Guinea-pig cardiac & ileal histamine receptors during hyperthyroid state.
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Biomedical subjects
Publications and source records attributed to S C Verma.
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1. Cimetidine produced dose-dependent contractions in isolated guinea pig ileum and these responses were not blocked by mepyramine the H1-receptor antagonist. 2. Atropine competitively inhibited the cimetidine-induced contractions in the guinea pig ileum. 3. Cimetidine-induced responses were potentiated in the presence of eserine. Magnesium ions non-competitively inhibited the contractions due to cimetidine. Our findings suggest that cimetidine excites the guinea pig ileum through muscarinic receptors by releasing acetylcholine.
The effects of 5-hydroxytryptamine (5HT) and noradrenaline (NA) have been studied on rat anococcygeus muscle. 1. 5HT and NA produced a dose-dependent contraction of rat anococcygeus muscle. Cyproheptadine (1.0 X 10(-6) M), a specific 5HT receptor blocker, failed to inhibit the responses to either 5HT or NA. 2. However, phentolamine, a specific alpha receptor antagonist competitively blocked the responses to 5HT and NA. 3. The responses to 5HT were inhibited in the reserpinized (5 mg/kg i.p. 24 h) and 6-hydroxydopamine (6-OHDA) pre-treated preparations. 6-OHDA produced a leftward shift of the dose-response curve of NA. Reserpine pre-treatment potentiated lower doses of NA and the threshold dose of NA was significantly decreased. 4. Nialamide (2.2 x 10(-6) M), the mono-amine oxidase inhibitor produced a significant leftward shift of the dose-response curve of both 5HT and NA. Pyrogallol (2.3 x 10(-5) M), the catechol-o-methyl transferase inhibitor also potentiated the responses to both 5HT and NA, but the potentiation was significant at lower doses of 5HT and NA. 5. Our data suggest that 5HT- and NA-induced contractions in rat anococcygeus muscle are mediated through common alpha adrenoceptors. 5HT actions are probably indirect, mediated through the release of NA.
The effects of histamine and its analogs 2-(2-pyridyl) ethylamine (PEA) and 4-methylhistamine (4 MH) have been studied on uterine preparations obtained from estrogen-primed guinea pigs and rats. (1) Histamine and 4 MH, a specific H2-receptor agonist produced relaxation in estrogen-primed rat uterus, whereas these agonists produced contraction in the estrogen-primed guinea pig uterus. (2) PEA, a specific H1-receptor agonist produced contraction in the guinea pig uterus but had no effect on the rat uterus. (3) Metiamide blocked responses to histamine and 4 MH in the rat uterus, whereas mepyramine blocked responses to histamine and PEA in the guinea pig uterus. (4) Propranolol produced competitive antagonism with histamine in the rat uterus, whereas it had no significant effect on the histamine or PEA responses in the guinea pig uterus. (5) Reserpine pretreatment completely abolished the responses to histamine and 4 MH in the rat uterus but did not alter the response in the guinea pig uterus. (6) Our data suggest that in rat uterus only H2-receptors are present and they are indirectly through the release of noradrenaline. In the guinea pig uterus both H1- and H2-receptors are present and are excitatory and directly acting.
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Histamine produces contractions of the guinea pig vas deferens. The present investigation was undertaken to characterize the nature of histaminergic receptors in this tissue. Histamine (1.6 X 10(-6) M to 3.2 X 10(-5) M) produced dose-related contractions of guinea pig vas deferens (GPVD). Mepyramine (5.3 X 10(-8) M and 1 X 10(-9) M) blocked the responses to histamine competitively. Metiamide (1.23 X 10(-5) M) did not block the responses to histamine significantly. Specific H1 and H2 receptor agonists, namely 2-(2'-pyridyl)ethylamine (PEA) (2.55 X 10(-6) M to 3.0 X 10(-5) M) and 4-methylhistamine (4-MH) (2.52 X 10(-5) M to 3.0 X 10(-4) M), respectively, produced dose-related contractions of GPVD. The responses to PEA were blocked competitively by mepyramine, whereas the responses to 4-MH were blocked by metiamide. Reserpine pretreatment (5 mg/kg, i.p., 24 h) did not alter the responses to histamine and PEA. Our data suggest the presence of both H1 and H2 receptors in the GPVD which are excitatory in nature.
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Histamine, 2-(2-pyridyl)ethylamine (PEA), a specific H1 receptor agonist, and 4-methylhistamine (4-MH), a specific H2 receptor agonist, produced a dose-dependent contraction of estrogen-primed guinea pig uterus and taenia coli. Mepyramine (10(-7) M), a specific H1 receptor antagonist, competitively blocked the responses to histamine and PEA in both the preparations. Metiamide (10(-6) M), a specific H2 receptor antagonist, inhibited the responses to histamine and 4-MH in the guinea pig uterus and taenia coli. Our data suggest the presence of both H1 and H2 receptors in the guinea pig uterus and taenia coli. Both receptors appear to be excitatory in nature.
Histamine can produce inotropic and chronotropic responses in both guinea pig and rabbit heart. In the guinea pig the responses are mediated primarily through stimulation of H2 receptors with H1 receptors being found mainly in left atria. In the rabbit H1 receptors predominate; H2 receptors are found only in right atria and are partially responsible for the chronotropic effect. H2 receptors are always associated with cyclic AMP, whereas H1 receptors are not. H2-histamine receptors and beta-adrenergic receptors have a number of properties in common. Stimulation of either receptor results in positive inotropic and chronotropic effects and increases in cyclic AMP and phosphorylase a. H2 and beta-adrenergic agonists will also both restore the action potential in K+-depolarized cardiac muscle. H1 and alpha-agonists, on the other hand, will also produce an inotropic effect. The effect is not dependent on cyclic AMP and can only be demonstrated under certain conditions. Neither agonist will restore the action potential in depolarized cardiac tissue. It is concluded that, although H2 and beta-agonists and H1 and alpha-agonists may have a common mechanism of action, the two groups of drugs (H2, beta versus H1, alpha) differ from each other with regard to mechanism.
