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It is the same thing as waving the American flag in a poorly constructed play.(Hurston 1990a: 24)

Detection of cytomegalovirus (CMV) antigenemia was compared with shell vial centrifugation cultures for rapid detection of CMV infection. In a prospective study, 59 CMV seropositive patients were monitored weekly during the first 100 days after allogeneic marrow transplantation for virus excretion from urine, throat, and blood and for antigenemia by direct staining of peripheral leukocytes using an antibody pool directed against pp 65. Antigenemia was present in 21 of 22 patients with culture-proven CMV infection and in 3 of 37 without culture-proven CMV infection (sensitivity 95%, specificity 91%). The median time of onset of antigenemia and shell vial cultures was day 47 and 55 after transplant, respectively (P = .0006). Among patients who developed CMV disease without preceding cultures, antigenemia was detected in all patients with CMV pneumonia (N = 6) and in two of three patients with gastrointestinal disease by a median of 10 and 7 days, respectively, before the onset of disease (P = .0002). Levels of antigenemia were significantly higher in patients with disease or viremia than in patients with excretion from urine or throat (P less than .05). Whether the antigenemia assay is more sensitive than rapid culture methods to focus antiviral prophylaxis in marrow transplant patients must be determined in controlled studies.

Previous studies of risk factors for acute graft-versus-host disease (GVHD) involved patients receiving predominantly single-agent prophylaxis. Therefore, a retrospective analysis was performed on 446 patients, from a single institution, who received transplants of marrow from HLA-identical siblings and the combination of cyclosporine (CSP) and methotrexate (MTX) to determine risk factors for acute GVHD associated with this more effective form of GVHD prophylaxis. The incidences of Grades II-IV and Grades III-IV (severe) acute GVHD were 35% and 16%, respectively. Increased clinical grades of acute GVHD in patients without advanced malignant disease were associated with a decreased survival. In a multivariate Cox regression analysis, risk factors associated with the onset of Grades II-IV acute GVHD were sex mismatch and donor parity (P = .001), increased dose of total body irradiation (TBI) (P = .001), and reduction to less than 80% of the scheduled dose of MTX (P = .02) or CSP (P = .02). The multivariate analysis indicated a relative risk of 1.37 for acute GVHD in a group defined as having advanced malignant disease at transplant; however, this difference failed to reach conventional levels of statistical significance (P = .07). Reduction of MTX and CSP occurred in up to 36% and 44% of patients, respectively, primarily because of renal or hepatic dysfunction. The periods of increased risk for the onset of acute GVHD were up to 1 week after a reduction of MTX and 2 weeks after a reduction in CSP. When only patients who developed Grades II-IV acute GVHD were considered, the more severe acute GVHD of Grades III-IV was associated with increased patient age of 40 years or greater (P = .05) and dose reductions of CSP (P = .008). Serologic status of patient and donor for cytomegalovirus (CMV), HLA antigens in the A and B loci, and isolation in a laminar air flow room during marrow transplantation, all previously identified as risk factors for acute GVHD, were not confirmed as risk factors in this study population. The toxicity of MTX and CSP and the development of acute GVHD from inadequate immunosuppression because of dose reduction warrants further trials with potentially less toxic immunosuppressive agents. Risk factors for acute GVHD should be considered in clinical management and in the design of clinical trials.

We investigated the possibility that selective blockade of postjunctional a-adrenergic receptors results in an enhanced antihypertensive response relative to that observed with a-adrenergic antagonists, which are less selective and thus block both pre- and postjunctional a-receptors. The antihypertensive efficacy of prazosin (a selective postjunctional antagonist) was compared with that of phenoxybenzamine (a less selective postjunctional antagonist) in a double-blind, placebo-control, randomized, crossover study in 11 patients with essential hypertension. Both drugs produced similar significant reductions in standing mean arterial pressure (MAP) from 124 ± 3 to 104 ± 5 mm Hg (p< 0.001) and 122 ± 3 to 109 ± 7 mm Hg (p< 0.025), respectively, after four weeks of therapy. However, the increments in plasma norepinephrine (PNE) concentration associated with these falls in MAP from 622 ± 90 to 1,025 ± 100 pg/ml (p< 0.01) and from 554 ± 80 to 1,029 ± 168 pg/ml (p< 0.01), respectively, were not significantly different for the two drugs. Heart rate also increased significantly, although the increase after prazosin was not sustained. In contrast to the responses in the standing position, only prazosin produced a significant fall in supine MAP from 118 ± 3 to 107 ± 3 mm Hg (p< 0.001) and an increase in PNE concentration from 283 ± 39 to 415 ± 50 pg/ml (p< 0.05). Heart rate increased marginally after prazosin and remained unchanged with phenoxybenzamine therapy. Thus prazosin is a more effective antihypertensive agent than phenoxybenzamine. However, the present study suggests that the enhanced antihypertensive efficacy of prazosin is not due to its selectivity for the postjunctional a-adrenergic receptor.

