Impaired hemorrhage tolerance in the obese Zucker rat model of metabolic syndrome.

As obese Zucker rats (OZR) manifesting the metabolic syndrome exhibit enhanced vascular adrenergic constriction and potentially an enhanced adrenergic activity vs. lean Zucker rats (LZR), this study tested the hypothesis that OZR exhibit an improved tolerance to progressive hemorrhage. Preliminary experiments indicated that, corrected for body mass, total blood volume was reduced in OZR vs. LZR. Anesthetized LZR and OZR had a cremaster muscle prepared for in situ videomicroscopy and had renal, splanchnic, hindlimb, and skeletal muscle perfusion monitored with flow probes. Arterial pressure, arteriolar reactivity to norepinephrine, and tissue/organ perfusion were monitored after either infusion of phentolamine or successive withdrawals of 10% total blood volume. Phentolamine infusion indicated that regional adrenergic tone under control conditions differs substantially between LZR and OZR, whereas with hemorrhage OZR exhibit decompensation in arterial pressure before LZR. Renal, distal hindlimb, and skeletal muscle perfusion decreased more rapidly and to a greater extent in OZR vs. LZR after hemorrhage. In contrast, hemorrhage-induced reductions in splanchnic perfusion in OZR lagged behind those in LZR, although a similar maximum reduction was ultimately attained. With increasing hemorrhage, cremasteric arteriolar tone increased more in OZR than LZR, and this increase in active tone was entirely due to an elevated adrenergic contribution. Norepinephrine-induced arteriolar constriction was greater in OZR vs. LZR under control conditions and during hemorrhage, with arterioles from OZR demonstrating early closure vs. LZR. These results suggest that a combination of reduced blood volume and elevated peripheral adrenergic constriction contribute to impaired hemorrhage tolerance in OZR.     

Effect of central naloxone on hormone and blood pressure responses to hemorrhage in conscious sheep

The role of the brain opioid system in the control of hypothalamic-pituitary-adrenal activity was studied in 10 conscious sheep with an indwelling cannula in a cerebral lateral ventricle. On separate days, sheep received infusions of artificial CSF (control) and the opiate antagonist, naloxone (100 micrograms/hr) before and during acute moderate hemorrhage (15 ml/kg over 10 min). Infusion of naloxone before hemorrhage raised plasma ACTH and resulted in a significant increase in cortisol compared to the control infusion. In contrast, ACTH and cortisol responses to hemorrhage tended to be blunted by central naloxone infusion. The responses of vasopressin, aldosterone and the catecholamines remained unaffected by naloxone. The fall in blood pressure and the rise in heart rate accompanying hemorrhage were likewise unaltered. These results suggest that brain opioid peptides have an inhibitory effect on basal ACTH secretion but do not play a major role in modulating the hemodynamic or pituitary-adrenal responses to acute moderate hemorrhage in conscious sheep.     

Bimodal effects of chronically administered neurokinin B (NKB) on in vivo and in vitro cardiovascular responses in female rats

The in vivo cardiovascular effects of acutely administered neurokinin B (NKB) have been attributed both to direct effects on vascular tone and to indirect effects on central neuroendocrine control of the circulation. We proposed: 1) that a modest long-term increase in plasma NKB levels would decrease mean arterial pressure (MAP) due to attenuated peripheral vascular tone, and 2) that chronic high-dose NKB would increase MAP, due to increased sympathetic outflow which would override the peripheral vasodilation. We examined the in vivo and in vitro cardiovascular effects of chronic peripheral NKB. Low- (1.8 nmol/h) or high- (20 nmol/h) dose NKB was infused into conscious female rats bearing telemetric pressure transducers. MAP, heart rate (HR) and the pressor responses to I.V. phenylephrine (PE, 8 microg) and angiotensin II (Ang II, 150 ng) were measured. Concentration-response curves of small mesenteric arteries were constructed to PE using wire myography. Low-dose NKB reduced basal MAP (88+/-2 mm Hg to 83+/-2 mm Hg), did not affect resting HR, reduced the pressor responses to PE, and attenuated the maximal constriction of mesenteric arteries to PE and KCl. By contrast, high-dose NKB increased basal MAP (86+/-1 mm Hg to 89+/-1 mm Hg), increased HR (350+/-3 beats/min to 371+/-3 beats/min), increased the pressor responses to Ang II and, contrary to our hypothesis, increased the maximum contractile responses of mesenteric arteries to PE and KCl. The cardiovascular effects of NKB are thus dose-dependent: whereas chronic low-dose NKB directly modulates vascular tone to reduce blood pressure, chronic high-dose NKB induces an increase in blood pressure through both central (indirect) and peripheral (direct) pathways.     

