Altered heart rate and blood pressure variability in mice lacking the Mas protooncogene

Abstract

Heart rate variability is a relevant predictor of cardiovascular risk in humans. A significant genetic influence on heart rate variability is suggested, although the genes involved are ill-defined. The Masprotooncogene encodes a G-protein-coupled receptor with seven transmembrane domains highly expressed in testis and brain. Since this receptor is supposed to interact with the signaling of angiotensin II, which is an important regulator of cardiovascular homeostasis, heart rate and blood pressure were analyzed in Mas-deficient mice. Using a femoral catheter the blood pressure of mice was measured for a period of 30 min and 250 data values per second were recorded. The mean values and range of heart rate and blood pressure were then calculated. Neither heart rate nor blood pressure were significantly different between knockout mice and controls. However, high resolution recording of these parameters and analysis of the data by non-linear dynamics revealed significant alterations in cardiovascular variability in Mas-deficient animals. In particular, females showed a strong reduction of heart rate variability. Furthermore, the data showed an increased sympathetic tone in knockout animals of both genders. The marked alterations detected in Mas-deficient mice of both genders suggest that the Mas-protooncogene is an important determinant of heart rate and blood pressure variability.

Enhanced baroreflex sensitivity in free-moving calponin knockout mice

“…Moreover, after sinus denervation, the percentage period of the negative correlation was markedly diminished in both groups. In addition, the baroreflex sensitivity determined by the spontaneous method in the WT mice agreed well with previously reported findings in mice by the drug-induced method (13) and spontaneous method (25). Thus the baroreflex sensitivity by the spontaneous method in the present study was reliable enough to clarify the difference in the sensitivity between the WT and KO mice.…”

“…Recently, the baroreflex sensitivity was evaluated from the pulse interval response to spontaneous change in arterial pressure in conscious cats (2), humans (6, 7), and anesthetized mice (25). It was determined that the sensitivity from the slope of the pulse intervals and the systolic pressure, based on the findings that changes in three or more consecutive pulse intervals in response to the preceding systolic arterial pressure were positively correlated.…”

Impairment of In Vitro and In Vivo Heart Function in Angiotensin-(1-7) Receptor Mas Knockout Mice

“…Interestingly, the time to the peak of Ca 2ϩ current was statistically different when To further discard the possibility that the changes in collagen expression in cardiac function in vivo were secondary to increased BP, an additional group of animals at the same age of those used for echocardiograph measurements (6 months) were instrumented for acute BP recordings. As expected, 24,27 …”

“…Accordingly, associated with the important deficit of systolic function, we have also found a significantly lower dimension of the left ventricle at the end of diastole and a decreased ϪdT/dt in isolated hearts of Mas Ϫ/Ϫ . Walther et al 27 have reported an increased BP variability and indirect evidence for an increased sympathetic tonus in male Mas Ϫ/Ϫ mice as compared with control mice (presumably C57BL/6 mice) using spectral analysis of BP data sampled at a relatively low frequency (250 Hz). Whether these changes contribute or are consequence or adaptative responses to the lower cardiac function remains to be established.…”

A Place in Our Hearts for the Lowly Angiotensin 1-7 Peptide?

“…NEP gene inactivation actually caused a drop in blood pressure, 20 quite possibly because NEP is also key in the degradation of the vasodilatory bradykinin and natriuretic atrial natriuretic peptide (ANP). In contrast, mas inactivation had no apparent effect on mean systolic pressure but was reported to slightly decrease blood pressure variability in female, but not male, mice, 21 perhaps as a consequence of increased sympathetic tone. 22 Likewise, ACE2 inactivation had no detectable effect on blood pressure in animals up to 3 months of age.…”