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Biomedical subjects

Michael J Joyner

Publications and source records attributed to Michael J Joyner.

At least 37 records · Page 2Linked to original sources
PubMed2006

Effects of pioglitazone versus glipizide on body fat distribution, body water content, and hemodynamics in type 2 diabetes.

OBJECTIVE: Pioglitazone, a peroxisome proliferator-activated receptor agonist and glipizide, an insulin secretagogue, are commonly used to treat type 2 diabetes. Our study was designed to examine the effects of pioglitazone versus glipizide on body water, body composition, and hemodynamic parameters in the presence of comparable glycemic control between groups. RESEARCH DESIGN AND METHODS: We studied 19 diabetic subjects randomly assigned to either 45 mg pioglitazone (n = 8) or 10 mg (median dose) glipizide (n = 11) for 12 weeks. Body water content was measured with deuterated water, body composition by dual-energy X-ray absorptiometry and computed tomography, and cardiac output and systemic vascular resistance by acetylene rebreathing technique both before and after therapy. RESULTS: Pioglitazone increased (P < 0.001 from baseline) total body water (+2.4 +/- 0.5 l) accounting for 75% of the total weight gain (+3.1 +/- 2.0 kg) but did not alter vascular endothelial growth factor concentrations. Total abdominal (-32.2 +/- 19 cm(2)) and visceral fat area (-16.1 +/- 8 cm(2)) tended to decrease with pioglitazone but increased (P < 0.02 for differences between groups) with glipizide (+38.4 +/- 17 cm(2) abdominal; +19.1 +/- 9 cm(2) visceral). Pioglitazone tended to reduce (P = 0.05) diastolic (-8.4 +/- 4 mmHg) and mean (-9.5 +/- 5 mmHg; P = 0.08) blood pressure and reduced (P < 0.001) systemic vascular resistance (2,785 +/- 336 vs. 2,227 +/- 136 dynes/s per m(2)), while there were no differences in these parameters with glipizide. Neither therapy altered circulating catecholamine concentrations. CONCLUSIONS: When pioglitazone and glipizide are given in doses sufficient to achieve equivalent glycemic control in people with type 2 diabetes, pioglitazone increases total body water, thereby accounting for the majority of weight gain, tended to decrease visceral and abdominal fat content and blood pressure, and reduces systemic vascular resistance.

Adult↗
PubMed2005

Arg16Gly polymorphism of the beta2-adrenergic receptor is associated with differences in cardiovascular function at rest and during exercise in humans.

In humans, subjects homozygous for arginine (ArgArg) at codon 16 of the beta2-adrenergic receptor (beta2AR) have been shown to have greater agonist-mediated desensitization than subjects homozygous for glycine (GlyGly). We sought to determine if this substitution differentially influenced cardiovascular function during short duration (9 min) low and high intensity exercise (40 and 75% of peak work). Healthy Caucasian ArgArg (n = 16), GlyGly (n = 31) and ArgGly (n = 17) subjects matched for age, sex and peak oxygen uptake were studied. There were no differences in adrenaline (ADR) at rest or with heavy exercise, but the ArgArg group had lower ADR with light exercise (P = 0.04). Resting heart rate (HR) was higher in ArgArg (P < 0.01), while cardiac output (Q), stroke volume (SV), and mean arterial pressure (MAP) were lower than the other groups (HR = 86+/-2, 78+/-2, 80+/-1 beats min(-1); Q = 5.7+/-0.81, 6.1+/-0.18, 6.7+/-0.22 l min(-1); SV = 68+/-3, 82+/-3, 89+/-4 ml beat(-1); MAP = 92+/-1, 103+/-2, 98+/-1 mmHg-- for ArgArg, ArgGly and GlyGly, respectively, means +/-s.e.m., P < 0.01), however, no differences were observed in systemic vascular resistance (SVR). With low intensity exercise and high intensity exercise the ArgArg group continued to have a lower , SV and MAP compared to the other groups (P < 0.05), with no differences observed in SVR. During recovery, the ArgArg subjects continued to have a lower MAP but there were no differences in HR, , or SVR. These data suggest that subjects homozygous for Arg at codon 16 of the beta2AR have reduced and MAP at rest that persist during exercise with no evidence for differential changes over the course of exercise despite large changes in catecholamines. This may suggest possible genotype-related differences in baseline receptor function or density which causes phenotypic differences at rest that are sustained during short-term exercise.

