Biomedical subjects

E J Sybertz

Publications and source records attributed to E J Sybertz.

80 records · Page 5Linked to original sources

PubMed1977

Facilitation of Chemoreceptor-induced reflex vasoconstriction by intravertebral arterial administration of clonidine.

The influence of clonidine on the reflex vascular responses to stimulation of carotid body chemoreceptors and bilateral carotid occlusion was studied in morphine, chloralose-urethane anesthetized dogs. Bilateral carotid occlusion and intracarotid injection of nicotine (30 and 100 microgram) or sodium cyanide (200 and 500 microgram) elicited reflex vasoconstriction in the perfused gracilis muscle vascular bed. Infusion of clonidine (2-4 microgram/kg) into the vertebral artery significantly lowered blood pressure. Reflex vasoconstrictor responses to chemoreceptor stimulation were significantly enhanced after clonidine administration whereas reflex vasoconstrictor responses to carotid occlusion were markedly reduced. The facilitation of chemoreceptor reflex responses by clonidine was observed in dogs with intact or sectioned vagi and in animals in which the carotid arteries were perfused at constant blood flow. Inhibition of carotid occlusion responses by clonidine was observed in dogs with intact or sectioned vagi. Infusion of clonidine directly into the carotid arteries did not significantly alter responses to chemoreceptor stimulation. These experiments demonstrate that clonidine antagonizes the reflex vasoconstriction caused by carotid occlusion while potentiating the vasoconstriction elicited by chemoreceptor stimulation. The data suggest that clonidine exerts central actions which result in a facilitation of the chemoreceptor reflex and a simultaneously occuring hypotension which is probably due to an action on baroreceptor pathways.

Animals↗

PubMed1975

Uptake of 14C-angiotensin by canine cutaneous blood vessels.

The uptake of 14C-angiotensin was studied in canine cutaneous blood vessels in vitro. T/M ratios of 14C were 0.4, 0.5, 0.8 and 1.5 after 7.5, 15, 30 and 60 min of incubation, respectively. The T/M of 14C-sorbitol, an extracellular marker, was 0.4. No difference in the T/M ratios of C14 was found between normal and chronically denervated vessels incubated with 14C-angiotensin; however, the uptake of 3H-norepinephrine was markedly decreased in the denervated preparation. The 14C taken up by the vessels after 30 min of incubation appeared to comprise both intact angiotensin and metabolites. These results suggest that a small quantity of intact angiotensin may be bound by vascular tissue, but is not concentrated in adrenergic nerve endings.

Angiotensin II↗

PubMedDate not supplied

Studies on the mechanism of the acute antihypertensive and vasodilator actions of several beta-adrenoceptor antagonists.

Several new beta-adrenoceptor antagonists (sulfinalol, MK 761, and prizidilol) have been reported to possess direct vasodilator activity in addition to blocking beta-receptors. The mechanism of the hypotensive and vasodilator actions of these agents was examined and compared to that of pindolol and hydralazine. Intraarterial injection of each agent increased blood flow in the sympathetically denervated hindlimb of anesthetized dogs. Doses increasing flow by 50 ml/min (ED50) were 0.48, 0.24, 331, 0.3, and 51 micrograms for sulfinalol, MK 761, prizidilol, pindolol, and hydralazine, respectively, Intravenous injection of each agent reduced blood pressure of anesthetized, ganglion-blocked dogs. Vasodilation and hypotension to sulfinalol, MK 761, and pindolol, but not prizidilol or hydralazine were attenuated by propranolol pretreatment. Oral administration of sulfinalol (2.5 mg/kg), MK 761 (2.5 mg/kg), prizidilol (10 mg/kg), pindolol (0.1 mg/kg), and hydralazine (2.5 mg/kg) reduced pressure of conscious spontaneously hypertensive rats. Antihypertensive actions of sulfinalol and pindolol, but not MK 761, prizidilol, and hydralazine were inhibited by propranolol pretreatment (25 mg/kg, p.o.). With the exception of hydralazine, each agent demonstrated effective beta-adrenergic blockade at the antihypertensive dose tested as judged by inhibition of the chronotropic responses to sympathetic stimulation and isoproterenol in pithed rats. These data suggest that the acute vasodilator and blood pressure lowering effects of sulfinalol, MK 761, and pindolol, but not prizidilol and hydralazine, are mediated, at least in part, through activation of vascular beta-receptors.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Angiotensin-converting enzyme inhibitory activity of SCH 31846, a new non-sulfhydryl inhibitor.

