Combined Alpha Research Articles

Labetalol Does Not Lengthen Asystole During Electroconvulsive Therapy

Labetalol, a combined alpha- and beta-adrenergic blocker is often used to attenuate the transient increases in heart rate and blood pressure that accompany electroconvulsive therapy (ECT). It has been suggested that labetalol should not be administered during ECT without the protection provided by anticholinergic medications, because of its potential severe bradycardic effects. We present our experience with 32 patients from all age groups who received labetalol without anticholinergic treatment during ECT. None of the patients demonstrated adverse bradycardic effects. We conclude that administration of labetalol during ECT does not routinely require premedication with anticholinergic drugs and does not lengthen asystole.

Study of LiOH etching of polyethyleneterephtalate irradiated with 11.4 MeV/amu Pb ions by neutron depth profiling and alpha particle transmission

Polyethyleneterephtalate (PETP) foils, 23 μm thick, irradiated with 11.4 MeV/amu Pb ions to the fluence of about 1×107 cm−2 were etched in 5M LiOH solution at the temperature of 40°C for 30–570 min and the etching process kinetics was examined by combined alpha particle transmission (APT) and neutron depth profiling (NDP) techniques. The etching process was visualized from very initial stages up to the breakthrough and the appearance of first openings after about 300 min of etching. Several parameters characterizing the etching process were determined and the pore internal profile was determined by comparing the measured APT spectra with those simulated by Monte-Carlo method.

Epinephrine and insulin stimulate different mitogen-activated protein kinase signaling pathways in rat skeletal muscle.

Little is known about the regulation of the mitogen-activated protein (MAP) kinase signaling cascades by hormonal stimulation in vivo. The extracellular signal-regulated kinase (ERK) and the c-jun kinase (JNK) are two MAP kinase signaling pathways that could play a role in the cellular response to hormones such as insulin and epinephrine. We studied the effects of insulin (20 U/rat) and epinephrine (25 microg/100 g body wt) injected in vivo on ERK and JNK signaling in skeletal muscle from Sprague-Dawley rats. Insulin significantly increased ERK phosphorylation and the activity of its downstream substrate, the p90 ribosomal S6 kinase 2 (RSK2), by 1.4-fold, but it had no effect on JNK activity. In contrast, epinephrine had no effect on ERK phosphorylation or RSK2 activity, but it increased JNK activity by twofold, an effect that was inhibited by the presence of combined alpha and beta blockade. Furthermore, the phosphorylation of both p46 and p55 isoforms of JNK, measured by phosphospecific antibody, was increased severalfold. The activity and phosphorylation of MAP kinase kinase (MKK)-4, an upstream regulator of JNK, was unchanged by epinephrine. Incubation of isolated soleus muscles in vitro with epinephrine (10(-5) mol/l) also increased JNK activity by twofold. These data are the first to demonstrate that epinephrine can increase JNK activity. Insulin and epinephrine have different effects on MAP kinase signaling pathways in skeletal muscle, which may be one of the underlying molecular mechanisms through which these hormones regulate opposing metabolic functions.

Cardiovascular effects of the novel Ca2+-sensitiser EMD 57033 in pigs at rest and during treadmill exercise.

