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Biomedical subjects

G L Jennings

Publications and source records attributed to G L Jennings.

At least 37 records · Page 2Linked to original sources
PubMed2000

Supplemental oxygen does not modulate responses to acetylcholine or ascorbic acid in the forearm of patients with congestive heart failure.

Despite providing symptomatic relief in patients with congestive heart failure (CHF), supplemental oxygen (O(2)) has been demonstrated to increase total peripheral resistance. The present study investigated the possibility that O(2) inhalation reduces nitric oxide (NO) bioavailability, using endothelium-dependent (acetylcholine) and -independent (phentolamine) vasodilators, and the antioxidant ascorbic acid. Ten patients (nine male and one female) with primary left ventricular failure participated in the study. Forearm venous occlusion plethysmography was used to study blood flow responses to acetylcholine and the alpha-adrenergic antagonist phentolamine during inhalation of either room air or 100% O(2), with and without the simultaneous infusion of ascorbic acid. Neither O(2) inhalation (3.9+/-0.4 compared with 3.8+/-0.3 ml.min(-1).100 ml(-1)) nor ascorbic acid infusion (5.2+/-0.4 compared with 5.5+/-0.4 ml.min(-1).100 ml(-1)) affected resting forearm blood flow. The percentage increase from basal blood flow after acetylcholine infusion was not altered by either O(2) inhalation or ascorbic acid infusion (room air, 140+/-55%; O(2), 118+/-46%; ascorbic acid, 147+/-39%; ascorbic acid+O(2), 109+/-31%). O(2) inhalation did, however, reduce the dilation induced by phentolamine (room air, 131+/-24%; O(2), 80+/-14%; P<0.05). These data indicate that oxygen inhalation does not increase forearm vascular resistance. Secondly, preservation of reactivity to acetylcholine during O(2) inhalation suggests that degradation of NO by O(2)-derived free radicals is not enhanced. Attenuation of phentolamine-induced vasodilation during O(2) inhalation, however, implies increased adrenergic activity, which may possibly exacerbate the detrimental effects of elevated sympathetic activity in CHF.

Acetylcholine↗
PubMed1999

Antiadrenergic effect of chronic amiodarone therapy in human heart failure.

OBJECTIVES: The aim of the present study was to evaluate the influence of amiodarone on neurochemical parameters of sympathetic nervous activity in patients with congestive heart failure. BACKGROUND: Unlike most antiarrhythmic agents, amiodarone has been shown to exert a beneficial effect on survival in some studies of patients with congestive heart failure. The pharmacology of this agent is complex, and as such, the mode of its action is unclear in humans. Some experimental studies suggest that amiodarone exerts a sympatholytic effect. METHODS: To evaluate the effect of amiodarone on sympathetic nervous activity, we measured the total systemic and cardiac norepinephrine (NE) spillover rate by isotope dilution in 58 patients with severe heart failure (left ventricular ejection fraction 20 +/- 1%), 22 of whom were receiving chronic amiodarone treatment. Release rates for dihydroxyphenylalanine (DOPA, a precursor of NE), and endogenous and radiolabeled dihydroxyphenylglycol (DHPG and 3H-DHPG, intraneuronal metabolites of NE and 3H-NE, respectively) were also determined to assess sympathetic neuronal integrity. RESULTS: Amiodarone-treated patients had significantly lower cardiac spillover rates for NE (42%, p = 0.001), DOPA (74%, p < 0.001), DHPG (44%, p < 0.01) and 3H-DHPG (51%, p < 0.01) than those patients not treated with amiodarone. Hemodynamic assessment of amiodarone-treated patients revealed higher cardiac output (4.4 +/- 0.2 vs. 3.7 +/- 0.2 liters/min, p < 0.01), and slightly lower pulmonary capillary wedge pressure (18 +/- 2 vs. 22 +/- 1, p = NS) than in untreated patients. After correction for the potential confounding effect of hemodynamic differences, amiodarone-treated patients continued to demonstrate significantly lower spillover rates of NE, DOPA and DHPG from the heart. CONCLUSIONS: These data indicate that amiodarone may exert beneficial effects on the failing human heart through a sympatholytic process, and this action appears to be relatively cardioselective.

Adrenergic Antagonists↗
PubMed1999

Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover.