Exercise-induced increase in skeletal muscle vasodilatory responses in obese Zucker rats

The purpose of this study was to test the hypothesis that exercise training improves microvascular function in obese Zucker rats, a model of obesity and type II diabetes. Animals were divided into four age-matched groups: lean sedentary (LS), lean exercise (LE), obese sedentary (OS), and obese exercise (OE). The exercise groups were treadmill-exercised from 5 to 11 wk of age, including a 2-wk acclimation period. Mean arterial pressure (MAP) was not significantly different between any of the groups. The OS had significantly higher mean body weight, blood glucose, insulin, IL-6, and leptin levels compared with the LS, whereas the OE had significantly lower blood glucose, insulin, and IL-6 levels compared with the OS. Functional hyperemia and endothelial-dependent vasodilation were tested in the spinotrapezius muscle using intravital microscopy. Functional hyperemia and acetylcholine (0.1 microM, 1 microM, and 10 microM) responses were significantly attenuated in OS compared with the LS, while the contraction and ACh-induced (1 microM and 10 microM) vasodilation were significantly increased in both LE and OE compared with the sedentary animals. These results suggest that exercise training can improve vascular function in this model of type II diabetes. Moreover, the impaired vasodilation observed in 11-wk-old OZR suggests that the microvascular dysfunction is not likely due to an elevated blood pressure.     

Pressure dependence of baroreceptor-mediated vasoconstriction in rat skeletal muscle

To determine whether microvessels in resting or contracting skeletal muscle constrict during baroreceptor activation, vascular diameters were measured in the spinotrapezius muscle of adult rats (n = 12) during occlusion of the common carotid arteries. Neural and myogenic components were distinguished using two types of occlusion: 1) "normal" (arterial pressure was allowed to increase with baroreceptor activation) and 2) "isobaric" (arterial pressure was maintained constant by decreasing blood volume). During normal occlusions, intermediate and small arteriolar diameters decreased in resting and contracting muscle (10-15% and 25-30%, respectively). Large arterioles and all-sized venules distended slightly (approximately 5%) in resting muscle, but diameters were maintained or decreased in contracting muscle. When arterial pressure was maintained constant (isobaric), the microvascular responses to baroreceptor activation in both resting and contracting muscle were essentially eliminated. We conclude that nearly all the arteriolar constriction observed in the spinotrapezius muscle during normal carotid artery occlusion is myogenic in origin, secondary to increased arterial pressure. This pressure-dependent constriction is augmented during skeletal muscle contraction and functional vasodilation.     

Impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type II diabetic rats

The goals of this study were to determine the effects of type II diabetes mellitus on nitric oxide synthase-dependent responses of cerebral arterioles and on endothelial nitric oxide synthase (eNOS) protein in cerebral arterioles. We examined dilatation of cerebral (pial) arterioles in 13-15 week old male lean and diabetic obese Zucker rats in response to nitric oxide synthase-dependent agonists (acetylcholine and adenosine diphosphate (ADP)) and a nitric oxide synthase-independent agonist (nitroglycerin). We found that acetylcholine (10 microM) increased cerebral arteriolar diameter by 10 +/- 3% (mean +/- SE) in lean Zucker rats, but by only 2 +/- 2% in diabetic obese Zucker rats (p<0.05). In addition, ADP (100 microM) increased cerebral arteriolar diameter by 20 +/- 2% in lean Zucker rats, but by only 8 +/- 2% in diabetic obese Zucker rats (p<0.05). In contrast, nitroglycerin produced similar vasodilatation in lean and diabetic obese Zucker rats. Thus, impaired dilatation of cerebral arterioles in diabetic obese Zucker rats is not related to non-specific impairment of vasodilatation. Following these functional studies, we harvested cerebral microvessels for Western blot analysis of eNOS protein. We found that eNOS protein was significantly higher in diabetic obese Zucker rats than in lean Zucker rats (p<0.05). Thus, type II diabetes mellitus impairs nitric oxide synthase-dependent responses of cerebral arterioles. In addition, eNOS protein from cerebral blood vessels is increased in diabetic obese Zucker rats.     

