Serum trypsinlike immunoreactivity measurement for the diagnosis of subclinical exocrine pancreatic insufficiency.

Dogs (n = 158) with serum trypsinlike immunoreactivity (TLI) concentrations < or = 5.0 microg/L were studied. The diagnosis of clinical exocrine pancreatic insufficiency (EPI) was made in 114 of 158 dogs based on TLI concentration < 2.5 microg/L and clinical signs typical of EPI (eg, polyphagia, voluminous feces, weight loss). In 44 of 158 dogs, a single TLI measurement and clinical signs were not diagnostic. In 9 of 44 dogs, TLI was < 2.5 microg/L, indicating EPI, but the gastrointestinal signs were atypical or the dogs were asymptomatic. In 35 of 44 dogs, TLI was 2.5-5.0 microg/L. All 44 dogs were retested for TLI within 1-27 months (mean, 11.9 months). In 20 of 44 dogs, the retested TLI was normal (> 5.0 microg/L). In 4 of 44 dogs with clinically diagnosed EPI, the retested TLI was < 2.5 microg/L. In the remaining 20 of 44 dogs, TLI was persistently < 5.0 microg/L (range, 1.0-4.9 microg/L; mean, 3.1 microg/L). Of these dogs, 15 had no clinical signs of gastrointestinal disease, and 5 had occasional clinical signs atypical for EPI. Gross examination of the pancreas (12 dogs) showed that the amount of normal pancreatic tissue was remarkably diminished. These dogs were diagnosed with subclinical EPI. The TLI-stimulation test, in which TLI is measured before and after stimulation with secretin and cholecystokinin, showed a significant response (P < .05) both in dogs with subclinical EPI and in control dogs, but showed no response in dogs with clinical EPI. In this study, EPI was diagnosed in its subclinical phase by TLI concentrations persistently < 5.0 microg/L, and a single TLI concentration < 5.0 microg/L was not diagnostic. Retesting after TLI concentrations < 5.0 microg/L is recommended even in clinically normal dogs, because of the possibility of subclinical EPI.

Effects of calcium supplementation and deoxycorticosterone on plasma atrial natriuretic peptide and electrolyte excretion in spontaneously hypertensive rats.

The effects of calcium and the mineralocorticoid deoxycorticosterone (DOC) on blood pressure were studied in four groups of spontaneously hypertensive rats (SHR): (1) control; (2) calcium; (3) deoxycorticosterone and; (4) deoxycorticosterone + calcium. Calcium was given as 1.5% calcium chloride in drinking fluid and deoxycorticosterone by weekly subcutaneous injections (25 mg kg-1). During the nine weeks of treatment the increase in systolic blood pressure was enhanced in the deoxycorticosterone and attenuated in the calcium group, whereas the deoxycorticosterone + calcium group did not deviate from control. Total plasma calcium was elevated in the calcium group. Plasma concentrations of sodium and atrial natriuretic peptide (ANP) were increased by deoxycorticosterone while neither of the calcium-treated groups differed from control in these respects. Urinary excretions of calcium and sodium were increased in both groups receiving calcium, and also the deoxycorticosterone group excreted more calcium into urine than the control. Adrenergic nerve density in a section of the mesenteric artery and the urinary excretion of noradrenaline and adrenaline were similar in all study groups. The results indicate that calcium supplementation can attenuate the development of hypertension and prevent the deoxycorticosterone-induced blood pressure rise in SHR, possibly by influencing sodium metabolism as seen in increased natriuresis, and by preventing the actions of deoxycorticosterone on sodium balance.

Effects of single doses of quinapril and atenolol on autonomic nervous function and exercise capacity in healthy volunteers.

The effects of single oral doses of the angiotensin converting enzyme (ACE) inhibitor quinapril (CI-906) 40 mg and the cardioselective beta-adrenoceptor blocker atenolol 100 mg on sympathetic and parasympathetic function and on exercise capacity have been studied in 8 healthy young men. The trial followed a double-blind, placebo controlled, randomized cross-over design, with at least one week between treatments. Blood pressure (BP) and heart rate (HR) at rest were slightly reduced by atenolol but were not affected by quinapril. Atenolol impaired the sympathetically mediated increases in HR and BP caused by standing, immersion of the hand into melting ice, the Valsalva manoeuvre and isometric forearm exercise. Quinapril did not influence those responses nor the vagally mediated bradycardia of the diving reflex. Atenolol, however, augmented the vagal bradycardia, presumably by sympathetic inhibition. In a dynamic bicycle ergometer test with a stepwise increasing work load, exercise performance was decreased by atenolol but not by quinapril. Inhibition of the renin-angiotensin system by quinapril was shown by a marked decrease in serum ACE activity and a several-fold increase in plasma renin activity (PRA). Atenolol produced a moderate reduction in PRA. Before or during exercise, plasma noradrenaline and adrenaline were not influenced by either drug. The results indicate that, unlike the atenolol-induced beta-adrenoceptor blockade, ACE inhibition by a single dose of quinapril had no clear effect on autonomic nervous function or exercise capacity.

