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(Circulation. 1997;95:2293-2297.)
© 1997 American Heart Association, Inc.

Articles

Effects of Inhibition of the L-Arginine/Nitric Oxide Pathway on Vasodilation Caused by ß-Adrenergic Agonists in Human Forearm

Matthew Dawes, BSc, MRCP; Philip J. Chowienczyk, BSc, MRCP; James M. Ritter, MA, DPhil, FRCP

From the Department of Clinical Pharmacology, United Medical and Dental Schools of Guy's and St. Thomas' Hospitals, London, UK.

Correspondence to Dr M. Dawes, Department of Clinical Pharmacology, St Thomas' Hospital, Lambeth Palace Rd, London, SE1 7EH UK. E-mail j.ritter{at}umds.ac.uk

	Abstract

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Background We examined whether vasodilator responses to ß-agonists in human forearm vasculature are mediated in part through the nitric oxide pathway.

Methods and Results We measured forearm blood flow responses to brachial artery infusions of ß-adrenergic agonists in healthy men. Salbutamol was more than 100 times as potent as dobutamine. Cumulative doses of salbutamol (0.3 to 3.5 nmol·min^-1) did not cause tachyphylaxis to an identical repeated infusion after a 24-minute recovery period. Vasodilators were infused with this sequence during coinfusion of saline and N^G-monomethyl-L-arginine (L-NMMA, 4 µmol·min^-1), an inhibitor of nitric oxide synthase. L-NMMA coinfusion inhibited responses (area under the dose-response curve) to isoproterenol (0.01 to 0.1 nmol·min^-1) by 59±7% (n=5) and inhibited those to salbutamol (0.3 to 3.5 nmol·min^-1) by 52±6% (n=8). L-NMMA had no significant effect on vasodilator responses to nitroprusside (2.7 to 11.0 nmol·min^-1, n=8), verapamil (20 to 80 nmol·min^-1, n=8), or prostacyclin (0.08 to 0.24 nmol·min^-1, n=8).

Conclusions These results suggest that ß-adrenergic vasodilator responses in human forearm vasculature are mediated predominantly through ß₂-adrenergic receptors and are dependent on nitric oxide synthesis.

Key Words: blood flow • endothelium-derived factors • receptors, adrenergic, beta • vasodilation

	Introduction

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Stimulation of ß-adrenergic receptors increases cAMP.¹ This provides a potentially endothelium-independent mechanism of vasodilation. In contrast, endothelium-dependent vasodilation by agonists such as acetylcholine is initiated by endothelial receptors linked through Ca²⁺/calmodulin to ecNOS, endothelium-derived NO acting on vascular smooth muscle guanylyl cyclase to increase cGMP. We recently observed that forearm blood flow responses to isoproterenol are impaired in men with hypercholesterolemia, a condition associated with dysfunction of the L-arginine/NO pathway.^{2 3} In the present study, we therefore investigated whether responses to ß-agonists in human forearm vasculature are mediated in part through the NO pathway. Preliminary experiments suggested that ß-adrenergic vasodilation in this vascular bed is mediated predominantly by ß₂-receptors. We therefore measured the effect of L-NMMA, an inhibitor of ecNOS, on blood flow responses to salbutamol (a ß₂-selective agonist) and isoproterenol (a nonselective ß-agonist). Control studies were performed with nitroprusside (an endothelium-independent NO donor), verapamil (an L-type Ca²⁺ antagonist that is an NO-independent vasodilator), and prostacyclin, which activates vascular smooth muscle adenylyl cyclase.⁴

	Methods

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Studies were performed on 28 healthy normotensive, normocholesterolemic white men 18 to 30 years of age who gave written informed consent. The study was approved by the West Lambeth Health Authority Research Ethics Committee. Forearm blood flow (milliliters per minute per 100 mL forearm volume) was measured in both arms simultaneously by use of venous occlusion plethysmography with temperature-compensated strain gauges.^{5 6} One minute before measurements, the hands were excluded from the circulation by inflation of wrist cuffs to 180 mm Hg.⁷ Upper arm cuffs were inflated intermittently to 40 mm Hg. A 27-gauge needle (Cooper's Needle Works) was inserted under sterile conditions into the left brachial artery under local anesthesia (1% lidocaine) and sterile saline (140 mmol/L sodium chloride) or drugs dissolved in saline infused at 1 mL min^-1 by a pump (Braun).

