Intestinal transport of water and electrolytes during extracellular volume expansion in dogs.

The effects of extracellular fluid volume expansion on intestinal transport of salts and water were studied in dogs by perfusing loops of bowel in vivo. Saline loading caused depression of duodenal and jejunal absorption with net secretion of salt and water into the lumen. Studies of unidirectional transport of (22)Na(+) revealed that the negative net sodium flux was due primarily, and perhaps exclusively, to increased serosal to mucosal transport, for mucosal to serosal sodium transport was not changed during volume expansion. Net transport of water and potassium paralleled net sodium flux. Administration of deoxycorticosterone did not affect the intestinal response to saline loading. Hemodilution, accomplished by equilibrating the dogs' blood with a reservoir of saline, did not affect intestinal absorption, but isotonic, iso-oncotic expansion of the extracellular fluid produced by reinfusing the saline-blood mixture from the reservoir resulted in negative net transport of water, sodium, and potassium by the duodenum. It is suggested that the small bowel is capable of secreting salts and water through intercellular spaces, and that this process is stimulated by extracellular fluid volume expansion.

Amiloride stimulation of sodium transport in the presence of calcium and a divalent cation chelator.

Amiloride in nM to microM concentrations stimulates the short circuit current (Isc) of the toad urinary bladder by as much as 120% when applied in conjunction with apical Ca2+ and a divalent cation chelator. A significant decrease in transepithelial resistance (Rt) is observed simultaneously. This response is spontaneously reversible and its amplitude is dependent upon apical sodium concentrations. The stimulated Isc persisted when acetazolamide (1 mM) was introduced, HPO2-4 substituted for HCO-3 or SO2-4 replaced Cl-. Consequently, the increase in Isc is not due to the change of Cl-, H+ or HCO-3 flux. This behavior in a 'tight' epithelium may be related to the mechanism controlling apical sodium permeability.

Catecholamine stimulation of ion transport in the toad urinary bladder.

We have observed that serosal catecholamines increase the amplitude of the short-circuit current (Isc) in the toad urinary bladder by as much as 450%. Chemical sympathectomy with 10(-6) M 6-hydroxydopamine and the sympathomimetic effects of 10(-5) M tyramine indicate a reservoir of amines in the serosal stroma of the tissue. The urinary epithelium from the toad responds to six adrenoceptor agonists: (-)-epinephrine, (-)-norepinephrine, (-)-phenylephrine, clonidine, methoxamine and oxymetazoline. The alpha 2-adrenoceptor agonist clonidine is most potent for stimulating Isc. Some agonists were found to diminish Isc. Apparently this is related to a simultaneous increase in the transepithelial flux of both chloride and sodium. The Isc response to the catecholamines is also inhibited by several adrenoceptor antagonists. The alpha 2-adrenoceptor antagonist yohimbine is more effective than the alpha 1-antagonist prazosin for blocking the stimulation of epithelial transport. As a result of these studies, we have tentatively classified the serosal adrenoceptor of the toad urinary bladder as alpha 2.

Norepinephrine stimulation of sodium transport in Necturus urinary bladder.

Norepinephrine alters the transepithelial electrical properties of an open-circuited urinary bladder from the mud puppy, Necturus maculosus. When 10(-5) M norepinephrine is superfused over the serosa of the epithelium, the transepithelial voltage (Vt) and short-circuit current (Isc) increase as the resistance (Rt) decreases. The norepinephrine-mediated changes are reversed by the addition of amiloride (5.10(-5) M) to the mucosal Ringer's solution. The serosal adrenoceptors mediating the Na+ transport are more sensitive to norepinephrine (EC50 = 1.2.10(-6) M) than to epinephrine or isoproterenol. Since the Isc is blocked selectively by the antagonist, phenoxybenzamine, stimulation of active transepithelial Na(+)-flux by catecholamines is mediated by an alpha-adrenoceptor. The apical cell membrane voltage (Va) and fractional resistance (fRa) were recorded using conventional KCl-filled microelectrodes. Untreated tissues have Va close to 0 mV while the basolateral membrane voltage (Vb) is between -85 and -95 mV. About 90% of Rt is apical cell membrane resistance (fRa). When amiloride inhibits sodium transport, Va becomes negative, Vb hyperpolarizes slightly and fRa increases to 97%. On the other hand, if the bladders are treated with norepinephrine, fRa decreases to 79% as Va becomes positive and Vb depolarizes. When Rt changes, the resistance of the paracellular pathway (Rp) is unaltered. Changes in the electrical properties of the tissue appear to be mediated primarily by alterations in Ra. Since the Necturus bladder does not respond to antidiuretic hormone, this study implies that biogenic amines regulate Na+ transport in the epithelium.

