Laurent Monassier

Enhancing Repair of the Mammalian Heart

The injured mammalian heart is particularly susceptible to tissue deterioration, scarring, and loss of contractile function in response to trauma or sustained disease. We tested the ability of a locally acting insulin-like growth factor-1 isoform (mIGF-1) to recover heart functionality, expressing the transgene in the mouse myocardium to exclude endocrine effects on other tissues. supplemental mIGF-1 expression did not perturb normal cardiac growth and physiology. Restoration of cardiac function in post-infarct mIGF-1 transgenic mice was facilitated by modulation of the inflammatory response and increased antiapoptotic signaling. mIGF-1 ventricular tissue exhibited increased proliferative activity several weeks after injury. The canonical signaling pathway involving Akt, mTOR, and p70S6 kinase was not induced in mIGF-1 hearts, which instead activated alternate PDK1 and SGK1 signaling intermediates. The robust response achieved with the mIGF-1 isoform provides a mechanistic basis for clinically feasible therapeutic strategies for improving the outcome of heart disease.

Selectivity of rilmenidine for the nucleus reticularis lateralis, a ventrolateral medullary structure containing imidazoline-preferring receptors

Neuronal metabolic activity was studied by in vivo electrochemistry in two brain areas of the anesthetized rat: the nucleus reticularis lateralis (NRL) region of the ventrolateral medulla oblongata - site of the hypotensive action of clonidine-like imidazolines - and the locus coeruleus (LC), which is involved in the sedative effect of these drugs. Hypotensive doses of i.v. rilmenidine (0.3 and 1.5 mg/kg), which is structurally related to clonidine, induced a dose-related inhibition of the metabolic activity of catecholaminergic neurons in the NRL region whereas higher doses (50-fold) were required to inhibit the activity of the catecholaminergic neurons in the locus coeruleus. On the other hand azepexole, another centrally acting antihypertensive drug that is not structurally related to the imidazolines failed to inhibit the neuronal metabolic activity of the NRL region when administered i.v. in hypotensive doses (1 mg/kg). Taken together, these findings suggest that the central hypotensive action of clonidine-like drugs requires the imidazoline structure or pharmacologically compatible compounds like rilmenidine. Our results also show that rilmenidine is twice as selective as clonidine for the NRL region, which contains imidazoline-preferring receptors, compared with the LC, which contains mainly alpha 2-adrenoceptors. In conclusion, this study provides a functional confirmation of the dissociation between the therapeutic (hypotensive) and untoward (sedative) effects of rilmenidine.

Cardiovascular and survival effects of sympatho‐inhibitors in adriamycin‐induced cardiomyopathy in rats

Adriamycin (ADR) is a widely used drug for the treatments of cancers. This study evaluates the effects of moxonidine and metoprolol on cardiac hemodynamics and survival in ADR‐induced left ventricular dysfunction (total dose of 20u2003mg/kg in a 4‐week regimen). Rats were treated with the centrally acting I1R agonist sympatho‐inhibitor, moxonidine, or with the non‐selective β‐adrenergic antagonist, metoprolol, during 1u2003month or until death. Treatments began 1u2003week after the onset of the ADR administration. Low doses (0.5 and 1u2003mg/kg/day) of moxonidine and metoprolol (10u2003mg/kg/day) improved cardiovascular function. High doses of moxonidine (3u2003mg/kg/day) and metoprolol (150u2003mg/kg/day) were cardiodepressive. Moxonidine and metoprolol both failed to improve survival. These data indicate that a treatment with these sympatho‐inhibitors can reduce the left ventricular dysfunction induced by ADR. Moreover, these cardioprotective effects where obtained even when ADR was used at a dose regimen usually employed for its antineoplastic effects in rodents. Nevertheless, in this particular cardiomyopathy, we did not find any association between improvements of functional parameters and survival whatever the drug and the dose used. This problem points out the difficulty to prevent, at least with sympatho‐inhibitory drugs alone, the mortality linked to the chronic cardiotoxicity of ADR.

Assessment of right and left ventricular function in healthy mice by blood-pool pinhole gated SPECT

The feasibility of blood-pool pinhole ECG gated SPECT was investigated in healthy mice to assess right and left ventricular function analysis. Anaesthetized (isoflurane 1-1.5%) adult CD1 mice (n=11) were analyzed after intravenous administration of 0.2 ml of 550 MBq of (99m)Tc human albumin. For blood-pool gated SPECT imaging, 48 ventral step and shoot projections with eight time bins per RR over 180 degrees with 64 x 64 word images were acquired with a small animal gamma camera equipped with a pinhole collimator of 12 cm in focal length and 1.5 mm in diameter. For appropriate segmentation of right and left ventricular volumes, a 4D Fourier analysis was performed after reconstruction and reorientation of blood-pool images with a voxel size of 0.55 x 0.55 x 0.55 mm(3). Average right and left ejection fractions were respectively 52+/-4.7% and 65+/-5.2%. Right end diastolic and end systolic volumes were significantly higher compared with the corresponding left ventricular volumes (P<0.0001 each). A linear correlation between right and left stroke volumes (r=0.9, P<0.0001) was obtained and right and left cardiac outputs were not significantly different 14.2+/-1.9 and 14.1+/-2 ml/min, respectively.