1. To date no study has described the cardiovascular effects of increased myofilament Ca2+ responsiveness in awake animals both under resting conditions and during treadmill exercise. In the present study we therefore investigated the systemic, pulmonary and coronary haemodynamic actions of the Ca2+ sensitizer EMD 57033 in 16 chronically instrumented awake pigs at rest and during treadmill exercise, and compared these to the haemodynamic actions of the Ca2+ sensitizer/phosphodiesterase inhibitor pimobendan. 2. Under resting conditions EMD 57033 (0.2, 0.4 and 0.8 mg kg(-1) min(-1), i.v.) produced dose-dependent increases in LVdP/dt(max) (up to 65+/-17% (mean+/-s.e.mean), P < or = 0.05) and stroke volume (up to 20+/-3%, P < or = 0.05), with an increase in heart rate only after the highest dose (22+/-5%, P < or = 0.05), while mean aortic blood pressure and LVdP/dt(min) were not altered. EMD 57033 had also no effect on pulmonary vascular resistance, but produced dose-dependent decreases in systemic vascular resistance (32+/-4%, P < or = 0.05), and coronary vascular resistance (44+/-2%, P < or = 0.05). These effects were essentially unchanged when animals were pretreated with non-selective beta-adrenoceptor blockade, indicating that phosphodiesterase inhibition did not contribute to the positive inotropic actions of EMD 57033. 3. During exercise at 2, 3, and 4 km h(-1), the positive inotropic actions of EMD 57033 gradually waned at higher levels of exercise. This may have been caused by the exercise-induced increase in beta-adrenergic activity, because after pretreatment with propranolol the positive inotropic actions of EMD 57033 were preserved at all levels of exercise. In contrast, the positive inotropic and chronotropic effects of pimobendan were amplified during exercise, but were abolished (at rest) or markedly attenuated (during exercise) after pretreatment with propranolol. 4. The responses to EMD 57033 during exercise after combined alpha- and beta-adrenergic receptor blockade were not different from those after beta-adrenergic receptor blockade alone, indicating that the positive inotropic actions of EMD 57033 were not mediated via or did not depend on intact alpha-adrenergic receptor activity. 5. In conclusion, EMD 57033 increases left ventricular myocardial contractility in awake pigs. During exercise this effect is partially offset by the increased beta-adrenergic activity, with no effect of alpha-adrenergic activity, suggesting that EMD 57033 may be most effective in patients with severe loss of beta-adrenergic responsiveness.

Radioactivity in zircon and building tiles.

Zircon (ZrSiO4) is commonly used in the manufacture of glazed tiles. In this study we found high concentrations of the radionuclides 226Ra, 232Th, 40K in zircon sand. The average radium equivalent (A(Ra) + 1.26 A(Th) + 0.086 A(k)) in zircon sand is 17,500 Bq kg(-1), which is 106 times as much as that in ordinary building materials. The external radiation (gamma + beta) dose rates in air at 5 cm from the surface of piles of zircon sand sacks range from 1.1 to 4.9 x 10(-2) mGy h(-1) with an average of 2.1 x 10(-2) mGy h(-1). Although no elevated gamma-ray radiation or radon exhalation rate was detected in rooms decorated with glazed tiles, which is characteristic of combined alpha, beta and gamma emitting thin materials, the average gamma-ray radiation dose rate at the surface of the tile stacks in shops is 1.5 times as much as the indoor background level. The average area density of total beta emitting radionuclides in glazed floor tiles and glazed wall tiles is 0.30 Bq cm(-2) and 0.28 Bq cm(-2), respectively. It was estimated that the average beta dose rates in tissue at a depth 7 mg cm(-2) with a distance 20-100 cm from the floor tiles were 3.2 to 0.9 x 10(-7) Gy h(-1). The study indicates that the beta-rays from glazed tiles might be one of the main factors leading to an increase in ionizing radiation received by the general public. Workers in glazed tile manufacturing factories and in tile shops or stores may be exposed to elevated levels of both beta-rays and gamma-rays from zircon sand or glazed tile stacks. No elevated radiation from unglazed tiles was detected.

Unforgettable tetanus

Unforgettable tetanus

Uterine arterial vasoconstrictions mediated by ovarian nerves in virgin and postpartum rats.

In most mammals, including humans, pregnancy results in the loss of most uterine vasomotor fibers. These experiments determined whether, despite this denervation, sympathetic nerves mediated uterine vasoconstrictions in the rat 24 h after delivery. Both virgin and uniparous postpartum rats were anesthetized with urethan. Femoral vessels were cannulated for measurement of arterial pressure and intravenous administration of fluids and drugs. Blood flow was measured in a uterine artery after ligation of all anastomotic ovarian vessels. Electrical stimulation of ovarian nerve efferents elicited frequency-dependent uterine vasoconstrictions in both virgin and postpartum rats. Vasoconstrictions in postpartum rats were not significantly different from those observed in virgins. In both virgin and postpartum rats, neurogenic vasoconstrictions were reduced by combined alpha 1- and alpha 2-adrenergic blockade. We conclude that the uterine branches of the ovarian nerve mediate adrenergic uterine vasoconstrictions. In the largely denervated uterus of the postpartum rat, these vasoconstrictions may be mediated by surviving innervation of the uterine artery and its major branches. Sympathetic vasoconstriction acting at these sites would constitute an effective defense against postpartum hemorrhage.

Hypertension in obese Zucker rats. Role of angiotensin II and adrenergic activity.

