase cyclic AMP.

An overdose of propranolol, a widely used nonselective beta-adrenergic receptor blocking agent, can result in hypotension and bradycardia leading to irreversible shock and death. In addition, the blockade of adrenergic receptors can lead to alterations in neurotransmitter receptors resulting in the interruption of the activity of other second messengers and the ultimate cellular responses. In the present experiment, three agents, aminophylline, amrinone, and forskolin were tested in an attempt to reverse the potential lethal effects of a propranolol overdose in dogs. Twenty-two anesthetized beagle dogs were given a 10-min infusion of propranolol at a dose of 1 mg/kg/min. Six of the dogs, treated only with intravenous saline, served as controls. Within 15-30 min all six control dogs exhibited profound hypotension and severe bradycardia that led to cardiogenic shock and death. Seven dogs were treated with intravenous aminophylline 20 mg/kg 5 min after the end of the propranolol infusion. Within 10-15 min heart rate and systemic arterial blood pressure returned to near control levels, and all seven dogs survived. Intravenous amrinone (2-3 mg/kg) given to five dogs, and forskolin (1-2 mg/kg) given to four dogs, also increased heart rate and systemic arterial blood pressure but the recovery of these parameters was appreciably slower than that seen with aminophylline. All of these animals also survived with no apparent adverse effects. Histopathologic evaluation of the hearts of the dogs treated with aminophylline showed less damage (vacuolization, inflammation, hemorrhage) than the hearts from animals given propranolol alone. Results of this study showed that these three drugs, all of which increase cyclic AMP, are capable of reversing the otherwise lethal effects of a propranolol overdose in dogs.     

Adrenergic regulation of HSL serine phosphorylation and activity in human skeletal muscle during the onset of exercise

Skeletal muscle hormone-sensitive lipase (HSL) activity is increased by contractions and increases in blood epinephrine (EPI) concentrations and cyclic AMP activation of the adrenergic pathway during prolonged exercise. To determine the importance of hormonal stimulation of HSL activity during the onset of moderate- and high-intensity exercise, nine men [age 24.3 +/- 1.2 yr, 80.8 +/- 5.0 kg, peak oxygen consumption (VO2 peak) 43.9 +/- 3.6 ml x kg(-1) x min(-1)] cycled for 1 min at approximately 65% VO2 peak, rested for 60 min, and cycled at approximately 90% VO2 peak for 1 min. Skeletal muscle biopsies were taken pre- and postexercise, and arterial blood was sampled throughout exercise. Arterial EPI increased (P < 0.05) postexercise at 65% (0.45 +/- 0.10 to 0.78 +/- 0.27 nM) and 90% VO2 peak (0.57 +/- 0.34 to 1.09 +/- 0.50 nM). HSL activity increased (P < 0.05) following 1 min of exercise at 65% VO2 peak [1.05 +/- 0.39 to 1.78 +/- 0.54 mmol x min(-1) x kg dry muscle (dm)(-1)] and 90% VO2 peak (1.07 +/- 0.24 to 1.91 +/- 0.62 mmol x min(-1) x kg dm(-1)). Cyclic AMP content also increased (P < 0.05) at both exercise intensities (65%: 1.52 +/- 0.67 to 2.75 +/- 1.12, 90%: 1.85 +/- 0.65 to 2.64 +/- 0.93 micromol/kg dm). HSL Ser660 phosphorylation (approximately 55% increase) and ERK1/2 phosphorylation ( approximately 33% increase) were augmented following exercise at both intensities, whereas HSL Ser563 and Ser565 phosphorylation were not different from rest. The results indicate that increases in arterial EPI concentration during the onset of moderate- and high-intensity exercise increase cyclic AMP content, which results in the phosphorylation of HSL Ser660. This adrenergic stimulation contributes to the increase in HSL activity that occurs in human skeletal muscle in the first minute of exercise at 65% and 90% VO2 peak.     