The afferent signals that evoke changes in energy intake with regard to body weight regulation are presumed to arise partly from body stores, with the most likely candidate being adipose tissue depots. However, clinical investigation of the neuronal circuitry involved in the central nervous system's processing of such satiety signals remains largely unexplored. Using percutaneously placed catheters in either the right or left internal jugular veins, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters in 64 weight-stable male subjects with varying degrees of adiposity. Veno-arterial plasma concentration differences and internal jugular blood or plasma flow were used, according to the Fick Principle, to quantify the amount of neurotransmitter stemming from the brain. By combining this technique with a noradrenaline and adrenaline isotope dilution method for examining neuronal transmitter release, we were able to examine the association between central nervous system neurotransmitters and efferent sympathetic nervous outflow and adrenomedullary function in human obesity. We found that brain 5-hydroxytryptamine (serotonin) turnover is chronically elevated in proportion to adiposity and is increased postprandially to a similar degree in lean and obese individuals. There was no difference in the degree of sympathetic nervous activity or rate of adrenaline secretion in the subjects examined. It therefore seems that in human obesity, in the face of a chronic elevation in peripheral satiety signals, brain serotonergic processes are switched on accordingly, but the subsequent physiological response involving a reduction in food intake, increased thermogenesis and sympathetic activity is in some way impeded.

Adult↗
PubMed1999

Left ventricular mass and microalbuminuria: relation to ambulatory blood pressure. Hypertension Diagnostic Service Investigators.

1. Both microalbuminuria and left ventricular hypertrophy may reflect target organ damage in essential hypertension. Both are related to the prevailing level of blood pressure and both are associated with an increase in morbidity and mortality. 2. The database of the Hypertension Diagnostic Service, a multicentre secondary referral clinic for patients with essential hypertension, was analysed in order to clarify the level of association between microalbuminuria and left ventricular hypertrophy, which might explain the observed increase in morbidity and mortality in patients with microalbuminuria. Microalbuminuria was measured semiquantitatively by urine dip-stix. After the exclusion of patients with potential secondary hypertension, renal disease and diabetes mellitus, patients with complete data for microalbuminuria, left ventricular mass (LVM) and 24 h blood pressure monitoring were selected. 3. Data were complete for 704 patients (47% male, age 51 +/- 12 years) and 42% tested positive for microalbuminuria. Microalbuminuria was positively related to 24 h systolic blood pressure and weight and was negatively related to age. Left ventricular mass was higher in patients with microalbuminuria (men, 265 +/- 69 g; women, 207 +/- 61 g) than in those without (men, 250 +/- 64 g, P < 0.05; women, 185 +/- 50 g, P < 0.001). After correction for the effects of gender, body mass index and 24 h systolic blood pressure, the presence of microalbuminuria was associated with an increase in LVM of 10 g (P < 0.05, 95% confidence interval, 2-19 g).

Adult↗
PubMed1999

Withdrawal of hormonal therapy for 4 weeks decreases arterial compliance in postmenopausal women.

BACKGROUND: We demonstrated in a previous cross-sectional study that arterial compliance is elevated in postmenopausal women taking estrogen-containing hormonal therapy, which may partially account for the reduction in cardiovascular risk observed. OBJECTIVE: To investigate the effects of withdrawal and recommencement of hormonal therapy, each for 4 weeks, on arterial compliance. METHODS: Seventeen postmenopausal women [aged 56 +/- 4 years (mean +/- SD)] taking long-term hormonal therapy (+HT group) were studied at baseline, 4 weeks after withdrawal of hormonal therapy and again 4 weeks after recommencement. Systemic arterial compliance (SAC), pulse wave velocity (PWV) in the aorto-femoral and femoral-dorsalis pedis regions, and hemodynamic variables were measured at baseline, and at the end of each study intervention. As a time-control, seventeen postmenopausal women (aged 63 +/- 7 years) not taking hormonal therapy (-HT group) were also investigated. RESULTS: SAC significantly decreased from 0.47 +/- 0.06 to 0.40 +/- 0.05 arbitrary compliance units (mean +/- SEM; P < 0.05) after 4 weeks withdrawal from hormonal therapy. PWV in the femoral-dorsalis pedis region was elevated significantly by the withdrawal of hormonal therapy (8.4 +/- 0.4 to 9.4 +/- 0.5 m/s; P < 0.05), but PWV in the aortofemoral region did not change. After therapy had been recommenced for 4 weeks, SAC and PWV in the femoral-dorsalis pedis region were restored to baseline values. The -HT group showed no difference in SAC or PWV, and mean arterial pressure did not change in either group throughout the study period. CONCLUSION: These data suggest that hormonal modulation of distal arterial vascular tone may account for short-term changes in arterial compliance associated with estrogen-containing hormonal therapy.

