American journal of physiology. Heart and circulatory physiology
-
Am. J. Physiol. Heart Circ. Physiol. · Jun 2009
Clinical TrialTransient receptor potential melastatin 8 channel involvement in the regulation of vascular tone.
The transient receptor potential melastatin 8 (TRPM8) channel has been characterized as a cold and menthol receptor expressed in a subpopulation of sensory neurons but was recently identified in other tissues, including the respiratory tract, urinary system, and vasculature. Thus TRPM8 may play multiple functional roles, likely to be in a tissue- and activation state-dependent manner. We examined the TRPM8 channel presence in large arteries from rats and the functional consequences of their activation. ⋯ Vasodilatation was markedly reduced or abolished by prior application of l-NAME (passive application, 10 mM) or atropine (iontophoretic application, 100 nM, 30 s at 70 microA). We conclude that TRPM8 channels are present in rat artery vascular smooth muscle and on activation cause vasoconstriction or vasodilatation, dependent on previous vasomotor tone. TRPM8 channels may also contribute to human cutaneous vasculature control, likely with the involvement of additional neuronal mechanisms.
-
Am. J. Physiol. Heart Circ. Physiol. · Jun 2009
Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension.
We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle (day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 microg*kg(-1)*day(-1) ip) or a similar volume of saline, resulting in four groups: sham (n = 11), sham-AP (n = 11), MCT (n = 16), and MCT-AP (n = 13). ⋯ Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation.
-
Am. J. Physiol. Heart Circ. Physiol. · Jun 2009
Endogenous cardiac natriuretic peptides protect the heart in a mouse model of dilated cardiomyopathy and sudden death.
Ventricular myocytes are known to show increased expression of the cardiac hormones atrial and brain natriuretic peptide (ANP and BNP, respectively) in response to pathological stress on the heart, but their function during the progression of nonischemic dilated cardiomyopathy remains unclear. In this study, we crossed a mouse model of dilated cardiomyopathy and sudden death, which we generated by cardioselectively overexpressing a dominant-negative form of the transcriptional repressor neuron-restrictive silencer factor (dnNRSF Tg mice), with mice lacking guanylyl cyclase-A (GC-A), a common receptor for ANP and BNP, to assess the effects of endogenously expressed natriuretic peptides during progression of the cardiomyopathy seen in dnNRSF Tg mice. ⋯ The survival rates among dnNRSF Tg;GC-A(+/-) and dnNRSF Tg mice were comparable, but dnNRSF Tg;GC-A(+/-) mice showed greater systolic dysfunction and a more severe cardiomyopathic phenotype than dnNRSF Tg mice. Collectively, our findings suggest that endogenous ANP/BNP protects the heart against the death and progression of pathological remodeling in a mouse model of dilated cardiomyopathy and sudden death.