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Biomedical subjects

M R Goldberg

Publications and source records attributed to M R Goldberg.

At least 73 records · Page 4Linked to original sources
PubMed1986

Abdominal aortic aneurysm resection in patients more than 80 years old.

Improvement in anesthetic and surgical techniques has prompted a more aggressive approach to repair of abdominal aortic aneurysms in patients more than 80 years old. In order to determine if surgical treatment is justified, all of the patients who were more than 80 years old admitted to the hospital during the ten year period from 1974 to 1983 with the diagnosis of abdominal aortic aneurysm were reviewed. A total of 90 patients were available for analysis. The mortality of the 18 patients treated conservatively for ruptured aortic aneurysms was 100 per cent. Ten of the 27 patients operated upon for a ruptured aneurysm died yielding a mortality of 37 per cent. Eleven patients with symptomatic aneurysms had urgent repair with a mortality of 27 per cent. Only one of the 34 patients undergoing elective aneurysm repair died. There was no difference in the size of aneurysms among the groups. Although the ruptured aneurysms required more blood (10.2 +/- 3.7 units), there was no difference between the other two groups (symptomatic 4.5 +/- 3.1 units, elective 4.6 +/- 2.8 units). There was significantly fewer myocardial and renal complications in the elective group, although the sole death in this group was from myocardial infarction. Based upon these observations, we recommend aggressive elective therapy for selected patients who are more than 80 years of age with asymptomatic abdominal aortic aneurysms. Although the mortality is higher in those patients with symptomatic or ruptured aneurysms, it is not formidable, and therefore, repair should not be ruled out on the basis of age alone.

Aged↗
PubMed1985

Hemodynamic and humoral effects of caffeine in autonomic failure. Therapeutic implications for postprandial hypotension.

We examined the effects of caffeine and meals on blood pressure and heart rate in 12 patients with autonomic failure. The influence of caffeine on plasma norepinephrine, epinephrine, and renin activity was also studied. Caffeine 250 mg, raised blood pressure by 12/6 mm Hg, from 129 +/- 25/78 +/- 12 (mean +/- S.D.) to a maximum of 141 +/- 30/84 +/- 16 mm Hg at 45 minutes (P less than 0.01), but did not change heart rate, levels of norepinephrine, or epinephrine, or plasma renin activity. Blood pressure fell by 28/18 mm Hg after a standardized meal, from 133 +/- 32/80 +/- 15 to a minimum of 105 +/- 21/62 +/- 12 mm Hg at 60 minutes (P less than 0.01). After pretreatment with 250 mg of caffeine, the standardized meal induced a fall of only 11/10 mm Hg, from 140 +/- 33/79 +/- 7 to 129 +/- 31/69 +/- 13 mm Hg at 60 minutes (P less than 0.05 vs. values after the control per day for seven days) in five patients, postprandial blood pressures remained higher after caffeine than after placebo (P less than 0.05). We conclude that caffeine is a pressor agent and attenuates postprandial hypotension in autonomic failure, and that this effect is not primarily due to elevations in sympathoadrenal activity or activation of the renin-angiotensin system. Caffeine may be useful in the treatment of orthostatic hypotension due to autonomic failure, especially in the postprandial state.

Aged↗
PubMed1985

Prostacyclin biosynthesis and platelet function in autonomic dysfunction.

We measured urinary excretion of the principal metabolite of prostacyclin, PGI-M (2,3-dinor-6-keto-PGF1 alpha) in two patients with Shy-Drager syndrome and three with idiopathic orthostatic hypotension. All patients had a rise in blood pressure (30 +/- 6 mm Hg) after ingestion of 50 mg indomethacin. Urinary excretion of PGI-M was normal and fell 57 +/- 11% after administration of indomethacin. In two subjects, there was no evidence of any circulating inhibitor of platelet aggregation when hypotension was induced by upright posture or ingestion of a meal. Despite the efficacy of indomethacin, these patients with autonomic dysfunction did not show increased production of the vasodilator prostanoid prostacyclin.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Caffeine and hypertension.

