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Michael J Joyner

Publications and source records attributed to Michael J Joyner.

69 records · Page 4Linked to original sources
PubMed2003

alpha1- and alpha2-adrenergic vasoconstriction is blunted in contracting human muscle.

Sympathetic vasoconstriction is blunted in the vascular beds of contracting skeletal muscles. We sought to determine whether this blunted vasoconstriction is specific for post-junctional alpha1- or alpha2-adrenergic receptors. We measured forearm blood flow (Doppler ultrasound) and calculated the vascular conductance (FVC) responses to brachial artery infusions of tyramine (which evokes endogenous noradrenaline release), phenylephrine (an alpha1 agonist) and clonidine (an alpha2 agonist) in 10 healthy men during rhythmic handgrip exercise (10-15 % of maximum) and during a control non-exercise vasodilator condition (intra-arterial adenosine). Steady-state FVC during exercise and adenosine was similar in all trials (range: 243-272 and 234-263 ml min-1 (100 mmHg)-1, respectively; P > 0.5). During exercise the percentage reductions in FVC in response to tyramine (-24 +/- 7 vs. -55 +/- 6 %), phenylephrine (-12 +/- 8 vs. -37 +/- 8 %) and clonidine (-17 +/- 6 vs. -49 +/- 4 %) were significantly less compared with adenosine (all P < 0.05). The magnitude of the blunted vasoconstrictor responses was similar for both receptor subtypes. These findings are in contrast to those from studies in animals demonstrating that alpha2-adrenergic receptor-mediated vasoconstrictor responses are much more sensitive to contraction-induced inhibition than alpha1-mediated responses. We conclude that vasoconstrictor responses mediated via both post-junctional alpha1- and alpha2-adrenergic receptors are blunted in contracting human skeletal muscles.

Adrenergic Uptake Inhibitors↗
PubMed2003

Beta(2)-adrenergic receptor polymorphism and nitric oxide-dependent forearm blood flow responses to isoproterenol in humans.

Polymorphisms in the gene encoding the beta(2)-adrenoceptor have been associated with interindividual differences in blood pressure and the diagnosis of hypertension. A common polymorphism resulting in a change from arginine to glycine at amino acid 16 (Arg16-->Gly) enhances agonist-promoted downregulation of receptor expression in vitro. It is unknown whether genotype-dependent differences in nitric oxide generation contribute to differences in vasodilator responses to beta(2)-agonists in vivo. To address this question, venous occlusion plethysmography was used to measure forearm blood flow responses to graded brachial artery infusions of the beta-agonist isoproterenol in 41 healthy normotensive Caucasian adults (mean age (+/- S.D.) = 29 +/- 6 years), who were either Arg16 (n = 18) or Gly16 (n = 23) homozygotes. Compared to Arg16 homozygotes, Gly16 homozygotes demonstrated significantly greater blood flow responses to isoproterenol (P = 0.02). After inhibition of nitric oxide synthase by N(gamma)-monomethyl-L-arginine, blood flow responses did not differ significantly between genotype groups (P = 0.27). Consequently, effects of the Arg16 Gly polymorphism on forearm blood flow responses to isoproterenol appear to be dependent on differences in endothelial generation of nitric oxide. In contrast to previous reports based on systemic infusions of beta(2)-agonists, our findings indicate that regional blood flow responses to locally infused isoproterenol are significantly greater in Gly16 than in Arg16 homozygotes.

Adrenergic beta-Agonists↗
PubMed2003

Nitric oxide and physiologic vasodilation in human limbs: where do we go from here?

This brief review highlights human studies on the role of nitric oxide (NO) and limb vasodilation conducted at the Mayo Clinic over the last 10 years. These studies have attempted to determine whether NO is responsible for the "unexplained" limb vasodilation seen with body heating, limb ischemia, exercise, and mental stress. Our findings are placed in context with data from others, and possible future areas of study are identified.

