Medicine

It is impossible to predict what compounds of pharmacological interest may be present in an unexamined species. The extinction of such species may result, therefore, in the loss of therapeutically significant compounds. The fact that science will never know what has been lost does not lessen the significance of the loss. A number of species are discussed to exemplify the potential loss. Ginkgo biloba is an ancient plant, apparently saved from a natural extinction by human intervention. From this tree, the ginkgolides have been isolated. These are potent inhibitors of platelet activating factor and hold promise in the treatment of cerebral ischemia and brain edema. Two species, the tree Taxus brevifolia and the leech Hirudo medicinalis, are threatened as a result of human activity. Both have recently yielded complex compounds of therapeutic importance. The antitumor agent, taxol, is obtained from T. brevifolia and the thrombin inhibitor, hirudin, is found in H. medicinalis. Catharanthus roseus, source of the anticancer agents vincristine and vinblastine, although not threatened, derives from a largely unexamined but severely stressed ecosystem of some 5000 plant species. In other examples, ethnobotanical knowledge of certain plants may be lost while the species survive, as exemplified by the suppression of the Aztec ethnobotany of Mesoamerica by the invading Spanish. Finally, the fallacy of the 'snail darter syndrome', where species may be viewed as too insignificant to worry about, is exposed by consideration of the pharmacological activities of a sea hare (a shell-less marine mollusc) and various leeches.

1 The alkaloid, monocrotaline, causes significant pulmonary damage in many species, including the rat. We, therefore, determined whether the inactivation of biogenic amines by perfused lungs of rats was modified by prior treatment of the animals with monocrotaline. 2 Young rats (45 to 50 g) treated for 21 days with monocrotaline (22 1tg/ml) in their drinking water developed right ventricular hypertrophy. Treated animals gained weight more slowly and consumed less food and water than control rats that drank tap water. Lungs from monocrotalinetreated animals were heavier and had a higher protein content than control lungs.

Differential effects of amrinone on contractility and taurine influx in rat and guinea pig hearts, European J. Pharmacol. 67 (1980) 347--353. Amrinone (5-amino-3,4t-bipyridin-6(IH)-one) is a non-glycoside, non-catecholamine, positive inotropic agent with an unknown mechanism of action. In the Langendorff-perfused isolated guinea pig heart, we found that amrinone produced a maximum increase in contractile force of 33% at a concentration of 10 pg/ml (10.7 x 10 -s M), without change in heart rate. Maximum response occurred within 2 rain of initiating perfusion, and increased contractility persisted for several minutes of drug-free washout. Amrinone neither alleviated nor aggravated spontaneous arrhythmias. At the time of maximum inotropic response, amrinone produced no change in cyclic AMP levels. In contrast to the guinea pig, the Langendorff-perfused isolated rat heart responded with a decreased contractility when perfused with amrinone. Furthermore, whereas amrinone stimulated the influx of taurine in guinea pig hearts, taurine influx remained unaltered in rat hearts. This is the first case of stimulated taurine influx not being associated with an increase in cAMP concentrations. In the guinea pig heart, amrinone increased markedly the half life of exchange of intracellular calcium. It has been suggested that amrinone is positively inotropic because of a direct action on the contractile proteins. On the basis of our observations, We think it more likely to be due to the alterations in calcium flux caused by amrinone.

The & vivo release of six radiolabeled amino acids or amines in the hippocampus was investigated in genetically seizure-resistant and seizure-susceptible rats. No differences were found in the spontaneous or high K+-evoked efflux of 7-aminobutyric acid, norepinephrine or its metabolites, taurine or ~-aminoisobutyrate. However, seizure-susceptible rats released significantly more D-aspartic acid on K+-depolarization. The initial rate of release (flux) was also higher. In view of the ubiquity of synapses in the mammalian brain utilizing excitatory amino acids as their transmitter, we propose that an exaggerated release of these excitants might be a determinant of the innate seizure susceptibility in these animals.