Vasodilator Effects of ß-Agonists
Cumulative dose-response studies were performed to examine the relative potencies of isoproterenol (a nonselective ß- agonist), salbutamol (a ß₂-selective agonist), and dobutamine (a ß₁-selective agonist). Blood flow was allowed to stabilize after arterial line placement. Baseline measurements were recorded during a 12-minute infusion of saline, followed by three doses of agonist administered cumulatively. Doses used were 0.01, 0.03, and 0.1 nmol·min^-1 (isoproterenol); 0.3, 1.0, and 3.5 nmol·min^-1 (salbutamol); and 60, 150, and 300 nmol·min^-1 (dobutamine). Each dose was administered for 6 minutes. Blood flows were measured repeatedly for the last 3 minutes of each infusion period, and the mean of the last five readings was used for analysis. Each agonist was studied on a separate occasion.

Effect of L-NMMA on Vasodilator Responses
Baseline measurements were recorded after arterial line placement and blood flow stabilization as above. Two sequential cumulative dose infusions of salbutamol (0.3, 1.0, and 3.5 nmol·min^-1) were performed in initial experiments. Each dose was administered for 6 minutes, with blood flow measurement done the last 3 minutes of each infusion as above. Eighteen minutes after the conclusion of the first cumulative infusion of salbutamol, saline was administered at 1 mL·min^-1 for 6 minutes and was then coinfused during a second identical infusion of salbutamol. Tachyphylaxis was not evident with this sequence, and effects of L-NMMA on isoproterenol, salbutamol, nitropusside, verapamil, and prostacyclin were examined by use of the same protocol. After baseline measurements, subjects received a control cumulative dose infusion of agonist, followed after 18 minutes by L-NMMA dissolved in saline. L-NMMA was given alone at a rate of 4 µmol·min^-1 (volume flow rate being the same as for the tachyphylaxis control) for 6 minutes and then coinfused during a second identical cumulative dose infusion of the same vasodilator agonist. Blood flow was measured during the final 3 minutes of L-NMMA alone to provide a baseline before the second agonist infusion. Doses of agonists were 0.01, 0.03, and 0.1 nmol·min^-1 (isoproterenol); 0.3, 1.0, and 3.5 nmol·min^-1 (salbutamol); 2.7, 5.4, and 11.0 nmol·min^-1 (nitroprusside); 20, 40, and 80 nmol·min^-1 (verapamil); or 0.08, 0.16, and 0.24 nmol·min^-1 (prostacyclin).

Materials and Drugs
Drugs were obtained from Pharmax (isoproterenol), Allen and Hanbury's (salbutamol), Roche (nitroprusside), Baker Norton (verapamil), Clinalfa (L-NMMA), Baxter Healthcare (saline), and Wellcome (prostacyclin). Prostacyclin was dissolved in glycine buffer and diluted in saline immediately before use.

Statistical Analysis
Results are presented as mean±SE. Vasodilator responses were measured as the increase above the immediately preceding baseline period. Inhibitory effects of L-NMMA were expressed as the percent reduction in response during L-NMMA/agonist coinfusion compared with that during agonist infusion alone and were summarized as reduction in the AUC (expressed in arbitrary units).⁸ Data were analyzed by repeated measures ANOVA. Differences were considered significant at a value of P<.05 (two-sided).

	Results

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Blood flow in the noninfused (control) arm did not change significantly in response to drug infusions in the contralateral arm on any study day, confirming that at the doses used, the drugs did not cause systemic effects when infused into the brachial artery.

Vasodilator Effects of ß-Agonists
All three ß-agonists produced significant vasodilation (P<.05 for each) but differed markedly in potency. Isoproterenol was the most potent (Fig 1). A semilogarithmic plot of blood flow response to salbutamol versus dose was similar in shape to the isoproterenol dose-response curve, and the potency was approximately one fifth that of isoproterenol. Dobutamine, however, produced little increase in blood flow at doses up to 300 nmol·min^-1.

View larger version (13K): [in this window] [in a new window]   Figure 1. Mean±SEM increase in forearm blood flow above baseline (increase in forearm blood flow, milliliter per minute per 100 mL forearm volume) during infusion of isoproterenol (, n=5), salbutamol (, n=8), and dobutamine (, n=3).