Body Temperature↗
PubMed2002

Angiotensin-converting enzyme genotype modulates pulmonary function and exercise capacity in treated patients with congestive stable heart failure.

BACKGROUND: The gene encoding ACE exhibits an insertion/deletion polymorphism resulting in 3 genotypes (DD, ID, and II), which affects serum and tissue ACE activity as well as other vasoactive substances. Pulmonary function is frequently abnormal in patients with congestive heart failure (CHF), the mechanism of which has not been completely characterized. ACE inhibition has been shown to improve diffusion across the alveolar-capillary membrane and to improve exercise capacity and gas exchange in CHF. The aim of the current study was to determine if ACE genotype is associated with altered pulmonary function and exercise intolerance in patients with treated CHF. METHODS AND RESULTS: Fifty-seven patients (stratified according to ACE genotype as 17 DD, 28 ID, 12 II) with ischemic and dilated cardiomyopathy, left ventricular ejection fraction (LVEF) <35%, and <10 pack-years of smoking history were studied. All patients were receiving standard therapy for left ventricular systolic dysfunction. Pulmonary function, LVEF, serum ACE, plasma angiotensin II, atrial natriuretic peptide, and brain natriuretic peptide were measured at baseline. Peak VO2 and gas exchange measurements were assessed with graded exercise. Resting LVEF was similar among the genotype groups (25% to 28%), and no differences were observed in diastolic function or pulmonary artery pressures (P>0.05). Mean peak VO2 and forced vital capacity (% Pred) were significantly reduced (P<0.05), whereas mean serum ACE activity and plasma angiotensin II concentration were highest in DD homozygotes. Subjects homozygous for the D-allele also demonstrated higher mean ventilatory equivalents for carbon dioxide (VE/VCO2) during exercise (P<0.05). CONCLUSIONS: ACE DD genotype is associated with decreased exercise tolerance in CHF, possibly mediated by altered pulmonary function. Pharmacological strategies effecting more complete inhibition of serum and tissue ACE and/or potentiation of bradykinin may improve exercise capacity in patients with CHF and ACE DD genotype.

Angiotensin II↗
PubMed2002

Aging and forearm postjunctional alpha-adrenergic vasoconstriction in healthy men.

BACKGROUND: Muscle sympathetic vasoconstrictor nerve activity increases with age in healthy humans but does not result in an augmented forearm vasoconstrictor tone. We tested the hypothesis that this is due to a reduction in postjunctional alpha-adrenergic responsiveness to endogenous norepinephrine (NE) release and determined whether this was specific to alpha1- or alpha2-adrenergic receptors. METHODS AND RESULTS: Forearm blood flow (FBF, by strain-gauge plethysmography) responses to local intra-arterial infusions of tyramine (which evokes endogenous NE release), phenylephrine (selective alpha1-agonist), and clonidine (alpha2-agonist) were determined in 10 young (aged 26+/-1 [mean+/-SEM] years) and 10 older (aged 65+/-1 years) healthy normotensive men after local beta-adrenergic blockade with propranolol. Basal forearm vascular tone was not different in young men and older men. The percentage reduction in FBF in response to the highest dose of tyramine was blunted in older men compared with young men (-37+/-3% versus -49+/-3%, respectively; P<0.01) despite a greater increase in deep venous NE concentration in older men (910+/-103 versus 565+/-69 pg/mL, respectively; P<0.001). Maximal reductions in FBF to phenylephrine were also blunted in older men (-47+/-2% versus -58+/-3% in young men, P<0.05). In contrast, the reductions in FBF (-36+/-7% versus -40+/-3% for older versus young men, respectively) and also in venous NE concentration (-79+/-24 versus -84+/-13 pg/mL for older versus young men, respectively) to clonidine were similar in the 2 groups. Finally, forearm sympathetic alpha-adrenergic vasoconstrictor tone (assessed via nonselective alpha-blockade with phentolamine) was significantly lower in older men. CONCLUSIONS: Our results indicate that human aging is associated with a reduction in forearm postjunctional alpha-adrenergic responsiveness to endogenous NE release and that this might be specific to alpha1-adrenergic receptors. Furthermore, the contribution of sympathetic alpha-adrenergic vasoconstriction to basal forearm vascular tone is reduced with age in healthy men.