Over the past two decades the incidence of stroke and myocardial infarction in hypertensive populations has decreased, yet the incidence of end-stage renal disease attributed to hypertension has increased. This apparent paradox has raised questions about the adequacy of blood pressure control in hypertensive patients with renal disease. Chronic renal failure is commonly associated with hypertension, and is often severe and difficult to control, particularly in patients with hypertensive nephrosclerosis. The optimal level of blood pressure control in these patients has not been established. Long-term diastolic blood pressure control to a level lower than 90 mm Hg is associated with stable or improving renal function in hypertensive nephrosclerosis and with slowing of the deterioration in renal function from other causes of renal failure. Moreover, recent studies indicate that when blood pressure control is achieved and maintained at a level of about 130/86 mm Hg (systolic/diastolic), deterioration in renal function can be halted even in black patients with hypertensive nephrosclerosis. Therefore, in hypertensive nephrosclerosis we attempt to control diastolic blood pressure at 80 to 85 mm Hg. Newer antihypertensive agents such as calcium channel blockers and angiotensin-converting enzyme inhibitors contribute to lowering blood pressure and preserving renal function. However, they have yet to be proven superior to conventional agents in double-blind randomized clinical trials in humans with hypertensive nephrosclerosis. Importantly, minoxidil is still relied on for aggressive control of blood pressure in many patients with hypertensive nephrosclerosis.

AbstractObjective:To investigate compliance with isolation precautions.Design:A prospective observational study carried out during ten weeks of 1989. Participants were unaware of the study.Setting:The isolation bay of a 24-bed surgical intensive care unit in a 900-bed university tertiary care facility.Participants:Study participants included any healthcare worker or visitor entering the patient room during designated 15-minute intervals.Results:We observed 467 subjects entering patient rooms. Compliance with strict isolation (65%) was better than with wound/skin (40%) or excretion/secretion (36%) isolation (p<.01). Visitors were more compliant than healthcare workers (88% versus 41%; p<.01). Spending more time in the room was associated with improved compliance (p<.01). Compliance was higher for subjects entering with a group compared with those entering alone (51% versus 41%; p<.05). The compliance rate for nurses improved as the nurse/patient ratio improved (p= .14). Compliance was independent of severity of illness. Multivariate analysis revealed that the amount of time spent in the room, being a visitor, and use of strict isolation were independent predictors of compliance.Conclusions:Noncompliance was wide-spread. When increased demands are placed on the time of physicians and nurses in the name of cost containment, unperceived consequences, such as those resulting from decreased compliance, must be considered.

Since substance P is a potent natriuretic, diuretic, and vaso-dilatory peptide, a radioimmunoassay for substance P was developed, and its levels measured in the plasma of normal subjects and patients with essential hypertension. The plasma substance P levels were 186±14 pg/ml in normal subjects and 164±3 pg/ml in hypertensive patients. When the sodium content of their diet was reduced to 10 mEq/day, substance P levels failed to change, but plasma renin activity and urinary kallikrein increased. An acute saline infusion also failed to alter plasma substance P levels. Assuming an upright posture increased plasma renin activity, but not substance P, in both groups of subjects. Thus, it appears that substance P is not involved in the control of blood pressure, kallikrein excretion or renin release in man.

Using the restriction endonuclease, Bgl I, Samani et al. found a restriction fragment length polymorphism (RFLP) for the renin gene in spontaneously hypertensive rats (SHR) and its normotensive control Wistar-Kyoto (WKY) rats (1). This RFLP was confirmed in our laboratory in SHR and WKY rats using a rat renin cDNA probe. The correlation of blood pressure and the renin RFLP was examined in 106 F2 rats produced from F1 rats, the offspring of a cross between SHR males and WKY females. Systolic blood pressure was measured by the tail cuff method at 12 weeks of age. Mean arterial blood pressure of anesthetized rats was measured by cannulation of the femoral artery prior to sacrifice. The frequency of ranin genotype showed a typical 1:2:1 Mendelian ratio in F2 rats of SHR and WKY cross. The mean arterial blood pressure of F2 rats homozygous with the SHR allele was significantly higher than F2 rats that were heterozygous or homozygous for the WKY allele. No significant difference in systolic blood pressure was observed in F2 rats with different genotypes. Thus, the renin gene RFLP cosegregates with an increase in mean arterial blood pressure in the F2 rats of SHR and WKY cross.

Second harmonic generation (SHG) generation was employed to study adsorption of sulfate at the Au(111) electrode surface. The experiments were carried out using both pp and ss polarisations for the input and output photons. The amplitudes of the isotropic, one-fold and three-fold symmetry elements of the electrode susceptibility were determined. The isotropic term is a complex number. Its real part displays this same linear dependence on the electrode charge density in the absence and presence of adsorbed sulfate. The phase angle of the complex number is also not changed by sulfate adsorption. These features indicate that adsorbed sulfate changes the static electric field at the interface, however it does not affect the electronic structure of the metal. The one-fold symmetry amplitude changes with potential. This change displays lifting of the surface reconstruction. We observed similar effect of sulfate on the structure of the electrode surface to that reported earlier by Magnussen et al. [Faraday Discuss. 94 (1992) 329].

We examined the funetional significance of the presynaptic alphaadrenergic receptor, inhibitory to stimulus-induced norepinephrine release. The effects of prazosin and phentolamine. alpha-adrenergic receptor antagonists with different in vitroselectivities for the presynaptic alpha-receptor. on mean arterial pressure and serum renin activity were determined in the conscious rat. Both drugs resulted in dose-related reductions in mean arterial pressure and dose-related increases in heart rate and serum renin activity. However, consistent with the greater selectivity of prazosin for the postsynaptic alpha-receptor, a given reduction in arterial pressure was associated with a lesser increment in heart rate and serum renin activity after prazosin than after the nonselective agent phentolamine. The differential effects of these agents on heart rate and serum renin activity are consistent with different degrees of blockade of a functionally significant presynaptic alpha-receptor.

The effects of centrally administered autonomic drugs and hypertonic saline on renin release were studied in the conscious rat. A 0.3 μg intraventricular dose of isoproterenol, which is one-thirtieth of the intraperitoneal dose required to stimulate renin release, induced the release of renin into the systemic circulation. Norepinephrine had no effect on renin release in the same dose range. Hypertonic saline and carbachol suppressed renin release. Alterations in renin release were preceded by a reciprocal change in blood pressure. These results suggest a central nervous system site for sodium, beta-adrenergic, and cholinergic receptors in altering renin release and blood pressure.