Effects of calcium and deoxycorticosterone on blood pressure, plasma renin activity and vascular reactivity in spontaneously hypertensive rats.

The effects of calcium and deoxycorticosterone (DOC) on blood pressure, plasma renin activity (PRA), urinary sodium excretion and aortic responses were studied in spontaneously hypertensive rats (SHR). The animals (age 9 weeks) were divided into four treatment groups: control, calcium, DOC and DOC+calcium (n = 12 and the mean systolic blood pressure 174-177 mmHg in each). Calcium was given as 1.5% CaCl2 in drinking fluid, and DOC trimethylacetate by weekly injections (25 mg/kg s.c.). During the 4-week study systolic blood pressure rose in all groups, but the increase was attenuated by calcium (final levels: control 201 +/- 3, calcium 186 +/- 3, DOC 206 +/- 2, DOC + calcium 203 +/- 2 mmHg, mean +/- SE). PRA was reduced in both groups receiving DOC, but it was not affected by calcium. Calcium supplementation increased urinary excretion of sodium in DOC-treated animals. DOC enhanced the in vitro contractility of helically cut aortic strips to noradrenaline, and decreased the relaxation of the strips to nitroprusside and nifedipine. The results indicate that calcium supplementation attenuates the development of hypertension in SHR, and that this attenuation is not mediated by the renin-angiotensin system. DOC abolished this lowering effect of calcium on blood pressure possibly by its action on vascular smooth muscle, resulting in increased vascular contractility and impaired relaxation.

Deoxycorticosterone prevents the blood pressure-lowering effect of calcium in spontaneously hypertensive rats.

To study the effects of prolonged oral calcium loading on the development of hypertension in spontaneously hypertensive rats (SHR), 48 male animals (age 9 weeks) were divided into four groups according to the treatment: control, calcium, deoxycorticosterone (DOC) and calcium/DOC. Both calcium groups received 1.5% calcium chloride solution ad libitum as their drinking fluid. The animals in the DOC groups were treated with a mineralocorticoid, deoxycorticosterone trimethylacetate 25 mg kg-1 s.c. once a week. Systolic blood pressure (BP) was measured twice a week during the 4-week study period. Calcium loading alone lowered BP (p less than 0.01) after four weeks. Combined with DOC treatment, calcium administration had no significant effect on BP. Calcium loading increased the total plasma calcium concentration in the calcium group (p less than 0.05). Urinary excretions of sodium and potassium were augmented in both groups receiving calcium compared to DOC group. DOC treatment alone increased the excretion of calcium (P less than 0.05). Calcium supplementation decreased the plasma phosphate concentration in both groups (calcium p less than 0.05; calcium/DOC p less than 0.01) as well as the excretion phosphate (p less than 0.005) compared to control. The urinary excretion of cAMP remained unaffected by the calcium treatment. The present results indicate that mineralocorticoid treatment can prevent the BP-lowering effect of calcium in SHR. The mechanism of this action remains unclear, but it does not seem to depend on electrolyte or phosphate balance. The investigation of this action of DOC may provide a means for further exploration of the mechanisms by which increased calcium intake lowers BP in SHR.

Pharmacokinetics of clodronate in patients with metastatic breast cancer.

Pharmacokinetics of clodronate was studied in six breast cancer patients with only bone metastases. 14C-clodronate was administered intravenously (10 muCi/200 mg) and orally (20 muCi/400 mg) on separate occasions. Vc of clodronate averaged 6.3 +/- 3.0 (SD) 1 and Vdss 16.3 +/- 3.81 corresponding to the extracellular water volume. Distribution and elimination were fast with t1/2 alpha of 0.22 +/- 0.22 h and t1/2 beta of 2.3 +/- 0.9 h. The elimination occurred mainly by renal excretion of the unchanged drug CLP averaging 107 +/- 27 ml/min and CLR 80 +/- 18 ml/min. The protein unbound, free fraction in plasma was 64%. On the basis of urinary excretion data, there was a slow terminal elimination phase with a half-life of 12.8 +/- 6.9 h. Thus about 20% of the intravenous dose was retained in the body, most likely in the bones, 3 days after drug administration. About 75% of the intravenous dose was recovered in urine and 5% in feces. Based on cumulative excretion data into urine after both routes of administration, the bioavailability of oral clodronate was 1.9 +/- 0.4%. These findings correspond closely to those obtained in healthy volunteers in previous studies.

