Temperature alters the inotropic and chronotropic effect of D1-dopamine receptor stimulation in the mammalian atrium

Fig. 1. Scheme for the signal transduction of cardiac D1-dopamine receptors. Dopamine can stimulate D1-dopamine receptors (D1R) in the D1-TG mice. Then, stimulatory GTP binding proteins (Gs) contribute to more production of cAMP catalyzed by adenylyl cyclase (AC) located at the sarcolemma. This cAMP will bind to and activate the protein kinase A (PKA) that is typically activated by phosphorylation of regulatory proteins. A higher phosphorylation state of the inhibitory subunit of troponin (TnI) probably causes a faster relaxation of the heart. An enhanced phosphorylation state of the L-type Ca2+ current (LTCC) causes an increase in the Ca2+ inflow into the cell. This Ca2+ then releases Ca2+ through the ryanodine receptor (RyR in the sarcoplasmic reticulum). Phosphorylation of RyR increases the release of Ca2+ from the sarcoplasmic reticulum and thus hastens the time to peak tension. Phosphorylation of phospholamban (PLB) which activates SERCA and thereby accelerates the removal of Ca2+ from the cytosol, results in hastened mechanical relaxation. When more sodium ions pass through the sarcolemma via a sodium channel (Na +), the intracellular sodium ions will rise: they can now leave the…

Fig. 2. Measurements on a single contraction of WT and D1-TG mice. Typical original recording of a single contraction of WT and D1-TG mice after 300 nM dopamine application. The baseline and peak line were placed by the software LabChart 8 under the curves to plot time to peak tension (T1) and time to relaxation (T2) (blue lines for WT and red lines for D1-TG mouse). The tangents on the curves represent the maximum positive (dF/dtmax, black tangents) and negative rate of tension development (dF/dtmin, green tangents). Ordinate depicts developed force of contraction in millinewton (mN). Abscissa shows time in seconds (s)

Fig. 3. Dopamine increases force of contraction in D1-TG but not in WT mice. Original recordings of the effect of increasing concentrations of dopamine on electrically stimulated left atrial (LA) preparations from WT (A) or D1-TG mice (B) under normothermia (37 °C), hypothermia (24 °C) and hyperthermia (42 °C). In addition, the concentration-dependent effects of dopamine on force of contraction in LA were summarized for WT in absolute values (C) and in percent % (D) or for D1-TG in absolute values (E) and in % (F). In samples, we added 0.4 µM propranolol to the organ bath in order to block β-adrenoceptors. Ordinates in A, B, C, and E depict developed force of contraction in millinewton (mN). Abscissae indicate concentrations of dopamine in negative decadic molar concentrations. Temperatures of the organ baths are indicated as circles (37 °C), squares (24 °C), or triangles (42 °C). “n” indicates the numbers of experiments.* first p < 0.05 vs. Prop, + first p < 0.05 vs. 37 °C (ANOVA Bonferroni)

Fig. 4. Dopamine increases the rate of tension development and relaxation in left atrium in D1-TG. Original recordings of single contractions after 300 nM dopamine application (Fig. 4 A) and concentration response curves for dopamine in electrically stimulated mouse LA from WT (Fig. 4B) and D1-TG mice (Fig. 4 C) under normothermia (37 °C), hypothermia (24 °C) and hyperthermia (42 °C). We added 0.4 µM propranolol to the organ bath in order to block β-adrenoceptors. Dopamine induced an increase in the rate of tension development and relaxation in D1-TG mice under all thermal conditions. The ordinate in A depicts the developed force of contraction in millinewton (mN), and the ordinates in B and C depict the rate of tension development (dF/dtmax) and the rate of tension relaxation (dF/dtmin) in millinewton per second (mN/s). The abscissa in A shows time in seconds (s), whereas the abscissae in B and C indicate concentrations of dopamine in negative decadic logarithm of molar concentrations. Temperatures of the organ baths are indicated as circles (37 °C), squares (24 °C), or triangles with tip up (42 °C). “n” indicates the numbers of experiments. * first p < 0.05 vs. Prop, + first p < 0.05…

Fig. 5. Dopamine shortens time to peak tension and relaxation in left atrium. Time to peak tension curve of WT (A) or D1-TG (B) and time to relaxation curve of WT (C) or D1-TG (D) under normothermia (37 °C), hypothermia (24 °C) and hyperthermia (42 °C). We also added 0.4 µM propranolol to the organ bath in order to block β-adrenoceptors. Time to peak tension and time to relaxation under basal conditions (Prop) were longer under hypothermia than under normothermia or hyperthermia in both LA from WT (A and C) or D1-TG (B and D). In addition, dopamine shortens time to peak tension in D1-TG mice only under hypothermia and shortens time to relaxation under hypothermia and normothermia. Ordinates in A and B depict time to peak tension (T1) and in C and D time to relaxation (T2) in milliseconds (ms). Abscissae indicate concentrations of dopamine in negative decadic logarithm of molar concentrations. Temperatures of the organ baths are indicated as circles (37 °C), squares (24 °C), or triangles with tip up (42 °C). “n” indicates the numbers of experiments. * first p < 0.05 vs. Prop, + first p < 0.05 vs. 37 °C (ANOVA Bonferroni)

