Hypertension in Prenatally Undernourished Young-Adult Rats Is Maintained by Tonic Reciprocal Paraventricular–Coerulear Excitatory Interactions

Abstract

Prenatally malnourished rats develop hypertension in adulthood, in part through increased α1-adrenoceptor-mediated outflow from the paraventricular nucleus (PVN) to the sympathetic system. We studied whether both α1-adrenoceptor-mediated noradrenergic excitatory pathways from the locus coeruleus (LC) to the PVN and their reciprocal excitatory CRFergic connections contribute to prenatal undernutrition-induced hypertension. For that purpose, we microinjected either α1-adrenoceptor or CRH receptor agonists and/or antagonists in the PVN or the LC, respectively. We also determined the α1-adrenoceptor density in whole hypothalamus and the expression levels of α1A-adrenoceptor mRNA in the PVN. The results showed that: (i) agonists microinjection increased systolic blood pressure and heart rate in normotensive eutrophic rats, but not in prenatally malnourished subjects; (ii) antagonists microinjection reduced hypertension and tachycardia in undernourished rats, but not in eutrophic controls; (iii) in undernourished animals, antagonist administration to one nuclei allowed the agonists recover full efficacy in the complementary nucleus, inducing hypertension and tachycardia; (iv) early undernutrition did not modify the number of α1-adrenoceptor binding sites in hypothalamus, but reduced the number of cells expressing α1A-adrenoceptor mRNA in the PVN. These results support the hypothesis that systolic pressure and heart rate are increased by tonic reciprocal paraventricular–coerulear excitatory interactions in prenatally undernourished young-adult rats.

The Role of the Paraventricular-Coerulear Network on the Programming of Hypertension by Prenatal Undernutrition

“…(ii) In the PVN, noradrenaline stimulates transcription of the CRF gene very rapidly [ 87 ] by activating α 1 -adrenoceptors [ 88 ], with subsequent increase in cytosolic calcium in PVN neurons [ 89 ] and CRF release [ 90 ]. (iii) Microinjection of the α 1 -adrenoceptor agonist phenylephrine in the PVN excites parvocellular neurons [ 91 ] and increases blood pressure in eutrophic normotensive rats [ 92 , 93 ], while microinjection of the α 1 -adrenoceptor antagonist prazosin counteracts the hyperactivity of PVN neurons [ 52 ] and the hypertensive state observed in prenatally undernourished rats [ 24 , 52 , 93 ]. (iv) Electrical stimulation of the brainstem-PVN noradrenergic connection excites the majority of PVN neurons, the effects being counteracted by the α 1 -adrenoceptor antagonists ergotamine and prazosin and mimicked by the α 1 -adrenoceptor agonist phenylephrine [ 91 , 94 , 95 , 96 , 97 ].…”

“…In order for LC and PVN neurons to interact reciprocally as part of an excitatory closed loop between the LC and PVN in stressed and prenatally malnourished rats, where tonic neuronal activities in the two nuclei influence each other [ 52 , 93 , 99 , 100 , 102 , 103 ], in addition to the noradrenergic excitatory connection to the PVN there should be reciprocal excitatory pathways from the PVN to the LC. Available information in this regard indicates that such excitatory connections from the PVN to the LC are primarily provided by CRFergic innervation.…”

“…It is clear that in healthy normotensive animals (i) administration of norepinephrine or α 1 -adrenergic receptor agonists could activate PVN neurons [ 91 , 96 , 114 ], which results in hypertension and tachycardia [ 92 , 93 ], and (ii) CRF administration to the LC excites central LC neurons [ 109 , 110 ] through activation of CRF 1 receptors [ 111 , 112 ], which also leads to increased blood pressure and heart rate [ 24 , 52 , 93 , 115 ]. These observations are consistent with the aforementioned anatomical and functional studies showing that some PVN and LC neurons are reciprocally and monosynaptically interconnected via CRFergic and noradrenergic axons.…”

“…These observations are consistent with the aforementioned anatomical and functional studies showing that some PVN and LC neurons are reciprocally and monosynaptically interconnected via CRFergic and noradrenergic axons. Interestingly, unlike the effects of agonists in the PVN and LC in normotensive eutrophic rats, the administration of the same agonists in the same brain sites in hypertensive undernourished animals did not produce any cardiovascular effect [ 24 , 93 ]. In contrast, administration of the α 1 -adrenoceptor antagonist prazosin into the PVN or the CRF receptor antagonist α-helical CRF into the LC, lowered blood pressure and heart rate in hypertensive undernourished animals only, failing to modify these cardiovascular parameters in normotensive eutrophic controls [ 24 , 93 ].…”

Resveratrol in the Hypothalamic Paraventricular Nucleus Attenuates Hypertension by Regulation of ROS and Neurotransmitters

“…Hypertension is a serious threat to human health due to its high morbidity and mortality rate [ 1 ]. The hypothalamic paraventricular nucleus (PVN) influences cardiovascular activity by secreting various neural and humoral factors [ 2 , 3 ]. The PVN is crucial in controlling sympathetic nerve activity (SNA) and contributes to blood pressure regulation [ 4 ].…”