Blood pressure responses to enalapril in rats with one- and two-kidney DOC-NaCl hypertension.

Blood pressure responses to the angiotensin-converting enzyme (ACE) inhibitor enalapril were investigated in rats with salt-dependent hypertension. In both one- and two-kidney deoxycorticosterone (DOC)-NaCl hypertension, enalapril (50 mg/kg p.o.) caused a similar, slight blood pressure fall, which passed off with continuation of the treatment. Changes in the salt concentration of the drinking fluid (from 1% NaCl to 0.2% NaCl in the one-kidney rats and from 1% NaCl to 2% NaCl in those with intact kidneys) did not alter the depressor effect of enalapril. Plasma renin activity in all DOC-NaCl hypertensive groups was negligible. Our results indicate that in DOC-NaCl hypertensive rats, the presence of intact kidneys vs. one kidney has no influence on the blood pressure response to ACE inhibition. The blood pressure-lowering effect of enalapril may result from local converting enzyme inhibition in tissues.

Enhanced activation of the renin-angiotensin-aldosterone system in chronic cigarette smokers: a study of monozygotic twin pairs discordant for smoking.

Plasma renin activity (PRA) and aldosterone concentration were measured before and during submaximal exercise in 10 male monozygotic twin pairs who were discordant for smoking. In nine twin pairs PRA was higher in the smoker both at rest and during exercise. The mean PRA was 99% higher at rest and 84% higher during exercise than in nonsmokers. Plasma aldosterone levels were higher at rest in seven smokers and during exercise in eight smokers compared with the respective nonsmokers. The mean aldosterone level at rest was 23% and during exercise 40% higher in the smokers than in the nonsmokers. Chronic smoking induces increased PRA, which results in increased aldosterone formation, presumably via enhanced generation of angiotensin II. This may partly explain the greater vasoconstrictive reactivity typical of the arteries of chronic smokers.

Effects of the converting enzyme inhibitor quinapril (CI-906) on blood pressure, renin-angiotensin system, and prostanoids in essential hypertension.

Fourteen patients with mild to moderate essential hypertension were randomized, after a baseline placebo period of 4 weeks, to receive the angiotensin converting enzyme (ACE) inhibitor quinapril or a placebo. During a 12 week, double-blind phase, the dosage of quinapril was increased from 10 to 40 mg twice daily being doubled every 4 weeks. At the end of the baseline period and of each month of the double-blind phase, 12 h overnight urine collections were made and morning blood samples were taken about 12 h after the last dose of medication. During the double-blind phase, blood pressure in the quinapril group (n = 7) decreased from 159 +/- 3/105 +/- 1 to 141 +/- 6/94 +/- 2 mm Hg (mean +/- SEM). Serum ACE activity and plasma angiotensin II concentration were reduced to 4 +/- 1% and 14 +/- 1% of the pretreatment values, respectively. Neither the plasma concentrations nor the urinary excretions of prostaglandin E2, 6-keto-prostaglandin F1 alpha (a prostacyclin metabolite), or thromboxane B2 (a metabolite of thromboxane A2) were affected by quinapril. In the placebo group, blood pressure tended to decline but the biochemical variables remained essentially unchanged. These results indicate that prostanoids are not involved in the antihypertensive action of quinapril, the principal effect of which seems to be inhibition of the renin-angiotensin system.

Effects of indomethacin on hormonal and blood pressure responses to captopril in spontaneously hypertensive rats.

The possible role of vasodilatory prostanoids in the antihypertensive action of captopril was investigated in spontaneously hypertensive rats (SHR). Captopril (100 mg/kg/day for 5 days) decreased systolic blood pressure and increased water consumption, urine excretion and plasma renin activity (PRA). It also enhanced the urinary excretion of the prostacyclin metabolite 6-keto-PGF1 alpha, but did not change the excretion of PGE2. Indomethacin (3 mg/kg/day), given both alone and in combination with captopril, reduced markedly the urinary excretions of 6-keto-PGF1 alpha and PGE2 but did not alter PRA, compared with corresponding groups without indomethacin. The suppression of prostanoid synthesis caused by indomethacin did not affect the antihypertensive effect of captopril or the basal blood pressure in SHR. Neither did indomethacin influence drinking or urine excretion in SHR not receiving captopril, but it reduced the dipsogenic and diuretic effects of captopril. The results suggest that captopril augments the production of vasodilatory prostacyclin. Yet prostanoids have no significant role in the antihypertensive mechanism of captopril in SHR.