SCH 31846, 1-(N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanyl)-cis, syn-octahydro-(H-indole-2-S)-carboxylic acid; CI-907; PD 109, 763-2, is a new non-sulfhydryl-containing, angiotensin-converting enzyme (ACE) inhibitor. The present investigation describes its ACE inhibitory properties and compares them to those of MK 421. The diacid of SCH 31846 inhibited rabbit pulmonary ACE with an IC50 of 2.2 nM (MK 421 diacid 2.5 nM). The drug behaved as a competitive and specific inhibitor in vitro. SCH 31846 and its diacid effectively inhibited pressor actions of intravenous injection of angiotensin I (AI) in anesthetized rats. ID50 values were 27 and 11 micrograms/kg for SCH 31846 and SCH 31846 diacid, respectively (MK 421 and MK 421 diacid 57 and 15 micrograms/kg, respectively). Oral administration of SCH 31846 (0.03-1 mg/kg) inhibited pressor actions of AI in conscious rats with a duration of over 16 h at 0.3 and 1 mg/kg. SCH 31846 was 2.2 times as potent as MK 421 in this regard. The diacid of SCH 31846 was considerably less potent than the ester, implying poor oral absorption of the former. Effective ACE inhibition, as judged by attenuation of pressor actions of AI, was noted in dogs after both intravenous and oral administrations of SCH 31846. Onset of action was more rapid than that of MK 421. Intravenous administration of SCH 31846 inhibited the renal vascular actions of intrarenal injection of AI, indicating effective blockade of the renal enzyme. Intracerebroventricular administration of SCH 31846 diacid blocked pressor responses to intracerebroventricular AI, whereas oral administration of SCH 31846 (10 mg/kg) did not, implying that SCH 31846 inhibits brain ACE but does not gain access to the cerebral enzyme when administered orally. These data indicate that SCH 31846 is a potent and specific non-sulfhydryl ACE inhibitor. As such, it should be useful in the treatment of hypertension and heart failure.

Administration, Oral↗

PubMedDate not supplied

Antihypertensive activity of SCH 31846, a non-sulfhydryl angiotensin-converting enzyme inhibitor.

The antihypertensive, hemodynamic, and autonomic actions of SCH 31846, a new, potent and long-acting non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, were evaluated in several experimental preparations. Oral administration of 0.3-3 mg/kg caused dose-related decreases in blood pressure in spontaneously hypertensive rats (SHRs). Pretreatment with a diuretic augmented the maximum hypotensive response attainable. Single doses (3 mg/kg) of SCH 31846 reduced pressure for over 24 h. Five-day treatment lowered pressure progressively. Single oral doses of 3.2 and 10 mg/kg reduced blood pressure of conscious normotensive dogs. Diuretic pretreatment also enhanced the response. The antihypertensive action of SCH 31846 in SHRs was eliminated by nephrectomy, but not attenuated by indomethacin, indicating its dependency on renal renin but not on prostaglandin synthesis. Other studies using SHRs pointed to an absence of a central effect. SCH 31846 (1 mg/kg i.v.) decreased blood pressure and peripheral resistance of anesthetized dogs but did not alter cardiac output. Autonomic interactions were examined in normal and diuretic-pretreated SHRs and anesthetized dogs. SCH 31846 affected the response to sympathetic nerve stimulation and cardiovascular reflexes only minimally. It is concluded that SCH 31846 is a potent and long-lasting antihypertensive agent, the action of which is mediated, in all probability, by ACE inhibition.

Angiotensin-Converting Enzyme Inhibitors↗

PubMedDate not supplied

Hemodynamic actions of a synthetic atrial natriuretic factor.

The recently discovered atrial natriuretic factor (ANF), as well as synthetic ANF, has been demonstrated to produce diuresis and vasodilation. However, the vascular actions appear to be selective. In view of this apparent relative specificity, the hemodynamic actions of synthetic ANF (atriopeptin II, 23 amino acid rat sequence) were examined in intact animals and in vascular beds as well as in isolated cardiac preparations. Administration of 1-100 micrograms/kg of ANF i.v. into conscious spontaneously hypertensive rats (SHRs) resulted in a dose-related fall in blood pressure. Heart rate decreased at the lowest dose. Cardiac output was depressed. Infusion of 1 microgram/kg/min also reduced blood pressure and decreased cardiac output slightly (approximately 15%). Intraarterial (i.a.) administration or i.v. injection of ANF into the blood supply of a kidney of anesthetized SHRs augmented renal blood flow and reduced renal vascular resistance. In contrast, i.a. administration into the hindquarters failed to increase blood flow or decrease resistance of this bed significantly. The specific dopamine1 (DA1)-receptor agonist SKF 82526 was examined for comparative purposes and was found to augment both renal and hindquarter blood flow following i.a. administration. The renal vasodilator actions of SKF 82526 but not ANF were antagonized by the specific DA1-receptor blocker SCH 23390 (hindquarter effects were not evaluated). ANF did not affect the force of contraction or rate of beating of isolated guinea pig atria or isolated hearts and therefore does not appear to possess direct inotropic or chronotropic properties. In conclusion, ANF lowered blood pressure in conscious SHRs; the lowering of pressure was accompanied by a slight fall in cardiac output, but there was no reflex tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Role of beta 2-receptor stimulation in the peripheral vascular actions of the antihypertensive dilevalol.

