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SCH48461 is a selective and highly potent inhibitor of cholesterol absorption. In rats, SCH48461 is rapidly and completely metabolized in the first pass through the body. To compare the activity of the metabolites of SCH48461 with SCH48461 itself, an intestinally cannulated, bile duct-cannulated rat model for cholesterol absorption was developed. SCH48461 inhibited the absorption of cholesterol by 70%, whereas bile containing the metabolites of SCH48461 (henceforth, "metabolite bile") inhibited the absorption by greater than 95%. Very little of the recovered radioactive dose of SCH48461 was located in the intestinal lumen (7%) or wall (4%), whereas 85% appeared in bile. However, in rats treated with metabolite bile, 62% of the dose remained in the lumen, 13% was associated with the wall and only 24% reappeared in bile, which suggests that the activity of the metabolite bile may be related to its higher retention in the intestinal wall. Rats treated with metabolite bile had 64% and 84% less drug-related radioactivity in their plasma and livers, respectively, compared with animals treated with SCH48461, which indicates that the metabolites are systemically less available than SCH48461. The metabolites in bile were separated by high-performance liquid chromatography; the most active fraction in the bile duct-cannulated rat model was identified by mass spectrometry as the glucuronide of the C4-phenol of SCH48461. The other fractions had moderate or no activity. Through the identification of the most active biliary metabolites of SCH48461 in the rat, we have discovered SCH58235, a novel cholesterol absorption inhibitor which is 400 times more potent than SCH48461 in the cholesterol-fed rhesus monkey.

Leptin administration reduces obesity in leptin-deficient ob/ob mice; its effects in obese humans, who have high circulating leptin levels, remain to be determined. This longitudinal study was designed to determine whether diet-induced obesity in mice produces resistance to peripheral and/or central leptin treatment. Obesity was induced in two strains of mice by exposure to a 45% fat diet. Serum leptin increased in proportion to body weight (P < 0.00001). Whereas C57BL/6 mice initially responded to peripherally administered leptin with a marked decrease in food intake, leptin resistance developed after 16 d on high fat diet; mice on 10% fat diet retained leptin sensitivity. In AKR mice, peripheral leptin significantly decreased food intake in both 10 and 45% fat-fed mice after 16 d of dietary treatment. However, after 56 d, both groups became resistant to peripherally administered leptin. Central administration of leptin to peripherally leptin-resistant AKR mice on 45% fat diet resulted in a robust response to leptin, with a dose-dependent decrease in food intake (P < 0.00001) and body weight (P < 0.0001) after a single intracerebroventricular infusion. These data demonstrate that, in a diet-induced obesity model, mice exhibit resistance to peripherally administered leptin, while retaining sensitivity to centrally administered leptin.

The possible role of sympathoadrenal stimulation and endothelin release in cyclosporine (CS)-induced hypertension was ascertained in intact and pithed rats. CS (20 and 40 mg/kg), administered by i.v. infusion over 10 min, produced a dose-dependent increase in blood pressure: 19 +/- 5 and 31 +/- 2 mm Hg in intact rats and 13 +/- 4 and 18 +/- 2 mm Hg in pithed rats. In intact rats, pretreatment with reserpine (5 mg/kg, i.p.) or hexamethonium (10 mg/kg, i.v.) greatly blunted the pressor responses to CS (40 mg/kg) (7 +/- 3 and 11 +/- 2 mm Hg, respectively). In pithed rats, the blood pressure responses to CS (40 mg/kg) were significantly impaired, but were not further modified by phenoxybenzamine (3 mg/kg, i.v.), whereas adrenalectomy completely abolished the CS-induced pressor responses (0 +/- 1 mm Hg). CS (40 mg/kg) did not potentiate pressor responses to sympathetic nerve stimulation (0.1 and 0.3 Hz) or vasoconstrictors, including angiotensin II (0.03 microgram/kg, i.v.), phenylephrine (1 microgram/kg, i.v.) and arginine vasopressin (0.075 microgram/kg) in pithed rats. In addition, CS (40 mg/kg, i.v.) did not cause elevation of plasma immunoreactive endothelin-1 and -3. Furthermore, phosphoramidon (0.25 mg/kg/min x 30) abolished pressor response to big endothelin-1 (5 micrograms/kg, i.v.) but failed to affect CS-induced hypertension. It is concluded that the acute blood pressure response to CS manifests great dependence on sympathetic nervous system but appears independent of endothelin release.

Our studies with the prototypical NEP inhibitor SCH 34826 indicate the potential role of this class of compounds in cardiovascular modulation. The data assembled to date indicate that NEP inhibition elicits significant ANF-like effects in animals and man. The early data generated to date on SCH 34826, when considered with those data generated on other NEP inhibitors, indicate that NEP inhibition may have therapeutic utility in some forms of hypertension and congestive heart failure.