The dose-dependent selectivity of an irreversible binding antagonist, phenoxybenzamine (POB), for renal alpha-1 adrenoceptors, was biochemically and physiologically characterized. Receptors were quantified with the radioligands [3H]prazosin and [3H]rauwolscine for alpha-1 and alpha-2 adrenoceptors, respectively. Alpha-1 adrenoceptor function was quantified by the shift of the norepinephrine and phenylephrine pressor response in vivo and the vasoconstrictor response in the isolated perfused kidney preparation. A renal alpha-2 adrenoceptor response was demonstrated by showing that epinephrine could reverse the effect of vasopressin on water and sodium in the presence of beta blockade and alpha-1 destruction by POB. Doses of POB from 0.1 to 10.0 mg/kg progressively reduced [3H]prazosin binding to renal alpha-1 adrenoceptors until there was no specific binding at the 10.0-mg/kg dose. At this dose more than 60% of [3H]rauwolscine binding to renal alpha-2 adrenoceptors was still present. POB 1.0 mg/kg/hr decreased specific binding to renal alpha-1 adrenoceptors by approximately 40% (P less than .05) but reduced the alpha-1 adrenoceptor-induced vasoconstriction in the nonrecirculating isolated perfused kidney to 10 to 20% of the control. This was the maximal dose of POB studied which did not affect the alpha-2 adrenoceptor-induced antagonism of vasopressin. Higher doses of POB (3.0 mg/kg/hr) demonstrated some alpha-2 adrenoceptor binding as indicated by an attenuation of the antagonism by alpha-2 adrenoceptors. Thus, POB displays selectivity for renal alpha-1 over alpha-2 adrenoceptors. Our data indicate that a dose of 1.0 mg/kg/hr of POB will leave alpha-2 adrenoceptors intact while functionally incapacitating alpha-1 adrenoceptors to 10 to 20% of the control value.

We investigated physiological interactions between alpha2-adrenoceptors and parathyroid hormone (PTH) in the isolated buffer-perfused kidney. PTH infusion (10nM) caused a rapid and significant rise in cAMP excretion which diminished despite continued hormone infusion. PTH also caused a delayed phosphaturia which peaked 20-30 minutes following the start of PTH infusion. alpha2-Adrenoceptor stimulation with epinephrine (28nM) diminished PTH-stimulated cAMP accumulation by 68-71% (p < 0.05) but had no effect on PTH-induced phosphaturia. None of the experimental interventions affected renal hemodynamics. In additional studies, we used lithium (1mM) as a marker of proximal tubular sodium transport. PTH caused a rapid rise in lithium excretion which was temporally distinct (maximum response in 0-10 minutes) from the phosphaturia. alpha2-Adrenoceptor stimulation completely blocked the inhibitory effect of PTH on lithium reabsorption. These results suggest that alpha2-adrenoceptors regulate the stimulatory effect of PTH at proximal tubular adenylate cyclase. However, alpha2-adrenoceptors play no role in phosphate transport in this segment. alpha2-Adrenocep-tor stimulation reverses PTH-induced lithium excretion, suggesting physiological antagonism in the proximal tubule, most likely involving Na/H exchange.

We investigated the effect of captopril on plasma norepinephrine concentration and blood pressure in two groups of hypertensive patients. One group consisted of five severely hypertensive patients rendered hypernoradrenergic by administration of a minoxidil-propranolol-diuretic regimen. The other group was ten untreated mildly hypertensive patients.Two hours after 12.5mg of captopril, blood pressure was lowered (p<.05) in four of the five hypernoradrenergic patients from 180±8/102±8 to 132±7/77±8 mmHg. Chronic administration of 100-150mg of captopril tid caused no further blood pressure reduction.Precaptopril plasma norepinephrine concentration was 925±206 and two hours after the 12.5mg dose was 807±80 pg/ml. Three months later having advanced the dose to 300-450 mg/day it was lower (p<.05) at 752 pg/ml. The acute blood pressure response correlated (r=-0.72, p<.001) with the precaptopril plasma norepinephrine.Precaptopril blood pressure in the mild hypertensive patients was 146±4/98±1, after a 25-100mg dose it was 137±6/91±2 (diastolic p<.05) and at two months with the same captopril dose bid it was 141±8/88±4 mmHg (diastolic p<.01). Corresponding initial PNE was 425±72, two hours after captopril 405±47 and 310±63 pg/ml (p<.05) with chronic administration.Thus, captopril lowers blood pressure in both hypernoradrenergic and eunoradrenergic hypertensive patients without increasing plasma norepinephrine suggesting some unique dampening effect of this drug on the sympathetic nervous system. Also, addition of captopril to triple therapy lowered blood pressure in proportion to plasma norepinephrine levels suggesting importance to its action on this sympathetic nervous system effector.

Dahl sodium-sensitive and resistant rats were fed low and high sodium diets. Renal plasma membrane α2-adrenergic receptor concentrations were greater (p<.05) in sensitive than in resistant rats while ingesting a low sodium diet. On a high sodium diet the α2 receptor concentration increased (p<.01) in sensitive but not in resistant rats. Since α2 receptors are located in proximal tubules at sites where nor-epinephrine induces sodium reabsorption, we postulate that this genetically determined abnormal receptor regulation could lead to exaggerated sodium retention and possibly high blood pressure.