Aorta, Thoracic↗
PubMed1999

Neural mechanisms in human obesity-related hypertension.

OBJECTIVE: Two hypotheses concerning mechanisms of weight gain and of blood pressure elevation in obesity were tested. The first hypothesis is that in human obesity sympathetic nervous system underactivity is present, as a metabolic basis for the obesity. The second hypothesis, attributable to Landsberg, is that sympathetic nervous activation occurs with chronic overeating, elevating blood pressure. These are not mutually exclusive hypotheses, since obesity is a heterogeneous disorder. DESIGN AND METHODS: Whole body and regional sympathetic nervous system activity, in the kidneys and heart, was measured at rest using noradrenaline isotope dilution methodology in a total of 86 research voluteers in four different subject groups, in lean and in obese people who either did, or did not, have high blood pressure. RESULTS: In the lean hypertensive patients, noradrenaline spillover for the whole body, and from the heart and kidneys was substantially higher than in the healthy lean volunteers. In normotensive obesity, the whole body noradrenaline spillover rate was normal, mean renal noradrenaline spillover was elevated (twice normal), and cardiac noradrenaline spillover reduced by approximately 50%. In obesity-related hypertension, there was elevation of renal noradrenaline spillover, comparable to that present in normotensive obese individuals but not accompanied by suppression of cardiac noradrenaline spillover, which was more than double that of normotensive obese individuals (P<0.05), and 25% higher than in healthy volunteers. There was a parallel elevation of heart rate in hypertensive obese individuals. CONCLUSIONS: The sympathetic underactivity hypothesis of obesity causation now looks untenable, as based on measures of noradrenaline spillover, sympathetic nervous system activity was normal for the whole body and increased for the kidneys; the low sympathetic activity in the heart would have only a trifling impact on total energy balance. The increase in renal sympathetic activity in obesity may possibly be a necessary cause for the development of hypertension in obese individuals, although clearly not a sufficient cause, being present in both normotensive and hypertensive obese individuals. The discriminating feature of obesity-related hypertension was an absence of the suppression of the cardiac sympathetic outflow seen in normotensive obese individuals. Sympathetic nervous changes in obesity-related hypertension conformed rather closely to those expected from the Landsberg hypothesis.

Adolescent↗
PubMed1999

Higher systemic arterial compliance is associated with greater exercise time and lower blood pressure in a young older population.

OBJECTIVES: Arterial compliance is an important therapeutic target in older individuals in whom stiffening of the proximal arterial circulation is thought to underlie systolic hypertension and increased cardiac work. We have shown previously that arterial compliance is related to aerobic fitness and that it is increased in young (20 to 35 years old), previously sedentary individuals by a 4-week period of moderate aerobic training. The extent to which compliance relates to exercise performance in a random selection of young older patients has not been reported previously. Therefore, we examined the interrelationship between systemic arterial compliance (SAC) and time to cessation of exercise during a standard treadmill exercise test in an older population. DESIGN: A cross-sectional survey. METHODS: SAC was estimated at rest using simultaneous recordings of ascending aortic flow and carotid applanation tonometry in 43 subjects aged 67 +/- 7 years (mean +/- SD; 24 men and 19 women). Treadmill exercise testing was performed using a modified Bruce protocol. Aerobic capacity was assessed as Heart Rate-Blood Pressure product and exercise tolerance as total treadmill time. RESULTS: SAC and exercise tolerance were related to gender, with men exhibiting greater exercise reserve and higher SAC than women. There was a significant positive correlation between SAC and time to cessation of exercise (r = .34; P = .03), with a negative correlation between SAC and resting heart rate-blood pressure product (r = -.66; P < .001). SAC was correlated with height and blood pressure. Exercise tolerance was related to height (P < .02). CONCLUSIONS: These data indicate a positive association between SAC and fitness level in healthy older people and an inverse association between SAC and systolic blood pressure. Our findings are consistent with either (1) acquisition of a more compliant circulation and lower blood pressure through more physical activity or (2) that a more compliant arterial circulation and lower blood pressure permit greater athletic performance.

Aged↗
PubMed1998

Impaired endothelium-dependent relaxation in large, but not small arteries in rats after coronary ligation.