Effects of two structurally different angiotensin-converting enzyme inhibitors, captopril and quinapril (CI-906), in rats with one-kidney deoxycorticosterone-salt hypertension.

Possible non-renin antihypertensive actions of two angiotensin-converting enzyme inhibitors, the sulfhydryl compound captopril and the new nonsulfhydryl inhibitor quinapril (CI-906), were compared in rats with one-kidney deoxycorticosterone-salt hypertension. Plasma renin activity remained low during the 12-day treatments and showed very strong suppression of the renin-angiotensin system. Quinapril did not influence the rapidly increasing blood pressure. Although captopril tended to reduce the development of hypertension (p = 0.08), it did not have any significant effect, either. The results indicate that these ACE inhibitors with different chemical structures lack any significant blood pressure lowering mechanism in severe deoxycorticosterone-salt hypertension, a model in which they cannot act through their established antihypertensive mechanism, the inhibition of the renin-angiotensin system.

The effect of sodium load on the development of hypertension, plasma renin and kininogen in rats with renal artery constriction.

Effects of sodium load on the development of hypertension, plasma renin activity (PRA) and kininogen were studied in rats with renal artery constriction and untouched contralateral kidney. After the operation or sham-operation, 0.9% NaCl or water were given as drinking fluid. A marked hypertension (systolic pressure greater than 150 mmHg) developed in all operated rats on saline, but only in 2/3 of operated rats on water. In none of the sham-operated controls did systolic pressure exceed 150 mmHg during 7 postoperative weeks. Within the operated group on water, hypertensive rats had significantly higher PRA values than normotensive animals (P less than 0.05). Salt load slightly suppressed the PRA in sham-operated rats but not in animals with constriction renal artery, compared to sham-operated controls on water. The operated rats on salt excess had higher plasma kininogen levels than the operated normotensive rats on water (P less than 0.05), but there were no other significant differences in kininogen values between different study groups, regardless of whether blood pressure was increased or not. The results indicate that in this form of hypertension, the high blood pressure can be maintained without any increase in PRA if animals are subjected to a sodium load which sensitizes vascular beds to angiotensin. The increase in plasma kininogen, suggesting suppression of kallikrein-kinin system, is unlikely associated with the increase of blood pressure.

Inhibition of angiotensin-converting enzyme with quinapril (CI-906): investigation of antihypertensive mechanisms in spontaneously hypertensive rats.

Treatment for 8 days with a new nonsulfhydryl angiotensin-converting enzyme inhibitor, quinapril (CI-906), produced a marked and progressive reduction in the blood pressure of spontaneously hypertensive rats. Quinapril was given p.o. in a dose of 20 or 40 mg/kg once daily. Both doses increased plasma renin activity and decreased the urinary excretion of aldosterone. These results, together with a marked decrease in serum angiotensin-converting enzyme activity, indicate that the drug produced a considerable fall in circulating angiotensin II. The urinary excretion of vasopressin was not altered by the smaller dose of quinapril but was reduced by the larger dose, which increased water intake and urine excretion. Quinapril did not affect plasma kininogen or the urinary excretion of kallikrein. The urinary excretion of neither the prostacyclin metabolite 6-keto-prostaglandin F1 alpha nor the thromboxane metabolite thromboxane B2 were altered by the drug. However, quinapril did produce a temporary decrease in the excretion of prostaglandin E2, the effect passing off with the continuation of the treatment. These data indicate that vasodilatory prostanoids do not contribute to the blood pressure lowering effect of quinapril in spontaneously hypertensive rats. The inhibition of the renin-angiotensin system is probably the principal mechanism of the drug's antihypertensive action, but these results do not rule out the possibility that an increase in vasodilatory kinins may also be involved.

Inhibition of prostaglandin synthesis by indomethacin interacts with the antihypertensive effect of atenolol.

