Pharmacology of SB-273779, a nonpeptide calcitonin gene-related peptide 1 receptor antagonist.

Calcitonin gene-related peptide (CGRP), a potent vasodilatory and cardiotonic peptide, has a potential role for CGRP in diverse physiologic and pathophysiologic situations such as congestive heart failure, diabetes, migraine, and neurogenic inflammation. Although a peptide CGRP receptor antagonist, CGRP(8-37,) is available, its utility presents significant limitations for these indications. Here, we describe the properties of SB-(+)-273779 [N-methyl-N-(2-methylphenyl)-3-nitro-4-(2-thiazolylsulfinyl)nitrobenzanilide], a selective nonpeptide antagonist of CGRP(1) receptor. SB-(+)-273779 inhibited (125)I-labeled CGRP binding to SK-N-MC (human neuroblastoma cells) and human cloned CGRP(1) receptor with K(i) values of 310 +/- 40 and 250 +/-15 nM, respectively. SB-(+)-273779 also inhibited CGRP (3 nM)-activated adenylyl cyclase in these systems with IC(50) values of 390 +/-10 nM (in SK-N-MC) and 210 +/-16 nM (recombinant human CGRP receptors). Prolonged treatment (>30 min) of SK-N-MC cells with SB-(+)-273779 followed by extensive washing resulted in reduction in maximum CGRP-mediated adenylyl cyclase activity, suggesting that this compound has irreversible binding characteristics. In addition, SB-(+)-273779 antagonized CGRP-mediated 1) stimulation of intracellular Ca(2+) in recombinant CGRP receptors in HEK-293 cells, 2) inhibition of insulin-stimulated [(14)C]deoxyglucose uptake in L6 cells, 3) vasodilation in rat pulmonary artery, and 4) decrease in blood pressure in anesthetized rats. SB-(+)-273779 tested at 3 microM had no significant affinity for calcitonin, endothelin, angiotensin II, and alpha-adrenergic receptors under standard ligand binding assays. SB-(+)-273779 also did not inhibit forskolin and pituitary adenylate cyclase-activating polypeptide. These results suggest that SB-(+)-273779 is a valuable tool for studying CGRP-mediated functional responses in complex biological systems.

Human urotensin-II is a potent vasoactive peptide: pharmacological characterization in the rat, mouse, dog and primate.

The observation that the novel G-protein-coupled receptor (GPCR) GPR14 and its cognate ligand, urotensin-II (U-II), are expressed within the mammalian vasculature raises the possibility that they may influence cardiohemodynamic homeostasis. To this end, this study examined the vasoactive properties of U-II in rodents, dogs and primates. In vitro, human U-II was a sustained vasoconstrictor with a potency (pD2s < or = 9) approximately an order of magnitude greater than that seen with endothelin-1 (ET-1), making it one of the most, if not the most, potent mammalian vasoconstrictor identified to date. However, in vitro responses exhibited significant anatomical and/or species-dependency, that is, human U-II was a selective 'aorto-coronary' vasoconstrictor in rats and dogs, inactive in mice and contracted all primate arteries studied. In vivo, this peptide evoked a complex, dose-dependent hemodynamic response in the anesthetized primate, culminating in severe myocardial depression and fatal circulatory collapse. As such, U-II may represent a novel neurohumoral regulator of mammalian cardiovascular physiology and pathology in particular disorders characterized by aberrant vascular smooth muscle and/or myocardial function.

Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14.

Urotensin-II (U-II) is a vasoactive 'somatostatin-like' cyclic peptide which was originally isolated from fish spinal cords, and which has recently been cloned from man. Here we describe the identification of an orphan human G-protein-coupled receptor homologous to rat GPR14 and expressed predominantly in cardiovascular tissue, which functions as a U-II receptor. Goby and human U-II bind to recombinant human GPR14 with high affinity, and the binding is functionally coupled to calcium mobilization. Human U-II is found within both vascular and cardiac tissue (including coronary atheroma) and effectively constricts isolated arteries from non-human primates. The potency of vasoconstriction of U-II is an order of magnitude greater than that of endothelin-1, making human U-II the most potent mammalian vasoconstrictor identified so far. In vivo, human U-II markedly increases total peripheral resistance in anaesthetized non-human primates, a response associated with profound cardiac contractile dysfunction. Furthermore, as U-II immunoreactivity is also found within central nervous system and endocrine tissues, it may have additional activities.