Administration of monocrotaline, a pyrrolizidine alkaloid, to male Sprague-Dawley rats for up to three weeks increased dry lung weights by 64% and reduced the specific activity of lung angiotensin-converting enzyme activity by 64%. When the total activity per lung is calculated, however, there is no significant difference between control and monocrotaline-treated animals. The decrease in specific activity is due to increase in total lung protein (52% above control) and not to an actual reduction in the total angiotensin-converting enzyme activity in the lung.

The quantitative importance of diet versus biosynthesis as sources of taurine has been established in mice receiving dietary levels of 0.062% [3H]taurine and 0.74% [35S]methionine as sole sulfur-containing amino acids. After 15 days on diets radiolabeled with these levels of taurine and methionine, 16% of total-body taurine had been derived from diet and 24% from biosynthesis. By 30 days, these contributions had risen to 29% and 33%, respectively, and by 61 days to 46%. The half-life of turnover of taurine in the mouse was 18.6 days. These findings indicate that, like the rat and guinea pig, but unlike the cat and human, the mouse exhibits considerable biosynthetic capacity for taurine.

The influence of GSH concentration on metabolism of monocrotaline was examined in the isolated, perfused rat liver. Chloroethanol (0.37 mmol/kg), diethyl maleate (5.6 mmol/kg), and buthionine sulfoximine (72.9 mmol/kg) given in vivo reduced hepatic GSH from 3.7 mumol/g wet weight to 1.5, 0.6 and 0.9 mumol/g, respectively. Livers were then perfused in vitro for 1 hr with monocrotaline (0.5 mM). GSH depletion had no effect on the total release of pyrrolic metabolites of monocrotaline. Depletion, however, markedly affected the pattern of pyrrole release. Biliary release of 7-glutathionyl-6,7-dihydro-1-hydroxy-methyl-5H-pyrrolizine (GSDHP) was reduced by up to 72%. Pretreatment with diethyl maleate or buthionine sulfoximine increased the level of protein-bound pyrroles in the liver by 107 and 84%, respectively. Such pyrroles are probably responsible for liver toxicity. GSH depletion also led to a doubling of dehydromonocrotaline release into the perfusate. This metabolite is probably re...

Pyrrolizidine alkaloids (PAs) are a large group of structurally similar toxins. In animals, including man, they are hepatotoxic and in some cases pneumo- and neurotoxic. PAs are metabolized by the liver P450 system to reactive dehydroalkaloid (DHA) intermediates. PA toxicity is a result of alkylation of macromolecules by DHAs. We have measured the relative reactivity of a series of semi-synthetic DHAs by recording the rate at which they alkylate a model nucleophile, 4-(p-nitrobenzyl)pyridine. Rate data fit mono- or biexponential equations. Rank order of reactivity for the macrocyclic and open ester DHAs was the same as those measured for DHA hydrolysis. The reaction with 4-(p-nitrobenzyl)pyridine was easier to follow, however, as rates of reaction can easily be controlled by temperature or level of acid catalysis, and the final product can be measured colorimetrically. DHAs of the primarily hepatotoxic alkaloids, retrorsine and seneciphylline, were more reactive than DHAs of monocro...

The pathophysiologic mechanism by which chronic hypoxia causes pulmonary hypertension is unknown. If anti-platelet agents, or other pharmacologic interventions, altered the pulmonary vascular changes induced by hypoxia, information concerning the pathogenesis of the pulmonary hypertension or the potential therapeutic usefulness of the drugs might be obtained. In Study 1, rats exposed to chronic hypobaric hypoxia (PB = 520 mmHg) had a pulmonary arterial medial thickness of 6.7 +/- 0.6 mu compared to 4.1 +/- 0.2 mu* for control, normoxic rats (*p less than 0.05). Administration of dipyridamole (2mg/kg/day), or sulfinpyrazone (11 mg/kg/day) in the drinking water reduced the medial thickness to 5.0 +/- 0.3 mu* and 5.4 +/- 0.5 mu* respectively, thus suggesting the possible involvement of platelets in the response of the media to chronic hypoxia. In Study 2, hypoxic rats treated with the calcium blocker, flunarizine, were found to have less medial hypertrophy than a control group of hypox...