Daniel C. