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Biomedical subjects

E J Sybertz

Publications and source records attributed to E J Sybertz.

At least 73 records · Page 4Linked to original sources
PubMed1985

Cardiac, coronary and peripheral vascular effects of acetyl glyceryl ether phosphoryl choline in the anesthetized dog.

Acetyl glyceryl ether phosphoryl choline (AGEPC) is a potent vasodilator, platelet activator and inflammatory agent. The cardiac and peripheral vascular effects of AGEPC were assessed in anesthetized dogs in order to gain additional insight into the mechanism of action of this lipid. Injection of AGEPC (0.1-3.2 micrograms) directly into the femoral vasculature produced a dose-related vasodilation in the innervated and sympathetically denervated hindlimb. Vasodilator responses in the denervated limb were at least as great as those in the innervated limb, which indicates that the response is not due to inhibition of sympathetic vasoconstrictor tone. Vasodilator responses to AGEPC (1 microgram) were not significantly affected by theophylline (5 mg/kg), indomethacin (5 mg/kg) or BW755C (10 mg/kg), which implies that the effect is independent of purinergic P1 receptors, cyclooxygenase products and lipoxygenase products. Intracoronary injection of AGEPC (0.032-3.2 micrograms) reduced blood pressure, myocardial contractile force and coronary blood flow in a dose-related manner. Coronary vascular resistance was unchanged. In contrast, intracoronary injection of another activator of platelets, ADP (10 micrograms), increased blood flow. Responses of blood pressure, heart rate, contractile force and coronary flow to AGEPC were not affected by bilateral vagotomy or hexamethonium, which indicates that they are independent of reflexive mechanisms. Indomethacin attenuated the hypotension and coronary flow reductions to AGEPC. BW755C reduced the hypotensive response. Mechanical reduction of coronary flow by 30 to 40% did not affect blood pressure, heart rate or contractile force, which suggests that AGEPC-induced changes are not secondary to flow reduction. The data suggest that AGEPC produces direct myocardial depression and distinct effects on the coronary and femoral vasculature. The peripheral vascular effects are independent of the autonomic nervous system, purinergic mechanisms and arachidonic acid metabolites, whereas some coronary effects may be mediated through metabolites of arachidonic acid.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Angiotensin III-induced modulation of neurogenic responses in the rabbit vas deferens and portal vein.

The effects of prostaglandin synthesis inhibitors on the presynaptic actions of angiotensin (ang) II and III were examined in isolated rabbit vasa deferentia and portal veins. Ang II caused dose-dependent potentiation of low frequency, nerve stimulation in vasa deferentia and portal vein. Indomethacin (26 microM) enhanced the electrically-induced contractions in the vasa deferentia only but did not alter the potency of ang II in either preparation. In contrast, ang III decreased contractions in vasa deferentia induced by nerve stimulation by up to 36% (10(-6) M) and potentiated these contractions at concentrations higher than 10(-6) M. The inhibitory action of ang III on vasa deferentia was converted to potentiation by pretreatment with indomethacin or mepacrine. Exogenous PGE2 blocked low frequency nerve stimulation and not responses to norepinephrine. This prostaglandin appeared to mimic ang III in the vas deferens. No effects of ang III were observed if the contractions were induced by exogenous alpha adrenergic agonists. [Sar1, Ala8] ang II antagonized all responses to the angiotensins, whereas [Sar1, Cys-CH3(8)] ang II selectively antagonized the angiotensin-induced potentiation. Responses in field-stimulated portal veins were potentiated by ang III and this response was unaffected by indomethacin. This investigation strongly suggests the existence of at least two ang receptors in the vas deferens and demonstrates for the first time selective responses to the octa- and heptapeptides in the same effector organ.

Angiotensin II↗
PubMed1984

Mechanism of the pressor response to tetradecapeptide renin substrate in the rat.

The synthetic tetradecapeptide renin substrate (TDP; Asp-arg-val-tyr-ile-his-pro-phe-his-leu-leu-val-tyr-ser) has been employed frequently to elucidate the enzymatic action of renin in vitro and, to a lesser extent, in vivo. We assessed the utility of TDP as a renin substrate in vivo using conscious spontaneously hypertensive rats. Intravenous injection of TDP (1 and 3 micrograms/kg) increased diastolic pressure by 45 +r2 and 67 +/- 2 mmHg, respectively. The pressor response to TDP was significantly inhibited by captopril (3 mg/kg, po), indicating its dependence on conversion by ACE to some active molecule. Pressor responses to TDP also were less in animals subjected to bilateral nephrectomy 18-24 hr before study. However, responses to angiotensin I and II also were reduced, implying a non-specific effect of nephrectomy. Intravenous infusion of the renin inhibitor pepstatin (200 micrograms/min) inhibited pressor responses to hog renin by approximately 60%, but did not affect those to TDP. Intravenous infusion of the water soluble renin inhibitor, pepstatinyl-arginine-o-methyl ester (500 micrograms/min), also inhibited pressor responses to renin (approx. 80%) and did not affect those of TDP. Incubation to TDP (5 microM) with rabbit lung ACE resulted in generation of AI that was blocked by captopril (1 microM). These data suggest that TDP is a substrate for ACE and that the increase in blood pressure produced by TDP is due to its sequential cleavage by ACE to AII and can be independent of renin.