Plasma- and cerebrospinal fluid-immunoreactive endothelin-1: effects of nonpeptide endothelin receptor antagonists with diverse affinity profiles for endothelin-A and endothelin-B receptors.

Some endothelin (ET) receptor antagonists have been reported to elevate plasma immunoreactive endothelin-1 (irET-1). However, there is no information regarding the effects of ET receptor antagonists on cerebrospinal fluid (CSF) levels. To better understand the regulation of circulating and CSF ET-1, the effects of several nonpeptide antagonists with high, intermediate, or low affinity at the ETB receptor, as well as the potent ETB selective agonist sarafotoxin 6c (S6c), were characterized and compared. The effects of SB209670 (Ki ETA = 0.2 nM; Ki ETB = 12 nM), SB217242 (Ki ETA = 1.1 nM; Ki ETB = 111 nM), SB234551 (Ki ETA = 0.1 nM; Ki ETB = 500 nM), SB247083 (Ki ETA = 0.4 nM; Ki ETB = 467 nM), and S6c (Ki ETA = 950 nM; Ki ETB = 1 nM) on plasma irET-1 were determined by ELISA in the anesthetized dog after i.v. administration. Systemic administration of equivalent doses of the nonpeptide ET receptor antagonists produced dose-related elevations in plasma irET-1 which were correlated (p = 0.019) with affinity at the ETB receptor. There was no significant correlation with affinity at the ETA receptor. In addition, the plasma irET-1 and ET antagonist concentrations were linearly correlated (r = 0.98) throughout the time course after antagonist administration. There was no evidence of densensitization after three bolus administrations performed at 2-h intervals (SB209670, 1 and 3 mg/kg i.v.). Elevations in plasma irET-1 (four- to fivefold) were also observed after systemic administration of S6c (1 nmol/kg i.v.). The administration of L-NAME (200 micrograms/kg/min for 30 min), an inhibitor of nitric oxide (NO) synthase, increased blood pressure (33%) but did not alter plasma irET-1. In contrast, systemic administration of the ET receptor antagonists had little or no effect on the on irET-1 in the CSF. However, intracerebroventricular (i.c.v.) administration of SB209670 produced a dose-related (3-100 micrograms) increase in cisternal CSF levels of irET-1 without altering plasma irET-1. Systemic administration of ETB receptor antagonists and agonists rapidly increased plasma irET-1. These ETB receptor antagonist effects correlate linearly with affinity at the cloned human ETB receptor, do not exhibit desensitization, and do not appear to reflect inhibition of ETB-mediated NO production. The endothelial ETB receptor may represent a high-capacity storage/clearance site for circulating ET-1. ET receptor antagonists may also act extravascularly/abluminally to increase irET-1 in the CNS.

Identification, characterization, and functional role of phosphodiesterase type IV in cerebral vessels: effects of selective phosphodiesterase inhibitors.

The role of the phosphodiesterase type IV isozyme (PDE IV) in the regulation of cerebrovascular tone was investigated in the canine basilar artery in vitro and in vivo. The PDE isozymes extracted from the canine basilar artery were isolated by diethylaminoethanol (DEAE)-Sepharose affinity chromatography and identified based on sensitivity to isozyme-selective PDE inhibitors. [3H]cAMP hydrolysis was observed in one major and one minor peak of activity. The predominant peak was inhibited by the addition of cGMP (25%), siguazodan (26%), rolipram (39%), and the combination of siguazodan and rolipram (95%). Selective PDE IV inhibitors BRL 61063, rolipram, and denbufylline were equieffective inhibitors of [3H]-ccAMP hydrolysis mediated by PDE IV isolated from the canine basilar artery [concentrations producing 50% inhibition (IC50S) = 0.21 +/- 0.05 microM, 0.67 +/- 0.23 microM, and 0.73 +/- 0.16 microM, respectively]. In precontracted isolated ring segments of the canine basilar artery, selective PDE IV inhibitors produced potent and complete relaxation (IC50S < 150 nM). In contrast, zaprinast (a selective PDE V inhibitor) and siguazodan (a selective PDE III inhibitor) produced only weak relaxation of the basilar artery (IC50S = 4.5 microM and > 10 microM, respectively). Vasorelaxation produced by PDE IV inhibitors was not altered by removing the endothelium, 1-NAME, or adenosine receptor antagonism. In a canine model of acute cerebral vasospasm, all three selective PDE IV inhibitors reversed basilar artery spasm produced by autologous blood without altering mean arterial blood pressure. In contrast, prolonged treatment with BRL 61063 failed to alter the development of basilar spasm in the two hemorrhage canine models of chronic cerebral vasospasm. Denbufylline-induced relaxation in vitro was also significantly impaired in basilar arteries obtained from the model of chronic vasospasm. In conclusion, PDE IV appears to be the predominant isozyme regulating vascular tone mediated by cAMP hydrolysis in cerebral vessels. In addition, vasorelaxation modulated by PDE IV is compromised in chronic cerebral vasospasm associated with subarachnoid hemorrhage.

