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Biomedical subjects

S Gunther

Publications and source records attributed to S Gunther.

At least 19 recordsLinked to original sources
PubMed1993

Effect of oral captopril on premature ventricular complexes in patients with preserved left ventricular systolic function: a randomized clinical trial.

Some studies have suggested that angiotensin-converting enzyme (ACE) inhibition in patients with heart failure is associated with a decrease in frequency of spontaneous premature ventricular complexes (PVCs). It is not clear whether such a finding represents a primary effect of ACE inhibition or, instead, a secondary result of treatment of heart failure. For a primary drug effect to be present, PVC suppression during ACE inhibition should also occur in patients with preserved left ventricular systolic function. We therefore undertook a randomized double-blind placebo-controlled crossover clinical trial to assess the effect of oral captopril (50 mg. b.i.d.) on ventricular arrhythmia frequency in 11 patients with > 30 PVCs/h (during a 48-h ambulatory recording) and a left ventricular ejection fraction of > or = 45% (measured by radionuclide multigated acquisition scan). Pharmacologic activity of the administered drug was evidenced by an increase in median plasma renin activity to 2.4 ng/AI/ml/h from a value of 1.1 ng/AI/ml/h during placebo (p = 0.001) and an 8.5 +/- 10.3 drop in mean diastolic blood pressure during captopril versus placebo (p < 0.03). During captopril treatment, a mean of 491 +/- 378 PVCs/h were observed compared with 389 +/- 169 PVCs/h during placebo, a nonsignificant difference. There was also no significant change in left ventricular ejection fraction, plasma catecholamines, or serum potassium during captopril treatment. Thus, ACE inhibition in patients with preserved left ventricular systolic function fails to suppress ventricular ectopic activity. Extrapolated to patients with heart failure, our observations argue against a primary PVC suppressive action of ACE inhibitors but do not rule out possible secondary antiarrhythmic effects of these agents.

Administration, Oral↗
PubMed1992

Augmented norepinephrine and renin output in response to maximal exercise in hypertensive coarctectomy patients.

To evaluate a possible neural or renal contribution to the hypertension that occurs in some patients following coarctation of aorta repair, 35 patients underwent graded bicycle exercise with serial measurements of plasma norepinephrine concentrations and plasma renin activity. Sixteen patients with coarctectomy who had systolic or diastolic hypertension at peak exercise were compared with 19 normotensive patients with coarctectomy. The average time interval between coarctation repair and study was significantly longer (p less than 0.05) in the hypertensive group than in the normotensive patients (12.8 +/- 4.8 versus 8.7 +/- 2.2 years). The heart rate response to exercise was similar for both patient groups. The systolic blood pressure in the hypertensive group was higher than in the normotensive group at rest in the supine and upright positions and at 5 minutes of recovery, in addition to peak exercise, and the diastolic blood pressure was increased at peak exercise. Plasma norepinephrine concentrations were significantly higher at peak exercise and during recovery in the hypertensive group than in the normotensive patients. Plasma renin activity was also significantly higher in the hypertensive group at peak exercise. These data suggest that patients with coarctectomy who have a hypertensive response to exercise have an augmented sympathetic nervous system output and increased plasma renin activity that may lead to peripheral vasoconstriction at peak exercise and that may contribute to the development of their hypertension.

Adolescent↗
PubMed1991

A microcomputer-based device to simulate biomechanical environments for cultured cells.

We describe software and hardware for a microcomputer-based cyclic strain device which applies programmed cycles of elongation and relaxation to cultured cells. This system has the potential to simulate many of the complex mechanically active environments found in living systems. As a sample application, we use it to simulate the cyclic stresses to which vascular smooth muscle cells in the arterial system are exposed.

Arteries↗
PubMed1990

The role of adenosine in HgCl2-induced acute renal failure in rats.

