Effect of captopril on 99mTc-diethylenetriaminepentaacetic acid renograms in two-kidney, one clip hypertension.

In an effort to improve on the noninvasive detection of renal artery stenosis, we investigated the effect of angiotensin converting enzyme inhibition on computer-assisted 99mTc-diethylenetriaminepentaacetic acid (DTPA) renal flow studies in a canine model of two-kidney, one clip hypertension and compared these findings with clearances of inulin and p-aminohippuric acid in the stenotic and contralateral kidney before and after converting enzyme inhibition. The 99mTc-DTPA renal flow study with the converting enzyme inhibitor captopril (1.5 mg/kg bolus with 1.5 mg/min infusion) showed an increased sensitivity in the detection of unilateral renal artery stenosis over the use of the 99mTc-DTPA study alone. Captopril induced striking alterations that were most evident in the 15-minute 99mTc-DTPA renal flow study, in which all nine curves exhibited severely blunted uptake and excretion of the radionuclide. These changes were reversed during a recovery study without converting enzyme inhibition and were not seen when blood pressure was lowered with nitroprusside to a level similar to that observed during converting enzyme inhibition. The changes shown by the 99mTc-DTPA study during converting enzyme inhibition correlated with a decrease in the glomerular filtration rate of the stenotic kidney. Captopril infusion significantly decreased the glomerular filtration rate of the stenotic kidney (16.0 +/- 3.1 vs 11.0 +/- 2.5 mg/min, p less than 0.03) but not of the contralateral kidney (32.4 +/- 2.6 vs 28.4 +/- 2.8 mg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Technetium-99m DTPA renal flow studies in Goldblatt hypertension.

Computer-assisted dynamic renal studies were performed on a group of 14 mongrel dogs before and after the induction of unilateral renal artery stenosis. Ninety-second technetium-99m diethylenetriaminepentaacetic acid ( [99mTc]DTPA), 15-min [99mTc]DTPA, and 30-min iodine-131 orthoiodohippurate ( [131I]hippuran) time-activity curves were analyzed and correlated with reduction of renal blood flow as measured by electromagnetic flow probe and PAH clearance techniques. Parameters of the 90-sec [99mTc]DTPA curves found to be significantly different for the same kidney before and after stenosis were: upslope, curve width at 75% maximum, maximum activity value, and differential (stenotic/contralateral) maximum activity ratio. For blood flow reductions greater than 33%, the [99mTc]DTPA studies were judged diagnostic of unilateral renal artery stenosis in all cases, whereas the [131I]hippuran time-activity curves were indicative of stenosis in only six of ten studies. Thus, in this model we find the computer-assisted 90-sec [99mTc]DTPA renal flow study to be superior to conventional [131I]hippuran renography in the diagnosis of moderate-to-severe unilateral renal artery stenosis.

Captopril renography in two kidney and one kidney Goldblatt hypertension in dogs.

In order to improve on the technique of noninvasive detection of renal artery stenosis, we studied the effects of angiotensin converting enzyme inhibition with captopril on individual kidney hemodynamics and function as assessed by technetium-99m diethylenetriaminepentaacetic acid [( 99mTc]DTPA) renal flow studies and iodine-131 orthoiodohippurate [( 131I]hippuran) renography in experimental Goldblatt's hypertension. In two-kidney, one-clip (renin-dependent) hypertension, captopril (1.5 mg/kg bolus with 1.5 mg/min infusion) reduced mean arterial pressure (MAP) and ipsilateral glomerular filtration rate (GFR) without changes in the contralateral kidney. Captopril infusion resulted in alterations in both the [99mTc]DTPA and [131I]hippuran studies, which were most evident in the 15-min [99mTc]DTPA renal flow studies. In one-kidney, one-clip (volume-dependent) hypertension, captopril reduced MAP but did not alter GFR, renal plasma flow, or the radionuclide studies. These studies suggest that the [99mTc]DTPA renal flow study coupled with captopril challenge may unmask intrarenal angiotensin II-dependent functional and hemodynamic changes of the stenotic kidney, and offers promise in the detection of renin-dependent hypertension.

Refractoriness of the gravid rat uterus to tocolytic and biochemical effects of atrial natriuretic peptide.