A unique nuclease is released by Fusarium solani f. spp. pisi and phaseoli macroconidia during germination on pea pod endocarp tissue. This Fsp nuclease is produced in greater amounts by macroconidia germinating on pea pods than in Vogel's rich medium or in water. We have characterized the enzymatic activities, and physical properties of this enzyme. Fsp nuclease makes randomly situated single stranded nicks in single- or double-stranded DNA, leaving a 5' phosphate group and a 3' hydroxyl group on the nicked DNA strand. This nicking activity is stimulated by divalent cations over a range of 2 10 mM, with Mn²⁺ > Ca²⁺ > Co²⁺ > Mg²⁺. Zinc inhibited the nuclease, even in the presence of stimulatory divalent cations. Fsp nuclease is susceptible to treatment with proteinase K or SDS, indicating a proteinaceous identity, but surprisingly, is resistant to boiling. A 22 kDa molecular weight was estimated by renaturing the enzyme following denaturing electrophoresis. The possible role of this nuclease in virulence is being investigated. Copyright 1993, 1999 Academic Press

1. Six healthy men performed static and dynamic handgrip to local muscular fatigue in approximately 6 min under control conditions, i.e. without drugs and after combined para-sympathetic and β-adrenergic blockade with atropine and metoprolol. 2. From rest to exercise at fatigue, systolic, diastolic and mean arterial pressures increased by 32 ± 4 and 39 ± 3 mmHg, 24 ± 3 and 26 ± 4 mmHg, and 26 ± 3 and 30 ± 3 mmHg respectively for static and dynamic handgrip. There were no significant differences between the pressor responses for the two modes of contraction. Cardiac output increased significantly only during dynamic exercise. Total peripheral resistance increased by 2.3 ± 1.0 units for static handgrip (P < 0.05) and by 0.7 ± 0.8 unit (P > 0.05) for dynamic handgrip. Autonomic blockade abolished the heart rate response to both static and dynamic handgrip. For both modes of contraction the systolic arterial pressure responses were 9–12 mmHg lower (P < 0.05) after autonomic blockade, but the diastolic and mean pressure responses were not significantly affected. A significant increase in cardiac output persisted during dynamic exercise. The increase in peripheral resistance during static exercise tended to be greater after blockade. Plasma noradrenaline and adrenaline levels showed only minor elevations in response to static and dynamic handgrip and were not changed by autonomic blockade. 3. These data indicate that when performed to a common end-point with identical small muscle groups static and dynamic exercise produce an equally large pressor response, which is only slightly attenuated by autonomic blockade.

Our subjects were seven severely hypertensive patients with blood pressures (BPs) over 140/90 who were using minoxidil, propranolol, and diuretics. Clonidine followed by prazosin was added to their regimen on an outpatient basis to establish the dose-response for BP and catecholamines. Plasma renin activity (PRA), body weight, and renal function were measured. Clonidine was given in doses of 0.2, 0.4, 0.6, and 0.8 mg/day. Supine and standing systolic BP decreased at all dose levels of clonidine (P < 0.01, P < 0.05). Diastolic BP decreased in the standing position with doses of 0.4, 0.6, and 0.8 mg (P < 0.01, P < 0.05). Subjects were hypernoradrenergic initially with plasma norepinephrine (PNE) 895 ± 122 pg/ml. PNE was suppressed by 0.2 to 0.8 mg clonidine (P < 0.01) with near maximal suppression at 0.4 mg daily. Systolic BP correlated with PNE (r = 0.59, P < 0.001). Supine and standing PRA decreased after 0.2 mg clonidine (P < 0.05) but not after higher doses. Our findings suggest the antihypertensive action of clonidine is related to PNE suppression but not to that of PRA. Plasma epinephrine (PE), body weight, and renal function did not change. Prazosin was given after clonidine to the same patients in a dose range of 3 to 40 mg/day. With doses of 6 to 40 mg, systolic and diastolic and supine and standing BP fell (P < 0.001, P < 0.01). PNE remained elevated throughout all dose levels and did not correlate with BP. Weight rose with prazosin (P < 0.02) but PE, PRA, and renal function did not change. Hence, clonidine and prazosin induced additional lowering of BP but had different effects on PNE and weight.

AbstractThe antiaggregative pheromone 3-methyl-2-cyclohexen-1-one (MCH) of the Douglas-fir beetle (Dendroctonus pseudotsugaeHopk.) was diffused at three rates and three spacings around attractive felled trees. Optimum treatment was ca. 1–2 mg/day at 10-ft spacing (0.06–1.3 g/acre per day), which reduced Douglas-fir beetle attacks and progeny by 96% and 91%, respectively. Progeny in trees exposed to higher than optimum MCH concentration were less mature, but not significantly fewer than progeny in controls. Densities of immature stages of nine other taxa of insects, both entomophagous and commensal, were determined. Abundance of larvae of the predacious clerids Enoclerus sphegeusFab. and Thanasimus undatulusSay was significantly correlated with abundance of Douglas-fir beetle attacks and progeny. The predator Temnochila chlorodia(Mann.) and the associate Pseudohylesinus nebulosus(Lee.) were more dense on samples in the test area where Douglas-fir beetle population and damage were lowest. Density of the dipterous predator Medetera aldrichii(Wheeler) was correlated with numbers of beetle entrances, but decreased at high MCH concentrations. Abundance of Coeloides brunneriVier., a braconid parasite, was correlated with numbers of beetle brood. Presence of MCH appeared to increase abundance of the associate Pissodes fasciatusLec. and modify its distribution in trees. Use of methylcyclohexenone for preventing infestation of susceptible trees is a potential control strategy, but a more practical and effective formulation must be developed.