We designed our studies to determine whether blood pressure is elevated in obese Zucker rats compared with lean control rats and to test the importance of the renin-angiotensin and adrenergic nervous systems in long-term blood pressure control in this genetic model of obesity. We monitored mean arterial pressure 24 hours per day using computerized methods in 13- to 14-week-old lean and obese Zucker rats maintained on a fixed, normal sodium intake (3.3 mmol/d). Mean arterial pressure (average of 5 days) was higher in obese (100 +/- 1 mm Hg) than in lean (86 +/- 1) rats. Although control plasma renin activity was lower in obese than in lean rats (3.66 +/- 0.15 versus 5.48 +/- 0.11 ng angiotensin I/mL per hour), blood pressure sensitivity to exogenous angiotensin II was greater in obese than in lean rats. Blockade of endogenous angiotensin II receptors with losartan (10 mg/kg per day) for 7 days also caused a greater decrease in blood pressure in obese (36 +/- 2 mm Hg, n = 6) than in lean (25 +/- 1, n = 5) rats. However, combined alpha- and beta-adrenergic blockade with terazosin (10 mg/kg per day) and propranolol (10 mg/kg per day), respectively, for 8 days caused only modest decreases in blood pressure in obese (9 +/- 3 mm Hg, n = 8) and lean (4 +/- 2, n = 6) rats, despite effective alpha- and beta-adrenergic blockade. These results suggest that increased arterial pressure in obese Zucker rats depends in part on angiotensin II. However, additional mechanisms may also contribute to increased blood pressure in obese Zucker rats.

Combined systemic CDDP-interferon alpha (IFNα) in advanced pleural malignant mesothelioma (MM)

Combined systemic CDDP-interferon alpha (IFNα) in advanced pleural malignant mesothelioma (MM)

Regulation of Vascular Smooth Muscle Growth by α1-Adrenoreceptor Subtypes in Vitro and in Situ

Rat aorta smooth muscle cells which express all three alpha 1-adrenoreceptors (alpha 1A, alpha 1B and alpha 1D) were used to determine the effect of stimulation of alpha 1-adrenergic receptor subtypes on cell growth. "Combined" alpha 1-adrenoreceptor subtype stimulation with norepinephrine alone caused a concentration-dependent, prazosin-sensitive increase in protein content and synthesis: 48 h of stimulation at 1 microM increased cell protein to 216 +/- 40% of time-matched controls (p = 0.008) and RNA to 140 +/- 13% (p = 0.03); protein synthesis increased to 167 +/- 13% (p < 0.01) after 24 h. Stimulation with norepinephrine plus the selective alpha 1A/alpha 1D antagonist 5-methylurapidil produced greater increases in alpha-actin mRNA (270 +/- 40% at 8 h; p = 0.007), total cell protein (220 +/- 45% at 24 h; p = 0.004), and RNA (135 +/- 8% at 24 h; p = 0.01). These effects were prevented by pretreatment with the selective alpha 1B antagonist chloroethylclonidine. Comparable results were obtained for intact aortae. Stimulation with norepinephrine plus 5-methylurapidil increased (p < 0.05) tissue protein, RNA, dry weight, and alpha-actin mRNA; and as in culture cells, combined stimulation with norepinephrine alone attenuated these responses. By comparison, adventitia (fibroblasts) was unaffected. Removal of endothelial cells had no effect. alpha 1B mRNA decreased by 42 +/- 12% (p = 0.01) in cultured cells during combined alpha 1-adrenoreceptor stimulation and by 23 +/- 8% (p = 0.03) for intact aorta. alpha 1D and beta-actin mRNA were unchanged in cultured cells, aorta media, and adventitia. These findings suggest that prolonged stimulation of chloroethylclonidine-sensitive, possibly alpha 1B-adrenoceptors induces hypertrophy of arterial smooth muscle cells and that stimulation of 5-methylurapidil-sensitive, non-alpha 1B-adrenoreceptors attenuates this growth response.

The association of combined alpha and beta fibrinogen genotype on plasma fibrinogen levels in smokers and non-smokers.

OBJECTIVE--To determine in healthy men: (1) whether an extended genotype of the fibrinogen gene cluster using the G/A-455 and the BclI polymorphism of the beta fibrinogen gene and TaqI of...

