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Biomedical subjects

R H Becker

Publications and source records attributed to R H Becker.

27 records · Page 2Linked to original sources
PubMed1988

General pharmacology of ramipril.

General pharmacological properties of (+)-(1S,3S,5S)-2-[(S)-N-[(S)-1-ethoxycarbonyl-3-phenyl-propyl] alanyl]-2-azabicyclo[3.3.0]octane-3-carboxylic acid (ramipril, Hoe 498), a new prodrug non-sulfhydryl angiotensin converting enzyme inhibitor and its active diacid metabolite, ramiprilat, were examined. Both ramipril and ramiprilat were without effect on basal central and autonomic nervous systems in rats and mice. Ramipril given intravenously to anaesthetized normotensive dogs produced a slight fall in blood pressure but did not significantly alter other cardio-hemodynamic functions. Also, ramiprilat was without effect on isolated atria and airway resistance of guinea pigs. Oral administration of ramipril to dogs increased renal blood flow but did not significantly affect other renal parameters, for example, glomerular filtration rate and electrolyte excretion. Ramipril produced a competitive inhibition of late proximal tubular secretion which points to in part renal secretory excretion of ramipril and/or its metabolites. Compared to urea-induced diuresis in rats, ramipril was without direct diuretic activity. Ramipril exerted little, if any, influence on gastric bile and pancreatic secretion or intestinal transit in rats, as well as on concentration of glucose and lipoproteins, blood coagulation, platelet aggregation and vascular permeability in rats, rabbits or dogs. The carrageenin-induced rat paw edema was enlarged by ramipril, but there was no such effect on serotonin-, dextran- or ovalbumin-induced edemas which in contrast to carrageenin do not involve bradykinin. Thus, undesired cutaneous reactions might result from locally released bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

CE inhibition and natriuresis with ramipril in conscious SHR: different modes of action of loop and thiazide diuretics.

Acute effects of piretanide, a loop diuretic, on blood pressure (BP) and urinary output as well as long-term effects on serum electrolytes were compared in conscious spontaneously hypertensive rats (SHR) to that of hydrochlorothiazide (HCT) both given alone and in combination with the converting enzyme (CE) inhibitor ramipril. There were no acute or chronic falls in BP with low doses of either diuretic. Ramipril at a dose of 10 mg/kg normalized BP, which was accompanied by initial natriuresis and, over the long term, K+ preservation. Minimally effective doses of piretanide but not HCT given in combination with 1 mg/kg ramipril produced a greater fall in BP both acutely and chronically than ramipril alone at unaltered K+ preservation. To match this fall in BP with HCT, large doses were required, which caused hemoconcentration and impaired K+ preservation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

Effect of captopril on changes in plasma noradrenaline induced by sodium nitroprusside.

There is much animal data to suggest that angiotensin II has a regulatory role in noradrenaline release. We sought evidence for such a mechanism in man by pretreating six normal volunteers with captopril (50 mg) or placebo and then infusing them with incremental doses of sodium nitroprusside. Pretreatment with captopril had no significant effect on the mean arterial pressure, heart rate or plasma noradrenaline response to sodium nitroprusside, despite increasing plasma renin activity. This suggests that in normotensive salt replete man, normal levels of angiotensin II do not exert any tonic effect on noradrenaline release.

Adult↗
PubMed1985

Physical performance during sustained converting enzyme inhibition with Hoe 498 in conscious dogs.

The effect of sustained converting enzyme (CE) inhibition on modest levels of exercise performance was investigated using German Shepherds. The dogs were trained to run on an inclined treadmill and to tolerate repeated jugular venous puncture. The effects of exercise were assessed by monitoring heart rate and respiratory rate and plasma catecholamine- and serum electrolyte concentrations on each of two control runs. Plasma CE- and renin activity were also determined. Inhibition of CE-activity was established thereafter by high dose treatment with 10 mg/kg Hoe 498 p.o. once daily for one week and the run repeated. These large doses of Hoe 498 were well tolerated. Neither running performance nor cardiorespiratory responses were altered by CE-inhibition. Plasma K+ and catecholamines were taken as measures of peripheral sympathetic activity, and CE-inhibition did not alter the increase in either of these in response to exercise. It is concluded that converting enzyme inhibition with Hoe 498 does not impair exercise performance despite any direct effects the loss of angiotensin II may have on reflex sympathetic functions.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Pharmacological properties of the new orally active angiotensin converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl] -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498).