Influence of alpha and beta adrenergic receptors blockade on the adrenolytic effect of muscular work

The changes in the response of adrenergic receptors alpha and beta in the blood vessels in the working muscles in a hindlimb in cats were studied after intra-arterial administration of noradrenaline, isoprenaline and during electric stimulation of the sympathetic trunk. The experiments were carried out during alpha-adrenergic receptors blockade with dihydroergotamine (0.3 mg/kg) beta-adrenergic receptors blockade with propranolol (1 mg/kg) and blockade of acetylcholine M receptors with atropine (0.5 mg/kg). The investigations were performed at rest, during exercise (electric stimulation of the sciatic nerve) and after the exercise. The following results deserve attention: 1) beta-adrenergic receptors blockade reduced significantly the alpha-adrenolytic effect of exercise restoring the ability of blood vessel to constriction in response to noradrenaline; 2) the vasodilator effect of isoprenaline evident in resting state and maintained to some extent during exercise was abolished completely by preceding alpha-adrenergic blockade. The changes in the reactivity of resistance vessels in working skeletal muscles to noradrenaline, with abolition of its vasoconstrictor effect, have been shown by Rein [7] and others authors [2, 5]. Similarly, it is well known that the resistance vessels contain two types of adrenergic receptors alpha and beta, and that the response of the vessels to stimulation of these receptors are different [1]. In view of the recently published observations of Jarhult and Lundvall suggesting that the beta-adrenergic receptors play an important physiological role [6] in the arterial part of the microcirculation [6] and in view of the hypothesis put forward by Kunos and Szentivanyj that alpha and beta receptors can be transformed depending on the intensity of tissue metabolism [8] it seemed worth while to study more systematically the changes of the reactivity of alpha and beta adrenergic receptors in the vascular bed of the skeletal muscles during and after muscle exercise.     

Effect of hypoxia on bronchial circulation

We studied the effect of systemic hypoxia on the bronchial vascular pressure-flow relationship in anesthetized ventilated sheep. The bronchial artery, a branch of the bronchoesophageal artery, was cannulated and perfused with a pump with blood from a femoral artery. Bronchial blood flow was set so bronchial arterial pressure approximated systemic arterial pressure. For the group of 25 sheep, control bronchial blood flow was 22 ml/min or 0.7 ml.min-1.kg-1. During the hypoxic exposure, animals were ventilated with a mixture of N2 and air to achieve an arterial PO2 (PaO2) of 30 or 45 Torr. For the more severe hypoxic challenge, bronchial vascular resistance (BVR), as determined by the slope of the linearized pressure-flow curve, decreased acutely from 3.8 +/- 0.4 mmHg.ml-1.min to 2.9 +/- 0.3 mmHg.ml-1.min after 5 min of hypoxia. However, this vasodilation was not sustained, and BVR measured at 30 min of hypoxia was 4.2 +/- 0.8 mmHg.ml-1.min. The zero flow intercept, an index of downstream pressure, remained unaltered during the hypoxic exposure. Under conditions of moderate hypoxia (PaO2 = 45 Torr), BVR decreased from 4.6 +/- 0.3 to 3.8 +/- 0.4 mmHg.ml-1.min at 5 min and remained dilated at 30 min (3.6 +/- 0.5 mmHg.ml-1.min). To determine whether dilator prostaglandins were responsible for the initial bronchial vascular dilation under conditions of severe hypoxia (PaO2 approximately equal to 30 Torr), we studied an additional group of animals with pretreatment with the cyclooxygenase inhibitors indomethacin (2 mg/kg) and ibuprofen (12.5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Toxic effect of the combination of propranolol and phenformin combination in anesthetized dogs

Phenformin (20 mg/kg subcutaneously) as well as propranolol (0.3 mg/kg. i.v.) induced an increase in blood lactate level in the normal anesthetized log; with phenformin a slight decrease in the arterial pH was noted. The combined administration of phenformin (20 mg/kg subcutaneously) and propranolol (0.3 mg/kg. i.v.) induced a more rapid increase in lactate level, a slight reduction of arterial pH and led to the death of the animals in all cases. After a chronic treatment by phenformin (20 mg/kg daily orally during 7 days, the administration of phenformin (20 mg/kg subcutaneously) induced lactic acidosis in 3 out of the 8 animals and death within 150 minutes. In the animals pretreated by phenformin, the combined administration of phenformin (20 mg/kg subcutaneously) and propranolol (0.3 mg/kg i.v.) caused the death of all the animals without the occurrence of lactic acidosis. These results point to the possible toxicity of the propranolol-phenformin combination.     