Nonpeptide endothelin receptor antagonists. VIII: attentuation of acute hypoxia-induced pulmonary hypertension in the dog.

It has been proposed that endothelin-1 (ET-1), a potent endogenous vasoactive peptide, may play an important role in the regulation of pulmonary blood flow. The purpose of the present study was to characterize the effects of ET-1 and a nonpeptide mixed ET(A) and ET(B) receptor antagonist, SB 209670, in isolated segments of the canine pulmonary artery and to examine the effects of SB 209670 in a canine model of acute hypoxia-induced pulmonary hypertension. In isolated segments of the pulmonary artery, SB 209670 (3-300 nM) produced a concentration-dependent antagonism of contraction elicited by ET-1 (pA2 = 8.9; slope = 0.9) and had no effect on phenylephrine responses. In addition, SB 209670 antagonized the small, endothelium-dependent relaxation induced by sarafotoxin 6c in phenylephrine (10 microM)-precontracted vessels (pKB = 8.6). In anesthetized dogs, the driving pressure across the pulmonary circulation increased approximately 100% during the hypoxic period (area under the curve [AUC] = 267.1 +/- 25.3 mm Hg x min). SB 209670 treatment (3 and 30 microg/kg/min i.v.) reduced pulmonary vascular resistance and produced a profound dose-related inhibition of hypoxia-induced pulmonary hypertension (AUC = 158.3 +/- 22.7 mm Hg x min and 50.1 +/- 4.9 mm Hg x min, respectively). None of the other hemodynamic or arterial blood gas parameters differed significantly in the vehicle and treatment groups. In addition, SB 209670 produced a significant reversal of hypoxia-induced pulmonary hypertension (AUC = 267.1 +/- 25.3 mm Hg x min vs. 167.8 +/- 23.4 mm Hg x min) when administered at the plateau of the hypoxic response. It was found that SB 209670 administration significantly elevated plasma levels of ET-1-LI (> or = 25-fold). These results suggest that ET-1 is an important mediator of hypoxia-induced pulmonary hypertension in the dog and that SB 209670, a potent and selective mixed ET(A) and ET(B)receptor antagonist in the pulmonary circulation, may represent an important therapeutic approach to the treatment of pulmonary hypertension.

Nonpeptide endothelin antagonist. Cerebrovascular characterization and effects on delayed cerebral vasospasm.

BACKGROUND AND PURPOSE: (+/-)-SB 209670, a potent nonpeptide endothelin (ET) receptor antagonist, was used to investigate the potential role of ET in cerebral vasospasm associated with subarachnoid hemorrhage. METHODS: The effects of (+/-)-SB 209670 were evaluated in isolated segments of canine posterior cerebral arteries in vitro, vascular smooth muscle cells in culture, and in the canine two-hemorrhage model of delayed cerebral vasospasm in vivo. RESULTS: In the canine basilar and anterior spinal arteries, (+/-)-SB 209670 caused a dose-related inhibition of contractile responses mediated by ET (KB = 4.6 nmol/L and apparent KB = 2.7 nmol/L, respectively). The effects of (+/-)-SB 209670 were mediated by inhibition of ETA receptors since the ETB selective agonist sarafotoxin 6c did not contract these posterior cerebral vessels. (+/-)-SB 209670 also produced a concentration-dependent inhibition (IC50 = 1 nmol/L) of the mitogenic response induced by ET-1 in vascular smooth muscle cell culture. In the canine model of delayed cerebral vasospasm, animals received intracisternal vehicle (saline) or (+/-)-SB 209670 (360 +/- 10 micrograms/d) via osmotic minipump for 7 days. On day 7, the cross-sectional areas in the (+/-)-SB 209670 group were significantly greater than those in the vehicle group in both the basilar artery (68% versus 27%) and anterior spinal artery (78% versus 38%). No differences in blood pressure or heart rate were noted in the two groups, and the vasospasm in the vehicle group did not differ from that of historic controls in this model. CONCLUSIONS: The results suggest that ET plays a significant role in the development of delayed cerebral vasospasm via an interaction with ETA receptors. Furthermore, ETA receptor antagonists may represent a novel therapeutic approach to the treatment of subarachnoid hemorrhage.