It has been proposed that adenosine mediates the renal hemodynamic changes in acute renal failure (ARF) and that these changes are pathogenic in reducing glomerular filtration rate. Consistently, adenosine-receptor antagonists such as theophylline have been shown to have protective effects in several experimental models of ARF. The present experiments were designed to explore the potential role of adenosine in HgCl2-induced ARF in rats. In isolated perfused rat kidneys, HgCl2 increased adenosine production and induced a concentration-dependent vasoconstriction. However, the vasoconstriction was unrelated to adenosine production and was not antagonized by theophylline. During the initiation phase of HgCl2-induced ARF in intact rats (first 4 h after injection), theophylline failed to reverse the reduction in inulin clearance, and this failure could not be attributed to a loss of vascular responsiveness to adenosine, since N6-cyclohexyladenosine, a receptor agonist, produced a further reduction in inulin clearance. Furthermore, theophylline actually had deleterious effects during the maintenance phase of HgCl2-induced ARF in intact unanesthetized rats, as evidenced by higher mean serum creatinine values in theophylline-injected rather than in saline-injected rats, on both the second and third days after HgCl2 injection. Therefore HgCl2 acutely increases renal adenosine production, but increased adenosine does not mediate acute HgCl2-induced renal vasoconstriction, and adenosine-receptor antagonism does not have protective effects during the initiation or the maintenance phases of HgCl2-induced ARF in rats. These results provide no support for the hypothesis that increased adenosine mediates the hemodynamic changes in HgCl2-induced ARF.

Acute Kidney Injury↗
PubMed1984

Characterization of angiotensin II receptor subtypes in rat liver.

Radioligand binding studies identified two classes of 125I-angiotensin II-binding sites in rat liver membranes. High affinity binding sites (Kd = 0.35 +/- 0.13 nM, N = 372 +/- 69 fmol/mg of protein) were inactivated by dithiothreitol (0.1-10 mM) without any apparent change in low affinity binding sites (Kd = 3.1 +/- 0.8 nM, N = 658 +/- 112 fmol/mg of protein). Dithiothreitol inactivation was readily reversible but could be made permanent by alkylation of membrane proteins with iodoacetamide. Angiotensin II stimulation of glycogen phosphorylase in isolated rat hepatocytes (maximal stimulation 780%, EC50 = 0.4 nM) was completely inhibited by 10 mM dithiothreitol, a concentration which also abolished high affinity site binding; phosphorylase stimulation by glucagon and norepinephrine under these conditions was unaltered. Angiotensin II inhibition of glucagon-stimulated adenylate cyclase activity in hepatocytes required higher angiotensin II concentrations (EC50 = 3 nM) than phosphorylase stimulation and was not affected by dithiothreitol. Fractional occupancy of high affinity binding sites by 125I-angiotensin II correlated closely with angiotensin II-mediated phosphorylase stimulation, whereas occupancy of low affinity sites paralleled inhibition of adenylate cyclase activity. These data indicate that the physiologic effects of angiotensin II in rat liver are mediated by two distinct receptors, apparently not interconvertible, and provide the first evidence for angiotensin II receptor subtypes with differing biochemical features and mechanisms of action.

Adenylyl Cyclases↗
PubMed1982

Functional angiotensin II receptors in cultured vascular smooth muscle cells.

To study cellular mechanisms influencing vascular reactivity, vascular smooth muscle cells (VSMC) were obtained by enzymatic dissociation of the rat mesenteric artery, a highly reactive, resistance-type blood vessel, and established in primary culture. Cellular binding sites for the vasoconstrictor hormone angiotensin II (AII) were identified and characterized using the radioligand 125I-angiotensin II. Freshly isolated VSMC, and VSMC maintained in primary culture for up to 3 wk, exhibited rapid, saturable, and specific 125I-AII binding similar to that seen with homogenates of the intact rat mesenteric artery. In 7-d primary cultures, Scatchard analysis indicated a single class of high-affinity binding sites with an equilibrium dissociation constant (Kd) of 2.8 +/- 0.2 nM and a total binding capacity of 81.5 +/- 5.0 fmol/mg protein (equivalent to 4.5 x 10(4) sites per cell). Angiotensin analogues and antagonists inhibited 125I-AII binding to cultured VSMC in a potency series similar to that observed for the vascular AII receptor in vivo. Nanomolar concentrations of native AII elicited a rapid, reversible, contractile response, in a variable proportion of cells, that was inhibited by pretreatment with the competitive antagonist Sar1,Ile8-AII. Transmission electron microscopy showed an apparent loss of thick (12-18 nm Diam) myofilaments and increased synthetic activity, but these manifestations of phenotypic modulation were not correlated with loss of 125I-AII binding sites or hormonal responsiveness. Primary cultures of enzymatically dissociated rat mesenteric artery VSMC thus may provide a useful in vitro system to study cellular mechanisms involved in receptor activation-response coupling, receptor regulation, and the maintenance of differentiation in vascular smooth muscle.