Altered hemodynamic regulation and reflex control during exercise and recovery in obese boys

The aims of the present study were to assess in obese and lean boys 1) the hemodynamic responses and baroreflex sensitivity (BRS) to isometric handgrip exercise (HG) and recovery and 2) the muscle metaboreflex-induced blood pressure response and the variables that determine this response. Twenty-seven boys (14 obese and 13 lean boys, body mass index: 29.2 ± 0.9 vs. 18.9 ± 0.3 kg/m(2), respectively) participated. The testing protocol involved 3 min of baseline, 3 min of HG (30% maximum voluntary contraction), 3 min of circulatory occlusion, and 3 min of recovery. The same protocol was repeated without occlusion. At baseline, no differences were detected between groups in beat-to-beat arterial pressure (AP), heart rate (HR), and BRS; however, obese boys had higher stroke volume and lower total peripheral resistance than lean boys (P < 0.05). During HG, lean boys exhibited higher HR and lower BRS compared with their obese counterparts. In lean boys, BRS decreased during HG compared with baseline, whereas in obese boys, it was not significantly modified. In lean boys, TPR was elevated during HG and declined after exercise, whereas in obese boys, TPR did not significantly decrease after exercise cessation. In the postexercise period, BRS in lean boys returned to baseline, whereas an overshoot was observed in obese boys. Postexercise BRS was correlated with body mass index (R = 0.56, P < 0.05). Although the metaboreflex-induced increase in AP was similar between obese and lean children, it was achieved via different mechanisms: in lean children, total peripheral resistance was the main contributor to AP maintenance during the metaboreflex, whereas in obese children, stroke volume significantly contributed to AP maintenance during the metaboreflex. In conclusion, obese normotensive children demonstrated altered cardiovascular hemodynamics and reflex control during exercise and recovery.     

Visceral pain decreases tolerance to blood loss in conscious female but not male rabbits

Pain is a component of traumatic blood loss, yet little is known about how pain alters the response to blood loss in conscious animals. We evaluated the effects of colorectal distension on the cardiorespiratory response to blood loss in six male and six female conscious, chronically instrumented New Zealand White rabbits. The goal of these experiments was to test the hypotheses that 1) colorectal distension would increase tolerance to hemorrhage (i.e., increase the blood loss required to decrease mean arterial pressure 相似文献   

The cardiovascular responses to mu opioid agonist and antagonist in conscious normal and obese rats

Beta-endorphin decreases blood pressure in normal rats but increases blood pressure in obese rats. Since beta-endorphins can bind both mu opioid and kappa-opioid receptors we investigated the effect of a mu specific receptor agonist, D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and a mu specific antagonist, D-Phe-Cys-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) on cardiovascular responses in conscious control and obese rats. Rats were also implanted with telemetry transmitters and intracerebroventricular (ICV) cannulas for recording and peptide administration. The mu agonist, DAMGO, increased blood pressure (BP) in control rats. DAMGO also increased BP in obese rats but only at high concentrations. The heart rate responses paralleled the MAP responses. CTAP, the mu antagonist, paradoxically increased the MAP in both control and obese rats. The responsiveness to the mu agonist and antagonist was greater in controls. In other animals the brains were excised and the ventral medial hypothalamic area removed and mu receptor expression determined using PCR. The expression of mu opioid receptors was increased in obese rats. We conclude that the mu opioids can stimulate cardiovascular responses, but the excitatory responsiveness was not increased in conscious obese rats.     

Serotonin nerve terminals in the dorsomedial medulla facilitate sympathetic and ventilatory responses to hemorrhage and peripheral chemoreflex activation