Influence of adenosine on cerebral blood flow during hypoxic hypoxia in the newborn piglet

This study investigated the role of adenosine in the regulation of neonatal cerebral blood flow (CBF) during moderate (arterial PO2 = 47 +/- 9 Torr) and severe (arterial PO2 = 25 +/- 4 Torr) hypoxia. Twenty-eight anesthetized and ventilated newborn piglets were assigned to four groups: 8 were injected intravenously with the vehicle (controls, group 1); 13 received an intravenous injection of 8-phenyltheophylline (8-PT), a potent adenosine receptor blocker, either 4 mg/kg (group 2, n = 6, mean cerebrospinal fluid (CSF) levels less than 1 mg/l) or 8 mg/kg (group 3, n = 7, mean CSF levels less than 3.5 mg/l); and 7 received an intracerebroventricular injection of 10 micrograms 8-PT (group 4). During normoxia, CBF was not altered by vehicle or 8-PT injections. In group 1, 10 min of moderate and severe hypoxia increased total CBF by 112 +/- 36 and 176 +/- 28% (SE), respectively. Compared with controls, the cerebral hyperemia during moderate hypoxia was not altered in group 2, attenuated in group 3 (to 53 +/- 13%, P = NS), and completely blocked in group 4 (P less than 0.01). CBF increase secondary to severe hypoxia was attenuated only in group 4 (74 +/- 29%, P less than 0.05). CSF concentrations of adenosine and adenosine metabolites measured by high-performance liquid chromatography increased during hypoxia. Arterial O2 content was inversely correlated (P less than 0.005) to maximal CSF levels of adenosine (r = 0.73), inosine (r = 0.87), and hypoxanthine (r = 0.80).(ABSTRACT TRUNCATED AT 250 WORDS)     

Ontogeny of cholinergic and adrenergic cardiovascular regulation in the domestic chicken (Gallus gallus)

Adrenergic and cholinergic tone on the cardiovascular system of embryonic chickens was determined during days 12, 15, 19, 20, and 21 of development. Administration of the muscarinic antagonist atropine (1 mg/kg) resulted in no significant change in heart rate or arterial pressure at any developmental age. In addition, the general cardiovascular depressive effects of hypoxia were unaltered by pretreatment with atropine. In addition, the ganglionic blocking agent hexamethonium (25 mg/kg) did not induce changes in heart rate. The beta-adrenergic antagonist propranolol (3 mg/kg) induced a bradycardia of similar magnitude on all days studied, with a transient hypertensive action on days 19-20, indicating the existence of an important cardiac and vascular beta-adrenergic tone. Injections of the alpha-adrenergic antagonists prazosin or phentolamine (1 mg/kg) reduced arterial pressure significantly on all days of incubation studied. Collectively, the data indicate that embryonic chickens rely primarily on adrenergic control of cardiovascular function, with no contribution from the parasympathetic nervous system.     

Effect of surplus amount of oxygen on the cerebrocortical microcirculatory reactions associated to moderate arterial hypotension

The aim of the present study was to clarify whether tissue hypoxia is involved in the autoregulatory dilatation of cerebrocortical vessels occurring at moderate arterial hypotension. In order to avoid hypoxia that may occur during arterial hypotension, in one part of the experiments the brain cortices were superfused with oxygen saturated (pO2, approximately 500 mm Hg) artificial cerebrospinal fluid (mock CSF). In the other part of the experiments arterial hypotension was induced without superfusing the brain cortices (closed skull). Mean arterial blood pressure (MABP) was decreased in both experimental groups by bleeding to 75-85 mm Hg for approximately 5 min, then the shed blood was reinfused. Changes in cortical vascular volume (CVV), mean transit time of cortical blood flow (tm), and blood flow (CBF) were measured through a cranial window with a microscope reflectometer. Although CSF pO2 differed markedly between the superfused and nonsuperfused experimental groups, arterial hypotension led to similar changes in CVV and tm in both groups. Due to the proper dilatation of the cerebrocortical arterioles, CBF was not altered by arterial hypotension in either of the groups. These results suggest that the brain cortex does not become hypoxic at moderate arterial hypotension and, consequently, incipient tissue hypoxia has no role in the autoregulatory dilatation of the cerebrocortical arterial network.     