Angiotensin II↗
PubMed1981

Coronary vasoconstrictor effect of indomethacin in patients with coronary-artery disease.

Prostaglandins may be important regulators of coronary blood flow. To investigate this possibility, we studied the effect of blockade of prostaglandin synthesis by indomethacin in nine patients with coronary-artery disease. Coronary-sinus blood flow (determined with the thermodilution technique) was recorded, together with mean arterial blood pressure and the myocardial arteriovenous oxygen difference from simultaneously obtained arterial and coronary-sinus blood samples, before and 20 minutes after an intravenous dose of indomethacin (0.5 mg per kilogram of body weight). There were significant increases (P less than 0.05) in mean arterial pressure (from 99 +/- 4 to 118 +/- 5 mm Hg [+/- S.E.M.]), coronary vascular resistance (+73 per cent), and myocardial arteriovenous oxygen difference (from 107 +/- 5 to 138 +/- 4 ml per liter) after indomethacin, but coronary blood flow fell significantly, from 181 +/- 29 to 111 +/- 14 ml per minute (P less than 0.05). Thus, despite an increase in myocardial oxygen demand, coronary blood flow fell and coronary vascular resistance increased. This coronary vasoconstrictor effect may have been due to blockade of vasodilatory prostaglandin synthesis or to a direct drug effect. Whatever the mechanism, indomethacin should be used with caution in patients with severe coronary-artery disease.

Blood Pressure↗
PubMed1981

Therapy of coronary vasoconstriction in patients with coronary artery disease.

Patients with obstructive coronary artery disease and stable, exertional angina respond to the alpha adrenergic stimulus of the cold pressor test with an inappropriate increase in coronary vascular resistance. The clinical significance of this abnormal response and its possible role in the pathogenesis of ischemic heart disease are discussed. Comparison of the anti-anginal agents currently in use of undergoing investigation suggests that the calcium antagonists may be the most effective therapy for coronary vasoconstriction. Nifedipine, 10 mg buccally, successfully prevented the increase in coronary vascular resistance during the cold pressor test in 10 of 10 patients, whereas the response in placebo-treated patients was unaltered. This dose of nifedipine was without effect on systemic hemodynamics or myocardial oxygen consumption, suggesting a selective antivasoconstrictor effect on the coronary vasculature.

Angina Pectoris↗
PubMed1981

Prevention of nifedipine of abnormal coronary vasoconstriction in patients with coronary artery disease.

The hemodynamic and myocardial metabolic responses to the cold pressor test were studied in 15 patients with coronary artery disease and stable exertional angina. Every patient had abnormal coronary vasoconstriction during a control cold pressor test, even though 14 were receiving propranolol and 12 were receiving long acting nitrates. Mean coronary vascular resistance for the group increased 18 +/- 6% (SD) (from 0.80 +/- 0.12 to 0.94 +/- 0.20 mm Hg/ml/min, p less than 0.05); coronary sinus blood was unchanged, and the arterial-coronary sinus oxygen difference widened significantly (from 11.5 +/- 1.2 to 12.3 +/- 1.2 ml/100 ml, p less than 0.05). Four patients developed angina, accompanied in each instance by a negative arterial-coronary sinus lactate difference. After the administration of nifedipine (10 mg buccally) in 10 patients, the coronary vascular responses to a repeat cold pressor test were normal in each patient. Mean coronary sinus blood flow increased 27 +/- 12% (from 122 +/- 32 to 153 +/- 35 ml/min, p less than 0.05), coronary vascular resistance decreased 10 +/- 6% (from 0.85 +/- 0.16 to 0.76 +/- 0.16 mm Hg/ml/min, p less than 0.05), and the arterial-coronary sinus oxygen difference was unchanged. No patient experienced angina. The hemodynamic and coronary vascular responses to a repeat cold pressor test in five patients given placebo were unaltered from control responses. The protective effects of nifedipine were unaccompanied by any change in mean arterial pressure, left ventricular filling pressure or myocardial oxygen consumption either at rest or in response to the cold pressor test. Nifedipine appears to exert a selective antivasoconstrictor effect on the coronary vasculature.

Adult↗
PubMed1980

Regulation by angiotensin II of its receptors in resistance blood vessels.