Adult↗
PubMed2005

Reduced forearm alpha1-adrenergic vasoconstriction is associated with enhanced heart rate fluctuations in humans.

In the present study, we assessed whether heart rate (HR) or arterial pressure fluctuations are enhanced in healthy young humans with reduced alpha-adrenergic vasoconstrictor responses and, if so, whether this occurs for both alpha1- and alpha2-adrenergic receptor-mediated vasoconstriction. Arterial pressure (brachial artery catheter) and HR (ECG) were monitored continuously, and alpha1- and alpha2-adrenergic responsiveness was determined by assessing the effects of brachial artery infusions of phenylephrine (alpha1-adrenergic agonist) and dexmedetomidine (alpha2-adrenergic agonist), respectively, on forearm blood flow (strain gauge plethysmography). alpha1-Adrenergic responsiveness varied markedly among the subjects (n=20) and was inversely correlated with coefficient of variation for HR (R2=0.37, P<0.01), whereas the responsiveness was not correlated with the coefficient of variation for either systolic or diastolic arterial pressure. alpha1-Adrenergic responsiveness was inversely and more strongly correlated with baroreflex sensitivity (R2=0.62, P<0.0001), determined from beat-to-beat changes in HR and systolic arterial pressure, than the coefficient of variation for HR. On the other hand, alpha2-adrenergic responsiveness was not correlated with any of the parameters determined above. These results suggest that, in healthy young subjects, the enhanced HR response to changes in systolic pressure helps maintain the stability of arterial blood pressure when alpha1-adrenergic responsiveness is reduced.

Adult↗
PubMed2005

Baroreceptor function during exercise: resetting the record.

This paper briefly reviews the historical evolution of ideas about how baroreflexes operate and continue to regulate arterial blood pressure during exercise. Observations from studies conducted in conscious humans and animals are emphasized and three main questions are asked. First, do baroreflexes contribute to arterial blood pressure regulation during exercise? Second, if baroreflexes contribute to blood pressure regulation during exercise, how do they do it? Third, are there any pathophysiological conditions in which manipulation of baroreflexes or baroreflex 'dysfunction' might alter exercise responses? In this context, ideas related to baroreflex resetting during exercise are emphasized, and the potential improvement in exercise tolerance in cardiovascular disease that might be achieved by electrical stimulation of the carotid sinus nerve is highlighted. Additionally, the key contributions of John Shepherd and the late David Donald (along with their colleagues) on related issues are noted.

Animals↗
PubMed2005

Exercise hyperemia and vasoconstrictor responses in humans with cystic fibrosis.

ATP released from circulating erythrocytes is a potential signal regulating muscle blood flow during exercise (exercise hyperemia), and intravascular ATP appears to blunt sympathetic vasoconstriction during exercise. Erythrocytes from patients with cystic fibrosis (CF) do not release ATP. The goal of the present study was to determine whether increases in forearm blood flow during exercise are blunted in CF patients and whether CF patients exhibit greater vasoconstrictor responsiveness during exercise. Nine control subjects and 10 CF patients who were free of other disease complications (approximately 96% O2 saturation) performed incremental rhythmic forearm exercise at 5, 10, and 15% of maximum handgrip strength for 21 min (7 min at each workload). We used a cold pressor test to evoke sympathetic vasoconstriction under resting conditions and at each exercise workload. As a control, subjects performed a second exercise bout without the cold pressor test. Continuous brachial artery blood velocity was monitored beat-to-beat, and vessel diameter was assessed by Doppler ultrasound. Artery diameter, as well as blood pressure, heart rate, and O2 saturation, was measured at steady-state exercise and at 1 min into the cold pressor stimulus. Blood pressure and heart rate responses to the forearm exercise and each cold pressor test were similar in both groups (P > 0.05). Contrary to our hypothesis, forearm blood flow (P = 0.91) and forearm vascular conductance (P = 0.82) were similar at rest and at each level of exercise between CF patients and controls. Additionally, there was no difference in the degree of sympathetic vasoconstriction between groups at rest and at each level of exercise (P = 0.22). Our results suggest that ATP released from the deformation of erythrocytes is not an obligatory signal for exercise hyperemia in human skeletal muscle.