The interaction of inhibition of prostaglandin (PG) synthesis by indomethacin (75 mg/day) with the antihypertensive effect of atenolol (50 mg b.i.d.) was studied in 11 untreated otherwise healthy men 35 to 45 years old with essential hypertension. Atenolol for 3 weeks decreased supine blood pressure (BP) from 157/109 mm Hg during placebo to 148/97 mm Hg. Indomethacin alone for 1 week slightly increased BP and antagonized the antihypertensive action of atenolol. Atenolol reduced plasma renin activity (PRA) to 40% but did not modify either the urinary excretion of vasodilatory PGs (PGE2 and prostacyclin measured as 6-keto-PGF1 alpha) or plasma kininogen and urine kallikrein. Indomethacin suppressed PRA to 27% and PG excretion to approximately 70% but did not markedly change plasma kininogen and urine kallikrein excretion. The decreased excretion of 6-keto-PGF1 alpha, the metabolite of the main vasodilatory prostanoid prostacyclin, correlated with the increased BP measured in standing subjects. The effects of indomethacin were practically the same when given with atenolol as when given alone. We conclude that the slight increase in BP by indomethacin in essential hypertension is associated with the reduced production of vasodilatory PGs but not with alterations in activities of the renin-angiotensin or kallikrein-kinin systems.

Effects of a prostacyclin analog iloprost on kidney function, renin-angiotensin and kallikrein-kinin systems, prostanoids and catecholamines in man.

Iloprost (ZK 36 374), a stable analog of carbaprostacyclin, was infused for 72 h to nine patients with advanced obliterative arterial disease. Iloprost caused a marked vasodilation and a compensatory increase in cardiac output. The glomerular filtration rate increased by 45% and tubular reabsorption of sodium and water were reduced by 80% and 107%, respectively. The urine excretion rate increased by 122%. Tubular handling of potassium and calcium were not influenced by iloprost but magnesium reabsorption was stimulated. The renin-angiotensin system was not activated while serum angiotensin converting enzyme activity was decreased. Kallikrein excretion in urine was increased 4.4-fold but plasma kininogen, a substrate for kallikrein in producing vasoactive kinins, was unaffected by the drug. Plasma levels of 6-keto-PGF1 alpha and TxB2 were decreased and their excretion in urine increased. Plasma catecholamines were not changed by iloprost. Several of the changes persisted for at least the first postinfusion day. The results indicate that iloprost increases urine excretion rate by increasing glomerular blood flow and by inhibiting sodium and water reabsorptions. The kinin-forming system, but not the renin-angiotensin system or plasma catecholamines, may be activated. The decrease in plasma level of prostanoids can be, at least partly, due to their increased excretions in urine.

Pharmacological effects of iloprost (ZK 36 374), a stable prostacyclin analogue, in man.

Iloprost, a stable analogue of carbaprostacyclin, was infused for 72 h to 9 patients with advanced obliterative arterial disease. Total peripheral and pulmonary vascular resistances and blood pressure were decreased. Cardiac output was elevated with no marked extra cardiac load. The glomerular filtration rate was increased and tubular reabsorption of sodium and water reduced. Consequently, urine excretion increased. The renin-angiotensin system was not activated but excretion of renal kallikrein was augmented. Several patients showed clinical improvement. The drug was well tolerated except for gastrointestinal side-effects with the dose of 4 ng X kg-1 X min-1 or more.

Differing effects of two angiotensin converting enzyme inhibitors, captopril and CI-906, on diuresis and the urinary excretion of kallikrein and prostaglandins in spontaneously hypertensive rats.

The effects of two angiotensin I converting enzyme inhibitors on the kallikrein-kinin system and prostanoids were studied in spontaneously hypertensive rats. The doses of captopril were 20, 50 and 100 mg/kg X day given twice daily, and those of CI-906 20 and 40 mg/kg once daily. Both drugs were equally effective in reducing the systolic blood pressure. Captopril increased urine volume dose-dependently (up to 3-fold with the largest dose). Only the larger dose of CI-906 was slightly diuretic. Captopril decreased the 24-h urinary excretion of kallikrein, while the excretion of the prostacyclin metabolite 6-keto-PGF1 alpha was increased markedly and that of T X B2 to a lesser extent. CI-906 had no effect on the 24-h urinary excretion of kallikrein, 6-keto-PGF1 alpha and T X B2. Both drugs tended to reduce PGE2 excretion. Captopril and CI-906 did not alter plasma kininogen levels. The marked renal effects of captopril may be caused by a strong local inhibition of converting enzyme in the kidneys. Captopril is mainly excreted unchanged in urine, and it is secreted actively by the proximal tubular cells. CI-906 is eliminated predominantly by biliary excretion. It is also possible that direct stimulation of prostacyclin formation by captopril may be involved in the diuretic action of the drug. However, as it was shown with CI-906, the increase in urine flow and the associated changes in urinary kallikrein and prostanoids are not necessary for the antihypertensive effect caused by the inhibition of converting enzyme.