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Biomedical subjects

H R Brunner

Publications and source records attributed to H R Brunner.

At least 127 records · Page 7Linked to original sources
PubMed1995

Synergistic effects of fluid shear stress and cyclic circumferential stretch on vascular endothelial cell morphology and cytoskeleton.

The development of atherosclerosis is thought to be initiated by a dysfunctional state of the vascular endothelium. The proposal that mechanical forces play a role in the localization of this disease has led researchers to develop in vitro models to assess their effects on cultured endothelial cells. The arterial endothelium is exposed simultaneously to circumferential hoop stretch and wall shear stress, yet previous investigations have focused on the isolated effects of either cyclic stretch or shear stress. The influence of physiological levels of combined shear stress and hoop stretch on the morphology and F-actin organization of bovine aortic endothelial cells was investigated. Cells subjected for 24 hours to shear stresses higher than 2 dyne/cm2 or to hoop stretch greater than 2% elongated significantly compared with unstressed controls and oriented along the direction of flow and perpendicular to the direction of stretch. Exposure to more than 4% stretch significantly enhanced the responses to shear stress. Both shear stress and hoop stretch induced formation of stress fibers that were aligned with the cells' long axes. Simultaneous exposure to both stimuli appeared to enhance stress fiber size and alignment. These results indicate that shear stress and hoop stretch synergistically induce morphological changes in endothelial cells, which suggests that circumferential strain might modulate sensitivity of endothelial cells towards shear stress.

Animals↗
PubMed1995

Characterization of the angiotensin II receptor antagonist TCV-116 in healthy volunteers.

The purpose of this study was to assess the inhibitory effect of TCV-116, an orally active angiotensin II (Ang II) antagonist, on the pressor action of exogenous Ang II and to determine the compensatory rise in plasma renin activity and Ang II levels. Twenty-three male volunteers were treated for 8 days in a double-blind fashion with either placebo or TCV-116 (1, 2, or 4 mg PO daily) and challenged on the first, fourth, and eighth days with repeated bolus injections of Ang II. An additional 4 subjects received 8 mg PO daily in a single-blind fashion. The inhibitory effect on the systolic blood pressure response to Ang II was long lasting and clearly dose related. Six hours after 4 mg TCV-116, the systolic blood pressure response to a given dose of Ang II was reduced to 40 +/- 4% and 35 +/- 8% of baseline value on days 1 and 8, respectively. TCV-116 induced a dose-related increase in plasma renin activity and Ang II levels that was more pronounced on the eighth than on the first day of drug administration. Despite this compensatory mechanism, the relation between the time-integrated systolic blood pressure response to Ang II and the time-integrated CV-11974 levels, the active metabolite of TCV-116, was not different between days 1 and 8. In conclusion, TCV-116 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of Ang II in men.

Administration, Oral↗
PubMed1995

Short-term and sustained renal effects of angiotensin II receptor blockade in healthy subjects.

We investigated the short-term and sustained hormonal and renal effects of angiotensin II (Ang II) receptor blockade in normotensive healthy volunteers. Twenty-four subjects maintained on a fixed sodium diet were randomized to receive for 8 days a placebo or 10 or 50 mg doses of the Ang II antagonist irbesartan (SR 47436, BMS 186295) according to a double-blind, parallel group design. Plasma renin activity, plasma immunoreactive Ang II and aldosterone levels, blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 8 hours after the first and eighth administration of each dose of irbesartan or placebo. Ang II receptor blockade with irbesartan induced a dose-dependent compensatory increase in plasma renin activity and plasma angiotensin levels and a significant decrease in plasma aldosterone levels. The compensatory rise in plasma renin activity and Ang II levels was more pronounced on day 8, reflecting a long duration of the blocking effect of irbesartan. Irbesartan induced small changes in blood pressure and did not significantly modify renal blood flow and glomerular filtration rate. However, a significant decrease in filtration fraction was observed during receptor blockade on days 1 and 8. The tubular effects of irbesartan were characterized by a dose-dependent increase in sodium and chloride excretions. Interestingly, the cumulative natriuretic response to Ang II receptor blockade was similar on days 1 and 8, suggesting that in these subjects, renal Ang II receptors are not blocked over 24 hours during repeated administration even though this antagonist has a long duration of action (t1/2 of 15 to 17 hours).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Chronic nitric oxide synthase inhibition and carotid artery distensibility in renal hypertensive rats.

