Subhash C. Verma

Regulation of catecholamine release by presynaptic receptor system

The various presynaptic receptors on postganglionic sympathetic nerves control the release of neurotransmitter, norepinephrine, is well documented and established. Activation of some of these receptors by suitable agonists results in the inhibition of transmitter release whereas the activation of some other receptors results in an increase in the amount of transmitter released during nerve stimulation. This review will focus light on the existence as well as physiological and pharmacological roles of various presynaptic receptor mechanisms on the various postganglionic nerve terminals.

Biochemical and mechanical effects of phenylephrine on the heart

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.

Pharmacological investigations into the effects of histamine and histamine analogs on guinea pig and rat uterus.

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 estrogenprimed 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 estrogenprimed 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 responses in the guinea pig uterus.(6)Our data suggest that in rat uterus only H2-receptors are present and they act indirectly through the release of noradrenaline. In the guinea pig uterus both H1-and H2-receptors are present and are excitatory and directly acting.

Mechanism of action of histamine in the estrogen-primed rat uterus

Histamine produced a dose-dependent relaxation of uterine strips obtained from the estrogen-primed rat uterus. The responses to histamine were blocked competitively by metiamide (10(-8)-10(-8) M), a specific H2-receptor antagonist. Propranolol, a selective beta-receptor blocker also produced competitive antagonism of the responses to histamine in the same dose range (10(-8)-10(-6) M). The pA2 value obtained for metiamide (8.9) was not significantly different from that obtained for propranolol (8.6). Nialamide (2.2 X 10(-6) M), the monoamine oxidase inhibitor, and cocaine (4.3 X 10(-6) M), the selective noradrenaline uptake blocker, potentiated the responses to histamine. However bretylium (2.4 X 10(-5) M), and adrenergic neuron blocker inhibited the responses to histamine. The combined effect of tyramine and histamine was found to be additive. Our data suggest that the histamine-induced relaxation of rat uterus may be produced through the stimulation of presynaptic H2-receptors which causes the release of noradrenaline. The released noradrenaline acts on the postsynaptic beta-receptors and produces relaxation of the rat uterus.

Investigations into the cardiac effects of tolazoline in guinea pig atria and ventricular strips.

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.

Cyclic AMP-dependent and independent positive inotropic effects of phenylephrine☆

To summarize, a large number of studies indicate that the effects of phenylephrine on cardiac contractility are mediated through alpha-adrenoceptors, although not exclusively. There are an equally large number of reports indicating some beta-adrenoceptor stimulant effects of phenylephrine. Of the latter, some are based on the finding of antagonism by beta-receptor antagonists and some on the fact that phenylephrine is capable of elevating cyclic AMP levels, which is primarily a beta-, and not alpha-adrenoceptor effect. Although it is now widely accepted that phenylephrine elevates cyclic AMP levels, the contribution and significance of the elevated nucleotide levels to the overall positive inotropy of phenylephrine appears to be small. Alpha-Adrenoceptors may be involved with calcium, although the precise interaction between calcium and the alpha-adrenoceptor is not clear. Finally, the adrenergic effects seem to depend on the experimental and physiological conditions including calcium ion concentration, thyroid state and driving frequency.

The direct excitatory effects of cimetidine on the smooth muscle of guinea pig ileum

Abstract1.Cimetidine produced dose-dependent contractions in isolated guinea pig ileum and these responses were not blocked by mepyramine the H1-receptor antogonist.2.Atropine competitively inhibited the cimetidine-induced contractions in the guinea pig ileum.3.Cimetidine-induced reponses 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.

Comparative studies of the effects of 5-hydroxytryptamine and noradrenaline on the rat anococcygeus muscle

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 (1.0×10−6M), a specific 5HT receptor blocker, failed to inhibit the responses to either 5HT or NA.2.However, phentolamine, a specificalpha 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 (2.2×10−6M), the mono-amine oxidase inhibitor produced a significant leftward shift of the dose-response curve of both 5HT and NA. Pyrogallol (2.3×10−5M), 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 commonalpha adrenoceptors. 5HT actions are probably indirect, mediated through the release of NA.

α- Adrenoceptor activity of flutonidine (ST 600) in rat anococcygeus muscle and rabbit jejunum

is increased (lCF M) to give between 75-90% of the maximum tone, the sensitivity of the trachea to isoprenaline is significantly reduced and the ability of dimaprit to induce relaxation is virtually abolished. Duncan et a1 (1980) induced maximal contraction of the tracheal spiral with acetylcholine, and were unable to relax it with dimaprit. They concluded that there were no H, relaxant receptors in the guinea-pig airway smooth muscle. Drazen et a1 (1979) induced contractions of the tracheal spiral which were 6040% of the maximum obtainable with histamine, using either 2-(2-pyridyl)-ethylamine (2-PEA), a selective H, agonist, or carbachol. The tissue relaxed in response to dimaprit, suggesting a presence of H2 receptors. These differing results can be explained in terms of the degree of tone induced in the tissue, i.e. functional antagonism. The greater the tone induced, the less likely will dimaprit cause relaxation of the tissue. The results from this work also indicate that the receptor reserve of H2-receptors is significantly less than that of padrenoceptors. In conclusion, in order to demonstrate that a compound has broncho-relaxant properties it is preferable to use a preparation which exhibits spontaneous tone rather than induced tone, since this may significantly alter the conclusions reached.