A comparison of (+)SK&F 10047 and MK-801 on cortical spreading depression.

MK-801 and (+)SK&F 10047 produced a dose-related inhibition of the EEG suppression and cortical hyperemia associated with cortical spreading depression (CSD) and reduced the CSD propagation rate; ED50 = 1 mg/kg, i.v. and 15 mg/kg, i.v., respectively. MK-801 had a delayed onset of action (inversely related to dose) and a prolonged duration of action at all doses (> 2 h). In contrast, (+)SK&F 10047 had a rapid onset of action (< 30 min) and a predictable dose-related duration of action. These results suggests that an efficacious compound acting with moderate affinity as a non-competitive antagonist at the NMDA-receptor channel may possess a preferable time-course and toxicity profile when compared to agents acting similarly, but with high affinity.

Transient forebrain ischemia alters acutely endothelin receptor density and immunoreactivity in gerbil brain.

Pharmacologic studies suggest that endothelin (ET) plays an important role in the pathophysiology of hemorrhagic and ischemic stroke. In the gerbil, transient forebrain ischemia (10 min) resulted in profound motor deficits and a 15% reduction in ET receptor density in the hippocampus at 60 min post-reperfusion. A significant 2-fold increase in forebrain immunoreactive ET accompanied the maximum post-ischemic decrease in ET receptor density. These results suggest that the synthesis and availability of ET are increased acutely in the forebrain following transient cerebral ischemia.

Antithrombotic effects of a platelet fibrinogen receptor antagonist in a canine model of carotid artery thrombosis.

BACKGROUND AND PURPOSE: Platelet-fibrin thrombi in the lumen of atherostenotic carotid arteries may underlie transient ischemic attacks and cerebral infarction. For this reason, we investigated the antiplatelet and antithrombotic effects of a novel and potent platelet fibrinogen receptor (glycoprotein IIb/IIIa) antagonist (SK&F 106760). METHODS: The effects of 0.1-3.0 mg/kg i.v. SK&F 106760 on platelet aggregation were examined ex vivo in canine platelet-rich plasma (n = 20). In addition, the antithrombotic effects of SK&F 106760 were compared with those of aspirin in an acute canine model of extracranial carotid artery thrombosis with high-grade stenosis. Sham-operated (n = 4), vehicle-treated (n = 6), SK&F 106760-treated (n = 8), aspirin-treated (n = 9), and SK&F 106760+aspirin-treated (n = 5) dogs were examined. RESULTS: The intravenous administration of SK&F 106760 caused a dose-related inhibition of ex vivo platelet aggregation. In the carotid artery thrombosis model, an occlusive thrombus formed at stenotic sites in the region of the carotid bifurcation. The thrombogenic process caused a progressive reduction in carotid blood flow and reduced the cortical microvascular perfusion and electroencephalographic power. Based on nuclear magnetic resonance spectroscopy, the occlusive events depleted the stores of high-energy phosphates (adenosine triphosphate and phosphocreatine) and increased the lactate concentration in the forelimb somatosensory area of the parietal cortex. In this model, the administration of 1 mg/kg i.v. SK&F 106760 prevented thrombosis of the stenotic carotid artery. Consequently, neurophysiological, cerebral hemodynamic, and metabolic parameters were all improved significantly in the SK&F 106760-treated group. No dog receiving SK&F 106760 reoccluded during the 1-hour posttreatment observation period. In contrast, thrombosis of the carotid artery was associated with neurophysiological deterioration in six of the nine dogs treated with 5 mg/kg i.v. aspirin. Both spontaneous and evoked (increased carotid stenosis) aspirin-resistant thrombosis were abolished by SK&F 106760 treatment. CONCLUSIONS: These results suggest that antagonism of fibrinogen binding to platelet glycoprotein IIb/IIIa (the final common pathway for aggregation) may represent a new and more effective antithrombotic approach to the treatment of cerebral transient ischemic attacks and infarction associated with extracranial carotid artery disease.