1. Effects of atrial natriuretic peptide (ANP) on tension development, particulate guanylate cyclase activity and guanosine 3':5'-cyclic monophosphate (cyclic GMP) concentrations of uteri from oestrogen-treated, progesterone-treated, ovariectomized and pregnant rats were determined in vitro. 2. ANP inhibited the tension development by myometrial tissues from oestrogen-treated virgin rats and the sterile horn of 10 to 14 day pregnant rats but not of the uterus from pregnant and progesterone-treated rats. 3. Inhibition of cyclo-oxygenase and lipoxygenase activities did not restore the tocolytic activity of ANP on gravid uterus. ANP exerted a tocolytic effect on nongravid uterus submaximally stimulated by prostaglandin F2 alpha (PGF2 alpha), oxytocin, vasopressin, angiotensin II or 5-hydroxytryptamine (5-HT). 4. Ovariectomy decreased the tocolytic effects of ANP, which could be restored by oestrogen treatment. 5. The refractoriness to the tocolytic effect of ANP in pregnant rats was not accompanied by a decrease in its relaxant effects on isolated aortic strips. 6. Tocolytic effects of isoprenaline, isobutylmethyl xanthine and hydroxylamine were not influenced by pregnancy or progesterone treatment. Up to a concentration of 3 mM, sodium nitroprusside did not affect myometrial tension development. 7. Pregnancy and progesterone treatment markedly inhibited ANP-induced increases in myometrial particulate guanylate cyclase activity and cyclic GMP concentrations but did not influence the effects of ANP on aortic cyclic GMP concentrations. 8. It is concluded that exposure of the myometrium to circulating and placentally-produced progesterone is responsible for the pregnancy-induced decrease in the effects of ANP on myometrial particulate guanylate cyclase activity and cyclic GMP concentrations and in turn on myometrial tension development.

Inhibition of the tocolytic activity of atrial natriuretic factor by progesterone and potentiation by progesterone receptor antagonist RU486 in rats.

1. The influence of progesterone on the activity of atrial natriuretic factor (ANF) on rat myometrial motor activity was determined in vitro. 2. ANF inhibited the tension development by myometrium from cycling or oestrogen-treated rats in a dose-dependent manner; maximal inhibition was 100%. 3. Injections of progesterone into rats inhibited the tocolytic activity of ANF in a dose and time-dependent manner. The tocolytic effects of ANF were completely abolished by 3 daily injections of 1 mg kg-1 progesterone. 4. Pregnancy-related increase in plasma progesterone was accompanied by a corresponding decrease in the tocolytic effects of ANF; myometria from gestational day 10 to 21 were completely refractory and those from earlier gestational age and immediate postpartum were responsive to ANF to varying degrees. 5. Treatment of pregnant rats with the progesterone antagonist, RU486, caused abortions and vaginal bleeding, decreased plasma progesterone concentrations and restored the tocolytic activity of ANF. Tocolytic activity of ANF on virgin rat myometria was potentiated by RU486. 6. Progesterone also inhibited the effects of ANF on myometria from ovariectomized rats. 7. Tocolytic activity of isoprenaline was not modified by progesterone, pregnancy, RU486 or ovariectomy. 8. It is concluded that progesterone antagonizes myometrial effects of ANF by an oestrogen-independent mechanism and the pregnancy-induced refractoriness to the tocolytic effects of ANF is caused by progesterone.

Down-regulation of myometrial atrial natriuretic factor receptors by progesterone and pregnancy and up-regulation by oestrogen in rats.

We previously reported that pregnancy and progesterone treatment abolish and ovariectomy reduces the tocolytic activity of atrial natriuretic factor (ANF) on rat uterus. The present study was carried out to determine whether the hormonal state of the animal influences myometrial ANF receptors. A single high-affinity binding site for 125I-labelled ANF(1-28) was detected in myometrial membrane preparations partially purified by discontinuous sucrose gradient centrifugation. The specifically bound ANF could be displaced completely by unlabelled ANF(1-28) (biologically active circulating form of ANF), partially (approximately 50%) by the clearance receptor (ANF-R2) ligand, ANF(4-23), and insignificantly by angiotensin II, vasopressin, carbachol and progesterone. Maximum binding capacities (fmol/mg protein +/- S.E.M.) of myometrial membrane preparations for ANF were as follows: vehicle-treated cyclic rats, 30.2 +/- 5.9 (n = 6); oestrogen-treated virgin rats, 55.8 +/- 7.1 (n = 8); progesterone-treated virgin rats, 21.9 +/- 2.4 (n = 6); 20-day pregnant rats, 18.9 +/- 4.3 (n = 4); ovariectomized rats, undetectable (n = 3); ovariectomized rats treated with oestrogen, 50.2 +/- 4.1 (n = 3); virgin rats treated with progesterone antagonist RU 486, 64.5 +/- 5.2 (n = 3). Relative to cyclic rats, oestrogen and RU 486 caused a significant (P less than 0.05) increase and progesterone and pregnancy caused a significant (P less than 0.05) decrease in ANF myometrial receptors. The hormonal state did not change dissociation constants for ANF binding to myometrial preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Peptide YY (PYY) stimulates intrinsic enteric motor neurones in the rat small intestine.