Unidirectional absorption of gentamicin from the peritoneum during continuous ambulatory peritoneal dialysis.

Gentamicin kinetics were determined after intravenous or intraperitoneal injection in five patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Our objective was to determine rate of absorption of gentamicin from the peritoneum into the systemic circulation and vice versa. After intraperitoneal instillation of 1 mg/kg in the CAPD fluid during a 6-hr dwell time, the antibiotic appeared in the serum within 15 min in four of five patients. Peak serum concentrations ranged between 1.6 and 7.2 mg/l(mean +/- SD = 3.52 +/- 2.22) in all five patients and the time to reach peak concentration was 3.8 +/- 1.5 hr. Peritoneal gentamicin clearance was 13 ml/min. Percent extraction of gentamicin from the PD fluid within the 6 hr of intraperitoneal exposure ranged from 65% to 100% (mean +/- SD = 86.8 +/- 13.2). The fraction of the intraperitoneal dose absorbed into systemic circulation was found to be 0.84 independently by calculating the ratio of AUCip and AUCiv. When the same dose of gentamicin was injected intravenously (1 mg/kg), no gentamicin could be detected in the peritoneal fluid in three of five patients and only a very small amount of the drug was present for a brief period of time in the remaining two. The kinetic parameters of intravenous gentamicin were: volume of distribution, 0.3 l/kg; elimination rate constant, 0.028 hr(-1), plasma clearance 0.009 l/kg . min(-1), and half-life 27.4 hr. In two patients with acute peritonitis treated with intraperitoneal gentamicin, peak serum concentrations were found to range between 3.5 and 4.5 mg/l. These data suggest that gentamicin is rapidly absorbed from the peritoneal fluid into the blood compartment, but that occurrence of the reverse exchange is negligible. Thus, CAPD would not be expected to alter the elimination characteristics of intravenous gentamicin. Instillation of gentamicin in CAPD fluid may allow rapid absorption to reach therapeutic serum concentrations.

Ceftizoxime elimination kinetics in continuous ambulatory peritoneal dialysis.

We investigated the kinetics of ceftizoxime, a beta-lactamase stable cephalosporin, in eight subjects undergoing continuous ambulatory peritoneal dialysis (CAPD). A single 500-mg or 1-gm dose was injected IV, or a 500-mg dose was given intraperitoneally in the CAPD fluid during a 6-hr dwell time. The ceftizoxime (500 mg) serum kinetic parameters were as follows: peak concentrations, 21 to 46 mg/l; volume of distribution, 0.27 l/kg; elimination rate constant, 0.0784 hr-1; plasma clearance, 1.66 l/kg hr-1; and t1/2, 10.2 hr. The t1/2 after 1 gm was 12 hr. Dialysate ceftizoxime concentrations rose rapidly between 0.25 and 2 hr and slowly over the next 4 hr, but only 4.04 +/- 1.8 and 7.4 +/- 2.9 mg ceftizoxime/hr was eliminated by the peritoneal route over a 6-hr dwell time after 500 mg or 1 gm IV. This represents only 4% to 5% of the dose. After intraperitoneal instillation, the antibiotic appeared in the serum within 15 min in all four subjects, and the peak serum concentrations ranged from 12 to 19.8 mg/l (mean +/- SD = 16.4 +/- 3.3) between 5 and 6 hr. Approximately 78% of ceftizoxime was absorbed from the peritoneal dialysis fluid during a single 6-hr dwell time. Rate constant for absorption, ka, was 0.3959 hr-1 and absorption t1/2 was 1.75 hr (as calculated by the residual equation). These data suggest that ceftizoxime has bidirectional exchange characteristics through the peritoneal membrane. Instillation of ceftizoxime in CAPD fluid alone may permit rapid absorption to reach therapeutic serum concentrations.