The goal of the present study was to examine the viscoelastic properties of the carotid artery in genetically identical rats exposed to similar levels of blood pressure sustained by different mechanisms. Eight-week old male Wistar rats were examined 2 weeks after renal artery clipping (two-kidney, one clip [2K1C] Goldblatt rats, n = 53) or sham operation (n = 49). One half of the 2K1C and sham rats received the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 1.48 mmol/L) in their drinking water for 2 weeks after the surgical procedure. Mean blood pressure increased significantly in the 2K1C-water (182 mm Hg), 2K1C-L-NAME (197 mm Hg), and sham-L-NAME (170 mm Hg) rats compared with the sham-water rats (127 mm Hg). Plasma renin activity was not altered by L-NAME but significantly enhanced after renal artery clipping. A significant and similar increase in the cross-sectional area of the carotid artery was observed in L-NAME and vehicle-treated 2K1C rats. L-NAME per se did not modify cross-sectional area in the sham rats. There was a significant upward shift of the distensibility-pressure curve in the L-NAME- and vehicle-treated 2K1C rats compared with the sham-L-NAME rats. L-NAME treatment did not alter the distensibility-pressure curve in the 2K1C rats. These results demonstrate that the mechanisms responsible for artery wall hypertrophy in renovascular hypertension are accompanied by an increase in arterial distensibility that is not dependent on the synthesis of nitric oxide.

Amino Acid Oxidoreductases↗
PubMed1995

Postischemic blood flow response in hypercholesterolemic patients.

We undertook this cross-sectional study to compare the mechanical behavior and postischemic response of the radial artery of 15 newly diagnosed hypercholesterolemic patients with those of 15 age- and sex-matched normocholesterolemic control subjects and 21 hypercholesterolemic patients treated for 2 years with an 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (simvastatin, 10 to 20 mg/d). At the time of the study total cholesterol levels were at 7.9 +/- 0.2, 4.9 +/- 0.2, and 6.0 +/- 0.3 mmol/L in the three groups, respectively (mean +/- SEM, P < .001). High-resolution, noninvasive echotracking for assessment of internal arterial diameter was combined with measurements of blood flow velocity by Doppler and blood pressure by photoplethysmography. Radial cross-sectional compliance and distensibility were similar in all groups. Forearm blood flow and flow-mediated dilation were measured after a 5-minute upper arm occlusion. Flow was calculated from the vessel diameter and blood flow velocity recorded simultaneously at the same site. Flow-mediated dilation after ischemia was not significantly different among the three groups. However, forearm blood flow increase was markedly blunted (P < .01) in untreated hypercholesterolemic patients (211%) compared with the normocholesterolemic control subjects (411%) and treated patients (365%). These findings suggest that the distensibility of the radial artery, a muscular conduit vessel usually devoid of atherosclerotic lesions, and its flow-mediated dilation are preserved in hypercholesterolemic patients. In contrast, forearm resistance vessels exhibit a markedly reduced postischemic blood flow response that may be restored by prolonged lipid-lowering intervention.

Adult↗
PubMed1995

Vascular acetylcholine response during chronic NO synthase inhibition: in vivo versus in vitro.

