Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function

The sinoatrial node (SAN) is the primary pacemaker of the heart and is responsible for generating the intrinsic heartbeat. Within the SAN, spontaneously active pacemaker cells initiate the electrical activity that causes the contraction of all cardiomyocytes. The firing rate of pacemaker cells depends on the slow diastolic depolarization (SDD) and determines the intrinsic heart rate (HR). To adapt cardiac output to varying physical demands, HR is regulated by the autonomic nervous system (ANS). The sympathetic and parasympathetic branches of the ANS innervate the SAN and regulate the firing rate of pacemaker cells by accelerating or decelerating SDD–a process well-known as the chronotropic effect. Although this process is of fundamental physiological relevance, it is still incompletely understood how it is mediated at the subcellular level. Over the past 20 years, most of the work to resolve the underlying cellular mechanisms has made use of genetically engineered mouse models. In this review, we focus on the findings from these mouse studies regarding the cellular mechanisms involved in the generation and regulation of the heartbeat, with particular focus on the highly debated role of the hyperpolarization-activated cyclic nucleotide-gated cation channel HCN4 in mediating the chronotropic effect. By focusing on experimental data obtained in mice and humans, but not in other species, we outline how findings obtained in mice relate to human physiology and pathophysiology and provide specific information on how dysfunction or loss of HCN4 channels leads to human SAN disease.

Beta-1 adrenergic receptors modulate pacemaker activity of mouse sino-atrial myocytes through L-type Cav1.3 channels

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Doctoral program in Biology and Biotechnologies b1- and b2- adrenergic receptors (ARs) are co-expressed in different regions of the heart. The b2/ b1 expression ratio is higher in the sino-atrial node (SAN) than in atria and ventricles, but the specific contribution of either type of receptor to modulation of pacemaker activity is still not well established. Specific stimulation of b2-ARs in rabbit SAN myocytes is associated with a positive shift of the pacemaker "funny" current (If) activation curve. However, previous studies showed that L-type Cav1.3 channels play an important role in the generation of cardiac pacemaker activity by contributing to the diastolic depolarization (DD) in SAN myocytes. Since Cav1.3 channels are positively regulated by b-ARs activation2, we investigated which is the main b-ARs isoform that modulates Cav1.3-mediated ICaL andthe pacemaker activity of SAN myocytes. To address this point, we recorded spontaneous activity and Cav1.3-mediated ICaL from mouse SAN myocytes. We found that the positive chronotropic effect of the non-selective b-AR agonist isoproterenol (ISO, 0.1mM) was decreased by the b1-ARs antagonist CGP-20712 (0.3mM) and the b2-ARs antagonist ICI-118,551 (1mM) by -18% and -9%, respectively. Perfusion of CGP-20712 strongly reduced the positive chronotropic effect induced by ISO. Finally, we recorded Cav1.3-mediated L-type currents in presence of the b1-ARs antagonist. CGP-20712 reduced the basal Cav1.3-mediated ICaL. Furthermore, the increase in Cav1.3-mediated ICaL by isoproterenol was abolished during b1-ARs inhibition by CGP-20712. In conclusion, these preliminary data show that b1- and b2-ARs differently modulate the spontaneous activity of mouse SAN myocytes. In addition, b1-ARs play a predominant role in the adrenergic regulation of L-type Cav1.3 channels to increase pacemaker activity. Future studies will be performed to clarify the role of b2-ARs antagonist on Cav1.3-mediated ICaL and the functional relationships between b-ARs and Cav1.3 channels.

The dynamics of EEG correlates of activity of subcortical structures of the bird brain in conditions of chronic stress

In birds, acute stress (a three-day 12-hour inversion of the photomode) is associated with the dominant activity of the sympathetic hypothalamus and hippocampus, which suppress the tone of the parasympathetic section and the reticular formation of the midbrain. The effect of hyperglycemia on the background of a negative chronotropic effect indicates a mismatch of the functions of the autonomic sections of the hypothalamus on the 30th day. Chronic stress in birds (30-days crowding) causes persistent pathological stress of the functions of the anterior hypothalamus and reticular formation of the middle brain with the suppression of parasympathetic tone of the posterior hypothalamus and high functional activity of the hippocampus, determining the switching of the ventricles of the heart to a more economical mode of functioning by the 30th day. Using central cholinoblockers or tranquilizers, having a cholinoblocking component in the mechanism of its influence during neurogenic stress and in the post-stress period is excluded, but it is possible to use stressprotektors.

Heart reaction of male and female with streptozotocin induced diabetes on cholinergic impacts

The aim: Find out the nature of the changes sensitivity of the heart to the cholinergic influences the development of diabetes depending on gender. Materials and methods: In experiments on adult male and female rats, type 1 diabetes by momentary introduction of streptozotocin at a dose of 60 mg/ kg into the peritoneal cavity was modeled. Animals were examined after 15, 30, 60 and 90 days after introduction of streptozotocin. We studied the sensitivity of cholinoreceptors of sinus node by the intensity of bradycardia with intravenous injection of acetylcholine and electrical stimulation of the peripheral segment of the right vagus nerve. Results: It was established that the intensity of the negative chronotropic effect of heart of males by electric stimulation of the vagus nerve, which depends on the reserves of acetylcholine in the presynaptic section and sensitivity of postsynaptic cholinoreceptors, increased gradually and after 90 days prevailed the output value in 2.2 times. This occurred at the background of a slight (10 %) decrease in response to exogenous acetylcholine that reflected the decrease in sensitivity of cholinoreceptors. In females the maximum increase (in 4.4 times) of the intensity of the negative chronotropic effect of vagus nerve stimulation was observed after 30 days from the start of the experiment. After 90 days, this indicator prevailed the controlled one in 3.3 times, which occurred at the background of heart response decreasing to exogenous acetylcholine (in 1.7 times). Conclusions: Obtained results suggest a more significant change in state of cholinoceptor system of myocardium of females compared with males in the dynamics of development of streptozotocin-induced diabetes.

EXPERIMENTAL STUDY TO EVALUATE HAEMODYNAMIC ACTION OF HERBO-MINERAL COMPOUNDS

ABSTRACT : Aim: Every ¼ individuals die due to cardiac failure. Cardiac diseases are increasing and ranks 1st in top 10 causes of death as per WHO. In order to increase life span and mortal period we must find an alternative treatment and so we have the rich ancient wisdom from Ayurveda. We have to utilize this knowledge scientifically so that we can understand their action and use them to cure diseased person. Objective: To evaluate the heamodynamic action of herbo-mineral compound in healthy individual. Material & Method: Four healthy individuals were selected for the study. Each healthy individual consumed a different bhasma and post consumption the following parameters were checked Heart Rate (HR), Systolic blood pressure (SBP), Stroke volume (SV) , Cardiac output(CO), Systemic vascular resistance (SVR) ; were recorded at intervals of immediately after consumption, after 1 hour and after 2 hours. Rasa bhasma administered tamra bhasma, abhrak bhasma, suvarna makshik bhasma, mauktik bhasma. Method Of Evaluation: Deviation in parameters was observed from normal standard value leading to conclusion of heamodynamic effect. Result: Sr no Bhasma name Chronotropic effect Inotropic effect Tamra bhasma Positive Negative Abhrak bhasma Negative Negative Swarna makshik bhasma Neutral Negative Mauktik bhasma Neutral Negative Conclusion : Herbomineral compounds have a significant haemodynamic effect on the human body.