Serotonin neurons of the caudal raphe facilitate ventilatory and sympathetic responses that develop following blood loss in conscious rats. Here, we tested whether serotonin projections to the caudal portion of the dorsomedial brain stem (including regions of the nucleus tractus solitarius that receive cardiovascular and chemosensory afferents) contribute to cardiorespiratory compensation following hemorrhage. Injections of the serotonin neurotoxin 5,7-dihydroxytryptamine produced >90% depletion of serotonin nerve terminals in the region of injection. Withdrawal of ～21% of blood volume over 10 min produced a characteristic three-phase response that included 1) a normotensive compensatory phase, 2) rapid sympathetic withdrawal and hypotension, and 3) rapid blood pressure recovery accompanied by slower recovery of heart rate and sympathetic activity. A gradual tachypnea developed throughout hemorrhage, which quickly reversed with the advent of sympathetic withdrawal. Subsequently, breathing frequency and neural minute volume (determined by diaphragmatic electromyography) declined below baseline following termination of hemorrhage but gradually recovered over time. Lesioned rats showed attenuated sympathetic and ventilatory responses during early compensation and later recovery from hemorrhage. Both ventilatory and sympathetic responses to chemoreceptor activation with potassium cyanide injection were attenuated by the lesion. In contrast, the gain of sympathetic and heart rate baroreflex responses was greater, and low-frequency oscillations in blood pressure were reduced after lesion. Together, the data are consistent with the view that serotonin innervation of the caudal dorsomedial brain stem contributes to sympathetic compensation during hypovolemia, possibly through facilitation of peripheral chemoreflex responses.     

Remodeling of the skeletal muscle microcirculation increases resistance to perfusion in obese Zucker rats

Whereas previous studies have demonstrated that the development of syndrome X in obese Zucker rats (OZR) is associated with impaired arteriolar reactivity to vasoactive stimuli, additional results from these studies indicate that the passive diameter of skeletal muscle arterioles is reduced in OZR versus lean Zucker rats (LZR). On the basis of these prior observations, the present study evaluated structural alterations to the skeletal muscle microcirculation as potential contributors to an elevated vascular resistance. Isolated skeletal muscle resistance arterioles exhibited a reduced passive diameter at all levels of intralumenal pressure and a left-shifted stress-strain curve in OZR versus LZR, indicative of structural remodeling of individual arterioles. Histological analyses using Griffonia simplicifolia I lectin-stained sections of skeletal muscle demonstrated reduced microvessel density (rarefaction) in OZR versus LZR, suggesting remodeling of entire microvascular networks. Finally, under maximally dilated conditions, constant flow-perfused skeletal muscle of OZR exhibited significant elevations in perfusion pressure versus LZR, indicative of an increased resistance to perfusion within the microcirculation. These data suggest that developing structural alterations to the skeletal muscle microcirculation in OZR result in elevated vascular resistance, which may, acting in concert with impaired arteriolar reactivity, contribute to blunted active hyperemic responses and compromised performance of in situ skeletal muscle with elevated metabolic demand.     

High dietary salt reduces the contribution of 20-HETE to arteriolar oxygen responsiveness in skeletal muscle

The coupling of tissue blood flow to cellular metabolic demand involves oxygen-dependent adjustments in arteriolar tone, and arteriolar responses to oxygen can be mediated, in part, by changes in local production of 20-HETE. In this study, we examined the long-term effect of dietary salt on arteriolar oxygen responsiveness in the exteriorized, superfused rat spinotrapezius muscle and the role of 20-HETE in this responsiveness. Rats were fed either a normal-salt (NS, 0.45%) or high-salt (HS, 4%) diet for 4-5 wk. There was no difference in steady-state tissue Po(2) between NS and HS rats, and elevation of superfusate oxygen content from 0% to 10% caused tissue Po(2) to increase by the same amount in both groups. However, the resulting reductions in arteriolar diameter and blood flow were less in HS rats than NS rats. Inhibition of 20-HETE formation with N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS) or 17-octadecynoic acid (17-ODYA) attenuated oxygen-induced constriction in NS rats but not HS rats. Exogenous 20-HETE elicited arteriolar constriction that was greatly reduced by the large-conductance Ca(2+)-activated potassium (K(Ca)) channel inhibitors tetraethylammonium chloride (TEA) and iberiotoxin (IbTx) in NS rats and a smaller constriction that was less sensitive to TEA or IbTx in HS rats. Arteriolar responses to exogenous angiotensin II were similar in both groups but more sensitive to inhibition with DDMS in NS rats. Norepinephrine-induced arteriolar constriction was similar and insensitive to DDMS in both groups. We conclude that 20-HETE contributes to oxygen-induced constriction of skeletal muscle arterioles via inhibition of K(Ca) channels and that a high-salt diet impairs arteriolar responses to increased oxygen availability due to a reduction in vascular smooth muscle responsiveness to 20-HETE.     

