William B. Abrams

The human platelet as a pharmacologic model for the adrenergic neuron

The uptake of norepinephrine (NE) by the human platelet resembles that of the adrenergic neuron. Platelets incubated with d1‐14C‐NE (2.1 x 10−6M) for one hour at 37° C. concentrated the amine to a distribution ratio of 5.1 ± 0.1. Uptake was markedly reduced by cold and metabolic inhibitors such as cyanide, fluoride, dinitrophenol, and PCMB. NE uptake was also diminished by ouabain, quinidine, and substitution of lithium for sodium in the medium, suggesting the uptake mechanism is related to a sodium pump. Drugs which interfere with the uptake of NE by the neuron have a similar effect on the platelet. Uptake of 14C‐NE was impaired by serotonin (5HT), tryptamine, tyramine, amphetamine, bretylium, debrisoquin, guanethidine, desmethylimipramine, and various antihistamines. 14C‐NE accumulated in the platelet by a preliminary incubation was released by reserpine, tyramine, phenylephrine, and debrisoquin, less by guanethidine, but not by ephedrine or mephentermine. 14C‐5HT was released by reserpine, tyramine, debrisoquin, and mephentermine, less by ephedrine, but not by guanethidine or phenylephrine. Thus, release or failure of release of NE or 5HT from platelets will not necessarily reflect the action of a drug on sympathetic neurons.

The influence of debrisoquin on the accumulation and metabolism of biogenic amines by the human platelet, in vivo and in vitro.

Although the platelet has a specialized function in the control of hemostasis,13 its membrane resembles that of many other cells. For example, the platelet maintains hydrogen ions against a concentration gradient24 and actively transports certain amino acids and sugars. 23, 25 In addition its membrane is permeable to several relatively large, lipid‐insoluble organic compounds. 23 The membrane of the platelet also shares certain characteristics with that of the adrenergic neuron; both cells actively accumulate such drugs as guanethidine4, 7 and debrisoquin.5, 9 In addition, desmethylimipramine inhibits the active uptake of serotonin by the platelet20 and the active uptake of norepinephrine by the neuron.1, 12

Debrisoquin, a selective inhibitor of intraneuronal monoamine oxidase in man

Indices of MAO activity were monitored during administration of debrisoquin to 4 patients with hypertension. That there was no inhibition of MAO was indicated by unaltered urinary tryptamine and tyramine excretion, no depression of intestinal mucosal MAO activity, and no decrease of intestinal inactivation of orally ingested tyramine. Inhibition of sympathetic neuronal MAO is suggested by increased sensitivity to intravenous tyramine with a slight increase in norepinephrine sensitivity, decreased urinary VMA, and increased NMN excretion. It is suggested that anatomic selectivity of enzyme inhibition is related to drug‐concentrating mechanisms in sympathetic neurons.

A new approach to the use of histamine skin tests in the study of antihistamine drugs.

Data are presented to show that the histamine skin test is more variable than previously appreciated. Dose‐response studies with the use of this test to evaluate antihistaminics should therefore include placebo and the use of the double‐blind technique. In this study the wheal alone appeared to be a sufficient discriminator of antihistamine activity.

Adrenergic Mechanisms in the Treatment of Essential Hypertension

A LTHOUGH the etiology of essential hypertension is unknown, the primary physiologic defect is increased peripheral vascular resistance due to increased tone of the arteriolar smooth muscle.*-5 The cause or causes of this increased tone have not yet been determined. Factors currently under consideration include increased activity of the sympathetic nervous system,2,5 a “resetting” of the carotid sinus and other pressure receptors,1,2,6,7 increased sensitivity of the arterioles to circulating pressor agents,*,9 increased sodium and water in the arterioiar cells,‘,1° renal ischemia leading to the release of renin, aldosterone11-13 or other pressor agentq4.14 increased cardiac output5 and ischemia of the vasomotor center due to atheroma of the cerebral arteries.15,16 Although abnormal activity of the sympathetic nervous system has long received prominent consideration as a causative factor in essential hypertension,2,5,17 this has not been confirmed by experiments or close clinical scrutiny.2,4,5 It is clear, nevertheless, that even in the presence of sustained hypertension such neural mechanisms are still capable of altering the blood pressure in response to appropriate stimuli,5,‘8 and many effective drugs whose major action is to inhibit the transmission of tonic stimuli via the sympathetic nervous system are in wide clinical use today. The desire for specificity of action has evoked special interest in those antisympathetic agents which act at the arteriolar neuroeffector site. It is these agents, principall) reserpine, guanethidine and bretylium, with which we are concerned here. We will discuss their mechanisms of action in lowering blood pressure and how the identification of these mechanisms altered long-established physiologic concepts of the efferent sympathetic nervous system. Phenoxybenzamine (Dibenzyline@), piperoxan (benzodioxane) and phentolamine (Regitine@) belong to this group, but ineffectiveness, early tolerance and/or side effects have prevented their wide use in the treatment of essential hypertension. lg