The effect of prolonged caffeine administration on blood pressure in hypertensive subjects was assessed in a double-blind placebo-controlled study. Eighteen hypertensive subjects participated, nine of whom received placebo throughout the study and nine of whom received placebo during the first three days, caffeine during the subsequent seven days, and placebo during the final four days of the two-week study. Those who received caffeine were given 250 mg with meals three times daily. There were no untoward reactions in the course of the study, but one subject with unacceptably high blood pressures while receiving placebo had to be discharged from the study to resume antihypertensive therapy. Systolic blood pressure was immediately increased (9.2 +/- 3.4 mm Hg) within 15 minutes after the first dose of 250 mg of caffeine. On the first day of caffeine, systolic pressure was increased a mean of 7.3 +/- 4.0 mm Hg, but this was no longer significant after the initial day of caffeine administration. Diastolic pressure showed a trend toward increasing, but this never reached significance. The minor increases in plasma catecholamine levels and plasma renin activity were not significant on either a short- or long-term basis. After discontinuation of caffeine, no overshoot phenomena were observed. It is concluded that prolonged administration of caffeine is not associated with significant elevation in blood pressure, plasma catecholamine levels, or plasma renin activity in patients with borderline hypertension.

Adult↗
PubMed1984

Increased vascular beta2-adrenoceptor responsiveness in autonomic dysfunction.

Responsiveness to the vasopressor, vasodepressor and chronotropic effects of several sympathomimetic amines was assessed in 12 patients with severe autonomic dysfunction and in 8 age-matched control subjects. The patients with autonomic dysfunction showed a profound increase in responsiveness to both isoproterenol and phenylephrine as compared with control subjects. The mean bolus dose of isoproterenol required to increase heart rate by 25 beats/min was 0.9 + 0.2 microgram in the patients and 5.4 + 2.1 micrograms in the control subjects. The dose of isoproterenol required to reduce mean blood pressure by 25 mm Hg was 0.3 + 0.2 and 5.2 + 1.8 micrograms, respectively. Thus, although there is a 6-fold increase in responsiveness to the chronotropic effect of isoproterenol in autonomic dysfunction, the responsiveness to the drug's depressor effect is increased 17-fold. This enhanced depressor sensitivity is quite marked, even with oral beta-adrenoceptor agonists. Beta-adrenoceptor agonists must be used with caution in conditions associated with autonomic dysfunction if dangerous hypotension is to be avoided.

Aged↗
PubMed1984

Interactions of epinephrine, norepinephrine, dopamine and their corresponding alpha-methyl-substituted derivatives with alpha and beta adrenoceptors in the pithed rat.

The effects of alpha-methyl substitution of epinephrine, norepinephrine and dopamine were investigated at alpha-1, alpha-2, beta-1 and beta-2 adrenoceptors in the pithed rat. alpha-Methyl substitution of these three phenethylamines variably altered their capacity to elicit alpha adrenoceptor-mediated vasoconstriction, with slightly enhanced potency being observed for alpha-methyl substitution of norepinephrine and dopamine and a marked reduction in potency for alpha-methyl substitution of epinephrine. However, in all instances, alpha-methyl substitution resulted in a higher selectivity for alpha-2 adrenoceptors (over alpha-1 adrenoceptors). Thus, while epinephrine, norepinephrine and dopamine all produced vasoconstriction that was mediated equally by postsynaptic vascular alpha-1 and alpha-2 adrenoceptors, their corresponding alpha-methyl-substituted derivatives produced vasoconstriction exclusively by activation of postsynaptic vascular alpha-2 adrenoceptors. The beta-1 adrenoceptor-mediated chronotropic effects of these phenethylamines were inconsistently affected by alpha-methyl substitution, with an increase in potency being observed for alpha-methyl substitution of norepinephrine and decreases in potency being observed for alpha-methyl substitution of epinephrine and dopamine. In marked contrast, alpha-methyl substitution of epinephrine, norepinephrine and dopamine was associated with consistent and dramatic increases in potency for beta-2 adrenoceptor-mediated vasodepressor activity. These results indicate that alpha-2 and beta-2 adrenoceptors possess the unique ability to recognize and/or accept alpha-methyl substituents on phenethylamines and that this ability is not shared by their respective receptor subtypes, the alpha-1 and beta-1 adrenoceptors. Furthermore, the results show that alpha-methylepinephrine is a potent beta adrenoceptor agonist, with an apparent 500-fold selectivity for beta-2 adrenoceptors over beta-1 adrenoceptors.

Animals↗
PubMed1983

Clonidine raises blood pressure in severe idiopathic orthostatic hypotension.