OBJECTIVE: The aim of this study was to compare the response to NO-mediated vasodilators in vivo and in vitro during chronic NO synthase inhibition. METHODS: NG-Nitro-L-arginine-methyl ester (L-NAME, 0.4 g/l) or vehicle was administered in the drinking water for 6 weeks to male Wistar rats weighing 220-240 g. The effect of acetylcholine and sodium nitroprusside was examined in vivo, on systemic blood pressure and heart rate and in vitro, on the precontracted isolated mesenteric artery. The in vivo response to both vasodilators was examined in awake rats monitored by an indwelling catheter in the femoral artery. Isolated segments of the third-generation mesenteric artery were examined in vitro with a Mulvany dual myograph after precontraction with noradrenaline. RESULTS: In isolated mesenteric arteries obtained from rats chronically treated with L-NAME, the initial relaxant response to acetylcholine was significantly decreased whereas that to sodium nitroprusside was enhanced. A late acetylcholine-induced contractile response was present and abolished by indomethacin. In vivo, the hypotensive action of sodium nitroprusside was also enhanced in the L-NAME-treated rats. Acetylcholine reduced blood pressure in the L-NAME-treated hypertensive animals more than in normotensive controls, but less than in control rats infused intravenously with noradrenaline at a dose increasing their blood pressure to hypertensive levels. CONCLUSIONS: The NO-mediated vasodilation induced by acetylcholine is attenuated during chronic NO synthase inhibition, both in vivo and in vitro. The blunted hypotensive response to acetylcholine can be demonstrated only if blood pressure of control rats is acutely increased to hypertensive levels.

Acetylcholine↗
PubMed1995

Neutral endopeptidase versus angiotensin converting enzyme inhibition in essential hypertension.

OBJECTIVE: To evaluate the antihypertensive efficacy of sinorphan, an orally active inhibitor of neutral endopeptidase EC 3.4.24.11. DESIGN: The ability of sinorphan (100 mg twice a day) to lower blood pressure was compared with that of the angiotensin converting enzyme (ACE) inhibitor captopril (25 mg twice a day) using a randomized-sequence, double-blind crossover design in 16 patients with essential hypertension. Each treatment was administered for 4 weeks and treatments were separated by a 3-week placebo period. At the end of the last phase of treatment sinorphan was combined with captopril for a further 4-week period. The changes in systolic (SBP) and diastolic blood pressure (DBP) were monitored using repeated ambulatory blood pressure monitoring. RESULTS: When given as monotherapy for 4 weeks, neither sinorphan nor captopril significantly reduced the 24-h or the 14-h daytime mean SBP or DBP. However, a significant decrease in DBP was observed during the first 6 h after the morning administration of captopril. With sinorphan only a significant decrease in night-time SBP was found. With the combined therapy of sinorphan and captopril, significant decreases both in SBP and in DBP were observed, which were sustained over 24 h. After 4 weeks of sinorphan alone or in combination with captopril, no change in plasma atrial natriuretic peptide level was found. However, urinary cyclic GMP excretion increased transiently after administration of the neutral endopeptidase inhibitor. CONCLUSIONS: Neutral endopeptidase inhibition with sinorphan has a limited effect on blood pressure in hypertensive patients when given alone. However, simultaneous neutral endopeptidase and ACE inhibition induces a synergistic effect, and might therefore represent an interesting new therapeutic approach to the treatment of essential hypertension.

Adult↗
PubMed1995

Sympathetic nerve activity in conscious renal hypertensive rats treated with an angiotensin converting enzyme inhibitor or an angiotensin II antagonist.

OBJECTIVE: To assess in conscious two-kidney, one clip renal hypertensive rats whether angiotensin converting enzyme (ACE) inhibition with lisinopril, angiotensin II receptor blockade with losartan or vasodilation with sodium nitroprusside have similar effects on intra-arterial mean blood pressure, heart rate and splanchnic nerve activity. RESULTS: A bolus dose of lisinopril or losartan (both 10 mg/kg, intravenously) induced within 2 h an equal reduction in mean blood pressure, whereas sodium nitroprusside infused during the same period (at 10 micrograms/min) lowered mean blood pressure, but less strongly. The heart rate was accelerated significantly more during sodium nitroprusside infusion than during lisinopril or losartan treatment. Splanchnic nerve activity increased significantly only in those rats given sodium nitroprusside. No change in the parameters studied was observed in vehicle-treated rats. The doses of lisinopril and losartan were repeated after 12 and 24 h. Before administration of the last dose, the mean blood pressure was still low. Administration of lisinopril or losartan again 24 h after the initial dose had no further effect on the mean blood pressure, heart rate or splanchnic nerve activity. CONCLUSION: These results obtained in rats with a renin-dependent form of hypertension show that blockade of the renin-angiotensin system for 24 h produces an equivalent blood pressure reduction irrespective of whether it is due to ACE inhibition or angiotensin II antagonism. The results also indicate that there is less reflex activation of sympathetic nerve activity when blood pressure is lowered with a blocker of the renin-angiotensin system rather than with a direct vasodilator such as sodium nitroprusside.