Adrenergic Agonists↗
PubMed2002

Is sympathetic neural vasoconstriction blunted in the vascular bed of exercising human muscle?

Sympathetic vasoconstriction of muscle vascular beds is important in the regulation of systemic blood pressure. However, vasoconstriction during exercise can also compromise blood flow support of muscle metabolism. This study tested the hypothesis that local factors in exercising muscle blunt vessel responsiveness to sympathetic vasoconstriction. We performed selective infusions of three doses of tyramine into the brachial artery (n = 8) to evoke endogenous release of noradrenaline (norepinephrine) at rest and during moderate and heavy rhythmic handgrip exercise. In separate experiments, tyramine was administered during two doses of adenosine infusion (n = 7) and two doses of sodium nitroprusside (SNP) infusion (n = 8). Vasoconstrictor effectiveness across conditions was assessed as the percentage reduction in forearm vascular conductance (FVC), calculated from invasive blood pressure and non-invasive Doppler ultrasound blood flow measurements at the brachial artery. Tyramine evoked a similar dose-dependent vasoconstriction at rest in all three groups, with the highest dose resulting in a 42-46 % reduction in FVC. This vasoconstriction was blunted with increasing exercise intensity (e.g. tyramine high dose percentage reduction in FVC; rest -43.4 +/- 3.7 %, moderate exercise -27.5 +/- 2.3 %, heavy exercise -16.7 +/- 3.6 %; P < 0.05). In contrast, tyramine infusion resulted in a greater percentage reduction in FVC during both doses of adenosine vs. rest (P < 0.05). Finally, percentage change in FVC was greater during low dose SNP infusion vs. rest (P < 0.05), but not different from rest at the high dose of SNP infusion (P = 0.507). A blunted percentage reduction in FVC during endogenous noradrenaline release in exercise but not vasodilator infusion indicates that sympathetic vasoconstriction is blunted in exercising muscle. This blunting appears to be exercise intensity-dependent.

Adenosine↗
PubMed2002

Post-junctional alpha-adrenoceptors and basal limb vascular tone in healthy men.

Previous studies have demonstrated that post-junctional alpha(1)- and alpha(2)-adrenoceptors mediate vasoconstriction in the human forearm. However, the relative contributions of the alpha-adrenoceptor subtypes to basal limb vascular tone are unknown. In healthy young men, forearm blood flow (FBF; venous occlusion plethysmography) responses to brachial artery administration of prazosin (an alpha(1)-adrenoceptor antagonist), yohimbine (an alpha(2)-adrenoceptor antagonist) and phentolamine (a non-selective alpha-adrenoceptor antagonist) were determined after local beta-adrenoceptor blockade with propranolol. In 10 subjects, prazosin increased FBF from 2.4 +/- 0.3 to 5.8 +/- 1.0 ml (100 ml)(-1) min(-1) (approximately 140 %; P < 0.001 vs. baseline). Subsequently, phentolamine further increased FBF to 11.7 +/- 1.6 ml (100 ml)(-1) min(-1) (approximately 385 %; P < 0.001 vs. baseline). Thus, the average calculated increase in FBF due to removal of alpha(2)-vasoconstrictor tone was greater than that due to removal of alpha(1)-tone (5.9 +/- 0.8 vs. 3.4 +/- 0.8 ml (100 ml)(-1) min(-1); P < 0.01) and represented approximately 63 % of basal sympathetic tone. Complete alpha(1)-adrenoceptor blockade was confirmed by a minimal reduction in FBF in response to phenylephrine after prazosin (46 +/- 3 vs. 6 +/- 4 %; before vs. after blockade) and in a separate group of four subjects, increasing the dose of prazosin threefold did not evoke further forearm vasodilatation. Additionally, the reduction in FBF in response to tryamine (evokes endogenous noradrenaline release) was abolished after phentolamine (40 +/- 3 vs. 2 +/- 1 %; before vs. after blockade), documenting complete pharmacological sympathectomy. In another group of seven subjects, administering yohimbine prior to phentolamine resulted in similar findings. These observations indicate that vasoconstricting post-junctional alpha(2)-adrenoceptors contribute more to basal vascular tone than alpha(1)-adrenoceptors in the forearms of young healthy men. The potential physiological and pathophysiological implications of these findings are discussed.

