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Selective and Competitive Histamine H2-Receptor Blocking Effect of Famotidine on the Blood Pressure Response in Dogs and the Acid Secretory Response in Rats

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Selective and Competitive Histamine H2-Receptor Blocking Effect of Famotidine on the Blood Pressure Response in Dogs and the Acid Secretory Response in Rats Selective and Competitive Histamine H2-Receptor Blocking Effect of Famotidine on the Blood Pressure Response in Dogs and the Acid Secretory Response in Rats Keiji MIYATA, Takeshi KAMATO, Akira FUJIHARA and Masaaki TAKEDA Department of Pharmacology, Medicinal Research Laboratories I, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba , Ibaraki 305, Japan Accepted July 17, 1990 Abstract-Famotidine has been already demonstrated to be a competitive H2- receptor antagonist in the stomachs of dogs and cats. The present experiments were carried out to examine the effects of famotidine on changes in blood pressure induced by dimaprit and several other agonists in vagotomized, anesthetized dogs and on changes in gastric acid secretion induced by histamine in stomach-perfused, anesthetized rats. Famotidine caused a parallel displacement of the dimaprit dose-response curve to the right with a DR10 value of 0.059 ƒÊmol/kg, indicating that famotidine is 166 times more potent than cimetidine in vascular H2-blocking activity. On the contrary, famotidine did not affect the depressor responses to 2- pyridylethylamine and histamine that were antagonized by mepyramine. The histamine dose-response curve was displaced to the right more markedly after simultaneous administration of mepyramine and famotidine than after mepyramine alone. The effects of methacholine, phenylephrine and isoproterenol on blood pressure were not influenced by famotidine in doses up to 720 nmol/kg. In rats, famotidine also caused a parallel displacement of the acid dose-response curve to histamine to the right with a DR3 value of 24 ƒÊmol/kg/hr in stomach-perfused rats anesthetized with pentobarbital, exhibiting a potency 108 times greater than that of cimetidine. Analysis of the acid dose-response curve with the Edie-Hofstee trans formation showed that famotidine, like cimetidine, was a competitive H2-receptor antagonist. The actions of histamine on blood pressure tric H2-receptors (8, 9), whereas loxtidine are well-established to be mediated through inhibited histamine-induced gastric acid H1 and H2-receptors (1, 2), while its effects secretion in a non-competitive manner (9). on gastric acid secretion are mediated through Famotidine has been reported to be a H2-receptors (3). In in vivo tests on cats, potent H2-antagonist in vitro (10-14) and in metiamide antagonized the blood pressure vivo (7) with greater antisecretory and anti response to a selective H2-agonist, dimaprit ulcer activities than cimetidine (15-17). The (4), without affecting the vascular action of present paper describes the effects of famo other agonists including 2-pyridylethylamine tidine on blood pressure responses to dima (H1-agonist) and acetylcholine (2, 5). In prit and other vasoactive substances in anes contrast, metiamide and cimetidine inhibited thetized dogs, and on histamine-induced gastric acid secretion induced by not only gastric acid secretion in stomach-perfused, histamine or dimaprit but also pentagastrin anesthetized rats. and methacholine in dogs (6, 7). Among the H2-antagonists, cimetidine and ranitidine Materials and Methods competitively antagonized vascular and gas Animals and materials: Mongrel dogs of either sex weighing 8 to 15 kg and female cording to the method of Arunlakshana and Sprague-Dawley rats weighing 190 to 220 g Schild (18). When the effects of famotidine were used. Rats were deprived of food with on the deprssor response to 2-pyridylethyla free access to water for 18 hr before the mine and histamine were tested, mepyramine secretory tests. was also given at the end of the experiments Famotidine (molecular weight: 337.4), to study the combined effect of the an cimetidine (molecular weight: 252.3), dima tagonists on the action of the agonists. prit dihydrochloride, 2-pyridylethylamine By the same procedure, the effects of dihydrochloride and phenylephrine hydro famotidine on blood pressure responses to chloride were synthetized at the Central methacholine (0.1, 0.3, 1 and 3 nmol/kg), Research Laboratories, Yamanouchi Phar isoproterenol (0.3, 1, 3 and 10 nmol/kg) and maceutical Co., Ltd. Other drugs used were phenylephrine (10, 30, 100 and 300 nmol/ mepyramine maleate (Sigma Chemical), kg) were also examined. Throughout the histamine dihydrochloride (Wako Pure Chem present studies, all of the agonists were given ical), methacholine chloride (Nacalai Tes intravenously, and 4 to 6 animals were used que), I-isoproterenol hydrochloride (Nikken to analyze individual agonist and antagonist Chemicals) and glucose (Nacalai Tesque). interaction. Doses of the antagonists were ex The H2-antagonists were dissolved in 0.1 N pressed in terms of cumulative doses. The HCI solution, and the pH of the solution was ED50 values of antagonists, doses of hista adjusted to 6 with solid