Calcium entry blocker activity of cyproheptadine in isolated cardiovascular preparations.

Cyproheptadine was compared with nifedipine, verapamil and diltiazem for calcium entry blocker activity in isolated cardiovascular preparations. Using rat aortic strips, all compounds (10(-7) M) inhibited both the contraction caused by the readdition of calcium (1.0 mM) into regular buffer or buffer containing potassium (130 mM) or norepinephrine (10(-5) M) and the potassium-stimulated uptake of 45Ca. The rank order of potency for these experiments was in general nifedipine greater than cyproheptadine greater than or equal to verapamil greater than diltiazem. The same order of potency also was found for the four compounds in relaxing potassium (40 mM)-contracted aortic strips (IC50 values: nifedipine, 2.6 X 10(-9) M; cyproheptadine, 6.3 X 10(-8) M; verapamil, 7.6 X 10(-8) M; and diltiazem, 2.1 X 10(-7) M), but cyproheptadine was the least potent agent in antagonizing the spontaneous contractions of the rat portal vein (IC50 values: nifedipine, 6.6 X 10(-9) M; verapamil 7.7 X 10(-8) M; diltiazem 9.6 X 10(-8) M; and cyproheptadine 3.9 X 10(-7)M). None of the compounds (10(-7) M) inhibited the contraction to norepinephrine (10(-5) M) in rabbit aortic strips bathed in calcium-free buffer (1 mM ethylene glycol bis(beta-aminoethyl ether)-N, N'-tetraacetic acid). Nifedipine, verapamil and diltiazem were more potent in inhibiting the restoration of contractility by isoproterenol in potassium-depolarized rabbit papillary muscles than decreasing force in normally polarized muscles; cyproheptadine was equipotent when tested in these two preparations. Cyproheptadine was the least potent of the four compounds in lowering perfusion pressure in the perfused canine hindlimb.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro and its ethyl ester (MK-421) on angiotensin converting enzyme in vitro and angiotensin I pressor responses in vivo.

The parent diacid (N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro of MK-421 inhibited hog plasma angiotensin converting enzyme (ACE) by 50% (I50) at a concentration of 1.2 nM and was 17 times more potent than captopril. In vitro the I50 for MK-421, an ethyl ester, was 1200 nM because de-esterification did not occur. Similarly in the guinea-pig ileum, the diacid inhibitor and MK-421 potentiated the contractile effects of bradykinin at an AC50 of 77 pM and 18 nM, respectively. Inhibition of the pressor effects of angiotensin I by the diacid ACE inhibitor occurred at an ID50 of 8.2 micrograms/kg i.v. in rats and 6.4 micrograms/kg i.v. in dogs. Thus, the diacid was approximately 12 times more potent than captopril. The ID50 for MK-421 was 14 and 278 micrograms/kg i.v. in rats and dogs, respectively, because of differences in the rates of de-esterification. Oral ACE inhibitory activity was determined by blockade of the pressor effects of angiotensin I in conscious rats and dogs. In rats, but not in dogs, the diacid inhibitor was poorly absorbed, whereas MK-421 was well absorbed in both species. MK-421 inhibited the pressor effects of angiotensin I at 0.1 to 3.0 mg/kg p.o. for at least 6 hr in rats and dogs, and compared to captopril was 8.6 times more potent in rats and 4.6 times more potent in dogs. These data demonstrate that MK-421 and its parent diacid are potent, long-lasting orally active inhibitors of ACE. In addition, the low activity of MK-421 in vitro contrasts with its substantial in vivo activity, and supports the hypothesis that MK-421 is a prodrug that first must be de-esterified to permit full expression of its significant in vivo pharmacological activity.

Inability of indomethacin to modify hydrochlorothiazide diuresis and natriuresis by the chimpanzee kidney.

A drug interaction study in the chimpanzee by using indomethacin and hydrochlorothiazide has shown conclusively that the diuretic and saluretic properties of hydrochlorothiazide were not compromised by indomethacin. This was true whether hydrochlorothiazide or indomethacin was administered first. The renal clearance of hydrochlorothiazide was not influenced by indomethacin nor was the renal clearance of indomethacin significantly altered by hydrochlorothiazide. Indomethacin alone caused a small but significant increase in sodium, potassium and chloride excretion and in Curate/glomerular filtration rate. In control experiments with placebo, potassium excretion was also significantly increased. The implications of these observations remain obscure. In all experiments utilizing hydrochlorothiazide, the well known renal effects of this agent were clearly evident under these experimental conditions.

Diuretic and uricosuric activity of 6,7-dichloro-2,3-dihydro-5-(2-thienylcarbonyl)benzofuran-2-carboxylic acid and stereoisomers in chimpanzee, dog and rat.

The racemate and the d-isomer of 6,7-dichloro-2,3-dihydro-5-(2-thienylcarbonyl)benzofuran-2-carboxylic acid exhibited diuretic activity in the chimpanzee, dog and rat. In the chimpanzee, the diuresis and natriuresis presumably resulted from a site of action in the thick ascending limb of Henle's loop. The l-isomer was uricosuric but devoid of any diuretic action in the chimpanzee and similarly was not diuretic in the dog and rat. Various proportions of the two isomers were tested in the chimpanzee in an attempt to produce an optimal diuretic and uricosuric profile. It was concluded that the racemic mixture, under these experimental conditions, was responsible for the most effective overall response. This is apparently the first time in which there is a distinct separation of diuretic and uricosuric actions in the enantiomers of a racemic diuretic uricosuric agent.

Saluretic and uricosuric effects of (6, 7-dichloro-2-methyl=1-oxo-2-phenyl-5-indanyloxy) acetic acid (MK-196) in the chimpanzee.

The saluretic and uricosuric responses elicited by a novel agent, MK-196, have been studied in a great ape, the chimpanzee. This agent is orally active at very low doses and has a prolonged duration of action. Probenecid does not appear to influence the saluretic and uricosuric properties of MK-196. Net tubular secretion of urate was reduced by MK-196. Urinary pH changes did not compromise the efficacy of this new agent. On a dose basis, MK-196 was more saluretic (and uricosuric) than ethacrynic acid or furosemide and possessed a longer duration of action. Because of the marked natriuresis caused by MK-196, some increase in potassium excretion occurred.

Renal excretion of a slauretic-uricosuric agent (MK-196) and interaction with a urate-retaining drug, pyrazinoate, in the chimpanzee.

The excretory pattern for MK-196 is ocmpatible with that of other weak organic acids such as salicylate and probenecid. Tubular secretion of MK-196 is strongly inhibitied by probenecid and high loads of p-aminohippurate. Urinary excretion of MK-196 is increased 10-fold when the urine is alkaline. Clearances of MK-196 were not corrected for plasma protein binding of the drug which is very high (greater than 99%). Bidirectional transport processes are operative in that MK-196 is secreted by the renal tubule and passively back diffuses across the tubular epithelium by a pH-dependent process. MK-196 is able to overcome pyrazinoate-induced urate retention, whereas probenecid is not when studied by conventional clearance techniques. The uricosuric activity of MK-196 appears to be somewhat less with pyrazinoate than in its absence. When MK-196 is administered prior to pyrazinoate an attenuated uricosuric response was observed. This finding cannot be ascribed to a temporal decline in uricosuric action. Diuresis and saluresis produced by MK-196 are not influenced by pyrazinoate. The interaction of MK=196 and pyrazinoate on urate excretion is in direct contrast to results obtained with probenecid and pyrazinoate. A model has been proposed to explain this unique finding.