The role of alpha-adrenergic receptors in carbon monoxide hypoxia

The importance of alpha-adrenergic receptors in the cardiac output and peripheral circulatory responses to carbon monoxide (CO) hypoxia was studied in anesthetized dogs. Phenoxybenzamine (3 mg/kg i.v.) was injected to block alpha-receptor activity and the data obtained were then compared with those from a previous study of CO hypoxia in unblocked animals. Values for cardiac output, hindlimb blood flow, vascular resistance, and oxygen uptake were obtained prior to and at 30 and 60 min of CO hypoxia which reduced arterial oxygen content by approximately 50%. alpha-Adrenergic blockade resulted in a lower (p less than 0.05) control value for cardiac output than observed in unblocked animals, but no differences were present between the two groups at 30 or 60 min of CO hypoxia. Similarly, limb blood flow was lower (p less than 0.05) during the control period in the alpha-blocked group but rose to the same level as that in the unblocked animals at 60 min of COH. No change in limb blood flow occurred during CO hypoxia in the unblocked group. These findings demonstrated that during CO hypoxia alpha-receptor mediated venoconstriction does not contribute to the cardiac output response and alpha-receptor mediated vasoconstriction probably does prevent a rise in hindlimb skeletal muscle blood flow.     

Oxygen delivery and utilization in dogs with a sublethal dose of cobalt chloride.

Four groups of eight dogs each were anesthetized with pentobarbital, paralyzed with succinylcholine, and ventilated at constant rate. Control measurements were made for 30 min, then 15 mg/kg of cobaltous chloride was given slowly intravenously to one group. A second group was also given 1 mg/kg per h propranolol (beta-block); a third group was given NaHCO3 to correct pH changes after CoCl2; and a fourth group had both beta-block and NaHCO3. Vo2 was measured every 10 min for 4 h and blood was taken frequently for lactate, pyruvate, and blood gas measurements. Cobalt transiently decreased Vo2 in all groups but significantly more in those with beta-block (groups 2 and 4). Cardiac output and mean arterial pressure were also decreased in all groups but to similar extent. Recovery of Vo2 was complete, usually within 60 min with little evidence of deficit repayment. Total O2 transport (Q X Cao2) appeared to limit Vo2 below 12 ml/kg times min. Above that value, histotoxic effects of CoCl2 reduced Vo2 approximately 20%. Excess lactate (XL) in arterial blood was linearly correlated with measured O2 deficit during the acute reaction of CoCl2, in all but group 3, similar to results previously obtained in hypoxic hypoxia.     

Role of beta adrenoceptors in metabolic and cardiovascular responses of cold exposed humans

Effect of a nonspecific beta adrenergic blocker — propranolol (40 mg per os) on thermoregulatory responses of cold water immersed (12.5°C) humans was studied. Propranolol attenuates resting and cold induced thermogenesis, rectal temperature, heart rate and systolic blood pressure, but increases production of adrenaline and cortisol. Propranolol has no effect on the threshold body temperature for induction of cold thermogenesis and on central thermosensitivity. The following conclusions are drawn from consideration of the data presented: During the early phase of cooling (20 min after the start of cooling) the thermogenesis mediated by beta adrenergic receptors may cover about 80% of the total metabolic increase induced by cold. After about 30 min of cooling the relative proportion of beta adrenergic thermogenesis starts to decline, reaching 20% of the total cold thermogenesis at the end of cooling.

It can be suggested from consideration of the data that, in man, the beta adrenergic receptors in the heart, blood vessels, adipocytes and muscles participate in mediating effect of cold on cardiovascular and thermoregulatory responses. Furthermore, these data imply that human adrenergic thermogenesis is produced outside of the brown adipose tissue. Thus, physiological mechanisms mediating adrenergic thermogenesis in humans appear to be different from those in small mammals.     

Leg vasoconstriction during dynamic exercise with reduced cardiac output.

