Pyridobenzodiazepines: a novel class of orally active, vasopressin V2 receptor selective agonists.

Our efforts in seeking low molecular weight agonists of the antidiuretic peptide hormone arginine vasopressin (AVP) have led to the identification of the clinical candidate WAY-151932 (VNA-932). Further exploration of the structural requirements for agonist activity has provided another class of potent, orally active, non-peptidic vasopressin V2 receptor selective agonists exemplified by the 5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepine as a candidate for further development.

Metabolites of the angiotensin II antagonist tasosartan: the importance of a second acidic group.

Described in this paper is the synthesis and pharmacological activity of five metabolites of the angiotensin II antagonist tasosartan (1). Of particular interest is the effect of the additional acidic group of the enol metabolite (8) on activity. As suggested by the structural-activity relationship of other angiotensin II antagonist series, a second acidic group can improve receptor binding activity but decrease in vivo activity after oral dosing.

Characterization of serotonin receptors in isolated rat intramyocardial coronary artery.

The purpose of the present study was to characterize the receptor subtypes that mediate serotonin (5-HT)-induced contraction in isolated rat intramyocardial coronary artery. In coronary artery with and without endothelium, only 5-HT and alpha-methylserotonin maleate (5-HT2 agonist) elicited equipotent concentration-dependent contractions. The EC50 values for 5-HT and alpha-methylserotonin maleate in endothelium-intact arteries were 4.

Endothelium-dependent basilar and aortic vascular responses in normotensive and coarctation hypertensive rats.

The responsiveness of acetylcholine (ACh), nitroglycerin (NG) and norepinephrine (NE) (aorta only) in both basilar arteries (BA) and thoracic aortic (TA) rings from coarctation hypertensive rats (CHR) were studied and compared to their sham-operated normotensive control rats (SNR). The effects of these agents were also evaluated in TA or BA with and without endothelium from naive normotensive rats (NNR). Blood pressure (BP) and plasma renin activity (PRA) of CHR were significantly higher than their time-matched SNR.

Effect of gamma-aminobutyric acid (GABA) on vasodilation in resistance-sized arteries isolated from the monkey, rabbit, and rat.

The effect of gamma-aminobutyric acid (GABA) and papaverine on cerebral arteries of rat, rabbit, and monkey and the small mesenteric arteries of the rat were studied in vitro with a microvessel apparatus. GABA (1 x 10(-7) to 1 x 10(-3) M) did not affect the basal tension of arteries of rats at rest. In PGF2 alpha-contracted monkey basilar artery and middle cerebral artery and rat basilar artery, cumulative addition of GABA (1 x 10(-7) to 1 x 10(-3) M) did not produce any relaxation.

Relaxant actions of viprostol and prostaglandin E2 on tracheal muscle and their effects on calcium influx.

The relaxant effect of viprostol was studied in monkey and guinea-pig tracheal muscle rings in vitro and compared to that of prostaglandin E2 (PGE2), isoproterenol (ISO) and verapamil (guinea-pig trachea only). Viprostol, PGE2, ISO and verapamil produced a concentration-dependent relaxation of carbachol-contracted tracheal preparations. The rank order of potency in monkey trachea was viprostol = ISO greater than PGE2, while in guinea-pig treachea it was ISO greater than viprostol greater than PGE2 greater than verapamil.

Studies on the effects of viprostol in isolated small blood vessels and thoracic aorta of the rat.

1. The effects of viprostol, prostaglandin E2 (PGE2) and nitroglycerin were studied in basilar artery, small mesenteric artery and the vein parallel to it as well as thoracic aorta of the rat. 2.

The vasorelaxant effect of (+/-)-15-deoxy-16-hydroxy-16(alpha/beta)-vinyl-prostaglandin E2 (CL 115, 129) and its methyl ester (CL 115, 347) on the isolated ductus arteriosus preparation.

CL 115, 129 and its methyl ester, CL 115, 347, were studied for their vasorelaxant effects and compared to that of prostaglandin (PG) E2 and its methyl ester on isolated ductus arteriosus (DA) from fetal lambs and rabbits. CL 115, 129 and CL 115, 347 potently relaxed the oxygen-indomethacin constricted ductus in a concentration dependent manner. The threshold concentration was 1 X 10(-12)M and the estimated EC50's (M) were 6.

Effects of CL 115,347, (+/-)-15-deoxy-16-hydroxy-16-vinyl-PGE2 methyl ester, on cardiovascular responses and plasma catecholamines in pithed stroke-prone spontaneously hypertensive rats during sympathetic stimulation.