Antihypertensive effectiveness of the nifedipine gastrointestinal therapeutic system.

The results of a multicenter trial conducted in order to determine the therapeutic efficacy of the gastrointestinal therapeutic system (GITS) formulation of nifedipine in comparison with hydrochlorothiazide and placebo in the management of mild to moderate essential hypertension are presented. During a one-week wash-out phase, antihypertensive therapy was discontinued in all patients. After a three-week single-blind placebo period, eligible patients were randomly assigned in a double-blind fashion to one of three treatment groups for a one-week titration period and a nine-week efficacy period. Patients received either nifedipine GITS, 30 or 60 mg daily; hydrochlorothiazide, 25 or 50 mg daily; or placebo. Sitting and standing blood pressures decreased by an average 11.6/10.4 and 10.8/10.8 mm Hg, respectively, with nifedipine GITS therapy, and 14.8/10.8 and 14.3/8.2 mm Hg, respectively, with hydrochlorothiazide therapy. Compared with placebo, these changes were highly significant for both sitting (p less than or equal to 0.005) and standing (p less than or equal to 0.02) measurements. Heart rate remained essentially unchanged in all three groups. It was therefore concluded that monotherapy with nifedipine GITS, at doses of 30 or 60 mg given once daily, effectively reduces blood pressure in patients with hypertension to a degree comparable with that seen in hydrochlorothiazide therapy.

Ecotypic differences in responses of Arabidopsis thaliana L. to elevated polychromatic UV-A and UV-B+A radiation in the natural environment: a positive correlation between UV-B+A inhibition and growth rate.

The effects of supplementary ultraviolet-A (UV-A) and ultraviolet-B+A (UV-B+A) in the natural environment on the growth and morphology of various ecotypes of Arabidopsis thaliana were investigated. The ecotypes investigated were Columbia (Col-4), Landsberg erecta (Ler-0), Cvi-0, Wassilewskija, Enkheim-D, Aa-0 and Di-1. The mutant hy-4 was also used. Results varied with the radiation treatment, ecotype and parameter measured. Plants subjected to elevated UV-A were both insensitive (all parameters Cvi-0 and Col-4) and sensitive. When responses to UV-A occurred they were mostly inhibitory (all significant responses of Di-1 and Enkheim-D, most parameters of Wassilewskija, and some parameters of hy-4), however, promotive affects were observed for some parameters of Aa-0 and Ler-0. Supplementary UV-B+A inhibited all parameters of Di-1 and Enkheim-D and most parameters of Col-4, Ler-0 and hy-4, but Wassilewskija, Aa-0 and Cvi-0 were mostly insensitive. The magnitude of the UV-B+A response varied with ecotype (compare Di-1 with Ler-0). Some ecotypes were sensitive to UV-A but not UV-B+A (Aa-0), whereas others (Ler-0, Col-4) show the opposite sensitivities. A linear relationship is reported between the degree of UV-B+A inhibition of each ecotype and growth rate. The higher the growth rate the more susceptible the ecotype is to UV-B+A inhibition. This relationship holds for the majority of growth parameters measured.

Diagnosis, localization, and treatment of primary aldosteronism.

PA should be suspected in any hypertensive patient with evidence of renin suppression and should be confirmed by demonstration of inappropriate and excessive aldosterone production. Preoperative differentiation of unilateral and bilateral forms of the syndrome should be pursued to identify those patients most likely to benefit from surgical intervention. In patients with apparent bilateral disease, specific medical therapy should be pursued.

Prediction of response to biofeedback-assisted relaxation in hypertensives: development of a Hypertensive Predictor Profile (HYPP).