We evaluated whether a reduction in cardiac output during dynamic exercise results in vasoconstriction of active skeletal muscle vasculature. Nine subjects performed four 8-min bouts of cycling exercise at 71 +/- 12 to 145 +/- 13 W (40-84% maximal oxygen uptake). Exercise was repeated after cardioselective (beta 1) adrenergic blockade (0.2 mg/kg metoprolol iv). Leg blood flow and cardiac output were determined with bolus injections of indocyanine green. Femoral arterial and venous pressures were monitored for measurement of heart rate, mean arterial pressure, and calculation of systemic and leg vascular conductance. Leg norepinephrine spillover was used as an index of regional sympathetic activity. During control, the highest heart rate and cardiac output were 171 +/- 3 beats/min and 18.9 +/- 0.9 l/min, respectively. beta 1-Blockade reduced these values to 147 +/- 6 beats/min and 15.3 +/- 0.9 l/min, respectively (P < 0.001). Mean arterial pressure was lower than control during light exercise with beta 1-blockade but did not differ from control with greater exercise intensities. At the highest work rate in the control condition, leg blood flow and vascular conductance were 5.4 +/- 0.3 l/min and 5.2 +/- 0.3 cl.min-1.mmHg-1, respectively, and were reduced during beta 1-blockade to 4.8 +/- 0.4 l/min (P < 0.01) and 4.6 +/- 0.4 cl.min-1.mmHg-1 (P < 0.05). During the same exercise condition leg norepinephrine spillover increased from a control value of 2.64 +/- 1.16 to 5.62 +/- 2.13 nM/min with beta 1-blockade (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic and sympathoadrenal responses to mental stress during nitric oxide synthesis inhibition

Cardiovascular and sympathoadrenal responses to a reproducible mental stress test were investigated in eight healthy young men before and during intravenous infusion of the nitric oxide (NO) synthesis inhibitor N-monomethyl-L-arginine (L-NMMA). Before L-NMMA, stress responses included significant increases in heart rate, mean arterial pressure, and cardiac output (CO) and decreases in systemic and forearm vascular resistance. Arterial plasma norepinephrine (NE) increased. At rest after 30 min of infusion of L-NMMA (0.3 mg.kg(-1).min(-1) iv), mean arterial pressure increased from 98 +/- 4 to 108 +/- 3 mmHg (P <0.001) because of an increase in systemic vascular resistance from 12.9 +/- 0.5 to 18.5 +/- 0.9 units (P <0.001). CO decreased from 7.7 +/- 0.4 to 5.9 +/- 0.3 l/min (P <0.01). Arterial plasma NE decreased from 2.08 +/- 0.16 to 1.47 +/- 0.14 nmol/l. Repeated mental stress during continued infusion of L-NMMA (0.15 mg.kg(-1).min(-1)) induced qualitatively similar cardiovascular responses, but there was a marked attenuation of the increase in mean arterial blood pressure, resulting in similar "steady-state" blood pressures during mental stress without and with NO blockade. Increases in heart rate and CO were attenuated, but stress-induced decreases in systemic and forearm vascular resistance were essentially unchanged. Arterial plasma NE increased less than during the first stress test. Thus the increased arterial tone at rest during L-NMMA infusion is compensated for by attenuated increases in blood pressure during mental stress, mainly through a markedly attenuated CO response and suppressed sympathetic nerve activity.     

Canine bronchoconstriction, gas trapping, and hypoxia with methacholine

The effects of an intravenous methacholine infusion on cardiovascular-pulmonary function were measured in seven mongrel dogs (22.0 +/- 2.8 kg), anesthetized with chloralose and urethan and beta-adrenergically blocked with propranolol. In a volume-displacement plethysmograph, physiological measurements were made at base line and 25 min after establishing a methacholine infusion (0.1-1.0 mg X kg-1 X h-1). Methacholine significantly (P less than 0.05) increased airways resistance (1.9 +/- 0.8 to 8.2 +/- 2.9 cmH2O X l-1 X s), decreased static lung compliance (84.7 +/- 18.5 to 48.2 +/- 9.4 ml/cmH2O), depressed arterial PO2 (81 +/- 17 to 56 +/- 10 Torr), and lowered blood pressure (132 +/- 10 to 69 +/- 18 Torr) and cardiac output (5.7 +/- 1.9 to 4.1 +/- 1.2 l/min). These effects persisted during a further 80 min of methacholine infusion conducted in five of the animals. During the initial 25-min period of methacholine, the end-expired volume (volume-displacement Krogh spirometer) rose in all animals, indicating an increase in functional residual capacity from 997 +/- 115 to 1,623 +/- 259 ml (P less than 0.0005). Analysis of pulmonary pressure-volume curves revealed no change in total lung capacity but an increase in residual volume from 489 +/- 168 to 1,106 +/- 216 ml (P less than 0.001). Thus methacholine caused 617 ml of gas trapping, which was not detected by the Boyle's law principle, presumably because gas was trapped at high transpulmonary pressure. We suggest that intravenous methacholine-induced canine bronchoconstriction, which causes gas trapping and hypoxia, may be a useful animal model of clinical status asthmaticus.     

