Regulation of pancreatic endocrine function by cholecystokinin: studies with MK-329, a nonpeptide cholecystokinin receptor antagonist.

A cholecystokinin (CCK) receptor antagonist, MK-329, was used to explore the physiological role of CCK in regulating pancreatic endocrine function in humans. The ability of CCK to increase plasma pancreatic polypeptide (PP) concentrations and blockade of this effect with MK-329 were evaluated in a double blind, balanced, four-period cross-over study. Eight subjects received single oral doses of 0.5, 2, or 10 mg MK-329 or placebo, followed by an iv infusion of CCK-8 (34 ng/kg.h). In placebo-treated subjects, PP increased from basal levels of 70 +/- 15 (+/- SE) to peak values of 291 +/- 58 pg/mL after CCK infusion (P less than 0.05 compared to basal). This increase in plasma PP concentration was inhibited in a dose-dependent fashion by MK-329, with 10 mg antagonizing the stimulatory effect of CCK infusion by nearly 80%. Second, the effect of MK-329 on meal-stimulated pancreatic endocrine responses was evaluated by giving placebo or 10 mg MK-329 2 h before ingestion of a mixed meal. Eight subjects were treated in a randomized two-period cross-over fashion. With placebo treatment, peak postprandial plasma insulin, glucagon, and glucose concentrations were 101 +/- 8 microU/mL, 195 +/- 15 pg/mL, and 150 +/- 10 mg/dL, respectively (all P less than 0.05). The integrated PP response following the meal was 56.3 +/- 11.1 ng/mL.minute. With MK-329 treatment, the integrated PP concentration was reduced to 33.9 +/- 2.2 ng/mL.min (P less than 0.05 compared to placebo treatment). Mean postprandial insulin, glucagon, and glucose concentrations did not differ between placebo and MK-329 treatments. We conclude that CCK receptor blockade with 10 mg MK-329 does not alter plasma insulin, glucagon, or glucose responses to a mixed meal. However, the observation that physiological concentrations of CCK increase plasma levels of PP, and the finding that CCK receptor blockade selectively attenuates the postprandial increase in plasma PP concentrations support a physiological role for CCK in regulating PP secretion.

Clinical evaluation of a benzofuroquinolizine alpha 2-adrenoceptor antagonist.

The pharmacodynamics of MK-912, a benzofuroquinolizine alpha-adrenoceptor antagonist, were evaluated in healthy male volunteers. Eight subjects were treated with single oral doses of 0.1, 1.0, and 2.0 mg MK-912 and with a placebo in a four-period, double-blind, balanced, crossover study. Hemodynamic effects were observed with the 2.0 mg dose of MK-912 (peak increase from baseline in systolic and diastolic blood pressure +/- SEM, 14.8/9.2 +/- 2.9/2.1 mm Hg; peak increase in heart rate, 6.3 +/- 2.1 beats/min; p less than 0.05 versus placebo). Plasma concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG, a catecholamine metabolite) were increased 29% +/- 7% and 40% +/- 10% above baseline 2 hours after administration of 1.0 and 2.0 mg MK-912, respectively (p less than 0.01 compared with placebo). A modest dose-dependent reduction (5% to 10%) in fasting plasma glucose concentration was observed 1/2 to 1 hour after administration of 1.0 and 2.0 mg MK-912 (p less than 0.05 compared with placebo), without significant change in plasma insulin values. MK-912 was well tolerated, although it did have a mild anxiogenic effect. MK-912 is a potent, orally active agent with a pharmacologic profile consistent with alpha 2-adrenoceptor antagonism.

Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in humans. Implications for the physiology of CCK.

To explore the physiology of cholecystokinin (CCK) in humans, we investigated the effect on gallbladder contraction and gastric emptying of a recently developed CCK receptor antagonist, MK-329. In a double-blind, four-period crossover study eight subjects received single doses of 0.5, 2, or 10 mg MK-329, or placebo, followed by an intravenous infusion of CCK-8 (30 pmol/kg.h). In placebo-treated subjects gallbladder volumes decreased on average to 43% of initial volumes after 2 h of CCK infusion. MK-329 caused a dose-dependent inhibition of CCK-stimulated gallbladder contraction with 10 mg producing complete blockade (P less than 0.01, cf. placebo). Gallbladder contraction and gastric emptying rates after a mixed meal were then measured in a two-period crossover study. Subjects received placebo or 10 mg of MK-329 2 h before eating. Gastric emptying of both solids and liquids was measured simultaneously by gamma scintigraphy. In placebo-treated subjects plasma CCK levels increased postprandially to 2.3 pM, gallbladder volumes decreased 68.4 +/- 3.8% (SE), and the times for 50% emptying of liquids and solids from the stomach were 58 +/- 10 and 128 +/- 8 min, respectively. In MK-329-treated subjects there was a marked elevation in peak CCK levels to 13.8 pM (P less than 0.01, cf. placebo), and gallbladder contraction was completely inhibited. Solid and liquid emptying rates were unaffected. These findings demonstrate that (a) MK-329 is a potent, orally active antagonist of CCK in humans, and (b) CCK is the major regulator of postprandial gallbladder contraction. These data also support the concept of negative feedback regulation of CCK secretion and suggest that mechanisms other than CCK play a dominant role in the regulation of postprandial gastric emptying rates.