Dilevalol (SCH 19927) is a potent, long-acting, nonselective beta-blocker with marked vasodilator actions. Unlike classical beta-blockers, dilevalol promptly lowers blood pressure and vascular resistance in animal models of hypertension. The present studies address the peripheral vascular effects of dilevalol and explore the role of beta-receptor agonism in the acute vasodilator and antihypertensive effects of the compound. In the denervated dog hindlimb preparation, dilevalol (0.1, 0.3, 1.0 and 3.0 micrograms, i.a.) significantly increased femoral blood flow by 12 +/- 6, 27 +/- 6, 84 +/- 31 and 132 +/- 41 ml/min, respectively. In contrast, celiprolol, a beta-blocker with purported vasodilator activity, caused a significant increase in flow of 31 +/- 9 ml/min at a dose of 30 micrograms i.a. Systematic pretreatment with the selective beta 2-antagonist ICI 118,551 virtually abolished dilevalol's vasodilator effect in the dog hindlimb. In conscious spontaneously hypertensive rats, 3 mg/kg i.v. dilevalol reduced blood pressure by 58 +/- 8 mmHg (P less than 0.05) and vascular resistance by 171 +/- 27 dyne.sec.cm-5/100 g (P less than 0.05) but did not change cardiac output significantly. Pretreatment of spontaneously hypertensive rats with ICI 118,551 significantly reduced both dilevalol's antihypertensive and resistance-lowering effects. Oral doses of 10 and 25 mg/kg dilevalol lowered blood pressure by 19 +/- 3 (P less than 0.05) and 37 +/- 5 mmHg (P less than 0.05) in spontaneously hypertensive rats with chronically implanted Doppler flow probes. The lower dilevalol dose reduced mesenteric vascular resistance 38 +/- 6% (P less than 0.05) while the higher dose significantly lowered vascular resistance in the hindlimb, mesenteric and renal vascular beds of spontaneously hypertensive rats by 18 +/- 8, 33 +/- 2 and 43 +/- 4%, respectively. Propranolol lowered neither blood pressure nor regional vascular resistances at the above doses in spontaneously hypertensive rats. Thus, dilevalol promotes a generalized fall in vascular resistance. Furthermore, the present studies illustrate that beta 2-receptor stimulation plays an obligatory role in both the vasodilatory and antihypertensive actions of dilevalol.

Adrenergic beta-Agonists↗

PubMedDate not supplied

Comparative effects of verapamil, diltiazem and nifedipine on aortic compliance in anesthetized dogs.

We tested the ability of verapamil (V), diltiazem (DTZ) and nifedipine (NIF) to alter aortic compliance upon i.v. administration in anesthetized dogs. Sonomicrometry was used to measure aortic systolic (SD) and diastolic (DD) diameters. Aortic distention (AD) was calculated from SD-DD. Aortic compliance was computed from the ratio of AD to arterial pulse pressure. One aortic compliance unit (ACU) is defined as 10(-3) mm/mmHg. V (0.1-3.0 mg/kg) reduced blood pressure, SD and DD dose-dependently. DD was more affected than SD and AD rose significantly. Since pulse pressure was not significantly altered, V induced a dose-related increase in aortic compliance. The 3.0 mg/kg dose increased aortic compliance by 10.3 +/- 1.5 ACU from a basal value of 4.7 +/- 0.5 ACU. DTZ (0.1-3.0 mg/kg) produced effects on blood pressure, aortic dimensions and aortic compliance similar to those seen with V. Infusion of NIF (3.2-32 micrograms/kg/min) exhibited a similar profile, i.e., reduced blood pressure, SD, DD and increased AD and aortic compliance. NIF, however was limited in its ability to increase aortic compliance, i.e., increases of 3.2 +/- 1.0 or 3.8 +/- 0.6 from basal values of 4.9 +/- 1.0 ACU were obtained with 10 and 32 micrograms/kg/min NIF, respectively. Although these 3 prototype calcium entry blockers share a common profile of action, V and DTZ appear to have a greater efficacy on aortic compliance than NIF.

Anesthesia↗