A group of hypertensive patients who participated in a biofeedback-assisted relaxation program were divided into treatment successes and treatment failures based on the change in their blood pressure. Multiple regression analysis was used to characterize the successes and failures and to develop a hypertensive predictor profile. Hypertensives most likely to lower their blood pressure with biofeedback-assisted relaxation are those in whom there is evidence of autonomic overactivity, for example, cool hands, high heart rates, and evidence of a chronic response to stress, such as high anxiety scores and high normal cortisol levels.

Response of toad urinary bladder to vasopressin analogs possessing V1 or V2 specificity.

The urinary bladder of the toad Bufo marinus has been used to examine the effect on sodium transport, measured by short-circuit current, of natural antidiuretic hormones and several synthetic peptide analogs. In mammals, these synthetic analogs show specificity for different receptors, designated V1 and V2 receptors, whose biological responses are mediated by phosphatidyl inositol breakdown products or adenylate cyclase activity, respectively. All analogs stimulated SCC, with relative potencies AVT greater than AVP greater than Phe2 OVT (V1 agonist) much greater than d(CH2)5Tyr(Me)AVP (V1 antagonist) = d(CH2)5[D-Ile2,Abu4]AVP (V2 antagonist). The V1 and V2 antagonists inhibited the SCC response to AVT and Phe2OVT, with similar inhibitory potencies. We conclude that the stimulation of sodium transport by antidiuretic hormones involves one hormone receptor which does not show the selectivity of mammalian antidiuretic hormone receptors, and may represent a more primitive type of receptor.

Effect of repeated measurements of blood pressure on blood pressure in essential hypertension: role of anxiety.

Over the past years, we repeatedly observed that of the hypertensive population entered into our behavioral treatment programs, more than half were actually false hypertensives. With repeated measurements of blood pressure (BP), only one-third remained hypertensive, while two-thirds showed a significant decrease in BP. The purpose of this study was to determine which factors correlate with the decrease in BP and could be useful in distinguishing the true and the false hypertensives. Of the 24 patients in this study, 15 decreased their mean arterial pressure by at least 5 mm Hg during a 6-week period of home and clinic BP measurement, while 9 did not. The 9 patients with BPs that did not change had lower State Anxiety, Trait Anxiety scores, lower diastolic BP, and lower heart rates compared to the group whose BPs decreased. These results suggest that under certain conditions a relationship exists between anxiety and elevated blood pressure. In a segment of the hypertensive population, anxious patients may be placed on inappropriate antihypertensive medication if a BP measurement period is not conducted before intervention.

Quantitative relationship of renal glucose and sodium reabsorption during ECF expansion.

To investigate the quantitative relationship between glucose and sodium reabsorption during extracellular fluid (ECF) expansion and to examine the possible contribution to glucosuria of passive diffusion of glucose from peritubular blood to tubular fluid, renal clearance studies were carried out in dogs. It was found that ECF expansion with isotonic saline or Ringer solution causes a decrease in the maximal rate of glucose reabsorption (TmGlc), which is inversely and linearly related to fractional sodium excretion (FENa) over a range from less than 1% more than 25% FENa (r equals -0.394, P less than 0.001). A continuous relationship between TmGlc and FENa could be demonstrated as the ECF was expanded in individual animals as well as in pooled data. Infusion of albumin solution to preferentially expand the plasma volume and decrease proximal tubular sodium reabsorption produced a 24% fall in TmGlc suggesting that the proximal tubule is the site of interrelated glucose and sodium reabsorption. After pulse injections into the renal artery, [14-C]glucose and insulin had the same appearance time in the urine, thus failing to demonstrate diffusion of glucose from blood into the tubule in saline-loaded dogs as well as in dogs in normal sodium balance. It is suggested that ECF expansion exerts its effect on glucose reabsorption by inhibiting the coupled transport of glucose and sodium across the epithelium of the renal proximal tubule.

Interaction of biofeedback-assisted relaxation and diuretic in treatment of essential hypertension.