NaHCO3. Glucose mine and other agonists to elicite 40 and 30 was dissolved in distilled water, and the other mmHg changes in diastolic blood pressure, drugs were dissolved in physiological saline. respectively, were calculated from the dose Blood pressure responses to dimaprit and response curves and used for calculation of other agonists: Dogs were anesthetized with the agonist-dose ratios. i.v. injection of pentobarbital (30 mg/kg). Gastric acid secretion: The effects of The animals were artificially respired with famotidine and cimetidine on gastric acid room air through an endotracheal tube at a secretion were studied using a perfused rate of 20 strokes/min (Shinano Seisakusho, stomach preparation of rats (19). Rats were SN-480-4) and vagotomized bilaterally at anesthetized with i.p. injection of pentobar the neck level. Systemic blood pressure was bital (50 mg/kg). Perfusion of the stomach recorded on a polygraph (Nihon Kohden, RM and administration of drugs were performed 150 or RM-2600) through a pressure trans according to Brittain et al. (9). The jugular ducer (Nihon Kohden, MPU-0.5) connected vein was cannulated for drug administrations, to a catheter placed in the femoral artery. The and a perfusion cannula was inserted into the femoral vein was also cannulated for drug in stomach to facilitate perfusion of acid secre jection and anesthetic supplement. ting mucosa at 3 ml/min with 5% glucose Dose-response curves were constructed solution, pH 7.0, at 37'C. The gastric effluent for peak changes in diastolic blood pressure was passed continuously over a pH electrode caused by dimaprit, a selective H2-agonist (TOA Electronic, GS-80) and the pH recorded (4): 2-pyridylethylamine, a selective H , via a pH meter (TOA Electronic, HM-16S) on agonist (1); and histamine. Four doses of the a flat-bed recorder (Graphtec, MC6621). In agonists were successively given at intervals each anesthetized rat, one secretory dose of 3 min or longer before and 10 min after response curve was obtained to histamine by each dose of the antagonists, which was infusing progressively increasing doses for given at intervals of approximately 1 hr. The 1 hr each. In the control experiments, saline shifts in the dose-response curves to the right alone was infused for 1 hr; and then histamine were expressed as the ratios of two agonist was infused at 0.09, 0.27, 0.9 and finally 2.7 doses to cause the half maximal response in /Lmol/kg/min, i.v. In the test experiments, an the presence and absence of antagonists. The i.v. bolus dose of famotidine or cimetidine dose of antagonists required to produce an was given at time zero followed by i.v. in agonist dose-ratio of 10 (DR10) and the slope fusion throughout the experiment. One hour of the regression lines were calculated ac later, infusion was started, and the doses of histamine were increased hourly up to the maximum tolerated dose of 9 or 27 /tmol/kg/ Results min. Gastric acid secretion was measured im Depressor response to dimaprit in anes mediately before starting the histamine in thetized dogs: Dimaprit decreased blood pres fusion and at the peak secretory response to sure dose-dependently in a dose range from each dose of histamine. Results were ex 0.1 to 3 icmol/kg. The i.v. bolus injection of pressed as changes in acid output in /tmol H+/ famotidine and cimetidine produced a parallel min, which were calculated according to the displacement to the right of the dimaprit following formula: dose-response curve (Fig. 1). As shown in Fig. 2 and Table 1, the Schild slope parameters [H+] secretion= [10-iP" measured)-10-7]mol/I _ [10-(P" measured) _ 10-7] for the H2-antagonists were not significantly x [3/1000] x 106 /tmol/min different from unity. Famotidine was 166 times more potent than cimetidine in blocking Mean±S.E. values were then calculated for the depressor action of the H2-agonist on the each histamine dose level in the control and basis of the DR10 values. test groups. The control and each dose level Depressor response to 2-pyridylethylamine of famotidine and cimetidine were tested in in anesthetized dogs: Famotidine in i.v. doses 3 to 5 rats. up to 234 nmol/kg did not affect the depres The shifts in the dose-response curves to sor action of 2-pyridylethylamine. On the con the right were expressed as the ratios of hista trary, mepyramine caused a parallel shift of mine doses to cause the half maximal re the dose-response curve to the right (Fig. 3). sponse in the presence and absence of the The DR10 and slope (95% confidence limits, antagonist. The dose of the antagonists 6 experiments) derived from the Arunlaks required to produce a histamine dose-ratio of hana-Schild plot for mepyramine were 0.45 3 (DR3) and the slopes of regression lines (0.33-0.59) itmol/kg and 0.93 (0.67-1.20), were calculated according to the method of respectively. In the presence of famotidine Arunlakshana and Schild (18). The data used (0.41 /tmol/kg), mepyramine (0.4 itmol/kg) for the dose-response curves were also an diplaced the 2-pyridylethylamine dose-re alyzed by the Edie-Hofstee transformation to sponse curve to the right with a dose-ratio of examine the nature of antagonism (20).
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