2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S) - 2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) can be characterized as a novel orally active non-sulfhydryl containing angiotensin converting enzyme inhibitor. Designed as a prodrug to improve the bioavailability Hoe 498 has to be deesterified to its active moiety Hoe 498-diacid to develop full inhibitory potency. The present study compares the basic pharmacological properties of Hoe 498 in rats and dogs to those of enalapril. In vitro assays revealed equal potency of both Hoe 498-diacid and enalaprilat. In vivo the inhibitory potency was judged by the ability to attenuate the pressor response induced by angiotensin I. The results indicate that Hoe 498 was approximately 10 times more potent than enalapril after oral intake in conscious rats or after intraduodenal administration in anaesthetized rats, whereas after intravenous injection both compounds exhibited equal potency. Hoe 498 was at least twice as potent as enalapril after oral or intraduodenal administration in dogs but about 4 times more potent than enalapril after intravenous injection. In conclusion, the obtained data point to a prodrug pathway for Hoe 498 which should be advantageous with regard to bioavailability, onset and duration of action and therefore promises to be favourable in the treatment of different cardiovascular diseases.

Angiotensin I↗
PubMed1984

Cardiovascular and antihypertensive activities of the novel non-sulfhydryl converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498).

The cardiovascular and antihypertensive activities of the novel orally active non-sulfhydryl converting enzyme (CE) inhibitor 2-[N-[(S)-1-Ethoxycarbonyl-3-phenyl-propyl]-L-alanyl] -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) were evaluated in several experimental preparations. The hemodynamic profile of Hoe 498 in anesthetized animals was characterized by a reduction in systemic blood pressure which was associated with a decrease in total peripheral and renal vascular resistance. These effects were enhanced upon sodium depletion. In conscious normotensive rats a single oral administration of Hoe 498 reduced systemic blood pressure for more than 5 h. The development of acute renovascular hypertension in anesthetized rats was prevented by oral pretreatment with Hoe 498. In conscious rats with renovascular hypertension (two-kidney, one clip) single oral doses of Hoe 498 induced a long lasting antihypertensive effect. Chronic oral treatment of spontaneously hypertensive rats with Hoe 498 lowered arterial blood pressure more effectively than enalapril. The threshold antihypertensive dose for Hoe 498 was 0.01 mg/kg/d, for enalapril 1 mg/kg/d. In conscious hypertensive dogs (two-kidney, two wrapped) Hoe 498 at a single oral dose of 10 mg/kg reduced systemic blood pressure for more than 6 h. Oral administration of Hoe 498 in a dose of 1 mg/kg/d for 5 d normalized systemic blood pressure in conscious hypertensive dogs. These findings demonstrate that in various models of experimental hypertension the novel orally active converting enzyme inhibitor Hoe 498 exerts marked cardiovascular and potent prolonged antihypertensive activities, which merit exploration with respect to possible therapeutic benefits.

Anesthesia↗
PubMed1982

A microsphere study on the effects of somatostatin and secretin on regional blood flow in anesthetized dogs.

The endogenous peptides somatostatin and secretin are effective in the therapy of upper gastrointestinal tract bleeding and acute pancreatitis. The clinical effects may be partly brought about by changes in the regional blood flow. To evaluate the effects of somatostatin (50 and 100 micrograms/min over 6-8 min) and secretin (0.1 and 0.5 U X kg-1 X min-1 over 3-5 min) on tissue blood flow, particularly of the gastrointestinal tract, the tracer microsphere reference sample method was used in anesthetized dogs. Infusion of somatostatin significantly diminished gastric and pancreatic blood flow whereas no changes of duodenal and ileal blood flow could be obtained. Blood flow through spleen, kidneys and adrenal glands was increased but no changes were observed in the blood flow of other tissues. Cardiac hemodynamics remained unchanged. Secretin increased the blood flow of the duodenum, the kidneys and the adrenal glands and diminished gastric blood flow without changing pancreatic, ileal, hepatic, pulmonary and muscle blood flow. Cerebral, pituitary and myocardial blood flow was increased by a higher dose of secretin. It also evoked a slight but significant positive ino- and chronotropic effect. Since secretin and somatostatin differ in their respective effects on gastrointestinal blood flow it is suggested that the previously reported beneficial effects of both peptides on upper gastrointestinal bleeding cannot solely be attributed to changes in regional blood flow.

Animals↗