The effects of peptide YY (PYY) on motor activity of the rat small intestine, were studied using isolated organ bath preparations arranged for recording muscle activity in the longitudinal axis. PYY induced TTX sensitive concentration-dependent contractions and/or relaxations of the longitudinal muscle in different regions of the small intestine. In the duodenum PYY evoked only "cholinergic" contractions (3 x 10(-8)-3 x 10(-7) M). In the jejunum, PYY-evoked concentrations were non-cholinergic, and contractions were never seen in the ileum. In the jejunum and ileum, PYY-evoked relaxations (3 x 10(-8)-3 x 10(-7) M) were unaffected by adrenoceptor or cholinergic receptor blockade, thus indicating that these relaxations were mediated by non-adrenergic, non-cholinergic (NANC) inhibitory nerves. Another action of PYY was to cause inhibition of field stimulation-evoked cholinergic concentrations. This inhibitory action was primarily due to antagonism of post-junctional, cholinergic receptor mediated events. In addition, PYY inhibited histamine evoked contractions of the longitudinal muscle. All regions of the small intestine could be desensitized to PYY. Such PYY-densensitization did not affect the ability of the longitudinal muscle to relax in response to applied ATP or papaverine. These results suggest PYY has potent concentration-dependent stimulatory actions at intrinsic inhibitory and excitatory motor nerves. In addition, PYY interferes with contractions but not relaxations of the longitudinal muscle.

Computer model for simulation of first transit cardiac radionuclide curves--I.

A discrete-time, lumped-parameter mathematical model of the human cardiopulmonary circulation as it appears during a first-transit radionuclide study is developed. Eleven compartments, four delays, and 26 transfer paths are modeled, including the entire circulation from an input compartment before the vena cava to an output compartment after the aorta. The 26 transfer paths include forward and reverse flow through the heart valves, backflow from the atria into the veins, and five types of shunts. A method of modeling continuously-variable delay segments with only discrete-time sample points is devised to allow more versatility in specifying delays. The model simulates discrete time-activity curves for the various compartments of the cardiopulmonary system. The curves are obtained for end-systole and end-diastole. Simulation of curves indicative of a normal heart and several heart defects is presented. The use of this model for computer analysis of first-transit cardio-radionuclide curves is discussed.

Optimal fitting of computer model simulations to first transit cardiac radionuclide curves--II.

A discrete-time, lumped-parameter mathematical model of the human cardiopulmonary circulation as it appears during a first-transit radionuclide study has been described. An optimal fitting process is used to match curves obtained from the model to curves obtained from first transit studies in order to estimate the parameters of the subject's heart. The development of the optimization technique is described in this paper. The results of testing the effects of overlapping compartments and errors in delay estimates are presented. A parameter determination analysis is performed by applying the optimization algorithm to simulated data. This analysis technique provides a method of estimating many parameters of heart function using a single, simple, rapid procedure. Results of clinical studies will be presented subsequently.

Bronchodilator activity of atrial natriuretic peptide in guinea pigs.

Atrial natriuretic peptide (ANP) produced concentration-dependent relaxation of isolated guinea pig tracheal chains contracted with histamine, serotonin, carbachol, and arachidonic acid. ANP was a full agonist. ANP was two- to three-fold less potent when compared with isoprenaline in relaxing histamine-, serotonin-, and arachidonic acid-contracted tracheal chains. However, ANP was 20-fold less potent than isoprenaline in relaxing carbachol-contracted tracheal chains. The relaxant potencies of isoprenaline and sodium nitroprusside were similar regardless of the agent used to induce the tone. ANP was less potent and efficacious than isoprenaline in inhibiting the serotonin-, histamine-, and carbachol-induced increases in pulmonary inflation pressure in pentobarbitone-anesthetized guinea pigs. Neither ANP nor isoprenaline inhibited the arachidonic acid-induced increase in pulmonary inflation pressure. ANP decreased and isoprenaline increased arterial pressure. The data suggest that ANP possesses limited bronchodilator activity especially in vivo.

Selective increase in placental blood flow by atrial natriuretic peptide in hypertensive rats.

Effects of atrial natriuretic peptide on systemic, renal, uterine, and placental hemodynamics were determined in 16-day pregnant normotensive and hypertensive rats and in 20-day pregnant normotensive rats under pentobarbital anesthesia. Relative to 16-day pregnant normotensive rats, the total peripheral resistance was higher in 16-day pregnant hypertensive and 20-day pregnant normotensive rats; atrial natriuretic peptide significantly (p less than 0.05) decreased the total peripheral resistance in the latter two groups of animals. Atrial natriuretic peptide increased the placental blood flow in each of the three groups of animals without significantly affecting renal blood flow. This selective increase in placental blood flow normalized placental hemodynamics in hypertensive rats.