Vasopressin: An essential pressor factor for blood pressure recovery following hemorrhage

Two experimental approaches were used to evaluate the importance of the pressor effects of vasopressin in blood pressure recovery following hypotensive hemorrhage. Experiments using homozygous Brattleboro rats demonstrated that the hemodynamic recovery of these animals was subnormal, even though the activation and efficacy of the sympathetic nervous and renin-angiotensin systems were intact. Experiments using an antipressor vasopressin analogue in normal rats during hypotensive hemorrhage demonstrated significantly blunted blood pressure recovery in the presence of the analogue. Thus, both experiments indicate that the pressor effects of circulating vasopressin play an essential role in blood pressure recovery following hypovolemic hypotension induced by hemorrhage.     

Exercise alters cardiac myosin isozyme distribution in obese Zucker and Wistar rats

Recent evidence suggests that exercise training may significantly increase the expression of the cardiac myosin isozyme V1 in the diabetic heart, a change associated with improved cardiac functional capacity. To test this hypothesis, cardiac myofibrillar adenosinetriphosphatase (ATPase) activity and myosin isozyme profiles were determined in trained and sedentary male hyperinsulinemic obese Zucker (OZT, OZS) and obese Wistar (OWT, OWS) rats. Lean sedentary (LZS, LWS) animals served as age-matched controls. Myofibrillar ATPase activity and the relative quantity of the high-ATPase isozyme V1 was significantly lower in both strains of sedentary obese rats than in the respective lean sedentary controls (P less than 0.05). Both 5 (OZT) and 10 wk (OWT) of moderate treadmill training increased these markers of cardiac myosin biochemistry in the obese animals (P less than 0.05). Thus, endurance exercise training remodels the cardiac isomyosin profile of hyperinsulinemic rats and, in doing so, may enhance cardiac contractility and functional capacity. Such changes may reflect an improvement in glucose availability and utilization in these hearts.     

Obese Adolescents Show Impaired Meal Responses of the Appetite‐Regulating Hormones Ghrelin and PYY

Ghrelin and peptide YY (PYY) stimulate hunger and satiety, respectively. The physiology of these hormones during normal meal intake remains unclear. This study was designed to compare the responses of these two hormones to meal intake between lean and obese Hispanic adolescents. A total of 10 obese and 7 lean Hispanic youth, aged 11–14 years, consumed two mixed meals, one small and one large, during which plasma measurements of active and total ghrelin and total PYY were obtained. Obese subjects tended to consume more calories during the small meal than lean subjects, although this did not reach statistical significance. Intake of the small meal significantly suppressed active ghrelin and stimulated PYY levels in the lean subjects, and these changes were further accentuated by the large meals. In obese subjects, the suppression of active ghrelin and stimulation of PYY by caloric intake were blunted. Interestingly, a paradoxical stimulation of active ghrelin levels was noted during the small meals in both lean and obese subjects. This stimulation was not seen during the larger meals in lean subjects, but remained present in the obese subjects. Thus, meal‐related changes in active ghrelin and PYY are blunted in obese as compared to lean Hispanic subjects. This blunting could contribute to the development or worsening of obesity.     

PPAR-alpha activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats

Previous studies have shown that the synthesis of renal cytochrome P-450 (CYP)-derived eicosanoids is downregulated in genetic or high-fat diet-induced obese rats. Experiments were designed to determine whether fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg.kg(-1).day(-1) for 4 wk) significantly reduced plasma insulin, triglyceride, and total cholesterol levels in obese Zucker rats. CYP2C11 and CYP2C23 proteins were downregulated in renal vessels of obese Zucker rats. Consequently, renal vascular epoxygenase activity decreased by 15% in obese Zucker rats compared with lean controls. Chronic fenofibrate treatment significantly increased renal cortical and vascular CYP2C11 and CYP2C23 protein levels in obese Zucker rats, whereas it had no effect on epoxygenase protein and activity in lean Zucker rats. Renal cortical and vascular epoxygenase activities were consequently increased by 54% and 18%, respectively, in fenofibrate-treated obese rats. In addition, acetylcholine (1 microM)-induced vasodilation was significantly reduced in obese Zucker kidneys (37% +/- 11%) compared with lean controls (67% +/- 9%). Chronic fenofibrate administration increased afferent arteriolar responses to 1 microM of acetylcholine in obese Zucker rats (69% +/- 4%). Inhibition of the epoxygenase pathway with 6-(2-propargyloxyphenyl)hexanoic acid attenuated afferent arteriolar diameter responses to acetylcholine to a greater extent in lean compared with obese Zucker rats. These results demonstrate that the PPAR-alpha agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.     