The effect of CL 115,347, a topically active antihypertensive PGE2 analog, and PGE2 on changes in blood pressure (BP), heart rate (HR) response and plasma epinephrine (E) and norepinephrine (NE) levels induced by stimulation of the sympathetic spinal cord outflow were studied in pithed stroke-prone spontaneously hypertensive rats (SHRSP). Surgical pithing significantly reduced plasma E but not NE levels suggesting that the sympathoadrenal medullary system differentially affects E and NE release. Sympathetic stimulation of the spinal cord of pithed SHRSP increased HR, BP, plasma E and NE levels.

Aortic vascular and atrial responses to (+/-)-1-O-octadecyl-2-acetyl-glyceryl-3-phosphorylcholine.

The effects of (+/-)-1-O-octadecyl-2-acetyl-glyceryl-3-phosphorylcholine (octadecyl-AGPC) were studied in three types of aortic vascular smooth muscle preparations, namely, strips, rubbed and unrubbed rings, and an atrial preparation in normotensive rats. In the resting tension state, octadecyl-AGPC did not elicit significant contractions in either rubbed or unrubbed ring preparations at concentrations lower than 1 X 10(-4) M. However, at a concentration of 3 X 10(-4) M, octadecyl-AGPC markedly contracted both types of ring preparations.

Effect of caloric restriction on cardiac reactivity and beta-adrenoceptor concentration.

The effect of a 21-day program of caloric restriction on cardiac reactivity and beta-adrenoceptor number was investigated in male Sprague-Dawley rats. Rats on the restricted diet (Restricted) exhibited significant decreases in body weight, epididymal fat pad, and retroperitoneal fat pad weight as well as the percent of body fat represented by these adipose tissue depots when compared with rats fed ad libitum (Fed). Fed rats exhibited significantly increased total heart weight and total heart protein, but the percent cardiac protein and ratio of heart weight to body weight were similar in Fed and Restricted rats.

Studies on the mechanism of the enhancement of the antihypertensive activity of captopril by a diuretic in spontaneously hypertensive rats.

Captopril (30 mg/kg/day orally for two days) in spontaneously hypertensive rats (SHR) inhibited serum angiotensin converting enzyme (ACE) activity 92.3%; increased plasma renin activity (PRA) 18-fold and reduced mean arterial blood pressure (MABP) 19 mm Hg. Hydrochlorothiazide (HCTZ) (100 mg/kg-day 1; 10 mg/kg-day 2, orally) increased PRA 3-fold but did not affect serum ACE or MABP.

A comparison of cardiac reactivity and beta-adrenoceptor number and affinity between aorta-coarcted hypertensive and normotensive rats.

1 The effects of noradrenaline (NA) and isoprenaline on isolated atria from aorta-coarcted hypertensive rats (AHR) at early (6 day) and chronic (28 day) stages of hypertension were studied and compared with time-matched, sham-operated, normotensive rats (SNR). The number and affinity of beta-adrenoceptor ((-)-[3H]-dihydroalprenolol binding sites) were also studied in cardiac membranes prepared from these animals. 2 Six and 28 days after complete ligation of the abdominal aorta between the two renal arteries, rats became hypertensive with significantly greater arterial blood pressures than time-matched SNR.

Effect of the time interval between blood sampling and assay on serum angiotensin I-converting enzyme activity from captopril-treated rats.

Intra-arterial injection of captopril (1 mg/kg) effectively lowered arterial blood pressure in aorta-coarcted hypertensive rats along with an associated reduction of serum angiotensin I-converting enzyme (ACE) activity. ACE activity in serum samples from captopril-treated animals that were assayed within 60 min after collection was inhibited 93%. However, this inhibition progressively decreased as the interval between time of assay and blood collection increased.

Effects of different stages of aortic coarctation hypertension on aortic contraction and relaxation in rats.

Contractile responses to norepinephrine, serotonin and potassium (K+) and relaxant responses to isoproterenol and papaverine were studied in vitro with spirally cut thoracic aortic strips from aortic coarcted hypertensive rats (AHR)2, 6, 14 and 28 days postoperatively and compared to time-matched, sham-operated normotensive controls. At every stage after coarctation, the rats developed hypertension with elevated plasma renin activity. In response to stimulation by norepinephrine and serotonin, aortic strips from 2 to 28 day AHR developed the same tension as controls, whereas aortas of 6 and 14 day AHR had reduced maximal responses.

On the mechanisms of coupling in adrenaline-induced bigeminy in sensitized hearts.

The mechanism of coupling in adrenaline-induced ventricular bigeminy in sensitized hearts has been investigated in intact animals, isolated preparations, and single cardiac fibers. The electrophysiological and cardiovascular dynamic changes during the development of fixed interval coupling strongly indicate that the coupled beats result from stretch of subsidiary pacemaker fibers in the specialized ventricular conduction system, induced by the mechanical response to the normally conducted sinus impulse. The resulting intraventricular pressure elicits an extrasystole when a certain critical end systolic pressure for a particular animal is reached.