Ontogeny of responses of rabbit aorta to atrial natriuretic factor and isoproterenol.

Ontogeny of the vasorelaxant effects of atrial natriuretic factor (ANF) and isoprenaline and of the vasoconstrictor effects of potassium and phenylephrine were studied on aortic strips from rabbits aged 1, 2, 3, 6, 10 and 32-48 (adult) weeks. ANF caused complete relaxation of phenylephrine- and potassium-contracted aortic strips from all age groups of rabbits and its potency was not altered by age and by the agent used to cause contractions. On the other hand, the vasorelaxant efficacy and potency of isoproterenol decreased with age. Also, isoprenaline was less potent and efficacious on aortic strips contracted with potassium than on strips contracted with phenylephrine. The sensitivity of aorta to phenylephrine increased after 2 weeks of age, but that to potassium remained the same at all ages. In conclusion, our data indicate that the vasorelaxant effects of ANF and the vasoconstrictor effects of potassium on rabbit aorta are not altered by age whereas the sensitivity of the vascular smooth muscle to isoproterenol decreases and that to phenylephrine increases with maturation.

Evaluation of encephalic ventricular volume from the magnetic resonance imaging scans of thirty-eight human subjects.

Accurate volume determination of the encephalic ventricles is of importance in several clinical conditions, including Alzheimer's presenile dementia, schizophrenia, and benign intracranial hypertension. Previous studies have investigated the accuracy with which magnetic resonance imaging (MRI) can be used in clinical practice to evaluate the encephalic ventricles. However, adequate evaluation of pathological conditions depends on a sufficient amount of morphometric data from normal subjects. To begin establishing this data base for "normal" subjects, we evaluated the MRI scans of 38 subjects found to have no apparent pathology and calculated the ventricular volume in each case by using methods previously developed in our laboratory. The results were then compared with published volumes determined from studies that used either ventricular casts or computerized tomographic scans. The average total ventricular volume for all 38 subjects was 17.4 cm3, while that for males was 16.3 cm3 and that for females was 18.0 cm3. A small but significant correlation was found between age of subject and ventricular volume, with ventricular size increasing with age.

Comparison of computerized tomography with magnetic resonance imaging (MRI) in the evaluation of encephalic ventricular volume.

The volume of the encephalic ventricles was determined from computerized tomographic (CT) and magnetic resonance imaging (MRI) scans of seven subjects without apparent pathology and three subjects with enlarged ventricles. Since there are many conditions in which the encephalic ventricles become enlarged such as Alzheimer's disease and hydrocephalus, accurate measurement of these structures provides (1) a valuable and safe means of aiding in the diagnosis of such conditions and (2) important follow-up information on affected patients. This paper presents the data obtained from the second phase of a three phase study. The first phase demonstrated the possibility of measuring fluid filled spaces by MRI in three phantom preparations (small, medium, and large "ventricles"). The results were compared with those obtained from the computerized tomography (CT) scans of the same preparations. This phase of the study compares the volumes obtained from CT scans with those obtained from MRI scans of the same individuals. The volumetric calculations were done with the aid of a Calcomp 9000 digital analyser programmed to compensate for the scale factor and slice thickness of the images. The results obtained from the MRI scans correlated closely with those obtained from the CT scans of the same subjects. The third and final phase of the project is the development of an MRI volumetric data base for the encephalic ventricles using a larger number of subjects.

Improved computer-assisted nuclear imaging in renovascular hypertension.

Computer-assisted dynamic renal studies using both the 90 second 99mTc-DTPA and the conventional 30 minute 131I-Hippuran methods were performed in nine patients with angiographically proven renal artery stenosis. Time activity curves for both studies were derived from regions of interest selected from the computer-acquired dynamic images. The following parameters were used to assess renal blood flow: differential maximum activity, minimum/maximum activity ratio, and peak width. The computer-assisted DTPA study accurately predicted (9/9) the stenotic side documented angiographically, whereas the conventional Hippuran scan was clearly predictive in only 57% (5/9). The best discriminatory factors for the 90 second 99mTc-DTPA scan, when compared to a normal template synthesized from curves obtained from normal subjects (20), were differential maximum activity and peak width. In conclusion, the computer-assisted 90 second 99mTc-DTPA renal blood flow scan was superior to the conventional 30 minute 131I-Hippuran scan in demonstrating unilateral renovascular disease. The DTPA study was highly predictive of the angiographic findings, and this noninvasive study may prove useful in the diagnosis and serial evaluation following surgery or angioplasty in patients having renal artery stenosis.