Dominant role of smooth muscle L-type calcium channel Cav1.2 for blood pressure regulation

Blood pressure is regulated by a number of key molecules involving G-protein-coupled receptors, ion channels and monomeric small G-proteins. The relative contribution of these different signaling pathways to blood pressure regulation remains to be determined. Tamoxifen-induced, smooth muscle-specific inactivation of the L-type Cav1.2 Ca2+ channel gene in mice (SMAKO) reduced mean arterial blood pressure (MAP) in awake, freely moving animals from 120 +/- 4.5 to 87 +/- 8 mmHg. Phenylephrine (PE)- and angiotensin 2 (AT2)-induced MAP increases were blunted in SMAKO mice, whereas the Rho-kinase inhibitor Y-27632 reduced MAP to the same extent in control and SMAKO mice. Depolarization-induced contraction was abolished in tibialis arteries of SMAKO mice, and development of myogenic tone in response to intravascular pressure (Bayliss effect) was absent. Hind limb perfusion experiments suggested that 50% of the PE-induced resistance is due to calcium influx through the Cav1.2 channel. These results show that Cav1.2 calcium channels are key players in the hormonal regulation of blood pressure and development of myogenic tone.     

Estrogen has opposing effects on vascular reactivity in obese, insulin-resistant male Zucker rats.

We hypothesized that estradiol treatment would improve vascular dysfunction commonly associated with obesity, hyperlipidemia, and insulin resistance. A sham operation or 17beta-estradiol pellet implantation was performed in male lean and obese Zucker rats. Maximal vasoconstriction (VC) to phenylephrine (PE) and potassium chloride was exaggerated in control obese rats compared with lean rats, but estradiol significantly attenuated VC in the obese rats. Estradiol reduced the PE EC50 in all groups. This effect was cyclooxygenase independent, because preincubation with indomethacin reduced VC response to PE similarly in a subset of control and estrogen-treated lean rats. Endothelium-independent vasodilation (VD) to sodium nitroprusside was similar among groups, but endothelium-dependent VD to ACh was significantly impaired in obese compared with lean rats. Estradiol improved VD in lean and obese rats by decreasing EC50 but impaired function by decreasing maximal VD. The shift in EC50 corresponded to an upregulation in nitric oxide synthase III protein expression in the aorta of the estrogen-treated obese rats. In summary, estrogen treatment improves vascular function in male insulin-resistant, obese rats, partially via an upregulation of nitric oxide synthase III protein expression. These effects are counteracted by adverse factors, such as hyperlipidemia and, potentially, a release of an endothelium-derived contractile agent.     

Role of Endogenous ET‐1 in the Regulation of Myocardial Blood Flow in Lean and Obese Humans

Endothelin is an important determinant of peripheral vascular tone, and increased endogenous endothelin activity contributes to peripheral vascular dysfunction in human obesity. The contributions of endothelin to the regulation of coronary vascular tone in health in humans have not been well studied. We hypothesized that the contribution of endothelin to the regulation of myocardial perfusion would be augmented in human obesity. Using [NH₃]ammonia positron emission tomography (PET), we measured myocardial perfusion under resting and adenosine‐stimulated conditions on two separate days, with and without concurrent exposure to BQ123, an antagonist of type A endothelin receptors (1 µmol/min IV beginning 90 min before measurement). We studied 10 lean and 9 obese subjects without hypertension, hyperlipidemia, or diabetes mellitus. We observed a BQ123‐induced increase in resting myocardial perfusion of ～40%, not different between lean and obese subjects (BQ123‐induced increase in flow: lean 0.12 ± 0.20, obese 0.32 ± 0.51 ml/g/min, P = 0.02 BQ123 effect, P = 0.27 comparing response across groups). Although basal flow rates varied by region of the myocardium, the BQ123 effect was seen in all regions. BMI and cholesterol were significantly related to BQ123‐induced increases in basal tone in multivariable analysis. There was no baseline difference in the adenosine‐stimulated increase in blood flow between lean and obese subjects, and BQ123 failed to augment these responses in either group. These observations suggest that endothelin is an important contributor to the regulation of myocardial perfusion under resting conditions in healthy lean and obese humans, with increased contributions in proportion to increasing obesity.