The hemodynamic effects of clonidine were studied in four patients with sever idiopathic orthostatic hypotension and one patient with baroreceptor dysfunction. No depressor response to clonidine was observed in any patient with idiopathic orthostatic hypotension at any dosage. Rather, two patients responded to 0.4 mg of oral clonidine with a 40 mm Hg increment in systolic blood pressure lasting several hours. Each has been receiving clonidine, 0.4 mg twice daily, for one year with greatly increased functional capacity. The other two patients with idiopathic orthostatic hypotension had an even greater pressor response to 0.8 mg of oral clonidine, but adverse effects prevented continued therapeutic use. In marked contrast, the patient with baroreceptor dysfunction had a profound depressor response to 0.2 mg of clonidine. In the treatment of idiopathic orthostatic hypotension, the major advantage of clonidine over other pressor agents is its longer duration of action. The major adverse effects of the drug in these patients are sedation, dry mouth, altered mentation, and excessive hypertension. The drug should not be given to patients with mild idiopathic orthostatic hypotension or selective baroreceptor dysfunction, since severe hypotension may result.

Aged↗
PubMed1983

Influence of alpha-methyldopa treatment on adrenergic receptor binding in rat forebrain.

We studied the influence of 6 days treatment with alpha-methyldopa (50 mg/kg s.c.) twice daily on radioligand binding to alpha 1 [3H)prazosin), alpha 2 [3H)clonidine) and beta[3H)dihydroalprenolol (DHA] receptors in rat forebrain. A 27% rise (p less than 0.05) in the Bmax for (3H)prazosin without change in Kd was found. Following alpha-methyldopa, the Kd for (3H)clonidine was increased from 1.78 +/- 19 to 3.03 +/- nM and Bmax fell from 197 +/- 20 to 167 +/- 19 fmoles/mg protein (p less than 0.05). These findings suggest that chronic alpha-methyldopa therapy induces changes in alpha 1 and alpha 2 receptors which may modify the antihypertensive effect of alpha-methyldopa.

Animals↗
PubMed1983

Central and peripheral cardiovascular effects of alpha-methylepinephrine.

We compared peripheral and central cardiovascular effects of (+/-)-alpha-methylepinephrine (alpha-ME) and (+/-)-alpha-methylnorepinephrine (alpha-MNE), two putative active metabolites of alpha-methyldopa to those of (-)-epinephrine in urethane-anesthetized normotensive rats. Intravenous administration of 1 microgram doses of alpha-ME (4.3 nmol) lowered blood pressure whereas alpha-MNE (4.5 nmol) and (-)-epinephrine (3.0 nmol) raised blood pressure. Heart rate responses to each were opposite to the blood pressure response, consistent with reflex buffering. When administered into the cerebral ventricle (5-20 micrograms) (15-90 nmol) and nucleus of the solitary tract (0.3-10 nmol), each catecholamine caused marked reductions in both blood pressure and heart rate. alpha-ME was more potent than alpha-MNE and the endogenous catecholamine, (-)-epinephrine, in its central depressor effect. The greater potency of alpha-ME relative to alpha-MNE and (-)-epinephrine suggests that it could contribute to antihypertensive actions of alpha-methyldopa.

Animals↗
PubMed1982

Caffeine down-regulates beta adrenoreceptors in rat forebrain.

We studied the influence of caffeine treatment (50 mg/kg for 3 doses) on catecholamine utilization and adrenergic receptor binding in female rats. Caffeine enhanced the reduction in forebrain norepinephrine levels following alpha-methyl-p-tyrosine without altering the reduction in dopamine levels. Caffeine reduced the apparent number of beta receptors in forebrain as measured by the Bmax for [3H]dihydroalprenolol binding. No changes in alpha1 or alpha2 receptor binding, as measured with [3H]prazosin and [3H]clonidine, respectively, were noted. These data show that caffeine selectively increases the rate of norepinephrine utilization in rat forebrain and that this is associated with a small, but significant, reduction in beta receptor density in this brain area.

Animals↗
PubMed1982

Evidence that alpha-methylepinephrine is an antihypertensive metabolite of alpha-methyldopa.

