The blood pressure responses to intravenous infusions of norepinephrine and angiotensin II, sympathetic and nonsympathetic vasoconstricting agents, respectively, were measured in 20 patients with cirrhosis (10 Child-Pugh grade A and 10 Child-Pugh grades B or C) and in 20 healthy subjects. The log PD20 (dose of agonist required to raise blood pressure by 20 mm Hg) for norepinephrine was 4.78 +/- 0.36 (mean +/- S.D.) in patients with severe cirrhosis and 4.36 +/- 0.37 in controls, p less than 0.01. Log PD20 for angiotensin II was 3.16 +/- 1.06 in patients with severe cirrhosis and 1.97 +/- 0.74 in controls, p less than 0.01. Cardiovascular responses to selective sympathetic agonists were measured in 10 other cirrhotic patients (all Child-Pugh grades B or C) and in 10 healthy controls. Log PD20s for phenylephrine, an alpha-1 adrenoceptor agonist, and for alphamethylnorepinephrine; an alpha-2 adrenoceptor agonist, were increased in cirrhosis (phenylephrine = 5.35 +/- 0.49 vs. 4.95 +/- 0.35, p less than 0.05; alphamethylnorepinephrine = 4.05 +/- 0.26 vs. 3.44 +/- 0.55, p less than 0.001). In contrast, log CD20 (dose of agonist required to raise the heart rate by 20 beats/min) for isoproterenol, a beta-adrenoceptor agonist, was similar in cirrhotic patients and controls (2.81 +/- 0.38 vs. 2.94 +/- 0.45, p = 0.49). These studies demonstrate that pressor reactivity to both sympathetic and nonsympathetic agonists is impaired in severe cirrhosis, that the impaired sympathetic responses are not caused by generalized sympathetic desensitization and that the site common to the four agonists with impaired responses is the peripheral vascular smooth muscle.
The site of omeprazole inhibition of adrenal steroidogenesis has been sought in vivo by analyzing the patterns of urinary steroid metabolite excretion after 6 days of treatment with placebo/omeprazole. Excretion rates of androsterone, aetiocholanolone, dehydroepiandrosterone, 11 beta hydroxyandrosterone, tetrahydrocortisone, tetrahydrocortisol and alpha cortolone were reduced, indicating a block at an early step in steroidogenesis, possibly cholesterol side-chain cleavage. In vitro studies have confirmed this finding by measuring conversion of added precursors to cortisol in isolated bovine adrenocortical cells. Cortisol synthesis from added 20 alpha hydroxycholesterol was inhibited by 83% in the presence of 100 micrograms omeprazole/ml. Conversion from pregnenolone and progesterone and their 17 alpha hydroxylated derivatives was inhibited by 20-40% whereas cortisol production from added 11 deoxycortisol was not affected. These data suggest that omeprazole primarily inhibits cholesterol cleavage and does not inhibit 3 beta hydroxysteroid dehydrogenase, 17 alpha hydroxylase or 11 beta hydroxylation; 21 hydroxylase activity may be marginally attenuated.
The retinal and neurological complications of abetalipoproteinaemia may be preventable by replacing vitamins A and E from an early age, but their role in adult presentations is less clear. Two adult females with abetalipoproteinaemia have received 8 and 10 years respectively of replacement therapy with vitamins A, E and linoleic acid. In Case 1, visual function improved objectively on commencing therapy but has subsequently deteriorated and her neuropathy has slowly progressed. The rate of progression of neurological impairment in Case 2 was slowed but not halted by therapy, and her severe visual disturbance was unaffected. Replacement by fat soluble vitamins has only a limited role in the management of abetalipoproteinaemia once irreversible neurological/retinal damage has occurred.
We have assessed the effect of omeprazole on various endocrine functions in man. Eight healthy subjects took 60 mg omeprazole or placebo daily for 1 week in a double-blind, randomized, cross-over study. On Day 7 basal concentrations of follicle-stimulating hormone (FSH), luteinising hormone (LH), prolactin, testosterone, thyroid-stimulating hormone (TSH), and serum thyroxine (T4) and tri-iodothyronine (T3) were measured, followed by the gonadotrophin response to luteinising hormone releasing hormone (LHRH) and the prolactin and TSH responses to thyrotrophin releasing hormone (TRH). There were no differences in basal or stimulated values between omeprazole and placebo. In a second study, a further 8 subjects were similarly treated, and on Day 7 serial measurements of cortisol and 11-deoxycortisol were made before and for 2.5 h after intravenous adrenocorticotrophin (ACTH). There were no differences in basal values or pattern of response to ACTH for either hormone. Omeprazole in clinical practice is unlikely to cause any significant interference in endocrine function.
Radioligand binding studies were performed on 10 patients with cirrhosis and 10 healthy subjects. Bm. and KD of platelet a2-adrenoceptors, studied using [3H]-yohimbine, were similar in both groups (Bmax 24.9 vs 22.1 fmoll109 platelets, P = 0.47; KD 4.6 vs 5.5 nmol -1, P = 0.56). Bmax and KD of lymphocyte 132-adrenoceptors, studied using [125I]_ iodocyanopindolol, were also similar in both groups (Bmax 24.0 vs 27.2 fmol mg-' protein, P = 0.55; KD 49.6 vs 55.3 pmol l1-, P = 0.65). In this model there is no evidence of adrenoceptor down-regulation in cirrhosis despite the increased sympathetic activity in this condition.
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