Angiotensin I↗
PubMed1995

[Physiopathology of left ventricular hypertrophy].

Left ventricular hypertrophy (LVH) is an early complication of hypertension. To a certain degree, this process counteracts the parietal stress induced by high blood pressure. Genetic factors, obesity, high salt diet and different growth factors, notably angiotensin II and noradrenaline, can also predispose to hypertrophic cardiomyopathy. Left ventricular mass is increased on echocardiography in about 20% of hypertensive subjects. LVH is initially associated with a change in myocardial diastolic function and later with abnormal systolic function. It is a major risk factor, a cause of cardiac failure, reduction in coronary reserve and of ventricular arrhythmias. Treatment of hypertension is associated with regression of LVH and preservation or improvement in myocardial diastolic and systolic functions. The decrease in left ventricular mass could reduce the incidence of cardiovascular complications in hypertension.

Electrocardiography↗
PubMed1995

Renal haemodynamic and protective effects of calcium antagonists in hypertension.

In recent years, the ability of the various antihypertensive drugs to provide renal protection has been the subject of increased attention. Whether calcium antagonists prevent or reduce the rate of progression of renal damage is still a matter of controversy. This paper reviews the findings of recent animal and human studies on the haemodynamic and renal protective effects of calcium antagonists. These agents preferentially vasodilate afferent arterioles, leading to an increase in renal blood flow and glomerular filtration rate. These effects are more pronounced in hypertensive patients than in normotensive subjects and persist even when renal function is impaired. In animal models of chronic renal failure, calcium antagonists can reduce glomerulosclerosis. However, the mechanisms involved in their renal protective effect appear to be different from those of angiotensin converting enzyme (ACE) inhibitors as they do not reduce intraglomerular pressure. Renal failure caused by vasoconstriction related to radiocontrast agents or cyclosporine can be partly prevented by the administration of a calcium antagonist. Furthermore, in patients with renal artery stenosis, calcium antagonists reduce blood pressure with less renal blood flow impairment than ACE inhibitors. Preliminary clinical studies suggest that verapamil or diltiazem may reduce proteinuria in hypertensive diabetic patients. Whether these compounds can also retard the progression of renal failure in these patients remains to be established with larger trials.

Animals↗
PubMed1995

Endothelial function of the mesenteric arteriole and mechanical behaviour of the carotid artery in rats with insulin resistance and hypercholesterolaemia.

OBJECTIVE: To examine whether insulin resistance and hypercholesterolaemia in obese Zucker rats are associated with a modification of the mechanical behaviour of a conductance (carotid) artery and with an altered endothelium-dependent response to acetylcholine of a small resistance (mesenteric) artery. DESIGN: Male obese Zucker rats, 6-8 months old, were compared with age-matched lean heterozygous and control Zucker rats. METHODS: The mechanical behaviour of the carotid artery was examined in anaesthetized rats by simultaneously monitoring the internal diameter with an A-mode ultrasonic echo-tracking device and the intra-arterial pressure with a computerized data-acquisition system. Furthermore, histometric measurements of the carotid artery were carried out after death. The response to acetylcholine was examined in vitro with a Mulvany dual myograph on precontracted isolated segments of the third-generation mesenteric artery. RESULTS: Obese Zucker rats exhibited high plasma insulin and cholesterol levels. Blood pressure was the same in the obese and control animals. There was no hypertrophy or change in the mechanical behaviour of the carotid arterial wall. Heart weight was slightly higher in the obese rats than in the controls, but smaller in relation to body weight. The relaxation to acetylcholine was significantly attenuated in isolated small mesenteric arteries obtained from the obese strain. CONCLUSION: Hyperinsulinaemia and hypercholesterolaemia in obese Zucker rats are associated with an abnormal response to acetylcholine in the mesenteric arterioles. This metabolic state does not, however, alter the mechanical behaviour or the geometry of the carotid artery.

