Hans-Jurgen E. Hess

Antiinflammatory and analgesic activity of a non-peptide substance P receptor antagonist

CP-96,345, a potent non-peptide antagonist of the substance P (SP) receptor, inhibited SP-, neurokinin A (NKA)- and neurokinin B-induced plasma extravasation in guinea pig dorsal skin. The inhibition was specific for the three tachykinins; CP-96,345 was not active against plasma leakage caused by histamine, bradykinin, platelet-activating factor or leukotriene D4. CP-96,345 inhibited capsaicin-induced plasma extravasation in the ureter, an inflammatory response caused by neuropeptides released from afferent C-fibers. Thus, the NK1 receptor appears to play a major role in vascular permeability increases induced by exogenous and endogenous tachykinins. In contrast, CP-96,345 was inactive against SP- and NKA-induced contraction of guinea pig ureter, suggesting that the smooth muscle contraction is not NK1-mediated. CP-96,345 exhibited analgesic activity in acetic acid-induced abdominal stretching in mice, indicating for the first time that SP plays a critical role in this model. The results of these studies support a pathophysiological role of SP and NK1 receptor under acute neurogenic inflammatory conditions and in pain.

The cardiovascular effects of trimazosin

Trimazosin, a quinazoline related to the antihypertensive agent prazosin, was studied in anesthetized animals and isolated tissue preparations for effects related to cardiovascular activity. In cats, there was no evidence for ganglion-, adrenergic neurons-, or beta -adrenoceptor blockade, but the pressor effect of epinephrine was reversed. In dogs, the hypotensive effect to trimazosin was due to selective blockade of vascular alpha 1-adrenoceptors. Trimazosin competitively antagonized norepinephrine-induced contraction of rabbit aorta, and in rabbit pulmonary artery it selectively blocked postsynaptic alpha 1-adrenoceptors. In spinal-pithed dogs and rats trimazosin lowered blood pressure, in contrast to the lack of such activity reported for prazosin in pithed rats. It is concluded that trimazosin lowers blood pressure by selective blockade of alpha 1-adrenoceptors, and has, in addition, a hypotensive effect in pithed animals which is not due to alpha -adrenoceptor blockade.

Structure activity studies leading to a tissue-selective hypotensive prostaglandin analog, 13,14-dihydro-16-phenyl-ω-tetranor PGE2

Abstract During our systematic search for prostaglandins with improved tissue selectivity and metabolic stability, we synthesized a series of PGE 2 analogs in which the n-amyl carbinol side chain was systematically substituted by a phenyl ring, based on structural considerations incorporating the 17,18- cis -double bond of PGE 3 into an aromatic ring. These compounds were evaluated for uterine stimulant, bronchodilator and hypotensive activity. Among the divergent biological profiles exhibited by these analogs, noteworthy was the tissue-selective hypotensive profile displayed by 13,14-dihydro-16-phenyl-ω-tetranor PGE 2 .

Chapter 6. Agents Affecting Gastrointestinal Functions

Publisher Summary This chapter analyzes agents that affect gastrointestinal functions. Digestive diseases include disorders of the stomach, intestine, biliary passages, liver, and pancreas. Development work in the chemistry of the hormonal substances occurring in the mucosa of various parts of the gastrointestinal tract was reviewed. The structures of the gastrim and of secretin were elucidated and confirmed by synthesis. Cholecystokinin (CCK) and pancreozymin (PZ), long considered to be separate entities, were reported to be a single polypeptide containing 33 amino acids. The partial structure was determined and the C-terminal pentapeptide sequence found to be identical with that of gastrin. CCK-PZ bears a close structural resemblance to the decapeptide caerulein, in a study, were isolated from the skin of the Australian amphibian Hyla caerulea. Various biological activities of gastrin, as well as the mechanisms by which it is released, were reviewed. Endogenously released gastrin stimulates not only gastric acid and pepsin secretion but also pancreatic flow, bicarbonate and enzyme secretion, and hepatic biliary flow. In other studies, evidences were obtained favoring the hypothesis that histamine is the physiological mediator of the effects of gastrin and other stimulants of gastric secretion. Effects of prostaglandins on gastric secretion and gastrointestinal motility were also analyzed.

Chapter 7. Diuretic Agents

Publisher Summary This chapter examines biochemical studies related to the mechanism of action diuretic agents. A quantitative correlation between inhibition of guinea pig Na + , K + -activated membrane ATPase in vitro and the pharmacological effects of ethacrynic acid in dogs has been established. The observation that rat membrane fractions are insensitive to inhibition unless pretreated with a detergent for the removal of endogenous cations, explains why ethacrynic acid is not diuretic in the rat. Pharmacological and metabolism studies of mefruside, a new, clinically useful sulfonamide diuretic have been reported. Mefruside belongs to the class of benzene-1,3-disulfonamides of the chlorphenamide type. It differs from chlorphenamide, however, in that it does not increase bicarbonate excretion at therapeutic doses, but predominantly promotes the excretion of water and sodium accompanied by chloride. The natrifuretic and potassium-conserving effects of amiloride in rats and dogs have been described in the chapter. The drug moderately increases sodium elimination, accompanied by bicarbonate and to a lesser extent chloride, and decreases potassium excretion and water diuresis is not pronounced. Amiloride is excreted unchanged by rats, dogs, and man. It increases the potential difference and the short circuit current of the isolated ventral skin of the frog and reverses the effects of vasopressin in this preparation. The hyperglycemic and potential diabetogenic effect of the benzothiadiazine group of diuretics is also elaborated.