alpha 1-Adrenoceptors are expressed in high density in the rat kidney. Recent studies have shown that alpha 1-adrenoceptors are heterogeneous and can be subtyped based on their affinity for the antagonists WB 4101 (alpha 1A greater than alpha 1B) and chloroethylclonidine (alpha 1B-selective). We therefore investigated the distribution of alpha 1-adrenoceptor subtypes using [3H]prazosin binding in membranes prepared from cortex, the outer stripe of the outer medulla (OSOM), the inner stripe of the outer medulla (ISOM) and inner medulla dissected from rat kidney. [3H]Prazosin binding was detectable in each region with the following maximum binding site values for [3H]prazosin (femtomoles per milligram of protein): cortex, 186 +/- 20; OSOM, 76 +/- 14; ISOM, 34 +/- 2; and inner medulla, 8 +/- 2. Pretreatment of membranes with chloroethylclonidine (10 microM for 10 min) reduced maximum binding sites to 41 +/- 4% (75 +/- 9 fmol/mg) of control in cortex, 41 +/- 9% of control in OSOM (29 +/- 8 fmol/mg) and 15 +/- 3% of control in ISOM (5 +/- 1 fmol/mg). In competition studies, WB 4101 labeled both high and low affinity sites in cortex (respective pKi values = 10.01 +/- 0.3 and 8.23 +/- 0.1) and OSOM (pKi values = 9.6 + 0.3 and 8.3 +/- 0.5), but only low affinity sites in ISOM (pKi = 8.41 +/- 0.1). The relative prevalence of high:low affinity sites revealed by WB 4101 was 53:47 for cortex, 52:48 for OSOM and virtually all low affinity for ISOM. Prior treatment with chloroethylclonidine greatly reduced the low affinity component of the WB 4101 competition curve in cortex and OSOM. We conclude that: 1) the density of alpha 1-adrenoceptors is highest in the cortex and decreases from cortex to papilla and 2) the alpha 1A and alpha 1B subtypes are approximately equally distributed in the cortex and OSOM, but the alpha 1B subtype predominates in ISOM.

The vasodilatory drugs, minoxidil and hydralazine, induce renin release in the rat, man and the dog. Previous reports suggest that the rat adrenal cortex was insensitive to angiotensin stimulation. As a result these studies were designed to obtain evidence for or against the hypothesis that the control of aldosterone release in the rat is unique among mammalian species. Minoxidil and hydralazine induced a time-related increase in both serum renin activity and serum aldosterone. Minoxidil caused a dose-related, proportional increase in serum renin and aldosterone. This response was blocked by prior bilateral nephrectomy but was not affected by hypophysectomy. A competitive angiotensin antagonist, saralasin (1-Sar-8-Ala angiotensin II), impaired minoxidil-induced aldosterone release in a dose-related manner while potentiating minoxidil-induced renin release. Pretreatment with propranolol, a beta adrenergic blocking drug, impaired minoxidil-induced renin and aldosterone release. Only small changes in serum corticosterone occurred after minoxidil or hydralazine administration. These results indicate that minoxidil-induced aldosterone release was mediated by the endogenous angiotensin II formed from renin release. They also support the unanesthetized rat as an appropriate animal model for study of the renin-angiotensin-aldosterone axis and its modification by drugs.

Des-Asp angiotensin II (des-Asp AII) is a naturally occurring heptapeptide metabolite of angiotensin II (AII) which is formed by the enzymatic action of aminopeptidase A. Angiotensin II and des-Asp AII were infused into unanesthetized rats while direct mean arterial pressure, serum aldosterone and serum corticosterone were measured. Both AII and des-Asp AII caused a dose-related increase in serum aldosterone with a significant increase occurring with a dose as low as 1 ng/min. This effect was blocked by pretreatment with 1-Sar-8-Ala-angiotensin II, a competitive inhibitor of AII; however, the inhibitor was more effective in blocking the effects of AII (101%) than of des-Asp AII (82%). Both angiotensins induced a dose-related increase in serum corticosterone and mean arterial pressure. Des-Asp AII was however only 1/10 as potent as AII in elevating mean arterial pressure. 1-Sar-8-Ala-AII was also effective in inhibiting the pressor effects of AII and des-Asp AII. These data illustrate a high degree of organ specificity or selectivity for des-Asp AII and a low specificity for AII. Aminopeptidase A and leucine aminopeptidase were identified in the adrenal cortex and medulla in large amounts. Des-Asp AII may thus be formed from AII locally in the adrenal gland prior to exerting its action at that site.

[3H]Dihydroergocryptine, a nonselective alpha adrenergic antagonist, the alpha-1 selective antagonist, [3H]prazosin and the alpha-2 selective antagonist, [3H]yohimbine, were used to study binding sites in rat renal membranes. To establish a correlation between binding and a biological function, the ability of alpha adrenergic agents to stimulate or inhibit vasoconstriction was quantified in vitro using an isolated perfused kidney preparation. Binding with each radioligand was rapid, saturable and specific. Moreover, the order of potencies of a variety of adrenergic agents, determined by competitive inhibition studies, suggested that the binding of each radioligand was to sites with alpha adrenergic specificity. The total number of binding sites in these rat renal membranes. determined with [3H]dihydroergocryptine (Bmax, 212 fmol/mg of protein; KD, 12.8 nM) was approximately equal to the sum of binding site concentrations determined with the alpha-1 and alpha-2 selective radioligands (Bmax, 57 and 170 fmol/mg of protein; KD, 0.85 and 20 nM, respectively). However, the alpha receptor mediating renal arteriolar vasoconstriction appeared to be of the alpha-1 subtype as there was a close correlation between the in vitro results and the binding data determined with [3H]prazosin (r = 0.93). In addition, in both the functional and [3H]prazosin binding studies, unlabeled prazosin ws 5 to 40-fold more potent than the nonselective antagonist, phentolamine, and 400- to 1500-fold more potent than the alpha-2 antagonist, yohimbine. These studies suggest that rat renal plasma membranes contain binding sites with both alpha-1 and alpha-2 adrenergic receptor specificity, in a ratio of approximately 1:3. Despite the preponderance of alpha-2 receptors, the alpha receptor mediating renal vasoconstriction appears to be of the alpha-1 type.

