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C Semeraro

Publications and source records attributed to C Semeraro.

25 records · Page 2Linked to original sources
PubMed1989

Cardiovascular and renal action of dopaminergic prodrugs.

The possibility of exploiting the cardiovascular and renal action of dopamine for therapeutic purposes is enhanced by its conversion into orally active prodrugs. Following an outline of the medicinal chemistry bases of the development of these prodrugs, laboratory and clinical pharmacology of ibopamine, levodopa, gludopa, and TA-870 are reviewed, pointing out the interesting indications of various preliminary studies in heart failure, essential hypertension, and renal failure on the one hand, and the extensive therapeutic experience with ibopamine as an "inodilator" in the chronic treatment of congestive heart failure on the other hand. New experimental results are also reported for ibopamine and for the novel prodrug Sim 2055, i.e., epinine-4-O-phosphate. The latter is shown to act as a selective renal vasodilator on oral administration in dogs and it is therefore proposed for clinical investigation in renal failure and in essential hypertension.

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PubMed1984

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.

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PubMed1980

Renal function studies with propildazine alone and in combination with propranolol in dogs.

The vasodilator antihypertensive propildazine acutely administered in awake dogs (0.1 mg/kg i.v.) produced an arterial blood pressure drop accompanied by tachycardia, decreased urine volume and urinary sodium excretion, and increased urinary potassium excretion. A transient, quickly reversible decrease in glomerular filtration rate was observed; on the contrary, the reduction in urine volume and urinary sodium excretion was longer lasting. There was indirect evidence that sodium retention was mainly caused by increased tubular reabsorption. Decreases in renal resistance, renal extraction of p-aminohippurate, and filtration fraction were observed together with an increase in renal plasma flow. Propildazine at the above dose in combination with propranolol (1 mg/kg i.v.) had a hypotensive effect with a smaller increase in heart rate and without significant variations in urine volume or urinary sodium excretion. These effects could be attributed to antagonism of the reflex-activated sympathoadrenal system by propranolol. In these conditions, the glomerular filtration rate was not significantly modified, while the effects on other renal parameters were similar to those observed with propildazine.

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PubMedDate not supplied

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.

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PubMedDate not supplied

Pharmacological studies on cadralazine: a new antihypertensive vasodilator drug.

Cadralazine is a new, orally effective antihypertensive vasodilator. Acute experiments indicate that the compound reduces blood pressure and increases heart rate. The doses which reduce systolic blood pressure by 25% (ED25) are very similar after oral and intravenous administration (spontaneously hypertensive rats, 1.8 mg/kg, p.o.; 2.3 mg/kg, i.v.; renal hypertensive dogs, 0.26 mg/kg, p.o.; 0.24 mg/kg, i.v.; awake normotensive dogs, 0.98 mg/kg, p.o.; 1.01 mg/kg, i.v.). By both routes the peak effect is reached after 3-5 hr, and the activity lasts more than 24 hr. Repeated oral administration in spontaneously hypertensive rats reduces blood pressure with no evidence of tolerance. Cadralazine reverses hypertensive responses to epinephrine in awake normotensive dogs and anesthetized cats. The inhibition of the increase in blood pressure induced by sympathetic outflow activation in pithed rats parallels the antihypertensive activity in onset, intensity, and duration. The effects of cadralazine are not due to a blockade of alpha-adrenoceptors, sympathetic neurons, or ganglionic transmission. Cadralazine has no antihistaminic, anticholinergic, or spasmolytic activity and no specific effect on behavioral tests. In comparison with hydralazine, cadralazine has less acute toxicity and a greater activity by the oral route.

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PubMedDate not supplied

The role of dopaminergic agonists in congestive heart failure.

Congestive Heart Failure is a clinical syndrome characterised by myocardial dysfunction and sympathetic activation. Plasma norepinephrine (NE) levels have been related to the poorest survival. Large-scale clinical trials have proved the clinical benefits of Angiotensin Converting Enzyme inhibitors in reducing the risk of death and hospitalisation. However, mortality remains high in the treated group underlining the need to explore new therapeutic approaches. Specific activation of peripheral dopamine receptors exerts profound hemodynamic effects and neurohormonal control such as peripheral and renal vasodilation, diuresis and natriuresis and inhibition of NE release. Z1046, a mixed D1/D2-like agonist, reduces peripheral and renal vascular resistance increasing renal blood flow. In anaesthetised dogs the compound strongly reduces plasma NE without increasing plasma renin activity and plasma aldosterone. The inhibition of NE could be the basis of Z1046 potent cardioprotective effect observed in a dog model of myocardial ischemia and reperfusion, in which the severity of ventricular arrhythmias was markedly reduced, resulting in higher survival. These findings suggest that chronic oral treatment with specific dopaminergic agonists is able to alleviate the hemodynamic burden on the myocardium, and to suppress the sympatho-adrenal activity.

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