Abstract-The role of the angiotensin II type-2 receptor (AT 2 R) in cardiac hypertrophy remains elusive despite its demonstrated involvement in cardiovascular development. We have previously shown that a lentiviral vector gene delivery system is able to transduce cardiac tissue with high efficiency in vivo. Using such an approach, our objectives in the present study were 2-fold: (1) to overexpress the AT 2 R in cardiac tissue after completion of natural embryonic development of the heart and (2) to determine the effects of this overexpression on cardiac hypertrophy and basal blood pressure (BP). A lentiviral vector encoding the AT 2 R (lenti-AT 2 R) was administered (1.5ϫ10 8 transducing units) into the left ventricular space of 5-day-old spontaneously hypertensive rats (SHRs). AT 2 R transgene expression increased in these animals and persisted for 30 weeks. In contrast, the expression of the angiotensin II type-1 receptor remained unchanged following lenti-AT 2 R treatment. At 21 weeks following gene transduction, the lenti-AT 2 R-treated SHRs exhibited decreased left ventricular wall thickness compared with control animals. In contrast, basal BP did not differ between the two SHR groups. Finally, heart weight to body weight ratios indicated a significant decrease in lenti-AT 2 R-treated SHRs compared with SHR controls. Our data indicate that AT 2 R overexpression attenuates cardiac hypertrophy in the SHR. This beneficial outcome was observed despite the existence of elevated BP. (LVH) is an adaptive response of the heart to preserve cardiac function. Chronic hypertrophy of the heart is a major risk factor for heart failure. Accumulating evidence indicates that both hemodynamic and nonhemodynamic factors are critical in the development of cardiac hypertrophy. 1-9 The local renin-angiotensin system (RAS) is one such nonhemodynamic factor, the dysregulation of which plays a role in the development of cardiac hypertrophy.Binding of angiotensin II (Ang II) to the Ang II type-1 receptor (AT 1 R) increases left ventricular hypertrophy, and blocking this interaction with an AT 1 R antagonist results in a regression in cardiac hypertrophy in a variety of animal models. [2][3][4][5][6][7][8] This view is further supported by gene transfer of the AT 1 R antisense (AT 1 R-AS). 9 These investigations indicated that AT 1 R-AS transduction prevents the development of cardiac hypertrophy in the spontaneously hypertensive rat (SHR) on a long-term basis. In addition, clinical studies have demonstrated that treatment with an AT 1 R antagonist results in a decrease of LVH. 10,11 Although the mechanism by which AT 1 R antagonists reduce LVH is still speculative, it has been suggested that unopposed Ang II stimulation of the Ang II type-2 receptor (AT 2 R) may contribute to its effectiveness. Evidence for this hypothesis is illustrated in a study conducted by Mukawa et al, which showed that simultaneous administration of an AT 2 R antagonist with an AT 1 R antagonist negated the antihypertrophic effects of the AT 1 R blocker alon...

We describe an experimental protocol that consistently yields positive FFRs in rat, dog and human LV muscle at stimulation rates between 1 and 4 Hz, without significant qualitative differences. We attribute previously observed negative FFR in rat muscle to an increase in SERCA activity early after excision and preparation of the muscle strips.

The sarcoplasmic reticular Ca2+ pump (SERCA) is thought to be the primary determinant of heart rate-dependent increases in myocardial contractile [Ca2+]i and force (force-frequency relationship (FFR)), an important mechanism to increase cardiac output. This report demonstrates a rate-dependent role for inward Ca2+ current (ICa) in the human and rat FFR. Human action potential plateau height increased linearly with contractility when heart rate increased in vivo, as measured by monophasic action potential catheter and echocardiography. Rat rate-dependent developed force and cytosolic [Ca2+]i transients were quantified in isolated left ventricular papillary muscles, and ICa and action potential duration in cardiomyocytes. ICa and SERCA measurements better reflected [Ca2+]i and force transients than SERCA activity alone. These data support a direct and (or) indirect contribution to myocardial contractility by ICa at heart rates from approximately 1 to 3-4 Hz (60 to 180-240 bpm) in tandem with SERCA to sustain the typical 'bell shape' of the FFR across species.

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