Fig. 6. Dopamine increases the beating rate and the force of contraction in the right atrium. Summarized concentration response curves for the effect of dopamine on the beating rate in spontaneously beating mouse right atrial (RA) preparations under normothermia (37 °C), hypothermia (24 °C) and hyperthermia (42 °C) in WT (A) or D1-TG mice (B) and on the force of contraction in millinewton (mN) in WT (C) or D1-TG mice (D). We also added 0.4 µM propranolol to the organ bath in order to block β-adrenoceptors. Ordinates in A and B depict beats per minute (bpm), ordinates in C and D depict developed force of contraction in millinewton (mN). Abscissae indicate concentrations of dopamine in negative decadic logarithm of molar concentrations. Temperatures of the organ baths are indicated as circles (37 °C), squares (24 °C), or triangles with tips up (42 °C). “n” indicates the numbers of experiments. * first p < 0.05 vs. Prop, + first p < 0.05 vs. 37 °C (ANOVA Bonferroni)

Fig. 7. Hyperthermia and hypothermia reduce the effect of dopamine on tension development and relaxation in right atrial preparations, and time to peak tension and relaxation is increased under hypothermia. Original recordings of single contractions under basal conditions (Fig. 7 A), after 300 nM dopamine application (Fig. 7B) and concentration response curves for dopamine in spontaneously beating right atrium (RA) from WT and D1-TG under normothermia (37 °C), hypothermia (24 °C) and hyperthermia (42 °C). We added 0.4 µM propranolol to the organ bath in order to block β-adrenoceptors. Dopamine increased time to peak tension in D1-TG mice under hypothermal and normothermal conditions but also increased time to relaxation in hypothermia only (D and F), whereas in WT mice, the peak was reached at higher dopamine concentrations (C and E). In addition, the effect of dopamine on tension development and relaxation was reduced under hypo- and hyperthermia compared to normothermia (G and H). Ordinates in A and B depict developed force of contraction (F in mN), C and D depict time to tension (T1 in ms), E and F depict time to relaxation (T2 in ms), G and H depict rate of tension development…

Fig. 8. Dopamine induces arrhythmias in WT and D1-TG mice under all thermal conditions. Occurrence of arrhythmias at indicated temperatures in right atrial (RA) preparations from WT and D1-TG mice. A Original recordings of the effect of increasing dopamine concentrations on the force of contractions in RA. We also added 0.4 µM propranolol to the organ bath in order to block β-adrenoceptors. Ordinate depicts developed force of contraction. The abscissa shows increasing logarithmic molar concentrations of dopamine. B Original recordings of various malignant arrhythmia types like bigeminy, salvo, trigemini, and asystole. C Temperature-dependent average duration of arrhythmias during dopamine addition in WT and D1-TG mice. Ordinate depicts the time in milliseconds. x p < 0.05 vs. WT, + p < 0.05 vs. 37 °C. D Temperature-dependent incidences of arrhythmias during dopamine addition in WT and D1-TG. Ordinate shows the incidences of the arrhythmias. x p < 0.05 vs. WT of dopamine-induced arrhythmias, + p < 0.05 vs. 37 °C of dopamine-induced arrhythmias (2-test). E Temperature-dependent average of incidences of benign and malignant arrhythmias before dopamine application (CTR) and during maximal…

Fig. 9. Dopamine increases force of contraction in human atrial preparations (HAP) in a concentration-dependent manner. Original recordings of the effect of increasing concentrations of dopamine in electrically stimulated (1 Hz) human atrial preparations (HAP) under normothermia (37 °C), hypothermia (24 °C) and hyperthermia (42 °C) (A). In addition, the concentration-dependent effects of dopamine on force of contraction were summarized in absolute values (B) and in % of propranolol (Prop; C). In samples, we added 0.4 µM propranolol to the organ bath in order to block β-adrenoceptors. Dopamine increases force of contraction in HAP under all thermal conditions. Ordinates in A and B depict developed force of contraction in millinewton (mN). Abscissae indicate concentrations of dopamine in negative decadic molar concentrations. Temperatures of the organ baths are indicated as circles (37 °C), squares (24 °C), or triangles with tips up (42 °C). “n” indicates the number of experiments. * first p < 0.05 vs. Prop, + first p < 0.05 vs. 37 °C (ANOVA Bonferroni)

Fig. 10. Dopamine increases the rate of tension development in HAP under normothermia and slightly increases relaxation time under hypothermia. Summarized concentration response curves for dopamine in electrically driven (1 Hz) right human atrial preparations. A Time to peak tension (T1 in ms), B relaxation time (T2 in ms) and C rate of tension development dF/dtmax and rate of tension relaxation dF/dtmin (in mN/s). Abscissae show negative decadic molar concentrations of dopamine. Temperatures of the organ baths are indicated as squares (37 °C), circles (23 °C), or triangles with tip up (42 °C). “n” indicates the numbers of experiments. * first p < 0.05 vs. Prop, + first p < 0.05 vs. 37 °C (ANOVA Bonferroni)