Vascular responses were studied in both large and small arteries of rats following 8 weeks of heart failure produced by coronary ligation. Responses to noradrenaline, acetylcholine and sodium nitroprusside were studied in isolated thoracic aorta and mesenteric arteries. In the aorta, concentration-response curves for noradrenaline were similar between heart failure and sham animals and unaffected by the nitric oxide synthase inhibitor, NG-nitro-L-arginine (L-NOARG). Relaxation by acetylcholine was impaired in heart failure rats (EC50-6.79 log M heart failure vs. -7.15 log M sham). In the presence of L-NOARG, relaxation by acetylcholine was completely abolished in rings from sham rats, whereas constriction was observed in rings from heart failure rats. Relaxation by sodium nitroprusside was not different between sham and heart failure rats. In mesenteric arteries, responses to noradrenaline, acetylcholine and sodium nitroprusside were not different between heart failure and sham rats. L-NOARG reduced the maximum response to acetylcholine in both heart failure (82% to 50%) and shams (89% to 49%) by a similar magnitude, with no effect on relaxation to sodium nitroprusside. These data suggest that acetylcholine-induced relaxation is impaired in the aorta, but not mesenteric arteries in rats with heart failure. The mechanism is not solely due to impaired nitric oxide release and may be due to acetylcholine-induced contraction.

Acetylcholine↗
PubMed1998

Panic disorder: coronary spasm as a basis for cardiac risk?

Patients with panic disorder often complain of angina-like chest pain during panic attacks, but this is not usually considered life-threatening. We describe three patients with panic disorder and documented cardiac ischaemia during episodes of chest pain. In two, it progressed to myocardial infarction. As none had atherosclerosis evident at coronary angiography, the mechanism was presumed to be coronary artery spasm. These cases illustrate that pain typical of angina during panic attacks may have an organic cause.

Adult↗
PubMed1998

Differential effect of acute baroreceptor unloading on cardiac and systemic sympathetic tone in congestive heart failure.

OBJECTIVES: The present study was designed to identify the hemodynamic factor or factors that reflexly contribute to activation of the cardiac sympathetic nerves in patients with severe congestive heart failure (CHF). BACKGROUND: We and others have previously shown that activation of the sympathetic nervous system is a key feature of CHF in humans. Furthermore, the degree of sympathetic activation shows marked regional heterogeneity and is most pronounced in the heart. Recent studies have shown a significant positive relation between pulmonary artery pressure and the magnitude of cardiac sympathetic activation. Of particular importance, the degree of cardiac sympathoexcitation has also been shown to be strongly associated with mortality in CHF. METHODS: We assessed total systemic and cardiac sympathetic activity (norepinephrine [NE] spillover method) in nine patients with severe CHF and significantly elevated pulmonary artery pressure (mean [+/-SEM] pulmonary artery pressure 46 +/- 3 mm Hg) at rest and during a titrated infusion of sodium nitroprusside (SNP). RESULTS: SNP infusion significantly reduced mean arterial blood pressure, pulmonary artery pressure and pulmonary capillary wedge pressure. During SNP infusion, the total body NE spillover rate (NESR) increased (from 7.9 +/- 1.7 to 11.2 +/- 3.1 nmol/min, p < 0.01), whereas the cardiac NESR decreased (from 522 +/- 86 to 409 +/- 71 pmol/min, p < 0.05). The ratio of cardiac/total NE spillover was also substantially reduced (from 7.8 +/- 1.3 to 4.9 +/- 0.9%, p < 0.001). CONCLUSIONS: There is a directionally opposite change in whole-body (increase) and cardiac (reduction) sympathetic nervous activity during SNP infusion, most likely due to unloading of arterial baroreceptors and specific cardiopulmonary baroreceptors, respectively, in severe CHF. These observations support the concept of a positive feedback relation between pulmonary artery pressure/filling pressure and cardiac sympathetic tone in CHF and serve to reinforce the importance of vasodilator therapy in this condition.

Antihypertensive Agents↗
PubMed1998

Sympathetic activity in patients with panic disorder at rest, under laboratory mental stress, and during panic attacks.

