Leukotriene effects upon the transgastric potential difference and pepsin secretion.

The effects of leukotrienes on gastric mucosal function in vivo, and on acid and pepsin secretion in vitro were investigated. In cats, treatment with leukotrienes C4 (LTC4), D4 (LTD4), and E4 (LTE4) caused significant decreases in the transgastric electrical potential difference (P.D.) and significant increases in pepsin secretion, which returned toward control levels over 30-90 min. No detectable changes were observed in either acid concentration or gastric secretion volume over the entire 210 min experimental period. Leukotriene B4 (LTB4) had no effect upon any of these parameters. Treatment with LTD4 in isolated rabbit gastric glands resulted in significant increases in pepsin secretion, with no changes observed in aminopyrine accumulation (acid secretion). These results indicate that exogeneous LTC4, LTD4 and LTE4 can affect certain gastric mucosal functions.

Effects of indomethacin, aspirin and related compounds on the transgastric potential difference in cats.

Indomethacin was effective orally (intragastrically) and intravenously at 5 mg/kg in producing decreases in the transgastric electrical potential difference of anesthetized cats. The onset of action was, however, delayed as compared with direct irritants administered intragastrically such as salicylic acid. Aspirin administered intragastrically at 50 mg/kg caused a biphasic effect, an initial rapid drop followed by partial recovery after washout and then a subsequent slow decline similar to that observed after intravenous administration of the same dose. The effects of intragastric indomethacin were prevented by the concomitant topical administration of prostaglandin E2 while those of aspirin were only attenuated. The results are consistent with a prostaglandin mechanism (depletion) for the gastric mucosal effects of indomethacin. Aspirin, on the other hand, may have a direct irritant effect on the gastric mucosa as well as acting as an inhibitor of prostaglandin synthetase (cyclooxygenase).

Antihypertensive and other cardiovascular effects of 2-(3-pyridyl)- and 2-(4-pyridyl)-4-trifluoromethylimidazoles.

2 new 4-trifluoromethylimidazole derivatives were found which lowered mean arterial pressure in renal and spontaneously hypertensive (SH) rats by the oral route. In SH rats, compounds A and B were 0.1 and 0.3 times, respectively, as potent as hydralazine. No tolerance development was observed in SH rats with either compound over a 1-week period. In anesthetized dogs, both compounds lowered arterial pressure and peripheral vascular resistance but increased cardiac output. By intraarterial administration, both compounds increased femoral arterial blood flow. These findings represent discovery of a new class of vasodilator durgs.

Some cardiovascular effects of ST-91 and clonidine.

St-91, 2(2,6-diethylphenylamino)-2-imidazoline, is a clonidine derivative which does not penetrate the blood-brain barrier. In spontaneously hypertensive (SH) rats is acutely increased arterial pressure and reduced heart rate while at 8 to 12 h after oral administration, it slightly lowered arterial pressure. In contrast, clonidine had acute antihypertensive activity at all doses used. By intracerebroventricular administration to SH rats, both drugs (St-91 and clonidine) reduced arterial pressure and heart rate; in this respect, clonidine was more potent then St-91. Cardiac acceleration induced by low frequency electrical stimulation of right cardiac sympathetic nerves in anesthetized and vagotomized dogs was reduced by St-91 at the same doses by clonidine. Phenoxybenzamine, phentolamine and desipramine antagonized the inhibitory effects of St-91 on electrically induced cardiac acceleration. It was concluded that St-91, like clonidine, stimulates inhibitory alpha-adrenergic receptors at the sympathetic nerve endings but, unlike clonidine, is substantially devoid of acute antihypertensive activity. This suggests that stimulation of peripheral presynaptic inhibitory alpha-adrenergic receptors is not likely to represent the sole mechanism of antihypertensive action of clonidine.

Effects of phentolamine, phenoxybenzamine and desipramine on clonidine-induced blockade of cardiac acceleration in the dog.

Clonidine reduced cardiac acceleration induced by low frequency electrical stimulation of cardiac sympathetic nerve fibers in anesthetized and vagotomized dogs. This effect of clonidine was abolished by short periods of high frequency electrical stimulation. The inhibitory effect of clonidine was observed with 10- as well as with 90-sec periods of electrical stimulation of sympathetic nerve fibers; it was antagonized by phentolamine, phenoxybenzamine and desipramine. This suggests the presence of alpha-adrenoceptors at the peripheral sympathetic nerve ending in the dog.