A new infrared laser Doppler blood flow instrument (Moor MBF3D) was evaluated using an in vitro model allowing measurements over a range of flow velocities and concentrations. The responses correlated well (r = 0·96, p < 0·01) with those obtained simultaneously using a Perimed PF3 laser Doppler instrument. The different processing bandwidths of the instruments were investigated and the wideband mode of operation is recommended for flow measurements where there may be fast moving red blood cells (rbcs). The infrared instrument is capable of dual-channel operation, and the two channels are shown to respond almost identically for similar changes in blood flow through the in vitro model (r = 0·999, p < 0·01). The main advantage of the dual-channel instrument is that continuous measurements may be made simultaneously at two different skin sites allowing dynamic flow responses to be compared.

This paper reports the results of a preliminary in vivo investigation in which laser Doppler blood-flow measurements were made in a variety of tissues in the anaesthetized rat using a twin wavelength laser Doppler system. The aim was to assess whether there was any detectable difference in the depth response of the laser Doppler system to blood-flow in skin, muscle and brain tissue using red light (633 nm) from a He - Ne laser source and near infrared (NIR) light (780 nm) from a semiconductor diode laser source. The results show that under normalized conditions, the flow signals obtained from the near infrared laser Doppler system is consistently larger than that recorded from the red He - Ne laser Doppler system. This suggests that laser Doppler flowmetry systems based on NIR laser sources sample larger volumes of tissue than those based on red He - Ne lasers.

Twenty-nine hypertensive patients refractory to conventional medications were treated continuously with minoxidil, sympathetic suppressants, and diuretics for six months to five years (mean, 30 months). All had evidence of hypertensive end-organ damage before minoxidil therapy. Good blood pressure control was obtained in 21 (72%) of 29 patients when minoxidil was given in dosages up to 40 mg/day. No tolerance was found. In the remaining eight, good control was obtained in three when phenoxybenzamine therapy was added, and in one when clonidine therapy was added. Renal failure requiring hemodialysis developed in five of 29, one had temporary hemiparesis, and one had fatal cerebral hemorrhage. In the remainder, myocardial infarctions and strokes were effectively prevented. Patients receiving minoxidil and propranolol hydrochloride had elevated plasma norepinephrine levels while those receiving clonidine had normal plasma norepinephrine levels.(JAMA 239:2131-2138, 1978)

Using the restriction endonuclease, Bgl I, Samani et al. found a restriction fragment length polymorphism (RFLP) for the renin gene in spontaneously hypertensive rats (SHR) and its normotensive control Wistar-Kyoto (WKY) rats (1). This RFLP was confirmed in our laboratory in SHR and WKY rats using a rat renin cDNA probe. The correlation of blood pressure and the renin RFLP was examined in 106 F2rats produced from F1 rats, the offspring of a cross between SHR males and WKY females. Systolic blood pressure was measured by the tail cuff method at 12 weeks of age. Mean arterial blood pressure of anesthetized rats was measured by cannuiation of the fomoral artery prior to sacrifice. The frequency of renin genotype showed a typical 1:2:1 Mendelian ratio in F2 rats of SHR and WKY cross. The mean arterial blood pressure of F2 rats homozygous with the SHR allele was significantly higher than F2 rats that were heterozygous or homozygous for the WKY allele. No significant difference in systolic blood pressure was observed in these F2 rats. Thus, the renin gene RFLP cosegregates with an increase in mean arterial blood pressure in the F2 rats of SHR and WKY cross.

We studied 11 previously refractory hypertensive subjects who were treated with minoxidil, propranolol, and diuretics for 2–7 years. During this time 70 random blood samples were collected in the supine position and analyzed for plasma norepinephrine (PNE) and plasma renin activity (PRA). The mean PNE was 546 pg/ml (normal mean ± SE, 173 ± 10) and was reciprocally related to log PRA. To determine if this elevated PNE would respond to clonidine, 5 of the patients were admitted to the General Clinical Research Center for administration of placebo and later of clonidine (0.1 or 0.2 mg). A single dose of clonidine suppressed PNE (p < 0.01) and lowered mean blood pressure (p < 0.02) for 12 hr. The PRA was not altered significantly by clonidine. Thus, high PNE in these treated patients can be suppressed by clonidine, and this suppression of PNE and blood pressure occurs without alteration of PRA.

