The cardiovascular effects of dopamine (DA) were studied in anesthetized dogs with special attention to the susceptibility of these effects to inhibition by catecholaminergic receptor blocking drugs. Dopamine given by rapid i.v. injection at 1 and 3 mug/kg produced depressor responses whereas doses from 9 to 81 mug/kg produced pressor resposes and increases in cardiac contractile force. Propranolol inhibited the increases in cardiac contractility whereas phenoxybenzamine potentiated the depressor effect of low doses of DA and reversed the pressor effect of high doses. Bulbocapnine blocked the depressor effect of DA in both phenoxybenzamine and propranolol-treated dogs. Pimozide, however, had no effect on the depressor response to DA. In hemodynamic studies, DA reduced blood pressure, total peripheral resistance and renal vascular resistance. Cardiac output and renal blood flow were increased. Bulbocapnine, but not pimozide, abolished the effects of DA on blood pressure, vascular resistance and renal blood flow. In conscious dogs, pimozide abolished apomorphine-induced emesis (an effect mediated by DA receptors in the central nervous system) whereas bulbocapnine had no effect. Therefore, the peripheral vascular and central dopamine receptors may be pharmacologically distinct.
Beta receptor blockade after propranolol and N-isopropyl- p -nitrophenylethanolamine (INPEA) was studied in both nonanesthetized and anesthetized dogs. In the conscious dog, inhibition of isoproterenol-induced tachycardia was dose-related after propranolol (0.2-3.2 mg/kg p.o.) and INPEA (3.2-38.4 mg/kg p.o.) treatment. Propranolol had no effect on resting heart rate whereas INPEA increased it at each dose level. In the anesthetized dog, propranolol (10-1250 µg/ kg i.v.) produced dose-related inhibition of the cardiac and vascular effects of a standard dose of isoproterenol and produced small reductions in resting myocardial contractile force. INPEA (0.5-12.5 mg/kg i.v.) produced similar inhibition of the agonist challenge and at low doses increased resting contractile force. The administration of 50 and 1250 µg/kg of propranolol produced significant reductions in mean blood pressure, coronary and aortic blood flow, left ventricular work and heart rate. Significant increases in coronary vascular resistance and mean left atrial pressure were also observed after each of these doses of propranolol, but total peripheral resistance was elevated significantly only after 50 µg/kg. Stroke volume remained unchanged after propranolol treatment. After doses of 2.5 and 12.5 mg/kg of INPEA, mean blood pressure and coronary blood flow were significantly lowered, while left ventricular work was reduced to a significant level only with the latter dose. In contrast to propranolol, INPEA slightly increased stroke volume and lowered total peripheral resistance, but had no effect on coronary resistance, aortic blood flow or mean left atrial pressure.
Application of bendroflumethiazide (BHFT) to the serosal surface of the isolated toad bladder promptly reduced short-circuit current (SCC) and conductance and later reduced the transepitheial potential difference. This effect can be reversed by removal of the drug. BHFT depressed the SCC largely by reducing the Na flux from the mucosal to the serosal medium. In control experiments there is a direct correlation between tissue conductance and the passive back flux of Na from serosa to mucosa. Despite the effect of BHFT on conductance, the drug did not consistently affect this flux. Mucosal application of BHFT stimulated SCC and potential difference. The effect of BHFT and that of antidiuretic hormone on SCC were additive. BHFT did not affect water flow or potentiate this effect of antidiuretic hormone. Exposure of both surfaces of the bladder to BHFT transiently stimulated SCC and then depressed it. BHFT entered the tissue from the serosal medium but did not cross into the mucosal medium. The drug did not enter the tissue when it was placed in the mucosal medium. BHFT did not affect tissue potassium concentrations.
In the rat, treatment with gastric inhibitory drugs may result in hypergastrinemia, an effect thought to be in response to increased gastric pH caused by inhibition of acid secretion. This study compared 24-hr profiles of plasma gastrin levels associated with three different compounds at equivalent, highly effective antisecretory doses. Ranitidine, famotidine and omeprazole at 60, 20 and 40 mg/kg p.o., respectively, inhibited basal acid secretion of chronic gastric fistula rats by greater than 95% and raised intraluminal pH to above 7.0 for 5 hr. The peak plasma gastrin levels associated with each agent were observed 5 hr after dosing. Ranitidine, famotidine and omeprazole induced statistically significant and distinct peak hypergastrinemic responses of 312 +/- 20, 483 +/- 28 and 616 +/- 27 pg/ml, respectively. After 8 hr ranitidine and famotidine associated gastrin values returned to control levels, whereas those of omeprazole remained substantially above control values until the 12th hr. Differences in peak gastrin levels between compounds disappeared at increased dose levels of 500 mg/kg for ranitidine, 200 or 2000 mg/kg for famotidine and 140 mg/kg for omeprazole. Unlike high dose famotidine, omeprazole (140 mg/kg) maintained peak plasma gastrin levels at 8, 12, and 16 hr after dosing. These studies demonstrate clearly hypergastrinemic responses to single dose administration of ranitidine, famotidine and omeprazole. The differences observed in peak plasma gastrin levels at equivalent antisecretory doses of these agents suggests the presence of luminal acid independent components that effect gastrin release. Moreover, these studies indicate that, in the rat, the most unique aspect of omeprazole-associated hypergastrinemia is the magnitude of its prolonged response.
3-Methyl-1,2,3,4-tetrahydro[1]benzothieno[3,2-c] pyridine hydrochloride (SK&F 7698) is a potent in vitro inhibitor of phenylethanolamine N-methyltransferase (PNMT) : its 150 in a standard assay was 7 x 10-7 M. The compound is a competitive inhibitor of the enzyme with respect to norepinephrine (NE) but is uncompetitive when S-adenosylmethionine is the variable substrate. In the rat, the compound selectively reduced the adrenal content of epinephrine (E) upon chronic oral administration. The adrenal NE levels were not decreased and no changes were produced in the heart and brain catecholamine content. Further evidence for in vivo PNMT inhibiting activity was the fact that the degree of conversion of a tracer dose of 3H-NE to 3H-E in the adrenal gland was inhibited by drug pretreatment. SK&F 7698 also produced alpha adrenergic blocking effects both in vitro and in vivo at doses approximating those required to inhibit PNMT and increased the rate of urinary excretion of both E and NE.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