Adenosine Triphosphate↗
PubMed2005

Arg16/Gly beta2-adrenergic receptor polymorphism alters the cardiac output response to isometric exercise.

Normotensive adults homozygous for glycine (Gly) of the Arg16/Gly beta2-adrenergic-receptor polymorphism have 1) greater forearm beta2-receptor mediated vasodilation and 2) a higher heart rate (HR) response to isometric handgrip than arginine (Arg) homozygotes. To test the hypothesis that the higher HR response in Gly16 subjects serves to maintain the pressor response [increased cardiac output (CO)] in the setting of augmented peripheral vasodilation to endogenous catecholamines, we measured continuous HR (ECG), arterial pressure (Finapres), and CO (transthoracic echocardiography) during isometric, 40% submaximal handgrip to fatigue in healthy subjects homozygous for Gly (n = 30; mean age +/- SE: 30 +/- 1.2, 13 women) and Arg (n = 17, age 30 +/- 1.6, 11 women). Resting data were similar between groups. Handgrip produced similar increases in arterial pressure and venous norepinephrine and epinephrine concentrations; however, HR increased more in the Gly group (60.1 +/- 4.3% increase from baseline vs. 45.5 +/- 3.9%, P = 0.03), and this caused CO to be higher (Gly: 7.6 +/- 0.3 l/m vs. Arg: 6.5 +/- 0.3 l/m, P = 0.03), whereas the decrease in systemic vascular resistance in the Gly group did not reach significance (P = 0.09). We conclude that Gly16 homozygotes generate a higher CO to maintain the pressor response to handgrip. The influence of polymorphic variants in the beta2-adrenergic receptor gene on the cardiovascular response to sympathoexcitation may have important implications in the development of hypertension and heart failure.

Adult↗
PubMed2005

Impaired modulation of sympathetic alpha-adrenergic vasoconstriction in contracting forearm muscle of ageing men.

Recent evidence indicates that older healthy humans demonstrate greater vasoconstrictor tone in their active muscles during exercise compared with young adults. Therefore, we tested the hypothesis that the normal ability of muscle contractions to blunt sympathetic alpha-adrenergic vasoconstriction (functional sympatholysis) is impaired with age in healthy humans. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated the forearm vascular conductance (FVC) responses to alpha-adrenergic receptor stimulation during rhythmic handgrip exercise (15% maximum voluntary contraction) and during a control non-exercise vasodilator condition (intra-arterial adenosine infusion) in seven young (25 +/- 2 years) and eight healthy older men (65 +/- 2 year). FVC responses to intra-arterial tyramine (evokes endogenous noradrenaline release), phenylephrine (alpha1-agonist) and clonidine (alpha2-agonist) were assessed. In young men, the vasoconstrictor responses to tyramine (-25 +/- 1 versus -56 +/- 6%), phenylephrine (-11 +/- 4 versus -39 +/- 4%) and clonidine (-12 +/- 4 versus -38 +/- 5%; all P < 0.005) were blunted during exercise compared with adenosine. In contrast, exercise did not significantly blunt the response to tyramine (-30 +/- 2 versus -36 +/- 7%; P = 0.4) or phenylephrine (-16 +/- 2 versus -19 +/- 3%; P = 0.3) in older men, but did attenuate the response to clonidine (-22 +/- 3 versus -37 +/- 6%; P < 0.05). The magnitude of functional sympatholysis, calculated as the difference in the vasoconstrictor responses during adenosine infusion and exercise, was significantly lower in older compared with young men in the presence of tyramine (-6 +/- 7 versus -31 +/- 6%), phenylephrine (-3 +/- 3 versus -28 +/- 4%) and clonidine (-15 +/- 4 versus -26 +/- 3%; all P < 0.05). We conclude that ageing is associated with impaired functional sympatholysis in the vascular beds of contracting forearm muscle in healthy men. These findings might help explain the greater skeletal muscle vasoconstrictor tone and reduced blood flow during large muscle dynamic exercise in older adults.

