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The effect of temperature, frequency of stimulation and external calcium on myocardial contractility

University of British Columbia

Changing the temperature, frequency of stimulation and calcium concentration altered the dose-response curves for isoproterenol and histamine on guinea pig and rabbit papillary muscles. Basal developed force, maximal developed force and sensitivity to the agonists were all affected. Increasing the temperature stepwise from 25° to 42° resulted in a progressive decrease in BDF and sensitivity to the agonists. The response of MDF was different in the guinea pig and rabbit. In the guinea pig, MDF was not affected by changing the temperature, and the size of the response to isoproterenol and histamine was similar. In the rabbit, the largest MDF response was seen at 37.5° when the calcium concentration was maintained at 2.2 mM. At this calcium concentration the response to histamine was less than that to isoproterenol at each temperature, although the difference was not significant. Increasing the frequency of stimulation stepwise from 0.5 to 4 Hz in the guinea pig, and 0.2.to 3 Hz in the rabbit affected the dose-response curves in a slightly different manner. In both species, BDF was reduced by low frequency stimulation. At other frequencies BDF was not changed. With isoproterenol, the MDF was only reduced by high frequency stimulation, and the sensitivity increased stepwise with increasing frequency. With histamine, the MDF was reduced by both low and high frequency stimulation. In the rabbit the response to histamine was consistently less than that to isoproterenol. The sensitivity to histamine was not affected by changing the frequency in the guinea pig, but was increased by high frequency stimulation in the rabbit. Increasing the calcium content stepwise from 1.5 to 8 mM in the guinea pig, and 0.5 to 6 mM in the rabbit resulted in a progessive increase in BDF, MDF and sensitivity. In both species, the increase in MDF appeared to reach a maximum between 2.2 and 6 mM calcium. In the rabbit this effect was less noticeable in situations where the frequency or temperature was also reduced. The response to histamine was reduced compared to that of isoproterenol. We postulate that the response to histamine is reduced in rabbit papillary muscles due to stimulation of H₁- receptors in this tissue. It has been shown that stimulation of β and H₂- receptors results in an increase in cyclic AMP, while stimulation of H₁- receptors has no effect on cyclic AMP. The increase in cyclic AMP may enhance calcium binding by the SR resulting in an augmented response.. In the guinea pig papillary muscle which contains β- and H^- receptors, the inotropic responses to isoproterenol and histamine are similar, while in the rabbit papillary muscle which contains 3- and H₁- receptors, the response to histamine is reduced compared to that of isoproterenol. This difference may be due to the lack of cyclic AMP involvement in the response to histamine in this tissue. Use of the calcium antagonist D600 produced a decrease in the sensitivity of rabbit papillary muscles to isoproterenol, but did not depress the MDF. There was no difference in the sensitivity to histamine. D600 therefore could not distinguish any difference in dependence on extracellular calcium between isoproterenol and histamine in this tissue. Isoproterenol stimulated an increase in ⁴⁵Ca content of rabbit right ventricle strips at 2 minutes after administration. No effect could be detected at any other time, nor when histamine was used. It is sugges- ted that at times greater than 2 minutes any increase in ⁴⁵Ca content induced by isoproterenol was masked by a "pool saturation" phenomenon, and that this increase which was detected is consistent with a difference in the mechanism of action of isoproterenol and histamine in rabbit ventricular muscle.

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2010-03-30

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http://hdl.handle.net/2429/23110

Pharmaceutical Sciences

University of British Columbia

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