Thermal enhancement of both tumour necrosis factor alpha-induced systemic toxicity and tumour cure in rats

In vitro and in vivo studies have suggested synergistic anti-tumour activity of combined hyperthermia and tumour necrosis factor alpha (TNF-alpha). However, some studies indicated an increased systemic toxicity of TNF by additional hyperthermia. The aim of this study was to obtain starting dosages for a clinical phase I study on the application of deep local hyperthermia and systemic TNF. We investigated the effect of local hyperthermia on the toxicity and efficacy of systemic TNF. Rats (Wag/Rij) carrying a subcutaneously transplanted osteosarcoma in the hind leg received a single intravenous dose of recombinant human (rh) TNF-alpha, either at normothermia or at hyperthermia, by positioning the tumour bearing hind leg in a water bath of 43 degrees C. Dose-effect curves for lethality and tumour cure were established and LD50 and TCD50 values were calculated. Systemic toxicity was increased by local hyperthermia. The LD50 values (+/- s.e.) were 1088 (+/- 61) micrograms kg-1 at normothermia and 205 (+/- 23) micrograms kg-1 at hyperthermia, resulting in a thermal enhancement ratio (TER) of 5.3. Following normothermia, tumour cures were observed at TNF concentrations of 1000-1300 micrograms kg-1, while this was observed at doses of 50-300 micrograms kg-1 when combined with hyperthermia (TCD50 values of 1211 and 188 micrograms kg-1 respectively), resulting in a TER of 6.4. Systemic toxicity and anti-tumour activity of TNF are both increased by local hyperthermia. A safe starting dose for the combined clinical treatment would be 10% of the dose of TNF-alpha that has been recommended for phase II studies on intravenous bolus administration of TNF-alpha at normothermia. In view of the large variability in tumour sensitivity for TNF-alpha, the clinical usefulness of this combined treatment modality has to be determined.

Contribution of alpha- and beta- adrenoceptors and neuropeptide-Y to autonomic dysreflexia.

Modest increases in urinary bladder pressure result in acute hypertensive episodes in humans with spinal cord lesions above T5. The underlying mechanisms of this condition, referred to as autonomic dysreflexia, are not well understood. The aim of this study was to characterize the contribution of alpha- and beta-adrenoceptors as well as circulating neuropeptide-Y (NPY) to the pressor response to bladder distension in conscious cervical spinal rats. Rats were chronically instrumented with arterial and venous catheters. After 2-3 days, a complete spinal transection (C7) was performed, and the urinary bladder was catheterized: 24 h later, mean arterial pressure (MAP) responses to 5 min bladder distensions (+40) were measured under control conditions and after administration of specific autonomic antagonists. To assess the contribution of alpha and beta adrenergic mechanisms the alpha antagonist prazosin (0.45 mg/kg i.v.) and beta antagonist, propranolol (4 mg/kg i.v.), were administered individually or together. Blood samples were taken before, during and after bladder distension for determination of plasma NPY by radioimmunoassay. The pressor response to bladder distension was approximately 30 mmHg under control conditions. The response was attenuated (-38%), but not abolished, by prazosin. A similar attenuation (-41%) was observed with propranolol. There were no changes in plasma NPY in response to bladder distension. Finally, the pressor response was completely abolished by combined alpha- and beta-adrenergic blockade. These results suggest that autonomic dysreflexia is mediated exclusively by adrenergic receptors in the spinal rat. Moreover, both alpha and beta adrenergic receptors contribute to the pressor response induced by bladder distension in the conscious cervical spinal rat.

The relationship of plasma norepinephrine levels and aortic distensibility in elderly with isolated systolic hypertension

The present study evaluated the relationship of plasma norepinephrine (NE) and aortic distensibility (AOD) in a group of elderly patients with isolated systolic hypertension. Aortic distensibility was calculated as AOD = 2 x (delta aortic diameter)/diastolic aortic diameter) x (delta aortic pressure). Results indicate that the aortic diameters were significantly increased while the diastolic blood pressure and heart rate were decreased, in response to combined alpha- and beta-receptor blockade (labetalol). However, we found that AOD was not significantly related to plasma NE. We therefore conclude that AOD can be increased in elderly hypertensives by alpha-beta-blockade, as has been found in younger patients, but plasma NE is not a useful marker for AOD in this population.