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The positive inotropic, chronotropic and cyclic AMP producing effects of tolazoline were studied on atrial and ventricular preparations obtained from guinea pig heart. (1) The direct positive inotropic effects of tolazoline on the paced left atrial preparation from the guinea pig hearts was blocked by promethazine, but not by burimamide. Tolazoline did not elevate cyclic AMP levels in this preparation. (2) Tolazoline produced a positive chronotropic effect which was blocked by burimamide and not by promethazine and caused a 2-3 fold elevation of cyclic AMP in spontaneously beating right atria. (3) Burimamide antagonized the inotropic and cyclic AMP increasing effects of tolazoline on electrically driven ventricular strips. (4) The effects of tolazoline were unchanged by reserpine pretreatment of the guinea pigs or by prior exposure to phentolamine or propranolol. (5) These results suggest that tolazoline can activate both H1 and H2 receptors in the guinea pig heart. Furthermore the data suggests that H2 receptors are present in right atria and ventricle and that such receptors are associated with cyclic AMP. H1 receptors are present in the left atria and are not associated with the cyclic nucleotide.
Histamine can stiumulate the heart by directly interacting with cardiac histamine receptors. In the present study we have investigated the cardiac effects of histamine, 4-methylhistamine (a specific H2-receptor agonist) and 2-pyridylethylamine PEA, a specific H1-receptor agonist] on spontaneously beating right atria and electrically driven left atria and right ventricle strips of the guinea pig. Left atria were driven at 1 Hz and right ventricle strips at 2.5 Hz and at twice the threshold voltage. Histamine and PEA produced a dose-dependent positive inotropic effect on the left atria. The dose-response curves were shifted to the right in a parallel fashion by promethazine (3 x 10(-6)M)+... Burimamide did not affect either dose-response curve. Histamine and 4-methylhistamine had a positive chromnotropic effect on right atria and a positive inotropic effect on right ventricle strips.
Clonidine perfusion (1 muM) or injection (9.4 to 150.4 nmoles) into the isolated perfused guinea pig heart caused an increase in contractile force, phosphorylase a and cyclic adenosine monophosphate (cyclic AMP) levels. The effects of clonidine were blocked by burimamide (30 muM). Proranolol (1 muM), phentolamine (1 muM) or reserpine treatment (5 mg/kg i.p., 24 hours prior to the experiment) did not influence the cardiac effects of clonidine. Clonidine (0.1 - 100 muM) also produced a dose dependent positive inotropic effect on right ventricle strips but had a negative chronotropic effect on the spontaneously beating right atria at higher concentration (0.1 to 1.0 M). Burimamide did not block the clonidine-induced negative chronotropic effect. Clonidine did not increase contractile force in guinea pig left atria. It also did not influence the isoproterenol-and phenylephrine-induced increases in cardiac force of contraction but did antagonize the positive inotropic effect of 4-methylhistamine in the right ventricle. This observation suggests that clonidine may compete with 4-methylhistamine for the same receptor sites. The results indicate that the cardiac receptors for both biochemical and mechanical effects of clonidine are histamine receptors of the H2-type.
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Injections of phenylephrine into isolated perfused guinea pig hearts increased cyclic AMP and phosphorylase a. Reserpine pretreatment or propranolol decreased or abolished the phenylephrine-induced biochemical changes without affecting the contractile response. Phentolamine, on the other hand, shifted the phenylephrine dose-response curve for contractility to the right without affecting the other parameters. The biochemical effects of phenylephrine are apparently due to the release of noradrenaline while the contractile effect is mediated directly through stimulation of alpha-adrenoceptors.
Isoproterenol (10(-4) M), histamine (10(-3) M) and tyramine (10(-3) M) elevated cyclic AMP levels in incubated rat urerine segments. Promethazine (10(-6) M) an H1-receptor antagonist was ineffective in blocking the increase in cyclic AMP due to isoproterenol, histamine and tyramine. Buriamide (10(-6) M), an H2 receptor antagonist, was effective in almost abolishing the cyclic AMP elevation due to histamine, whereas burimamide did not affect the cyclic AMP levels elevated by tyramine and only slightly reduced the isoproterenol response. Propranolol was effective in reducing or abolishing the cyclic AMP accumulation by all three agonists. The respective blockade by burimamide or propranolol was overcome by increasing the concentration of the agonists. Histamine (10(-3) M) and tyramine (10(-3) M) failed to elevate cyclic AMP in uterine segments obtained from reserpine treated rats. The data supports the hypothesis that histamine, like tyramine, has an indirect effect on the rat uterus mediated through the release of endogenous norepinephrine.
Injection of 1.0 mg theophylline and 1.6 mg imidazole into guinea-pig hearts perfused by the Langendorff technique increased cardiac contractile force by 20.0 +/- 1.0% and 23.3 +/- 1.2% over control and activated phosphorylase without producing significant changes in cyclic AMP levels. When guinea-pig hearts were perfused with theophylline (10(-3) M) or imidazole (20 mM), injection of either imidazole or theophylline did not further increase cardiac contractility or phosphorylase a levels. In all cases there was no change in cycylic AMP levels. Data in the literature indicate that calcium plays a role in the cardiac biochemical and mechanical effects of theophylline and imidazole. Both drugs may thus produce their cardiac effects by a calcium rather than a cyclic AMP mediated mechanism.