Inhibition of the enzyme neutral metalloendopeptidase (NEP) potentiates responses to atrial natriuretic factor (ANF) and elicits reductions in blood pressure in deoxycorticosterone acetate sodium (DOCA Na) hypertensive rats. The present study evaluated the role of ANF and bradykinin in the antihypertensive response to NEP inhibition through the use of antibodies and antagonists, respectively. In addition, the pharmacokinetic mechanism by which NEP inhibition interferes with ANF metabolism was explored. The antihypertensive response to the NEP inhibitors SCH 34826 and 42495 was abruptly reversed by an intravenous injection of a polyclonal antiserum to ANF. In contrast, the antihypertensive response to SCH 34826 was unaffected by injection of the bradykinin antagonist [thi5,8-D-phe7] bradykinin, indicating that ANF, but not bradykinin, affects this response. The NEP inhibitor SCH 39370 significantly delayed the disappearance of trichloroacetic acid (TCA)-precipitable radioactivity and the appearance of TCA-soluble radioactivity in plasma following an intravenous bolus dose of 125I-ANF(99-126). The effects were enhanced in the presence of the C-receptor ligand des[gln18,ser19,gly20,leu21,gly22]r ANF(4-23)-NH2. These data suggest that the two clearance mechanisms interact to govern plasma levels of ANF.

Hormonal, renal and blood pressure effects of SCH 39370, a selective inhibitor of neutral metalloendopeptidase (endopeptidase 24.11, NEP), were studied in a chronic, congestive heart failure (CHF) model produced by coronary artery ligation in the rat. Sham-operated control rats and rats with CHF were treated either with vehicle or SCH 39370, 30 mg/kg s.c. b.i.d. for 2.5 days. Plasma levels of atrial natriuretic peptide (ANP) and urinary excretion of cyclic GMP (cGMP) were clearly raised in rats with CHF as compared with controls during vehicle treatment. SCH 39370 caused a further increase in plasma ANP in CHF rats but not in control rats. Urinary excretion of immunoreactive ANP and cGMP increased during SCH 39370 treatment both in CHF rats and in controls. SCH 39370 treatment resulted in an initial increase in urine volume in rats with CHF whereas urine sodium excretion did not change significantly. No changes in renal function due to SCH 39370 treatment were seen in control rats. Systolic blood pressure, plasma renin activity and urine excretion of catecholamine metabolites (4-hydroxy-3-methoxyphenyl acetic acid and metanephrines) did not change during SCH 39370 treatment either in controls or in CHF rats. We conclude that the NEP-inhibitory compound SCH 39370 is capable of increasing plasma ANP concentration and urinary excretion of cGMP in rats with chronic CHF. In this severe heart failure model, the possible beneficial effects of additional ANP increments may be blunted, however. NEP inhibitors offer a novel approach to study the significance of ANP elevation in chronic CHF.

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.

SCH 33844 is a new non-sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor. SCH 33844 diacid inhibited hydrolysis of the synthetic substrate hippuryl-histidyl-leucine by rabbit lung ACE in vitro with an IC50 (concentration inhibiting enzyme by 50%) of 0.81 nM. The ester was 83 times less active. Intravenous administration of SCH 33844 and its diacid inhibited pressor responses to angiotensin I (AI) in anesthetized rats with calculated ID50's of 16 and 8 micrograms/kg, respectively. Oral administration of SCH 33844 (0.03-1 mg/kg) inhibited AI pressor responses in conscious rats with a duration of 24 hr at the highest dose. The diacid was inactive. Intravenous administration of SCH 33844 (100-1000 micrograms/kg) or its diacid (30 micrograms/kg) to anesthetized dogs inhibited AI pressor activity and potentiated the depressor response to bradykinin. SCH 33844 inhibited AI responses in conscious dogs following oral administration of 0.3-3 mg/kg. Oral administration of SCH 33844 (1 mg/kg) to conscious monkeys inhibited AI pressor responses for the 4 hr duration of study. In conclusion, SCH 33844 is a potent, orally effective ACE inhibitor in rats, dogs and monkeys.

The effects of phorbol esters on endothelium-dependent relaxations evoked by ACh and the calcium ionophore A23187 were analyzed in isolated canine femoral and coronary arteries mounted in organ chambers or in a bioassay system. In rings of femoral and coronary arteries, phorbol 12,13-dibutyrate (PDBu) (10(-7) M) evoked contraction (ED50 2.9 x 10(-8) M) and depressed endothelium-dependent relaxations to ACh (4-fold increase in ED50 and 72% depression of maximal response). PDBu depressed maximal relaxations to A23187 by 50% but had no effect on ED50. The inactive phorbol ester 4-alpha-phorbol didecanoate (10(-7) M) did not evoke contractions and had no effect on endothelium-dependent relaxations to ACh or A23187. Endothelium-independent relaxations to sodium nitroprusside were not effected by PDBu (10(-7) M) in femoral or coronary arteries. In bioassay experiments, selective treatment of perfused femoral artery segments with PDBu (10(-8)-10(-6) M) caused concentration-dependent inhibition of basal and ACh- (10(-6) M) and A23187-(10(-6) M) induced release of endothelium-derived relaxing factor (EDRF) (as assessed by relaxation of superfused bioassay coronary artery rings without endothelium). PDBu inhibited these responses with different potency: basal (10(-8) M) greater than ACh (10(-7) M) much greater than A23187 (only partial inhibition at 10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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)