Time-course and frequency dependence of sympathetic stimulation-evoked inhibition of vagal effects at the sinus node

Vagally-induced chronotropic responses have been shown to be inhibited after the termination of sympathetic stimulation. We sought to characterize the onset and time-course of the sympathetically evoked inhibition of vagal effects by measuring vagally induced chronotropic responses during concomitant sympathetic stimulation. In anesthetized dogs we recorded lead II of the electrocardiogram, arterial pressure and cardiac cycle length. In 7 dogs, the vagi were stimulated for 15 s every minute before, during and after 10-min trains of sympathetic stimulation. The sympathetic stimulation was applied at frequencies of 0.5, 1, 2, 5 and 10 Hz. During the 1, 2 and 5-Hz trains of sympathetic stimulation, the vagally induced changes in cycle length diminished progressively and thus, were less ( P < 0.001) at 3, 5 and 10 min compared with 1 min into the sympathetic stimulation. The magnitude of the attenuation of vagal effects on cycle length depended ( P < 0.001) on the frequency of sympathetic stimulation. To determine the role of alpha- and beta-adrenergic receptors, we measured vagally-induced changes in cycle length during 5-min trains of sympathetic stimulation (1, 2, 5, 10 Hz) in the presence and absence of phentolamine and propanolol ( n = 6). Both before and after combined alpha- and beta-adrenergic receptor blockade, the vagally-induced changes in cycle length decreased ( P < 0.03) progressively during the 1, 2, 5 and 10-Hz trains of sympathetic stimulation and the magnitude of the inhibition depended ( P < 0.002) on the frequency of sympathetic stimulation. These data show that the effects of short trains of vagal stimulation on cardiac cycle length are inhibited progressively during continuous trains of sympathetic stimulation before and after combined alpha- and beta-adrenergic receptor blockade. Thus, substances other than norepinephrine may contribute to the inhibition of cardiac vagal effects that occurs during a continuous train of sympathetic stimulation.

Diameter and flow velocity changes of feline small pulmonary vessels in response to sympathetic nerve stimulation.

Using an X-ray television system, we measured directly changes in the internal diameter (ID), flow velocity, and volume flow of the small pulmonary vessels (100-500 microns ID) in response to electrical sympathetic nerve stimulation (SNS) in anaesthetized cats before and after adrenergic receptor blockade. Flow velocity was obtained by measuring the distance that the leading edge of the contrast medium moved per 0.1 s in the small arteries. Volume flow was obtained from the product of flow velocity and cross-sectional area calculated from the ID of the small arteries. SNS was accomplished with 10- to 15-V square-wave pulses of 2-ms duration at 20-30 Hz for 20-s periods. In response to SNS, arterial ID decreased significantly by 8-13% in the 200- to 500-microns vessels but not in the 100- to 200-microns vessels. In the veins, on the other hand, there was no significant ID decrease in any of the 100- to 500-microns vessels. After alpha-receptor blockade (phentolamine, 2 mg/kg i.v.), there were significant ID increases (4-9%) in the 100- to 500-microns arteries in response to SNS, the maximum increases being in the 100- to 200-microns arteries. After beta-blockade (propranolol, 2 mg/kg i.v.), the ID decrease due to SNS in the 200- to 500-microns arteries was enhanced (24-27%) and, in addition, the 100- to 200-microns arteries exhibited a significant ID decrease (18%). Combined alpha- and beta-blockade completely abolished the ID decrease due to SNS. In the veins, on the other hand, no ID change occurred even after alpha- or beta-blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive, antiatherosclerotic, and plasma lipid-lowering effects of monatepil, a novel calcium antagonist with alpha 1-adrenoceptor-blocking activity in experimental animals.