Sympathetic regulation of cutaneous circulation in the rat.

The purpose of the present study was to characterize, in vivo, the function and origin of peripheral alpha-adrenergic mechanisms in acral regions of the cutaneous microvasculature. Laser-Doppler flowmetry was used to continuously monitor changes in local cutaneous microvascular perfusion (CP) measured at the plantar surface of the terminal phalange in the rat. In ketamine-anesthetized rats, the intravenous administration of phentolamine (a nonselective alpha-adrenoceptor antagonist) elicited a dose-dependent (0.01-1.0 mg/kg, i.v.) increase in CP, a decrease in mean arterial pressure (MAP) and a marked reduction in cutaneous vascular resistance (CVR). These results demonstrate a high degree of endogenous alpha-adrenergic tone in the cutaneous microvasculature of the rat. In pithed rats, cutaneous vasoconstriction could be evoked by ganglionic stimulation with DMPP or by electrical stimulation of the peripheral cut end of the sciatic nerve trunk. DMPP and sciatic nerve responses were not altered by propranolol or atropine, but were inhibited by phentolamine. In addition, the effects of DMPP on CP were abolished by bilateral adrenal demedullation, but were unaltered by hindlimb denervation. These results suggest that the predominant vasoconstrictor tone in the cutaneous vasculature is mediated by a humoral action of circulating catecholamines at postjunctional alpha-adrenoceptors. The adrenal medulla appears to be the origin of this humoral tone. Postganglionic sympathetic nerves play an insignificant role in mediating cutaneous vasoconstriction elicited by ganglionic stimulation.

The role of alpha adrenoceptor subtypes in sympathetic control of the acral-cutaneous microcirculation.

In pithed and anesthetized rats, laser-Doppler flowmetry was used to evaluate the role of alpha-1 and alpha-2 adrenoceptors in mediating sympathetic responses in acral regions of the cutaneous circulation. The intravenous administration of the selective alpha-1 agonist, phenylephrine, was a more potent vasopressor agent than BH-T 933 (a selective alpha-2 adrenoceptor agonist) in pithed rats. However, BH-T 933 was more potent and more efficacious than phenylephrine in reducing cutaneous microvascular perfusion (CP). BH-T 933 also caused a greater increase in cutaneous microvascular resistance. Neural and humoral sympathetic effects on CP were characterized with selective alpha-1 and alpha-2 adrenoceptor antagonists (prazosin and rauwolscine, respectively). It was found that frequency-related reductions in CP elicited by sciatic nerve stimulation were antagonized by prazosin, but not by rauwolscine. In fact, rauwolscine enhanced neurally evoked reductions in CP at the highest stimulation frequencies. However, both prazosin and rauwolscine antagonized reductions in CP elicited by electrical stimulation of the thoracolumbar outflow (sympathoadrenal activation). Ganglionic stimulation (intravenous 1,1-dimethyl-4-phenylpiperazinium) also caused a profound, transient reduction in CP that was abolished by rauwolscine, but was not significantly altered by prazosin. In contrast, 1,1-dimethyl-4-phenylpiperazinium-induced increases in mean arterial pressure were reduced by prazosin, but not by rauwolscine. In ketamine-anesthetized rats, rauwolscine caused a dose-related increase in CP without altering mean arterial pressure, whereas prazosin lowered mean arterial pressure but did not alter CP. We conclude that acral regions of the cutaneous vasculature are more sensitive to alpha-2 vis-a-vis alpha-1 adrenoceptor-mediated vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Abluminal effects of endothelin in cerebral microvasculature assessed by laser-Doppler flowmetry.