SCH 39370 (N-[N-[1-(S)-carboxyl-3-phenylpropyl]-(S)-phenyl-alanyl]-(S)-isoserin e) is a potent and specific inhibitor of neutral metalloendopeptidase (NEP) from rabbit kidney (IC50 = 11.2 +/- 1.9 nM) and is devoid of angiotensin-converting enzyme inhibitory activity at 1 microM. We evaluated the effect of NEP inhibition with SCH 39370 on the inactivation of atrial natriuretic factor (ANF) and on cardiovascular function in rats. SCH 39370 effectively prevented in vitro degradation of ANF (99-126) by a purified rabbit kidney NEP. SCH 39370 (30 mg/kg s.c) significantly delayed the disappearance of immunoreactive (ir) ANF from plasma in rats after an i.v. infusion of ANF (1 microgram/kg/min for 30 min): the plasma ir ANF level at 15 min postinfusion was 1.5 +/- 0.3 ng/ml vs. 0.3 +/- 0.04 ng/ml in the control. SCH 39370 also delayed the disappearance of ir ANF after infusion of the peptide (0.1 microgram/kg/min for 30 min) which increased plasma levels to those observed during volume expansion. This effect was accentuated markedly in rats with bilateral nephrectomy. The hypotensive response to injection of ANF (30 micrograms/kg i.v.) in spontaneously hypertensive rats (-38 +/- 6 mm Hg vs. -13 +/- 2 mm Hg in the control) and the diuretic and natriuretic responses to ANF in normal rats were potentiated by SCH 39370 (30 mg/kg s.c.), respectively. The results suggest that NEP can play a role in ANF disposition in vivo and that potentiation of the biological activities of high doses of ANF by SCH 39370 may be consequent to its inhibitory effect on ANF degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study examined the actions of spiraprilic acid, a new non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor upon aortic compliance (AC) in anesthetized dogs. Enalaprilic acid was examined for comparative purposes. AC was determined via sonomicrometric determination of the ratio of aortic systolic-diastolic diameter (mm) and arterial pulse pressure (mmHg). One AC unit (ACU) equals 10(-3) mm/mmHg. In non-thiazide pretreated animals, spiraprilic acid (1 mg/kg i.v.), caused a sustained hypotensive response of 21 +/- 3 mmHg (P less than .05). At the same time, aortic systolic and diastolic dimensions were reduced from basal values of 8.17 +/- 0.45 and 7.95 +/- 0.40 mm by 0.19 +/- 0.07 (P less than .05) and 0.29 +/- 0.10 mm (P less than .05), respectively. The aortic systolic-diastolic dimension rose significantly by 0.10 +/- 0.01 mm. Since pulse pressure was unchanged, AC rose from a basal value of 4.6 +/- 0.8 ACU by 1.7 +/- .3 ACU (P less than .05). Similar effects were observed with enalaprilic acid. In dogs pretreated orally with 5 mg/kg hydrochlorothiazide (HCTZ) twice daily for 3 days, spiraprilic and enalaprilic acids caused slightly greater falls in blood pressure (34 +/- 7 and 30 +/- 4 mmHg, respectively) than in nonpretreated dogs. However, the onset of the hypotension effect was more rapid for both ACE inhibitors in HCTZ-pretreated dogs. Effects of spiraprilic and enalaprilic acid upon aortic dimensions were similar to those observed in non-HCTZ pretreated animals. The data illustrate that the ACE inhibitors spiraprilic and enalaprilic acids not only lower blood pressure but also enhance large artery compliance.

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.