The sensitivity of blood vessels to the vasoconstrictor effects of the hormone angiotensin II appears to be modulated by the activity of the renin-angiotensin system. Elevation of circulating angiotensin II levels by sodium depletion or renal artery stenosis is associated with a diminished pressor response to infused angiotensin II (refs 1-3). Conversely, the vasocontrictor response to the hormone is enhanced when endogenous angiotensin II levels are reduced by sodium loading or nephrectomy. The mechanisms of these varying effects are not known, but physiological and pharmacological experiments suggest involvement of the vascular smooth receptor for angiotensin II (refs 5-8). Modification of the interaction between angiotensin II and its vascular receptor, resulting in altered responsiveness to the hormone, could occur either via 'prior occupancy' of receptors by elevated levels of endogenous angiotensin II resulting in fewer free receptors available to respond to circulating angiotensin II (ref. 5), or, elevated levels of angiotensin II could result in a decrease in receptor affinity for the hormone or a decrease in total receptor number in the vascular smooth muscle cell. We now report the first direct evidence, by radioligand binding assay, that angiotensin II regulates the number of its own receptors in resistance vasculature.

Angiotensin II↗
PubMed1980

Beneficial effects of intravenous glyceryl trinitrate in a case of Prinzmetal angina.

A case is described of the successful use of intravenous glyceryl trinitrate in controlling ischaemia-induced high-grade ventricular ectopic activity occurring in a patient during a Prinzmetal angina attack. The intravenous form of glyceryl trinitrate is probably more effective than the sublingual form in controlling arrhythmias arising during acute ischaemic episodes because of prompt delivery of the drug to the coronary circulation where vasodilation occurs. In addition,the ability to control the quantity and rate of drug delivery with an intravenous infusion offers distinct advantages in cases of coronary spasm occurring during situations such as coronary arteriography where it can be administered with careful electrocardiographic and haemodynamic monitoring.

Angina Pectoris↗
PubMed1979

Inappropriate coronary vasoconstriction in patients with coronary artery disease: a role for nifedipine?

Coronary arterial vasoconstriction, well recognized in Prinzmetal's variant angina, may participate in the pathogenesis of classic angina as well. Several recent studies in patients with obstructive coronary artery disease suggest that apparently spontaneous reductions in coronary blood flow can result in myocardial ischemia and even infarction. Evidence supporting the alpha adrenergic nervous system as a cause of such coronary vasoconstriction is reviewed, particularly the results of provocative testing with the cold pressor stimulus. Upon exposure of the skin to cold, patients with coronary artery disease demonstrate an inappropriate coronary vasoconstrictor response, often sufficient to produce angina. Normal patients, by contrast, show no change in coronary vascular resistance. In patients with a diseases coronary circulation, inappropriate vasoconstriction further restricts myocardial perfusion and appears to be little affected by beta adrenergic blocking agents or nitrates in the usual dosages. Nifedipine has proved effective in preventing coronary arterial spasm in patients with Prinzmetal's angina. Studies currently in progress suggest that it is also effective in blocking inappropriate coronary vasoconstriction in patients with typical angina. Nifedipine may thus be a useful addition to the treatment of ischemic heart disease.

Angina Pectoris, Variant↗
PubMed1979

Myocardial contractile function in aortic stenosis as determined from the rate of stress development during isovolumic systole.

To assess myocardial contractile function in the chronically hypertrophied human left ventricle, the rate of stress development (dsigma/dt) as a function of developed stress (sigmaD) during isovolumic systole was examined. Results for eight patients with aortic stenosis were compared with those for seven subjects with normal left ventricular function and with those for five patients with idiopathic congestive cardiomyopathy. The rate of stress development (dsigma/dt) was nearly identical in patients with aortic stenosis and in normal subjects over a wide range of values of sigmaD but was significantly lower in patients with cardiomyopathy (P less than 0.01 versus control subjects and patients with aortic stenosis). Normal values for dsigma/dt held not only for patients with compensated pressure overload, but also for those patients with aortic stenosis with depressed left ventricular ejection fraction and overt congestive failure. Similar findings were obtained when the first derivative of left ventricular pressure (dP/dt) was examined as a function of developed left ventricular pressure in normal subjects and patients with aortic stenosis or cardiomyopathy. These results indicate that contractile function as characterized by the isovolumic rate of stress development is not necessarily impaired in chronic pressure overload hypertrophy.

Adult↗