Traditional antihypertensive therapy has been shown to reduce the incidence of hypertension-related vascular injuries; however, it is not fully effective against cardiovascular abnormalities. In some animal models, calcium antagonists have been demonstrated to possess antiatherogenic properties but to have no effects on plasma lipid levels, whereas alpha 1-adrenoceptor blockers have been shown to reduce plasma lipid levels. Monatepil is a new type of calcium antagonist that also has alpha 1-adrenoceptor-blocking activity. Therefore, it is thought that monatepil may have both antiatherosclerotic and plasma lipid-lowering effects in addition to its slow-onset and long-lasting antihypertensive effect. To determine the antiatherosclerotic effects of monatepil, we examined its effect on experimental atherosclerosis induced by feeding a high-cholesterol diet to monkeys, whose lipid metabolism resembles that of humans. Monatepil, at a daily dose of 30 mg/kg, at which plasma levels are equivalent to those in clinical antihypertensive therapy, was administered orally for 6 months. Monatepil suppressed elevation of cholesterol in the aorta and reduced the atherogenic (sudanophilic) area. Histologic examination revealed that monatepil-treated monkeys exhibited little aggregation of foam cells in either the aorta or coronary arteries compared with vehicle-treated atherogenic monkeys. In addition, monatepil showed preventive effects against increases in total cholesterol and low density lipoprotein (LDL), and against decreases in high density lipoprotein in plasma caused by cholesterol loading. The plasma lipid-lowering effect may be mediated through up-regulation of the number of hepatic LDL receptors by the alpha 1-adrenoceptor-blocking activity, and the antiatherosclerotic effect may be produced by the combined calcium antagonist, alpha 1-adrenoceptor-blocking, and antilipid peroxidation activities. In summary, monatepil is an antihypertensive agent belonging to a new class with antiatherogenic properties and the ability to reduce plasma lipid levels.

Combined systemic CDDP-interferon alpha (IFNα) in advanced pleural malignant mesothelioma (MM)

Combined systemic CDDP-interferon alpha (IFNα) in advanced pleural malignant mesothelioma (MM)

Angiotensin II and alpha 1-adrenergic tone in chronic nitric oxide blockade-induced hypertension.

Nitric oxide (NO) is a tonically produced vasodilator that maintains blood pressure (BP) in the normal animal. In these studies, we produced chronic NO blockade by oral administration of the NO synthesis inhibitor nitro-L-arginine methyl ester (L-NAME), which produced sustained hypertension and increased renal vascular resistance (RVR) in conscious rats. Acute blockade of the angiotensin II type 1 (AT1) receptor with losartan had little effect on BP and RVR in either chronically NO-blocked or normal conscious rats. Acute blockade of the alpha 1-adrenoceptor with prazosin produced moderate similar falls in BP in both chronically NO-blocked and normal rats. The combination of AT1 and alpha 1-adrenoceptor blockade was profoundly antihypertensive and was particularly effective in lowering BP in chronically NO-blocked rats where the hypertension was obliterated. In contrast, the increased RVR persisted in chronically NO-blocked rats receiving combined acute AT1 and alpha 1-adrenoceptor blockade. These observations indicate that, in the sustained phase of chronic NO blockade, the hypertension is largely due to the combined activities of alpha 1-adrenoceptor and AT1 stimulation.

Exercise-induced pulmonary vasoconstriction during combined blockade of nitric oxide synthase and beta adrenergic receptors.

We studied the effects of inhibition of nitric oxide (NO) (endothelium-derived relaxation factor) synthase in combination with alpha and beta adrenergic receptor blockade on pulmonary vascular tone during exercise. In paired studies, we exercised sheep on a treadmill at a speed of 4 mph, and measured blood flow and pressures across the pulmonary circulation with and without inhibition of NO synthase (N omega-nitro-L-arginine 20 mg/kg intravenous [i.v.]), alpha receptor blockade (phentolamine 5 mg i.v.), beta receptor blockade (propranolol 1 mg i.v.), and combined alpha and beta receptor blockade. Activation of both types of adrenergic receptors occurs with exercise, and because increased release in NO is hypothesized to occur during exercise, these studies were designed to determine the magnitude of effect and interactions of these competing dilator and constrictor influences. We found that inhibition of NO synthase raised pulmonary vascular resistance (PVR) at rest and that, although a reduction in PVR occurred with exercise from this new baseline, vasoconstriction persisted. Combined beta blockade and NO synthase inhibition unmasked unopposed alpha vasoconstriction; PVR rose at rest and continued to rise with exercise; and mean pulmonary arterial pressures approached very high levels, 43.8 +/- 4.4 cmH2O. Using a distal wedged pulmonary artery catheter technique, most of the vasoconstriction was found to be in vessels upstream from small pulmonary veins. During exercise in sheep there appears to be a high degree of alpha and beta adrenergic-mediated tone in the pulmonary circulation. Endogenous production of NO actively dilates pulmonary vessels at rest and opposes potent alpha-mediated pulmonary vasoconstriction during exercise.