Adenosine↗
PubMed2005

Selective alpha2-adrenergic properties of dexmedetomidine over clonidine in the human forearm.

We tested the hypothesis that dexmedetomidine (Dex) has greater alpha(2)- vs. alpha(1) selectivity than clonidine and causes more alpha(2)-selective vasoconstriction in the human forearm. After local beta-adrenergic blockade with propranolol, forearm blood flow (plethysmography) responses to brachial artery administration of Dex, clonidine, and phenylephrine (alpha(1)-agonist) were determined in healthy young adults before and after alpha(2)-blockade with yohimbine (n = 10) or alpha(1)-blockade with prazosin (n = 9). Yohimbine had no effect on phenylephrine-mediated vasoconstriction but blunted Dex-mediated vasoconstriction (mean +/- SE: -41 +/- 5 vs. -11 +/- 2%; before vs. after yohimbine) more than clonidine-mediated vasoconstriction (-39 +/- 5 vs. -28 +/- 4%; before vs. after yohimbine) (P < 0.02). Prazosin blunted phenylephrine-mediated vasoconstriction (-39 +/- 4 vs. -8 +/- 2%; before vs. after prazosin) but had similar effects on both Dex- (-30 +/- 4 vs. -39 +/- 6%; before vs. after prazosin) and clonidine-mediated vasoconstriction (-29 +/- 3 vs. -41 +/- 7%; before vs. after prazosin) (P > 0.7). Both Dex and clonidine reduced deep forearm venous norepinephrine concentrations to a similar extent (-59 +/- 12 vs. -55 +/- 10 pg/ml; Dex vs. clonidine, P > 0.6); this effect was abolished by yohimbine and blunted by prazosin. These results suggest that Dex causes more alpha(2)-selective vasoconstriction in the forearm than clonidine. The similar vasoconstrictor responses to both drugs after prazosin might be explained by the presynaptic effects on norepinephrine release.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2005

Blood pressure variation in healthy humans: a possible interaction with beta-2 adrenergic receptor genotype and renal epithelial sodium channels.

Renal control of Na(+) regulation is a critical component to blood pressure regulation. It has recently been suggested that the beta-2 adrenergic receptor plays a role in blood pressure regulation possibly via renal epithelial sodium channels (ENaC). In the kidneys, gain of function mutations of the ENaC leads to increased salt-sensitivity and hypertension (Liddle's syndrome). In contrast, loss of function mutations of the ENaC leads to pseudohypoaldosteronism and is characterized by hypotension. Polymorphic variation of the beta-2 adrenergic receptor (beta2AR, the Arg16Gly polymorphism) leads to differences in physiologic function, in vivo. Specifically, subjects homozygous for Glycine at amino acid 16 have been shown to have enhanced forearm blood flow in response to isoproterenol and better airway function at baseline and during exercise when compared to subjects homozygous for Arginine at amino acid 16. We hypothesize, therefore, that subjects that are homozygous for Gly at amino acid 16 of the beta2AR have higher baseline blood pressure than Arg16 homozygotes due to beta2AR-mediated increases in ENaC activity in the kidney, caused, at least in part, by greater beta2AR density or enhanced beta2AR function of the Gly16 group.

Adult↗
PubMed2005

A restrospective perspective.

Venous occlusion plethysmography is a simple but elegant technique that has contributed to almost every major area of vascular biology in humans. The general principles of plethysmography were appreciated by the late 1800s, and the application of these principles to measure limb blood flow occurred in the early 1900s. Plethysmography has been instrumental in studying the role of the autonomic nervous system in regulating limb blood flow in humans and important in studying the vasodilator responses to exercise, reactive hyperemia, body heating, and mental stress. It has also been the technique of choice to study how human blood vessels respond to a variety of exogenously administered vasodilators and vasoconstrictors, especially those that act on various autonomic and adrenergic receptors. In recent years, plethysmography has been exploited to study the role of the vascular endothelium in health and disease. Venous occlusion plethysmography is likely to continue to play an important role as investigators seek to understand the physiological significance of newly identified vasoactive factors and how genetic polymorphisms affect the cardiovascular system in humans.

Cardiovascular Diseases↗