Several medullary cardiovascular relay nuclei contain high concentrations of epinephrine and phenylethanolamine-N-methyl transferase (PNMT), the enzyme which catalyzes the conversion of norepinephrine to epinephrine. Since alpha-methylnorepinephrine, a metabolite of alpha-methyldopa, has been shown to be a substrate for adrenal PNMT, we postulated that alpha-methylnorepinephrine would also be a substrate for central PNMT, resulting in the synthesis of alpha-methylepinephrine. Therefore, alpha-methylepinephrine could be an active metabolite of alpha-methyldopa. We have investigated this hypothesis. 1) The centrally-active PNMT inhibitor SKF-64139 attenuated the hypotensive response to alpha-methyldopa in spontaneously hypertensive rats at doses that had little effect on the hypotensive response to clonidine. 2) In radioligand binding studies, alpha-methylepinephrine was as potent as norepinephrine in competing for alpha 2-receptors, more potent than epinephrine, norepinephrine, or alpha-methylnorepinephrine in competing for beta-receptors, and less potent than epinephrine, norepinephrine, or alpha-methylnorepinephrine in competing for alpha 1-receptors. 3) Intracerebroventricular administration of methylepinephrine (1-40 micrograms) to Sprague-Dawley rats elicited profound hypotension and bradycardia. alpha-Methylepinephrine was more potent than epinephrine in lowering blood pressure. We conclude that alpha-methylepinephrine is a centrally active depressor agent and could therefore be an active metabolite of alpha-methyldopa.

Animals↗
PubMed1982

Differential competition by L-alpha-methyldopa metabolites for adrenergic receptors in rat forebrain.

The capacity of a series of intraneuronal metabolites of L-alpha-methyldopa to compete for alpha-1 ([3H]prazosin, alpha-2([3H]clonidine and beta ([3H]dihydroalprenolol) receptor binding in rat forebrain was studied. Each metabolite studied had a unique order of activity at each receptor. These data show that (-)-erythro-alpha-methylnorepinephrine and (-)-erythro-alpha-methylepinephrine compete with high affinity for alpha-2 receptors, thereby supporting the suggestion that alpha-2 receptors mediate hypotensive effects of L-alpha-methyldopa . Furthermore, these metabolites of L-alpha-methyldopa competed with high potency for beta-1 receptors in forebrain and (-)-erythro-alpha-methylepinephrine was more potent than (-)-epinephrine, (-)-norepinephrine and (-)-erythro-alpha-methylnorepinephrine in competing for beta-2 receptors on human lymphocytes. These data suggest that beta receptor stimulation may be important in determining the net effects of L-alpha-methyldopa. L-alpha-Methyldopa metabolites were much less potent than (-)-epinephrine and (-)-norepinephrine in competition for alpha-1 receptors. (+/-)-alpha-Methyldopamine was less potent than other l-alpha-methyldopa metabolites at all three receptors, suggesting that it is unlikely to be an important hypotensive metabolite of L-alpha-methyldopa.

Animals↗
PubMed1981

alpha-Methylepinephrine, a methyldopa metabolite that binds to alpha-receptors in rat brain.

The presence of phenylethanolamine-N-methyl transferase in those brain-stem nuclei where methyldopa is thought to act suggested to us that methylepinephrine could be an active metabolite of methyldopa. We assessed the potential of methylepinephrine to be an active metabolite by determining its capacity to compete for ligands which bind to alpha-receptors in rat brain. Thus, the abilities of epinephrine, norepinephrine, methyldopa, (+/-)-methylnorepinephrine and (+/-)-methylepinephrine to compete for alpha 1-([3H]WB-4101) and alpha 2-([3H]clonidine) binding sites in rat brain wee compared. Order of potency at each binding site was: [3H]WB-4101 -- (-)epinephrine = (-)-norepinephrine greater than (+/-)-methylnorepinephrine greater than (+/-)-methylepinephrine much greater than (-)-methyldopa; [3H]clonidine -- (-)-epinephrine greater than (+/-)-methylnorepinephrine greater than (-)-norepinephrine greater than (+/-)-methylepinephrine much greater than (-)-methyldopa. Since it can compete with a specific ligand for alpha 2-receptors, methylepinephrine could be a centrally active metabolite of methyldopa.

Animals↗
PubMed1981

(alpha S)-erythro-alpha-methylepinephrine: preparation and stereoselective binding to adrenergic receptors in rat forebrain.

The enantiomers of a number of catecholamines, including (alpha S)- and (alpha R)-erythro-alpha-methylepinephrine, were evaluated for their capacity to compete for binding sites in rat forebrain homogenates with [3H]prazosin, a ligand which selectively binds to adrenergic receptors of the alpha 1 subtype. (alpha R)-erythro-alpha-Methylepinephrine is devoid of apparent biological activity, but the activity of the alpha S isomer is substantial. The latter is less active than the endogeneous catecholamines, (R)-norepinephrine and (R)-epinephrine, but the stereospecific competition for [3H]prazosin binding sites by the catecholamine isomers with the beta R configuration is additional evidence that (alpha S)-erythro-alpha-methylepinephrine may be a biologically active metabolite of L-alpha-methyl-3,4-dihydroxyphenylalanine.

Animals↗