Delta-opioid augments cardiac contraction through β-adrenergic and CGRP-receptor co-signaling

Cardiac epinephrine and calcitonin gene-related peptide (CGRP) are produced by intrinsic cardiac adrenergic cells (ICA cells) residing in human and animal hearts. ICA cells are neuroparicine cells expressing δ-opioid receptors (DOR). We hypothesized that δ-opioid stimulation of ICA cells enhances epinephrine and CGRP release, which results in the augmentation of heart contraction. Rats were injected with DOR-agonist DPDPE (100 μg/kg) with or without 10-min pretreatment with either β-adrenergic receptor (β-AR) blocker propranolol (2mg/kg) or CGRP-receptor (CGRPR) blocker CGRP(8-37) (300 μg/kg), or their combination. Hemodynamics were monitored with echocardiogram and systolic blood pressure (SBP) was monitored via a tail arterial catheter. Changes in left ventricular fraction-shortening (LVFS) and heart rate (HR) were observed at 5-min after DPDPE infusion. At 5-min DPDPE induced a 36 ± 18% (p<0.001) increase of the LVFS, which continues to increase to 51 ± 24% (p<0.0001) by 10 min, and 68 ± 19% (p<0.001) by 20 min. The increase in LVFS was accompanied by the decrease of HR by 9±5% (p<0.01) by 5 min and 11 ± 6% (p<0.001) by 15 min post DPDPE infusion. This magnitude of HR reduction was observed for the remainder of the 20 min. Despite the HR-reduction, cardiac output was increased by 17 ± 8% (p<0.05) and 28±5% (p<0.001) by 5- and 20-min post DPDPE administration, respectively. There was a modest (9 ± 9%, p=0.03) decrease in SBP that was not apparent until 20 min post DPDPE infusion. The positive inotropism of DPDPE was abrogated in animals pretreated with propranolol, CGRP(8-37), or combined propranolol+CGRP(8-37). Furthermore, in whole animal and cardiomyocyte cell culture preparations, DPDPE induced myocardial protein-kinase A (PKA) activation which was abrogated in the animals pretreated with propranolol+CGRP(8-37). DOR agonists augment myocardial contraction through enhanced β-AR and CGRPR co-signaling.     

Further evidence of the inhibitory role of perifornical hypothalamic beta-adrenergic receptors in the feeding behaviour of hungry rats

The reduction of food intake in hungry rats induced by salbutamol (10 mg/kg/i.p.) was prevented by IPS 339 (5 mg/kg, i.p.) a selective beta 2 adrenergic antagonist, but not by metoprolol (10 mg/kg i.p.), a blocker of beta 1 adrenergic receptors. Similarly, bilateral injections of IPS 339 (32 micrograms/1 microliter) but not metoprolol (80 micrograms/1 microliter) in the perifornical hypothalamic area completely antagonized the anorectic effect of intraperitoneal salbutamol, suggesting an involvement of beta 2 adrenergic receptors in this brain area. Clenbuterol, a beta 2 adrenergic agonist which readily crosses the blood-brain barrier, was 10-100 times more potent than salbutamol in inhibiting feeding consumption of deprived rats when injected intraperitoneally and this effect was also selectively antagonized by pretreatment with IPS 339. Neither IPS 339 nor metoprolol injected in the perifornical hypothalamus significantly modified the anorectic effect of diethylpropion (5 mg/kg i.p.) whereas it was partially prevented by intraperifornical injection of 1-propranolol (52 micrograms/2 microliter), a non-selective beta antagonist, suggesting that both beta 1 and beta 2 adrenergic receptors in the hypothalamus contribute to the mechanism by which diethylpropion causes anorexia.