Acetylcholine↗
PubMed1994

Interactions between NPY and its receptor: assessment using ant-NPY antibodies.

The present data show that monoclonal antibodies (NPY02, NPY03, NPY04, NPY05) directed against 4 distinct epitopes on NPY may have different actions on NPY binding and NPY-induced cellular responses. NPY02 and NPY05 recognize the 11-24 and 32-36 amidated form of NPY, respectively. These 2 antibodies block the binding of NPY to its receptor as well as the NPY-induced inhibition of cAMP accumulation caused in SK-N-MC cells by forskolin. NPY02 and NPY05 have also an inhibitory action on NPY-induced contraction of rabbit femoral arteries. NPY03 and NPY04 are directed against the 27-34 and 1-12 part of NPY, respectively. NPY03 and NPY04 inhibit the binding of NPY only at very high concentrations and have a weak effect on cAMP response to NPY. NPY02 and NPY05 might provide useful tools to study the effect of NPY in cellular systems and organ preparations.

Amino Acid Sequence↗
PubMed1994

Differential vascular effects of neuropeptide Y(NPY) selective receptor agonists.

Neuropeptide Y (NPY) increases blood pressure either directly or indirectly by potentiating the effect of various vasoconstrictors. Only one (the Y1-receptor) of two subtypes of receptors (Y1 and Y2) is thought to mediate the vascular smooth muscle contraction. To test this hypothesis we challenged isolated rat mesenteric arteries that had a functional endothelium with (1-36) NPY and with specific Y1-receptor ([Leu31, Pro34] NPY) and Y2-receptor ([Ahx5-24, gamma-Glu2-epsilon-Lys30] NPY) agonists. The Y1-receptor agonist elicited a contractile response similar to that of NPY, whereas the Y2-receptor agonist had no effect on wall tension. We also found that the presence of a functional endothelium has no influence on the contractile response to NPY. From these data we conclude that the direct contractile effect of NPY in the mesenteric artery is mediated by stimulation of Y1-receptors and is not endothelium-dependent.

Acetylcholine↗
PubMed1994

[Increased vascular sensitivity to nitroglycerin in patients with hypercholesterolemia and peripheral endothelial dysfunction].

The effects of the endothelium-dependent vasodilator acetylcholine, the endothelium-independent vasodilator nitroglycerin and a drug which inhibits basal nitric oxide (NO) release (L-NG-monomethyl-arginine [L-NMMA]) on the diameter of the radial artery and blood flow were studied in eight patients with hypercholesterolaemia (total cholesterol: 280 +/- 9 mg/dl, age 54 +/- 3 years) and eight healthy subjects of the same age (total cholesterol 197 +/- 12 mg/dl, age 51 +/- 4 years). Arterial diameter was measured by a recently developed high resolution ultrasound technique. Increasing concentrations of acetylcholine (10(-8) to 10(-6) mol/l) produced dose-dependent increases in flow rate in the healthy subjects (maximum +150% +/- 6% at 10(-6) mol/l), but much less in the patients with hypercholesterolaemia (+24% +/- 12%). L-NMMA caused comparable reductions in forearm blood flow in both groups. Nitroglycerin increased blood flow in the hypercholesterolaemia group to a significantly greater extent (+370% +/- 69%) than in the controls (+145 +/- 62%). The effects of acetylcholine, L-NMMA and nitroglycerin on radial artery diameter did not differ significantly between the two groups. The poor response (in terms of blood flow) to acetylcholine in the hypercholesterolaemia group points to an endothelial dysfunction in the arterial microcirculation. The fact that L-NMMA caused similar reductions in forearm blood flow in the controls and hypercholesterolaemia patients alike shows that basal NO synthase activity must be comparable in the two groups and therefore cannot be held responsible for the endothelial dysfunction. This endothelial dysfunction is linked with increased responsiveness to the endothelium-independent vasodilator nitroglycerin.

Acetylcholine↗
PubMed1994

Localization of neuropeptide Y and its C-terminal flanking peptide in human renal tissue.