FK-506 was evaluated either alone or combined with methotrexate (MTX) for prevention of graft-versus-host disease (GVHD) in dogs given 9.2 Gy total body irradiation and dog leukocyte antigen-nonidentical unrelated marrow grafts. Studies with marrow autografts showed gut toxicity and weight loss to be major side effects of FK-506. There was no hematopoietic toxicity with FK-506. In an initial allograft study, 5 dogs were given FK-506 intramuscularly at 0.3 mg/kg/day from days 0 to 8 and then orally at 0.5 mg/kg/day. All 5 died, 3 with intussusception most likely due to FK-506 toxicity, 1 with graft failure, and 1 with GVHD. Subsequently, the FK-506 dose was reduced and these drug schedules were used: FK-506 days 0–8 at 0.15 mg/kg/day i.m. and then orally at 0.5 mg/kg/day until day 90, with or without MTX intravenously at 0.4 mg/kg days 1, 3, 6, and 11. Twenty allografts were done, 10 with FK-506 alone, and 10 with MTX/FK-506. Results were compared with those in concurrent and historical controls given either no immunosuppression (n=64), MTX (n=114), CsA (n=15), or MTX/CsA (n=17). Five of 20 current dogs died with intussusception, too early to be evaluated for GVHD. The 10 dogs given FK-506 alone survived significantly better than those not given immunosuppression but not differently from those given short-term MTX or CsA alone. Three died from toxicity, 2 with graft failure, and 4 with GVHD. Only 1 dog became a long-term survivor, and this dog inadvertently received a single dose of MTX on day 7. Two of 10 dogs given MTX/FK-506 died from toxicity, 1 died with graft failure, 2 died with GVHD, and 5 became long-term survivors, a result that is significantly better than seen with either drug alone and similar to that seen with MTX/CsA. Four of the 5 survivors had no clinical GVHD. FK-506 blood levels were 15–35 ng/ml between days 8 and 15, when gut toxicity was most severe. Thereafter, levels were approximately 5 ng/ml. In conclusion, FK-506 prolonged survival of recipients of dog leukocyte antigen-nonidentical unrelated marrow grafts. When FK-506 was combined with MTX, graft-host tolerance was induced in 50 of dogs, even though FK-506 was stopped on day 90.

Six patients receiving minoxidil, propranolol, and diuretics had clonidine added in increasing dosage. Five patients received 0.2–0.8 mg/day clonidine and one patient 0.2–0.6 mg. Plasma catecholamines, renin activity, blood pressure, and serum creatinine were measured at each dose level. The patients had a hypernoradrenergic state prior to clonidine X± SE plasma norepinephrine (PNE), 924 ± 141 pg/ml]. Administration of clonidine, 0.2–0.8 mg/day, lowered supine PNE (p< 0.01, p< 0.02), and clonidine, 0.4–0.8 mg/day, lowered standing PNE (p< 0.01, p< 0.02). Maximal suppression of PNE occurred with 0.4 mg/day. Systolic blood pressure correlated with supine PNE (r= 0.55, p< 0.05) at 0.2–0.8 mg/day clonidine, and standing PNE correlated (r= 0.72, p< 0.01) at 0.2–0.6 mg/day. Plasma epinephrine concentration, plasma renin activity (PRA), and serum creatinine did not show any significant change. PRA did not correlate with blood pressure changes. Plasma clonidine concentration correlated reciprocally with the change in PNE (r= −0.59, p< 0.01). These findings indicate that clonidine can return elevated PNE to normal levels in the vasodilator β-blocker-treated patient and thus remove this abnormality as a contributing factor to pathogenetic mechanisms.

Thermodynamic analysis of charge density data was performed to describe sulfate adsorption at the Au(111) surface. The Gibbs excess, the Gibbs energy of adsorption, the number of electrons flowing to the interface per one adsorbed sulfate ion and the Esin-Markov coefficients were determined. The thermodynamic data indicate that sulfate adsorption at the Au(111) electrode has an ionic character and is driven by the interaction of the ion with its image charge on the metal. The surface dipole formed by the ion and its image is heavily screened by the metal and surface solvent molecules. The ionic character of sulfate adsorption at the Au(111) electrode is consistent with the results of independent second harmonic generation experiments. The second harmonic generation data indicate that adsorption of sulfate affects little the electronic structure of the metal surface.

We collected first-voided urine specimens from 659 males attending a sexually transmitted disease clinic and performed both enzyme immunoassay (EIA) for detection of chlamydial antigen and leukocyte esterase testing on these urine samples. The overall prevalence of chlamydial urethritis in the study population as determined by culture of urethral swabs was 11%. However, 46% of all men in the study had no symptoms of urethritis. Compared with urethral cultures for chlamydiae, the urine EIA had a sensitivity of 42% and a specificity of 99%. The sensitivity of the EIA strongly correlated with the amount of antigen present in culture as assessed by numbers of inclusion-forming units. The sensitivity of the leukocyte esterase test compared with that of chlamydia culture was 88%. We conclude that in this population of men, which included many patients without symptoms of urethritis, the urine EIA was a relatively insensitive means of screening for chlamydial infection.

A radioimmunoassay for the new angiotensin antagonist, saralasin (1‐Sar‐8‐Ala‐angiotensin II), was developed and applied to pharmacologic studies in rats and hypertensive man. Specificity of the assay was established using naturally occurring angiotensins, potential saralasin metabolites, and other synthetic angiotensin analogues. Saralasin pharmacologic half‐life of 3.9 min after intravenous administration to rats was similar to the biochemical half‐life of 4.2 min. The pharmacologic half‐life in high‐renin hypertensive patients averaged 8.2 with a biochemical half‐life of 3.2 min. These observations suggest that metabolites of saralasin do not accumulate in sufficient quantity in man or rat to interfere with the assay. The biochemical half‐life of 3.2 min is consistent with infusion time of less than 20 min required to achieve a stable plasma concentration and pharmacologic activity of saralasin during constant saralasin infusion into hypertensive man. These studies provide a rational basis of future experimental design for saralasin and possibly other peptide analogues.