Effects of L-NMMA on Vasodilator Responses
Baseline blood flow was similar in subjects receiving each of the agonists studied. Consecutive doses of salbutamol did not produce tachyphylaxis. AUC for the first infusion was 7.6±1.8; for the second, 7.2±1.9 (n=5, P=.68). L-NMMA inhibited responses to isoproterenol (P<.01 by ANOVA). At highest dose, isoproterenol (0.1 nmol·min^-1) increased blood flow by 6.5 mL·min^-1·100 mL^-1 during coinfusion with saline but by only 2.7 mL·min^-1·100 mL^-1 during coinfusion with L-NMMA (P<.001). Fig 2 shows typical plethysmograph traces illustrating the effect of L-NMMA on salbutamol (3.5 nmol·min^-1). L-NMMA inhibited responses to salbutamol and isoproterenol to a similar extent. At the highest dose, salbutamol (3.5 nmol·min^-1) increased blood flow by 8.4 mL·min^-1·100 mL^-1 during coinfusion with saline but by only 4.6 mL·min^-1·100 mL^-1 during coinfusion with L-NMMA (P<.001, Fig 3). Isoproterenol AUC was reduced by 59±7% and salbutamol AUC was reduced by 52±6% (see the Table). L-NMMA had no significant effect on vasodilator responses to nitroprusside or verapamil (Fig 4) or to prostacyclin (Fig 5). Results of the statistical analysis on the inhibitory effects of L-NMMA for each agonist remained unaltered when blood flow responses were expressed as percentage increase in flow from the immediately preceding baseline or as the ratio of blood flow in the infused to control arm. When infused alone, L-NMMA caused a 31±1.6% reduction in flow compared with the immediately preceding baseline period (this is greater than the effect estimated from the Table because there was a small drift, <1 mL·min^-1·100 mL^-1, in basal flow during the experiment).

View larger version (20K): [in this window] [in a new window]   Figure 2. Representative plethysmograph traces during brachial artery infusion of saline (baseline) and then salbutamol (3.5 nmol·min-1). Traces on the left were obtained during coinfusion of saline throughout; those on the right, during coinfusion of L-NMMA (4 µmol·min-1). The vertical axis represents strain-gauge resistance, which is proportional to forearm circumference, and the slope of the trace is proportional to forearm blood flow per 100 mL of forearm volume.

View larger version (14K): [in this window] [in a new window]   Figure 3. Mean±SEM increase in forearm blood flow during ß-agonist infusion with saline (open bars) and coinfusion of L-NMMA (4 µmol·min-1, closed bars): a, isoproterenol (n=5); b, salbutamol (n=8). *Forearm blood flow during L-NMMA coinfusion was significantly less than during saline coinfusion (P<.05). **Forearm blood flow during L-NMMA coinfusion was significantly less than during saline coinfusion (P<.01).

View this table: [in this window] [in a new window]   Table 1. Baseline Blood Flow and AUC for Vasodilator Agonists During Coinfusion of Saline or L-NMMA

View larger version (14K): [in this window] [in a new window]   Figure 4. Mean±SEM increase in forearm blood flow above baseline during endothelium-independent vasodilator infusion with saline (open bars) and coinfusion of L-NMMA (4 µmol·min-1, closed bars): a, nitroprusside (n=8); b, verapamil (n=8).

View larger version (17K): [in this window] [in a new window]   Figure 5. Mean±SEM increase in forearm blood flow above baseline during prostacyclin infusion (n=8) with saline (open bars) and coinfusion of L-NMMA (4 µmol·min-1, closed bars).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Isoproterenol has previously been shown to cause vasodilation in the human forearm. It is not known whether this is mediated by ß₁- or ß₂-receptors. The relative vasodilator potencies of ß₁- and ß₂-adrenergic agonists vary markedly in different animal preparations.^{9 10 11 12} The present finding that salbutamol is >100-fold more potent than dobutamine suggests that ß-adrenergic vasodilation is mediated predominantly by ß₂-receptors in human forearm resistance vessels. This has physiological implications because norepinephrine selectively activates ß₁-receptors, whereas epinephrine activates both ß₁- and ß₂-receptors with similar high potency. Circulating concentrations of epinephrine are low under basal conditions¹³ but increase in various disease states, including heart failure,¹⁴ acute myocardial infarction,¹⁵ and pheochromocytoma.¹⁶ Forearm blood flow is predominantly to striated muscle and skin, and if responses in forearm vasculature are representative of blood flow elsewhere in the body, epinephrine-induced vasodilation could influence hemodynamic responses in such disorders.