Adrenergic alpha-Agonists↗
PubMed2002

Geldanamycin attenuates NO-mediated dilation in human skin.

The binding of heat shock protein 90 (HSP90) to endothelial nitric oxide (NO) synthase (eNOS) can enhance eNOS activation. Studies have shown that the HSP90-specific inhibitor geldanamycin (GA) can cause attenuation of NO-mediated processes. Twenty subjects participated in one of two protocols. In each protocol, one forearm of each subject was instrumented with two intradermal microdialysis probes for drug delivery. Laser Doppler flowmeters were used to measure cutaneous blood flow. Skin sites were either treated with the endothelial agonist acetylcholine or locally heated to 42 degrees C, a maneuver that evokes NO-mediated dilation. Interventions were performed with and without GA. In the presence of GA, maximal cutaneous vascular conductance (CVC) to ACh was 20 +/- 3% lower than with ACh alone (P < 0.001). During local heating, maximal CVC in the presence of GA was 22 +/- 6% lower than during heating alone (P < 0.01). The results show that GA can attenuate NO-mediated dilation in human skin, suggesting a potential role for HSP90 in activation of eNOS in the microcirculation.

Acetylcholine↗
PubMed2002

Cardiorespiratory effects of inelastic chest wall restriction.

We examined the effects of chest wall restriction (CWR) on cardiorespiratory function at rest and during exercise in healthy subjects in an attempt to approximate the cardiorespiratory interactions observed in clinical conditions that result in restrictive lung and/or chest wall changes and a reduced intrathoracic space. Canvas straps were applied around the thorax and abdomen so that vital capacity was reduced by >35%. Data were acquired at rest and during cycle ergometry at 25 and 45% of peak workloads. CWR elicited significant increases in the flow-resistive work performed on the lung (160%) and the gastric pressure-time integral (>400%) at the higher workload, but it resulted in a decrease in the elastic work performed on the lung (56%) compared with control conditions. With CWR, heart rate increased and stroke volume (SV) fell, resulting in >10% fall in cardiac output at rest and during exercise at matched workloads (P < 0.05). Blood pressure and catecholamines were significantly elevated during CWR exercise conditions (P < 0.05). We conclude that CWR significantly impairs SV during exercise and that a compensatory increase in heart rate does not prevent a significant reduction in cardiac output. O(2) consumption appears to be maintained via increased extraction and a redistribution of blood flow via sympathetic activation.

Adolescent↗
PubMed2002

Effects of chronic sympathectomy on locally mediated cutaneous vasodilation in humans.