Angiotensin I↗
PubMed1983

Pharmacology of labetalol in experimental animals.

Labetalol represents the culmination of an effort to enhance the antihypertensive efficacy and to improve the hemodynamic profile of beta-adrenoceptor blockers by incorporating an additional anti-hypertensive action, that is, alpha blockade, into its pharmacologic mechanism. Reviewed here are the major aspects of the animal pharmacology of labetalol. The compound blocks beta1 and beta2-adrenoceptors nonselectively. Its blockade of alpha receptors is selective and directed at the alpha1 subset. Labetalol also dilates blood vessels independently of these mechanisms. This action is mediated by activation of vascular beta2 adrenoceptors. Thus, labetalol acts as a partial agonist on vascular smooth muscle. However, it differs markedly from other beta blockers with intrinsic sympathomimetic activity in that its agonism is directed specifically at beta2 receptors. Labetalol lowers blood pressure in a variety of animal models of hypertension. Unlike pure beta blockers, the compound reduces peripheral vascular resistance. On the basis of this profile, it is proposed that labetalol lowers blood pressure in human subjects by three independent mechanisms: (1) beta blockade, (2) alpha blockade, and (3) direct vasodilatation.

Animals↗
PubMed1983

Enkephalinase 'A' inhibition by thiorphan: central and peripheral cardiovascular effects.

On the basis of the distribution of enkephalins within the central and peripheral nervous systems as well as on responses to their administration, it has been suggested that these peptides participate in the regulation of the circulation. The present series of experiments examined the effects of thiorphan, an inhibitor of enkephalinase A, on cardiovascular responses to intracerebroventricular (i.c.v.) administration of [D-Ala2,Met5]enkephalin (DAME) and its amide and on peripheral interactions with the sympathetic nervous system and vasoactive peptides. Thiorphan (30 micrograms i.c.v.) potentiated the pressor response to i.c.v. DAME and DAMEamide in conscious spontaneously hypertensive rats. Responses to i.c.v. angiotensin I (AI) were unaffected suggesting lack of inhibition of central angiotensin converting enzyme (ACE). Peripheral administration of relatively large doses of thiorphan (30 and 100 mg/kg s.c.) attenuated the pressor response to i.v. AI by 30-40% and enhanced the depressor effect of i.v. bradykinin in anesthetized normotensive rats indicating inhibition of peripheral ACE. Pressor and tachycardic responses to activation of spinal sympathetic outflow were not altered by thiorphan in pithed normotensive rats. Thiorphan itself did not affect baseline blood pressure or heart rate in any of these experiments. In conclusion, inhibition of central enkephalinase A by i.c.v. administration of thiorphan potentiates the pressor response to i.c.v. DAME. The compound inhibits peripheral ACE but has little direct cardiovascular activity in its own right.

Amino Acids, Sulfur↗
PubMed1983

Attenuation of pressor responses to intracerebroventricular angiotensin I by angiotensin converting enzyme inhibitors and their effects on systemic blood pressure in conscious rats.

The components of the renin-angiotensin system exist in the brain but their physiological role is uncertain. The effects of two angiotensin converting enzyme (ACE) inhibitors, MK 421 (or its diacid) and captopril, on brain ACE activity, as measured by inhibition of the pressor response to intracerebroventricularly (i.c.v.) administered angiotensin I (AI), and the potential contribution of the central nervous system to their antihypertensive activity were evaluated in the present series of experiments. The diacid of MK 421 (1 and 10 micrograms) and captopril (3 and 10 micrograms) given i.c.v. to conscious normotensive rats reduced the pressor response to i.c.v. AI indicating that they can inhibit brain ACE. Responses to AII were unaffected. Oral administration of maximal antihypertensive doses of MK 421 (10 mg/kg) and of captopril (30 mg/kg) to normotensive rats did not attenuate pressor responses to i.c.v. AI indicating that brain ACE was not inhibited under these circumstances. Intracerebroventricular administration of MK 421 diacid, (10 and 30 micrograms) and captopril (30 and 100 micrograms) did not lower baseline blood pressure of spontaneously hypertensive rats. These experiments indicate that MK 421 and captopril can inhibit brain ACE but that the central renin-angiotensin system probably does not contribute to their antihypertensive activity.