Medical certification to return to work after coronary bypass surgery in occupations that carry a risk to public safety is controversial, particularly for airline pilots. To address this issue, 10,312 patients from the CASS registry who underwent coronary bypass surgery were studied and 2,326 men with clinical and postoperative characteristics similar to those of the average airline pilot who might apply to renew his license after surgery were selected.

(S)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide (ZD6169) is a novel ATP-sensitive potassium channel opener. Bladder activity and selectivity after oral dosing were studied in conscious, normotensive rats and dogs by monitoring cystometric and cardiovascular (CV) parameters. The reference ATP-sensitive K+ channel opener cromakalim was also evaluated in this study. ZD6169 significantly reduced micturition frequency in rats (ED50 = 0.16 mg/kg), but its effect on CV parameters was minimal (ED20 = 30 mg/kg), yielding a selectivity dose ratio of 187. The duration of action was between 7 and 24 hr at doses of 0.3 and 3 mg/kg, but it was more than 24 hr at 10 mg/kg. The ED50 value for bladder activity in dogs was less than 1.0 mg/kg, and the ED20 value for CV activity was slightly greater than 15 mg/kg but less than 20 mg/kg; the selectivity ratio was greater than 15. A significant improvement in bladder compliance was noted in dogs with ZD6169, and the bladder activity in rats was blocked by i.v. glibenclamide (3 mg/kg). Cromakalim had a bladder profile similar to that of ZD6169 but appeared to be more selective for CV parameters. In conclusion, ZENECA ZD6169 is a unique ATP-sensitive K+ channel opener with in vivo selectivity of relaxing bladder smooth muscle. This agent has the potential for treating patients with urge incontinence.

Catecholamines possessing alpha adrenergic receptor agonist properties induce lightening or reverse melanocyte stimulating hormone darkening of frog skin in vitro. The capacity to activate this alpha receptor by the methyldopa metabolites methyldopamine and methylnorepinephrine was compared with the capacity of the naturally occurring dopa metabolites, dopamine and norepinephrine. Melanocyte stimulating hormone-induced darkening or dispersion of the granules was reversed by each of these metabolites. Methylnorepinephrine was 10 times as potent as norepinephrine, and methyldopamine was 30- to 100-fold more potent than the naturally occurring dopamine. These inhibitory effects on melanocyte stimulating hormone could be blocked or partially impaired using the alpha adrenergic blocker, phentolamine. They were not affected by pretreatment of frogs with the monoamine oxidase inhibitor pheniprazine (Catron) nor by the application of pheniprazine, angiotensin or serotonin in vitro. This neuroendocrine model has alpha adrenergic receptor relationships analogous to those described in the central nervous system for methyldopa metabolites.

Model calculations are presented that yield in a straightforward manner the quantitative dependence of the specific adsorption of ions at electrode surfaces on the applied electrode potential (electrode charge). Furthermore, the double-layer capacitance and the potential at the outer Helmholtz plane (ø2) are obtained. The derivation is based on Devanathan's three-capacitor model for the interfacial electric-potential distribution. A convenient correction function for the ø1potential accounting for the discreteness-of-charge effect is derived, largely on the basis of recent work by Conway et al. The results are shown to be in very good agreement with published work by Lawrence and Parsons on the double layer between Br−electrolyte and the mercury electrode. Keywords: electrochemistry, specific adsorption, electric double layer, discreteness-of-charge effect.

In situ electromodulated reflectance Fourier transform infrared (FTIR) spectroscopy has been employed to study the adsorption of 4-cyanopyridine (4-CNPy) at an Au(111) electrode surface. The vibrational spectra have been used to study (i) the dependence of the band intensity on the surface coverage, (ii) the character of surface coordination, and (iii) the stability of adsorbed 4-CNPy molecules. It has been observed that the vibrational bands in the spectra acquired in the electroreflection experiment are significantly broader than the corresponding spectra acquired in a transmission cell. Some weaker bands seen in the spectra recorded in transmission were not observed in the electroreflectance experiment. The electroreflectance spectra were dominated by the two ring deformation bands observed at 1416 cm−1and 1554 cm−1. The intensities of these bands correlated well with the surface concentrations of 4-CNPy molecules determined from independent electrochemical studies. The integrated absorption intensities of the bands recorded in the electroreflection experiments were larger by a factor of five than the absorption intensities measured in the transmission cell. This indicates that the electric field of the photon acting on a molecule, present in front of the gold electrode, is significantly enhanced by reflection from the electrode. The infrared experiments suggest that at positive potentials the 4-CNPy molecules are coordinated to the metal surface through the nitrogen atom of the aromatic ring. The 4-CNPy molecules are oxidized at the Au electrode at potentials higher than 0.6 V (SCE) and are reduced to form (4-CNPy)−•ion at potentials lower than −1.1 V (SCE). Keywords: adsorption, infrared spectroscopy, 4-cyanopyridine, gold electrode.

The electrochemical interface between Ag(111) single crystal and NaF + NaOH electrolytes at various pH values has been studied using cyclic voltammetry and in situ Raman spectroscopy. Submonolayer oxidation starts well below bulk silver oxide formation at potential about −0.6 V vs. Hg|HgO electrode at pH 11. Two potential-dependent Raman bands ν1at 540 to 560 cm−1and ν2at 803 to 819 cm−1in basic NaF electrolytes are attributed to Ag—OH stretching and AgO—H bending vibrations of electrochemisorbed hydroxide species. Strong isotope effect is observed in D2O solutions, ν2being shifted to values of 550 to 570 cm−1. Fluoride stabilizes the adsorption of hydroxide species. A multistep scheme is proposed that describes the mechanism of formation of hydroxide/oxide species at the considered silver-electrode surface.