Renal function studies with cadralazine in conscious dogs: a comparison with hydralazine.

The effect of the antihypertensive vasodilator, cadralazine, on renal function in the conscious dog was compared to that of hydralazine using inulin and para-aminohippurate clearances. Both drugs were administered as intravenous bolus, at the dose of 1 mg/kg. As expected, hydralazine rapidly decreased mean blood pressure (from 110 to 89 mmHg), significantly increased heart rate (from 109 to 190 beats/min), markedly decreased urine volume (from 0.90 to 0.47 ml/min) and sodium excretion (from 101 to 45 microEq/min), and increased potassium excretion (from 28 to 53 microEq/min). Cadralazine displayed a similar activity on blood pressure and on heart rate, but differently from hydralazine, these effects appeared more slowly and were not accompanied by sodium and water retention. Hydralazine, but not cadralazine, caused a quick and transient decrease in glomerular filtration rate (from 55 to 40 ml/min), whereas both compounds increased renal plasma flow and reduced renal vascular resistance, renal extraction of para-aminohippurate and filtration fraction. Moreover, cadralazine increased plasma renin activity to a lesser extent than hydralazine, and this could explain the different effect on water and sodium excretion after acute administration of the two drugs.

The use of stable prostaglandins to investigate prostacyclin (PGI2)-binding sites and PGI2-sensitive adenylate cyclase in human platelet membranes.

Prostacyclin, (PGI2) is a potent but unstable inhibitor of platelet aggregation, probably acting through stimulation of adenylate cyclase. A stable analogue of prostacyclin with antiaggregatory properties, 5,6-dihydro-PGI2 (6 beta-PGI1), and PGE1 can compete for the binding sites labelled by 3H-PGI2 in human platelet membranes (the affinity being PGI2 greater than PGE1 greater than 6 beta-PGI1). Both 6 beta-PGI1 and PGE1, as well as PGI2, bind to two classes of binding sites. 6 beta-PGI1 and PGE1 activate adenylate cyclase to the same extent as PGI2, with a rank order of potency which parallels that observed in binding experiments. The stimulation of this enzyme is brought about by interaction of each of these prostanoids with two different classes of components. The comparison of binding and adenylate cyclase data suggests that the sites to which PGI2, 6 beta-PGI1 and PGE1 bind might be coupled to the activation of adenylate cyclase. Since 6 beta-PGI1 seems to act through the same molecular mechanisms as PGI2, because of its stability it is an useful tool to investigate the mode of action of prostacyclin in platelets.

Hemodynamic profile of the antihypertensive vasodilator cadralazine in conscious dogs.

Hemodynamic activity of cadralazine (ethyl-2-[6-(2-hydroxypropyl)-ethylaminol-3-pyridazinyl hydrazine carboxylate), a new, long-acting antihypertensive agent, was evaluated on systemic and regional circulation in conscious dogs. Cadralazine given i.v. (1 mg/kg) caused a sustained fall in total peripheral vascular resistances and mean blood pressure (from 103 to 90 mmHg) and an increase in heart rate (from 97 to 161 beats/min). Heart rate variations paralleled the drop in peripheral resistances. Cadralazine produced a consistent increase in cardiac output, and this effect was related to the increase in heart rate. No significant change in myocardial contractility was observed. Blood flow was increased and vascular resistances decreased in coronary, iliac and mostly in renal vascular beds, whereas the variations in the mesenteric district were not significant. This hemodynamic pattern characterizes cadralazine as a vasodilator. Changes in hemodynamic responses to epinephrine (1 microgram/kg i.v.) after cadralazine treatment were also evaluated. Cadralazine reduced hypertension and bradycardia effects, increased hypotension and tachycardia responses, and caused a further increase in cardiac output and coronary blood flow. These effects of cadralazine are not due to alpha-blocking or to beta-stimulating properties.

Effects of PGI2 on platelet aggregation and adenylate cyclase activity in human type IIa hypercholesterolemia.

The sensitivity to PGI2 of platelets of 20 selected type IIa hypercholesterolemic patients was studied and compared to that of platelets of 14 normocholesterolemic subjects. Type IIa subjects required higher concentrations of PGI2 to inhibit platelet aggregation elicited by 1 microM ADP, 1 microgram/ml collagen and 1.4 microM epinephrine. Adenylate cyclase activity was also measured in washed platelet membranes from the two groups of subjects. Adenylate cyclase activity, both basal and PGI2-stimulated, was not statistically different in the two groups examined. Therefore changes at the level of PGI2 receptors coupled to adenylate cyclase are not likely to be responsible for the different platelet sensitivity to prostacyclin.

New pharmacological aspects on the antiasthmatic activity of tiaramide-HCl.

Tiaramide hydrochloride (THC) is a benzothiazoline derivative with a remarkable antianaphylactic activity: in anaesthetized guinea-pig it shows protecting effects against histamine (H)- and bradykinin (Bk)-induced bronchoconstriction, preventing increase of lung resistance and decrease of dynamic compliance. At the same time THC inhibits formation of circulating thromboxane A2 brought about by H and Bk. THC is also able to antagonize the contractions induced by CaCl2 on isolated guinea-pig tracheal spirals and its mode of action seems to be of the competitive type. Furthermore THC abolishes the "tonic" phase of K+-induced contractions of guinea-pig taenia coli which are dependent on inward movement of calcium, whereas the "phasic" component of the contractions is left unaltered. THC is a very weak inhibitor of 3'-5' cyclic adenosine monophosphate phosphodiesterase which is affected only at very high dosage (10(-2) M). The calcium antagonistic activity of THC may explain both its bronchodilating and antianaphylactic properties.