Thirty patients with essential hypertension participated in a study designed to compare two treatments: diuretic medication alone (n = 10) and biofeedback assisted relaxation combined with diuretic (n = 20). One of 10 patients lowered BP with diuretic alone and 11 of 20 patients lowered BP with diuretic combined with biofeedback-assisted relaxation. The addition of the behavioral intervention to the diuretic therapy produced a decrease in blood pressure beyond that associated with the diuretic alone. The decrease in BP mediated by diuretic were related to high entry levels of BP, low anxiety, forehead muscle tension, anger expression and plasma renin activity. The BP decrease mediated by combined diuretic and biofeedback-assisted relaxation was associated with high pretreatment BP, anger controlled, low finger temperature and high/normal plasma renin activity.

Electrical properties of amphibian urinary bladder epithelia. I. Inverse relationship between potential difference and resistance in tightly mounted preparations.

In an attempt to find a high-resistance epithelium suitable for microelectrode work, we have studied the electrical properties of Necturus and Amphiuma urinary bladders in comparison to toad bladder. Improved mounting techniques were developed, which yield better reproducible degrees of distension and prevent electrical leaks around the edge of the preparation in the Ussing chamber. Transepithelial potential difference and resistance was measured with NaCl Ringer's on either surface of the epithelium, as well as under conditions of ion substitutions and in the presence of amiloride. Compared to data from conventionally mounted toad bladders reported in the literature, our experiments yielded higher potential differences and resistances in all three species. In Necturus values of up to 175 mV and 75 komega cm2 were recorded. Furthermore an inverse relationship was observed between potential difference and resistance, which was not noticed previously with the conventional mounting technique. The relationship is discussed quantitatively in terms of the two-membrane model of active Na+ transport, for which it provides further supportive evidence.

Exaggerated natriuresis in the conscious spontaneously hypertensive rat.

In response to an acute saline load, many patients with essential hypertension exhibit an exaggerated natriuresis relative to normotensive controls. In the present study, the urinary responses of conscious,Okamoto-strain, spontaneously hypertensive rats (SHR), and Wistar-Kyoto strain normotensive rats (NTR) to an acute saline load were evaluated to determine if a similar exaggerated natruiresis exists in this form of hypertension. Twelve rats of each strain per group (12 weeks of age) were housed in metabolism cages for 1 week. Systolic blood pressures (tail cuff) were significantly different (206+/- 9 mm. Hg in SHR and 135 +/- 3 mm. Hg in NTR). After a 4-hour control urine collection, 6 ml. of 0.9 per cent sodium chloride were given by gavage. Urine was collected again for 2 hours. Control urinary excretions of sodium, potassium, and creatinine in SHR and NTR were 11.2 +/- 4.8 muEq per hour, 50.1 +/- 7.6 muEq per hour, and 39.9 +/- 5.5 mg. per hour in SHR, and 13.8 +/- 2.4 muEq per hour, 34.9 +/- 5.5 muEq per hour, and 37.5 +/- 7.1 mg. per hour in NTR, respectively. The respective control values for sodium, potassium, and creatinine excretion in the two groups were not significantly different. Following the saline load, sodium and creatinine excretion rates were significantly elevated in both groups of rats. However, the increase in sodium excretion in SHR (60.8 +/- 7.2 MUEq per hour) was more than double and significantly different from that of the NTR (26.6 +/- 3.7 muEq per hour). In contrast, the increments in creatinine excretion in the two groups of rats were not significantly different from each other. In the NTS, urinary potassium excretion was significantly elevated (59.0 +/- 7.9 muEq per hour) whereas in SHR it was not significantly altered (12.0 +/- 8.8 muEq per hour). The change in urinary creatinine excretion as an index of change in glomerular filtration rate suggests that the greater increase in sodium excretion by the SHR was the result of decreased fractional reabsorption of sodium and not the result of a greater increase in glomerular filtration rate. The exaggerated natriuretic response to salt loading in SHR resembles that in hypertensive man except that in SHR, a simultaneous kaliuretic response is absent.