We produced and characterized three anti-C-flanking peptides of neuropeptide Y (CPON) monoclonal antibodies. The Ka for these antibodies ranged from 0.4 to 0.8 x 10(8) l/mol with an IC50 for CPON(1-30) at about 20 nM as determined by ELISA. All these antibodies are IgG1 and recognize the 16-30 part of CPON. These antibodies and a specific anti-NPY monoclonal antibody were used to study the localization of CPON and NPY in the human kidney. The avidin-biotin technique was employed. NPY and CPON immunoreactivities were present in large amount in the renal tubules of the human kidney but not in the glomeruli. No labeling was found within the renal arterioles and veins, but some immunoreactivity was evidenced in the perivascular area. Because no specific receptor for CPON has been described to date, the presence of this peptide in the tubules may be due to a tubular reabsorption or perhaps to a local synthesis of pro-NPY.

Adrenal Gland Neoplasms↗
PubMed1994

Reciprocal changes in vasoactive hormones in the rat myocardial infarction model of heart failure.

The purpose of this study was to determine (1) if there is a relationship between the changes in the plasma levels of atrial natriuretic peptide (ANP) and plasma renin activity (PRA) as rats compensated from 3 days to 6 weeks after coronary ligation and (2) if these changes are related to myocardial infarction (MI) size. Arterial blood was drawn twice from 34 conscious rats (control, n = 10; small MI, n = 10; large MI, n = 14). Histologic MI size correlated better with ANP 3 days (r = .72, P < .001) than with ANP 6 weeks after MI (r = .39, P = .021). The reverse was true for an electrocardiographic index of MI size that used the sum of the Q waves minus the sum of the R waves in leads I, aVL, and V5. Atrial natriuretic peptide at 3 days was increased in both MI groups and was highest in the large MI group (control, 25.6; small MI, 41.0; large MI, 58.6 pM). Atrial natriuretic peptide decreased significantly from 3 days to 6 weeks in the large MI group and normalized in the small MI group (control, 25.0; small MI, 26.4; large MI, 44.4 pM). Plasma renin activity was not elevated at either time. However, the change in ANP from 3 days to 6 weeks in the MI rats was negatively related to the change in PRA (r = .48, P = .016). Atrial natriuretic peptide levels early after MI may be a good predictor of infarct size. The pattern of ANP and PRA changing in opposite directions over time suggest a counterregulatory link between these two systems.

Animals↗
PubMed1994

Plasma kinins increase after angiotensin-converting enzyme inhibition in human subjects.

1. In patients treated with angiotensin-converting enzyme inhibitors, kinin-related effects have been postulated repeatedly, but information on changes in plasma kinin levels in these patients is sparse. Difficulties in the measurement of plasma kinins account for this, at least in part. 2. The main purpose of the present study was to investigate, in normal human subjects, the effect of the angiotensin-converting enzyme inhibitor quinapril on plasma kinins. 3. High-affinity antisera (Kd < 10(-11) mol/l) of C-terminal specificity were raised in rabbits for radioimmunoassay of immunoreactive kinins activating the bradykinin B2-receptor, and three different liquid- and solid-phase extraction methods for plasma kinins were evaluated. Ethanol and subsequent petroleum ether extraction of 5-40 fmol of bradykinin added to plasma yielded recoveries of 39 +/- 16% (mean +/- SD); normal kinin levels in human plasma were 18.6 +/- 3.3 pmol/l (mean +/- SEM). Solid-phase extraction on urea-equilibrated phenylsilylsilica produced recoveries of 89 +/- 5% and normal values of 36.4 +/- 18 pmol/l. Finally, with an assay based on ethanol extraction alone, recoveries of 100 +/- 16% and normal values of 16.8 +/- 5.8 pmol/l were obtained, with a detection limit of 1.5 fmol/ml of plasma. Blanks were below the detection limit. Serial dilution of plasma extracts (n = 4) provided linear kinin concentrations (r = 0.99). For two different plasma pools, coefficients of variation for within-assay precision were 16.7% and 21.7%, respectively. Between-assay coefficients of variation were 12.8% and 17.4%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