Administration, Oral↗
PubMed1983

Antihypertensive actions of an isomer of labetalol and other vasodilator-beta-adrenoceptor blockers.

Combinations of beta-adrenoceptor blockers and vasodilators have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of several agents that combine these effects within a single molecule are described in this report. Labetalol, SCH 19927, sulfinalol, MK-761, pindolol, and prizidilol, in contrast to propranolol, decreased blood pressure of spontaneously hypertensive rats (SHR). All except labetalol and SCH 19927 increased heart rate. In anesthetized dogs, all of these agents (except propranolol) produced vasodilatation on intra-arterial administration into the femoral vascular bed and, given i.v., lowered blood pressure after ganglionic blockade. In contrast to the other agents, labetalol and SCH 19927 caused only minimal increases in heart rate in ganglionically blocked dogs. The vasodilator and hypotensive actions as well as the antihypertensive effect in SHR of labetalol, SCH 19927, sulfinalol, and pindolol were inhibited by propranolol pretreatment but those of prizidilol were not, suggesting that the hypotensive and vascular effects of labetalol, SCH 19927, sulfinalol, pindolol, and MK-761 are mediated by activation of vascular beta-receptors. However, labetalol and SCH 19927 in particular differ from agents of this class as well as other beta blockers with strong intrinsic sympathomimetic actions in that their agonist activity is primarily directed at blood vessels and not the heart.

Adrenergic beta-Antagonists↗
PubMed1983

Analysis of the vasoconstrictor responses to potassium depolarization and norepinephrine and their antagonism by differing classes of vasodilators in the perfused rat hindquarters.

Although the role of calcium in activation of vascular smooth muscle has received considerable attention, few studies have analyzed responses of resistance vessels. We therefore evaluated the role of calcium in vasoconstriction induced by norepinephrine (NE) and by high potassium depolarization in the resistance vessels of the Krebs'-perfused rat hindquarters. In addition, responses to vasodilators of differing classes were assessed. Injection of NE (0.3-100 micrograms) into the hindquarters increased perfusion pressure in a dose-related manner. Perfusion of the hindquarters with a depolarizing salt solution (80 mM K+) produced a sustained vasoconstriction (perfusion pressure = 143 +/- 4 mm Hg). Vasoconstriction to NE and high K+ was abolished during perfusion with a Ca-free salt solution containing 2 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid. In addition, the potassium-induced vasoconstriction was slightly reduced (perfusion pressure = 119 +/- 4 mm Hg) in animals pretreated with reserpine (5 mg/kg i.p.) indicating a slight neurogenic contribution to the response. The calcium channel blockers nifedipine (0.03-10 micrograms), diltiazem (0.3-30 micrograms) and verapamil (0.1-10 micrograms) produced dose-related vasodilation of hindquarters constricted with either NE (7.1 microM) or high potassium. These drugs were 4 to 10-fold more potent against potassium-induced vasoconstriction. Reserpine pretreatment enhanced the vasodilator response to nifedipine in potassium-depolarized preparations. Nitroprusside and nitroglycerin relaxed both NE and potassium-constricted hindquarters. The calmodulin blockers trifluoperazine and W-7 likewise produced vasodilation; trifluoperazine being 12.5 times more potent against NE-induced vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Synthesis and comparison of some cardiovascular properties of the stereoisomers of labetalol.

A useful method for the separation of labetalol into its two racemic diastereomers, as well as a stereoselective synthesis of its four stereoisomers, is described. The absolute stereochemistry of each isomer was determined by analysis of the DC spectra and confirmed by X-ray analysis. The alpha- and beta 1-adrenergic blocking properties, as well as the relative antihypertensive activities, have been measured in rats. The R,R isomer, 2a (SCH 19927), possesses virtually all of the beta 1-blocking activity elicited by labetalol and displays little alpha-blocking activity. In contrast, the S,R isomer, 3a, has most of the alpha-blocking activity. Of the four isomers, only 2a has antihypertensive potency comparable to that of labetalol. These findings, coupled with published data showing that labetalol possesses beta-adrenergic mediated peripheral vasodilating activity deriving essentially from its R,R isomer, lead to the following conclusion: The antihypertensive activity of labetalol can be ascribed to at least three identified complementary mechanisms, beta-adrenergic blockade, beta-adrenergic mediated vasodilatation, and alpha-adrenergic blockade, whereas the antihypertensive activity of 2a derives from the first two mechanisms only.

Adrenergic alpha-Antagonists↗
PubMed1981

Influence of angiotensin converting enzyme inhibition with captopril on blood pressure and adrenergic function in normal and sodium restricted rats.