Phorbol esters activate protein kinase C and induce contraction in vascular smooth muscle. The role of Ca and the sensitivity of this response to nitrovasodilators were evaluated in rabbit aortic rings. Phorbol dibutyrate (PDB) (0.01-10 microM) elicited a concentration-dependent contraction of rabbit aortic rings. Responses to PDB in a salt solution (SS) containing 2.54 mM CaCl2 were not significantly different from those in SS containing 0 Ca and 2 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid. Contractions to PDB (1 microM) in zero Ca SS were not reduced by depletion of the norepinephrine-sensitive pool of intracellular Ca. The Ca entry blockers verapamil (100 microM) and nifedipine (100 microM) did not affect PDB (1 microM) responses. Nitroprusside (0.1-10 microM) and nitroglycerin (0.1-10 microM) inhibited PDB contractions in both normal SS and Ca-free SS. 8-Br-cyclic GMP (100 microM) also inhibited PDB responses. Effects of PDB on 45Ca fluxes were evaluated in separate experiments. PDB (1 and 10 microM) elicited contraction, but no change in 45Ca uptake or efflux. In contrast KCl (80 mM) and norepinephrine (10 microM) elicited an increase in both influx and efflux, reflecting a rise in cytosolic Ca. The data suggest that PDB-induced contractions in rabbit aorta are independent of extracellular Ca and are not associated with a rise in cytosolic Ca as detected by calcium flux studies.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

The venous compartment plays a critical role in circulatory control. The present series of experiments was conducted to assess simultaneously effects of vasoactive drugs on arterial resistance and venous capacitance vessels of the rat hindquarters perfused with physiological salt solutions (SS). Retrograde infusion of SS into rat hindquarters via the vena cava resulted in an increase in hindquarters venous pressure (Pv). The range of mean volumes required to increase Pv to 20 and 30 mm Hg was 1.7 +/- 0.1 to 2.9 +/- 0.4 and 3.8 +/- 0.3 to 6.9 +/- 0.3 ml, respectively, in various groups of rats during a control period. Perfusion of the hindquarters with an SS containing 80 mM K+ reduced the volume required to increase Pv to 20 and 30 mm Hg to 47 +/- 2 and 42 +/- 2% of control, respectively, indicating venoconstriction. K+ (80 mM) SS also increased aterial perfusion pressure (Pa; measured from a sidearm off of the inflow catheter) to 141 +/- 9 mm Hg, indicating arterial vasoconstriction. Arterial and venous responses to 80 mM K+ were attenuated markedly by perfusion with SS containing zero Ca and 2 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid, indicating dependence on extracellular Ca. Phentolamine (10(-5) M) attenuated the arterial and venous response to 80 mM K+, indicating an alpha adrenergic contribution. Arterial responses to 80 mM K+ were attenuated markedly by the Ca entry blockers nifedipine (10(-6) and 10(-5) M) and verapamil (10(-6) and 10(-5) M). In contrast, venous responses were not affected by nifedipine and were reduced slightly only at the high concentration of verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The present study evaluated the role of Na+-K+ -ATPase stimulation in the relaxant response to synthetic atrial natriuretic factor (atriopeptin II; ANF) in norepinephrine (0.18 microM)-contracted rabbit aorta. ANF (10(-10)-10(-7) M) produced a concentration-related relaxation of NE-contracted aortic rings. The calculated concentration required to produce 50 per cent relaxation (EC50) was 5 +/- 3 X 10(-9) M. ANF-induced relaxation was significantly attenuated by ouabain (30 microM). Likewise, ANF (10(-7) and 5 X 10(-9) M) elicited significantly less relaxation of aortic rings contracted with norepinephrine in a physiological salt solution containing zero KCl. Nitroprusside-induced relaxation also was attenuated by ouabain and in zero KCl salt solution. The data suggest that synthetic ANF induces relaxation in rabbit aortic rings by a ouabain and KCl sensitive mechanism, presumably Na+-K+ -ATPase.

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.

SCH 33844 is a new, potent and long-acting inhibitor of angiotensin converting enzyme (ACE). Antihypertensive, hemodynamic and autonomic actions of SCH 33844 were examined in the present series of experiments. Oral administration of 0.3-30 mg/kg reduced blood pressure of spontaneously hypertensive rats. The magnitude of the response was significantly enhanced by pretreatment of the animals with hydrochlorothiazide. Blood pressure remained significantly depressed 24 hr following doses of 3 and 10 mg/kg. Administration of SCH 33844 (3 mg/kg) twice daily to nonpretreated rats or once daily to diuretic-pretreated animals for 5 days resulted in a progressive decrease in blood pressure. The compound did not reduce blood pressure in nephrectomized rats demonstrating the dependence of its action on renal renin. SCH 33844 (1-10 mg/kg orally) also produced dose-related decreases in pressure in diuretic-pretreated conscious normotensive dogs. However, only a small fall in pressure occurred in non-pretreated dogs. Hemodynamic actions were examined in anesthetized dogs. SCH 33844 (1 mg/kg i.v.) reduced blood pressure, increased cardiac output and caused a large fall in peripheral resistance. Autonomic actions were assessed in pithed rats. The compound (10 mg/kg orally) tended to decrease pressor responses to sympathetic activation and to i.v. norepinephrine. This profile is probably due, at least in part, to vasorelaxation following suppression of angiotensin II generation. In conclusion, SCH 33844 is a potent, long-lasting antihypertensive agent which reduces peripheral vascular resistance and possesses only slight autonomic effects.