BACKGROUND: The sympathetic nervous system has long been believed to be involved in the pathogenesis of panic disorder, but studies to date, most using peripheral venous catecholamine measurements, have yielded conflicting and equivocal results. We tested sympathetic nervous function in patients with panic disorder by using more sensitive methods. METHODS: Sympathetic nervous and adrenal medullary function was measured by using direct nerve recording (clinical microneurography) and whole-body and cardiac catecholamine kinetics in 13 patients with panic disorder as defined by the DSM-IV, and 14 healthy control subjects. Measurements were made at rest, during laboratory stress (forced mental arithmetic), and, for 4 patients, during panic attacks occurring spontaneously in the laboratory setting. RESULTS: Muscle sympathetic activity, arterial plasma concentration of norepinephrine, and the total and cardiac norepinephrine spillover rates to plasma were similar in patients and control subjects at rest, as was whole-body epinephrine secretion. Epinephrine spillover from the heart was elevated in patients with panic disorder (P=.01). Responses to laboratory mental stress were almost identical in patient and control groups. During panic attacks, there were marked increases in epinephrine secretion and large increases in the sympathetic activity in muscle in 2 patients but smaller changes in the total norepinephrine spillover to plasma. CONCLUSIONS: Whole-body and regional sympathetic nervous activity are not elevated at rest in patients with panic disorder. Epinephrine is released from the heart at rest in patients with panic disorder, possibly due to loading of cardiac neuronal stores by uptake from plasma during surges of epinephrine secretion in panic attacks. Contrary to popular belief, the sympathetic nervous system is not globally activated during panic attacks.

Adrenal Medulla↗
PubMed1998

Inhibitory effects of tranilast on expression of transforming growth factor-beta isoforms and receptors in injured arteries.

Tranilast (N(3,4-dimethoxycinnamoyl)anthranilic acid), an agent which in cell culture inhibits transforming growth factor-beta (TGF-beta) secretion and antagonises the effects of TGF-beta and platelet-derived growth factor (PDGF) on cell migration and proliferation, has been reported to reduce the incidence of restenosis after angioplasty in angiographically validated human clinical trials. We investigated in a rat model of balloon angioplasty whether tranilast's effects in vivo could be attributed to inhibition of expression of TGF-beta and/or its receptor types. Using a standardised reverse transcriptase-polymerase chain reaction (RT-PCR) assay, we examined the effects of three doses of tranilast (25, 50 and 100 mg/kg) on the expression of two TGF-beta isoforms, the types I and II TGF-beta receptors and two putative TGF-beta responses, induction of integrins alpha(v) and beta3 mRNA, 2 h after oral administration and 26 h after vessel injury. Tranilast attenuated in a dose-dependent and reversible manner the injury-induced increases in mRNA levels encoding TGF-beta1, TGF-beta3, two type I TGF-beta receptors ALK-5 and ALK-2, and the type II receptor TbetaRII. At the highest dose mRNA levels encoding TGF-beta1 and TbetaRII were attenuated to levels approaching or below those observed in uninjured vessels. Messenger RNAs encoding TGF-beta3, ALK-5 and ALK-2 were all attenuated by between 70 and 74% (all P < 0.05). Tranilast also attenuated in a reversible manner the elevations in mRNA levels for integrins alpha(v) and beta3 observed after vessel injury, by 90 and 72%, respectively. We also investigated, in cultured smooth muscle cells derived from injured carotid arteries, the extent to which tranilast (300 mg/l) attenuated any increases in expression of type I and type II receptors stimulated by PDGF-BB and TGF-beta1, growth factors implicated in smooth muscle cell migration and proliferation in injured vessels. Increases in mRNA levels of the type I receptors ALK-5 and ALK-2 induced by PDGF-BB and TGF-beta1 were almost completely prevented by tranilast. Tranilast also prevented the PDGF-BB induced increases in TbetaRII but only partially inhibited the TGF-beta1 induced upregulation of TbetaRII. We conclude that tranilast can inhibit transcriptional mechanisms associated with the upregulation of TGF-beta and its receptor types in balloon catheter injured vessels. It is possible that these mechanisms contribute to its ability to reduce the frequency of restenosis after angioplasty.

Angioplasty, Balloon↗
PubMed1998

The failing human heart does not release nitrogen oxides.

It has been suggested that the myocardial production of nitric oxide, as a consequence of expression of the inducible isoform of nitric oxide synthase (NOS), plays an important role in the pathophysiology of heart failure. We determined the net cardiac production of nitrogen oxides (NOx), as a measure of NOS activity, by performing arterial and coronary sinus sampling in healthy control subjects (n=6) and patients with end-stage heart failure (n=10). The arterial plasma NOx concentration was significantly elevated in heart failure patients (58.4 +/- 7.0 vs 36.9 +/- 4.9 microM, p<0.05). However, we found net extraction of NOx across the heart, with no difference between the two groups. Therefore, the heart does not appear to be a source of NOx in heart failure, and this study does not support a pathophysiological role for NOx in this condition.

Cardiac Output, Low↗