Laser-Doppler flowmetry was used to assess the intraparenchymal effects of endothelin 1 (ET-1) on cortical microvascular perfusion (CP). The initial part of this study examined effects of the intraparenchymal microinjection technique on local cortical microvascular responsivity. In anesthetized rats, the microinjection of vehicle (saline) beneath the cortical surface did not alter CO2 responsivity or autoregulation of the cortical microvasculature. In addition, predictable monophasic changes in local CP were elicited by the intraparenchymal microinjection of known vasodilators and vasoconstrictors, i.e., nitroprusside and prostaglandin F2 alpha, respectively. These experiments demonstrate normal responsivity of the cortical microvasculature after intraparenchymal microinjection. In the second part of this study, intraparenchymal microinjections (100 nl) of ET-1 (1-1,000 fmol) were evaluated. Microinjections of less than 10 fmol of ET-1 did not alter CP. However, doses between 10 and 1,000 fmol of ET-1 elicited monophasic dose-related reductions in CP. At 1,000 fmol, the highest dose studied, ET-1 produced a complex microvascular response consisting of an initial profound reduction in CP followed by alternating cycles of increased perfusion ultimately lapsing back to a prolonged period of hypoperfusion. No significant changes in blood pressure were observed after ET-1 administration, and no significant changes in any of the hemodynamic variables were observed after vehicle microinjection. These results suggest that abluminal microvascular actions of ET-1 mediate cerebral vasoconstriction and hypoperfusion.

Local cutaneous hemodynamic effects of carvedilol and labetalol in the anesthetized rat.

The effects of labetalol and carvedilol and local cutaneous microvascular perfusion and calculated local cutaneous microvascular resistance were investigated in anesthetized rats at submaximal doses that produced equivalent reductions in blood pressure and heart rate. Labetalol decreased cutaneous perfusion (-25 +/- 3%) without significantly affecting cutaneous vascular resistance (-6 +/- 3%). In marked contrast, carvedilol dramatically increased cutaneous perfusion (+64 +/- 9%) and significantly reduced cutaneous vascular resistance (-57 +/- 3%). These results suggest that carvedilol and labetalol possess differences in the mechanisms by which they produce vasodilation in vivo.

Role of alpha-1 and alpha-2 adrenoceptors in the sympathetic control of the proximal urethra.

In the pithed rat, postjunctional alpha-1 and alpha-2 adrenoceptors mediate increases in proximal urethral perfusion pressure (UPP). The present study examined the role of alpha-1 and alpha-2 adrenoceptors in sympathetic control of the isolated in situ proximal urethra of the rat. An endogenous alpha adrenergic constriction was demonstrated in the proximal urethra by eliciting dose-related and phentolamine-sensitive increases in UPP after the systemic administration of tyramine. Transient dose-related and hexamethonium-sensitive increases in UPP were also elicited by ganglionic stimulation with 1,1-dimethyl-4-phenylpiperazinium (DMPP). Based on the relative sensitivity of the DMPP response to standard autonomic blockers, it was determined that constriction is the predominant autonomic response in the proximal urethra and this response is mediated by alpha adrenoceptor mechanisms. Prazosin, a selective alpha-1 adrenoceptor antagonist, substantially reduced (72%) the steady-state increases in UPP elicited by discrete low frequency electrical stimulation of the spinal hypogastric outflow. In contrast, selective alpha-2 adrenoceptor blockade with rauwolscine significantly increased (28%) the UPP response to hypogastric stimulation. Prazosin also abolished the increase in urethral tone elicited by tyramine, whereas rauwolscine had no effect on the tyramine. A different response profile was observed for prazosin and rauwolscine when the steady-state increase in UPP was evoked by simultaneously stimulating the midthoracic and hypogastric spinal outflow. Under these conditions of sympathoadrenal activation, UPP was reduced by both prazosin and rauwolscine (63 and 50%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic differences between carvedilol and labetalol in the cutaneous circulation.

The effects of labetalol and carvedilol on local cutaneous microvascular perfusion and calculated local cutaneous microvascular resistance were investigated in anesthetized rats at submaximal doses that produced equivalent reductions in blood pressure and heart rate. Labetalol decreased cutaneous perfusion (-25% +/- 3%) without significantly affecting cutaneous vascular resistance (-6% +/- 3%). In marked contrast, carvedilol dramatically increased cutaneous perfusion (+64% +/- 9%) and significantly reduced cutaneous vascular resistance (-57% +/- 3%). These results suggest that carvedilol and labetalol possess differences in the mechanisms by which they produce vasodilation in vivo.