In human skin, the vasodilator response to local heating includes a sensory nerve-dependent peak followed by a nadir and then a slower, nitric oxide-mediated, endothelium-dependent vasodilation. To investigate whether chronic sympathectomy diminishes this endothelium-dependent vasodilation, we studied individuals who had previously undergone surgical T(2) sympathectomy (n = 9) and a group of healthy controls (n = 8). We assessed the cutaneous vascular response (laser-Doppler) to 30 min of local warming to 42.5 degrees C on the ventral forearm (no sympathetic innervation) and the lower legs (sympathetic nerves intact). Lower body negative pressure (LBNP) was measured to confirm sympathetic denervation. During local warming in sympathectomized individuals, vascular conductance reached an initial peak at both sites [achieving 1.73 +/- 0.22 laser-Doppler units (LDU)/mmHg in the forearm and 1.92 +/- 0.21 LDU/mmHg in the leg]. It then decreased to a nadir in the innervated leg [to 1.77 +/- 0.23 LDU/mmHg (P < 0.05)] but not in the sympathectomized arm (1.69 +/- 0.21 LDU/mmHg; P > 0.10). The maximal vasodilation seen during the slower phase was not different between limbs or between groups. Furthermore, LBNP caused a 44% reduction in forearm vascular conductance (FVC) in control subjects, but FVC did not decrease significantly in sympathectomized individuals, confirming sympathetic denervation. These data indicate that endothelial function in human skin is largely preserved after sympathectomy. The altered pattern of the response suggests that the nitric oxide-dependent portion may be accelerated in sympathectomized limbs.

Adult↗
PubMed2002

Effects of chronic sympathectomy on vascular function in the human forearm.

To determine whether endothelial function is altered by chronic surgical sympathectomy, we infused ACh, isoproterenol, nitroprusside (NTP), and the nitric oxide synthase inhibitor NG-mono-methyl-L-arginine (L-NMMA) into the brachial arteries of nine patients 5-64 mo after thoracic sympathectomy for hyperhidrosis. Age- and gender-matched controls were also studied. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Lower body negative pressure was used to assess reflex vasoconstrictor responses. Tyramine, which acts locally and causes norepinephrine release from sympathetic nerves, was also administered via the brachial artery. FBF at rest was 2.5 +/- 0.4 ml x dl-1 x min-1 in the patients and 2.5 +/- 0.3 ml x dl-1 x min-1 in the controls (P = 0.95). The normal vasoconstrictor responses to lower body negative pressure were abolished in the patients. By contrast, tyramine produced dose-dependent vasoconstriction in the patients that was identical to that of controls. The dose-response curves to ACh were similar in patients and controls, with maximum values of 19.3 +/- 4.4 vs. 25.5 +/- 2.8 ml x dl-1 x min-1, respectively. L-NMMA reduced baseline FBF similarly and reduced the maximal FBF response to ACh in both groups (patients 8.9 +/- 3.5 vs. controls 9.7 +/- 2.5 ml x dl-1 x min-1). The vasodilation to isoproterenol was similar and blunted to the same extent in both groups by L-NMMA. The responses to NTP in patients and controls were similar and not affected by L-NMMA. We conclude that, in humans, chronic surgical sympathectomy does not cause major disruptions in vascular function in the forearm. The normal vasoconstrictor responses to tyramine indicate that there were viable sympathetic nerves in the forearm that were not engaged by LBNP.

Adult↗
PubMed2002

An obligation for primary care physicians to prescribe physical activity to sedentary patients to reduce the risk of chronic health conditions.

Physical inactivity increases the risk of many chronic disorders. Numerous studies have convincingly demonstrated that undertaking and maintaining moderate levels of physical activity (eg, brisk walking 3 hours a week) greatly reduces the incidence of developing many chronic health conditions, most notably type 2 diabetes mellitus, obesity, cardiovascular disease, and many types of cancers. However, the underlying mechanistic details of how physical activity confers such protective effects are not well understood and consequently constitute an active area of research. Although changing an individual's ingrained behavior is commonly perceived to be difficult, encouraging evidence suggests that intensive and repeated counseling by health care professionals can cause patients to become more physically active. Therefore, counseling patients to undertake physical activity to prevent chronic health conditions becomes a primary prevention modality. This article summarizes the vast epidemiologic and biochemical evidence supporting the many beneficial health implications of undertaking moderate physical activity and provides a rationale for incorporating physical activity counseling as part of routine practice in the primary care setting.

Adult↗