The observation that ß-adrenergic vasodilation in the human forearm is inhibited by L-NMMA has not been reported previously. The inhibition of responses to isoproterenol and salbutamol caused by L-NMMA is similar in magnitude to its inhibition of the endothelium-dependent agonist acetylcholine in the human forearm.^{17 18} Endothelial NO biosynthesis is regulated by shear stress.^{19 20} Effects of vasodilators on shear stress are difficult to predict because increased flow increases shear stress, but this is offset by increased vessel diameter, which reduces it. Failure of L-NMMA to inhibit responses to nitroprusside, verapamil, or prostacyclin demonstrates that nonspecific hemodynamic changes in response to vasodilation do not substantially stimulate NO biosynthesis under the experimental conditions used. Relaxation of vascular smooth muscle mediated by an increase in cAMP may be potentiated by cGMP.^{21 22 23 24} Inhibition of basal endothelial NO synthesis by L-NMMA and the consequent decrease in cGMP in underlying smooth muscle in resistance vessels could therefore explain the apparent involvement of NO in ß-adrenergic responses. To address this possibility, we examined the effects of L-NMMA on vasodilator responses to prostacyclin, which acts through elevation of cAMP.⁴ L-NMMA failed to inhibit responses to prostacyclin, suggesting that synergism between cAMP and cGMP within vascular smooth muscle is not an adequate explanation for inhibition of ß-agonist vasodilation by L-NMMA in human forearm vasculature. We conclude that inhibition of responses to ß-agonists by L-NMMA is best explained by activation of the endothelial L-arginine/NO pathway by ß-agonists.

ß₂-Receptors on the endothelium of human internal mammary artery have been demonstrated by autoradiography.²⁵ The most straightforward explanation for our findings is that such ß₂-receptors on the endothelium are linked directly to ecNOS, much like muscarinic receptors mediating the NO-dependent vasodilator response to acetylcholine.²⁶ Unlike acetylcholine, ß-agonists are not known to activate the inositol 1,4,5 trisphosphate signaling pathway, but activation of the K⁺ channels could cause endothelial hyperpolarization, increasing the driving force for Ca²⁺ entry and hence activating ecNOS by Ca²⁺/calmodulin.²⁷ Alternatively, cAMP synthesized within the endothelium subsequent to ß₂-receptor activation may potentiate the NO system by directly stimulating NO synthase.¹¹ Such an endothelium-dependent mechanism has been proposed in rat mesenteric artery⁹ and rat thoracic aorta, in which removal of the endothelium abolishes responses to isoproterenol.¹¹

Regardless of the exact mechanism by which actions of ß-adrenergic agonists are linked to the L-arginine/NO pathway, the finding that inhibition of ecNOS attenuates their vasodilator effects has important implications for studies of vascular reactivity. Attenuated forearm vascular responses to isoproterenol have recently been reported in black subjects,²⁸ and it has been suggested that altered ß-adrenergic–mediated vasodilation may play a part in the pathogenesis of hypertension in this ethnic group. The present findings suggest that the blunted response to isoproterenol in blacks could be due to impairment of the NO pathway in this ethnic group. Abnormalities of the L-arginine/NO pathway have been an inconsistent finding in essential hypertension.^{29 30 31} Such inconsistencies might be related to ethnic differences. Our study also has implications for physiological and pathophysiological states in which ß-adrenergic–mediated vasodilation occurs in response to blood-borne catecholamines. Such responses will be dependent on the integrity of the NO pathway.

The conclusion that ß-receptor stimulation increases NO biosynthesis has potential implications for the use and development of therapeutic drugs. Several common vascular disorders that predispose to atherosclerosis have been linked to endothelial dysfunction and reduced endothelial NO biosynthesis.^{2 29 32 33} Nebivolol is a selective ß₁-adrenergic antagonist that increases NO biosynthesis by an unknown mechanism³⁴ and is of interest in this context, as is celiprolol, a combined ß₁-adrenoceptor antagonist/ß₂-receptor agonist.³⁵ Such drugs could augment epinephrine-stimulated ß₂-adrenergic receptor–mediated endothelial NO synthesis with potentially beneficial consequences. Conversely, it is possible that vascular disorders that impair endothelial NO production will reduce the effectiveness as vasodilators of drugs such as celiprolol with ß₂-adrenoceptor agonist activity.

We conclude that ß-adrenergic vasodilation in the human forearm is initiated by ß₂-receptors and mediated, in substantial part, by increased activity of the L-arginine/NO pathway. This has physiological and potential therapeutic implications.

	Selected Abbreviations and Acronyms

 

AUC = area under the dose-response curve ecNOS = constitutive endothelial NO synthase L-NMMA = NG-monomethyl-L-arginine NO = nitric oxide

	Acknowledgments

 
This work was supported by the British Heart Foundation.

Received October 14, 1996; accepted December 1, 1996.

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