Observations with both captopril and teprotide suggest interplay of the renin angiotensin and sympathetic nervous systems during sodium depletion. We therefore examined adrenergic responses in normal or sodium restricted (8 days low sodium chow; trichlormethiazide 3 mg/kg, p.o., days 5-7) normotensive rats orally pretreated with placebo and captopril (3 or 10 mg/kg; twice on day 7, once on day 8) and pithed 2 hrs after the last dose. Consistent hypotension in conscious intact animals was observed only in sodium-depleted groups receiving captopril. Pressor responses to low frequency (2.5 Hz--5 sec) sympathetic stimulation and phenylephrine were reduced in normal sodium, pithed normotensive Sprague-Dawley rats receiving 10, but not 3 mg/kg captopril and low sodium animals receiving both doses. Suppression of phenylephrine by captopril was accentuated in sodium-depleted groups. Pressor responses to angiotensin II were less in all salt-depleted animals receiving either placebo or captopril. Captopril failed to reduce tachycardia to either sympathetic nerve stimulation or isoproterenol. These effects of captopril suggest that angiotensin plays a role in maintenance of vascular, but not cardiac adrenergic function. This role is manifested at a post-junctional site and becomes critical in the sodium deficient state.

Angiotensin II↗
PubMed1981

Alpha and beta adrenoceptor blocking properties of labetalol and its R,R-isomer, SCH 19927.

Labetalol is a mixture of four isomers. Its alpha and beta adrenergic blocking properties were compared to those of the R,R-isomer, SCH 19927. In anesthetized dogs, i.v. administration of both compounds produced competitive beta and alpha blockade as judged by inhibition of the tachycardia and vasopressor responses to i.v. injections of isoproterenol and phenylpherine, respectively. SCH 19927 was 3 to 4 times as potent as beta blocker, but only one-third as potent an alpha blocker as labetalol. Therefore, the separation of beta and alpha blocking activity of SCH 19927 clearly exceeded that of labetalol. SCH 19927 also demonstrated greater beta blocking potency than labetalol after oral administration to conscious dogs or rats that were subsequently pithed. SCH 19927 did not affect, whereas labetalol slightly reduced, pressor responses to sympathetic stimulation in the pithed rat. Both drugs were relatively devoid of intrinsic beta-1 sympathomimetic activity in the ganglion-blocked dog. It is concluded that SCH 19927 is a more potent beta adrenoceptor blocker and less potent alpha blocker than labetalol. The separation of adrenergic blocker activities indicates that steric requirements for alpha and beta blockade differ in the labetalol molecule.

Adrenergic alpha-Antagonists↗
PubMed1981

Antihypertensive and hemodynamic actions of SCH 19927, the R,R-isomer and labetalol.

SCH 19927, one of the four chiral forms of labetalol, is approximately 4 times as potent as a beta adrenergic receptor blocker as the parent racemate, but is only one-third as potent in blocking alpha receptors. The present report describes its antihypertensive and hemodynamic actions. SCH 19927 and labetalol lowered blood pressure in hypertensive rats and dogs. SCH 19927 was somewhat more effective at lower doses, but the two agents produced comparable responses at higher doses. Both reduced blood pressure and peripheral resistance and increased cardiac output in anesthetized dogs. Intraarterial injection in to the femoral vascular bed, either in the presence or absence of neurogenic vasoconstrictor tone, resulted in dose-related vasodilatation. In contrast, alpha blockers, e.g., phentolamine and prazosin, are essentially devoid of vasodilator activity in denervated beds. It is concluded that vasodilatation is largely responsible for the antihypertensive response to labetalol and particularly to SCH 19927. SCH 19927 is a potentially useful agent which would be expected to reduce pressure in humans by two complementary mechanisms, beta blockade and vasodilatation. It should possess less orthostatic potential than labetalol.

Animals↗
PubMed1980

The role of alpha receptors in the facilitation of the chemoreflex and inhibition of the carotid occlusion reflex by clonidine.

The influence of alpha receptor blockers on the facilitation of the chemoreflex by clonidine was examined in anesthetized dogs. Intravertebral arterial administration of clonidine reduced blood pressure, facilitated chemoreflex-induced vasoconstriction and inhibited carotid occlusion-induced vasoconstriction. Intravertebral arterial administration of phentolamine (0.01-0.03 mg/kg), yohimbine (0.01-0.02 mg/kg), or piperoxan (0.05 mg/kg) prevented the inhibition of carotid occlusion-induced responses by clonidine, and the latter two alpha blockers reduced the hypotensive effect. Facilitation of the chemoreflex by clonidine was decreased by yohimbine and piperoxan, but not affected by phentolamine. Intravertebral infusion of propranolol (0.1 mg/kg) had no influence on clonidine's effect on reflex responses, but appeared to accentuate its hypotensive effect. The results support a role for alpha receptor stimulation in clonidine-induced hypotension and inhibition of the carotid occlusion reflex and suggest participation of alpha receptors in the potentiation by clonidine of chemoreflex-induced vasoconstriction.

Animals↗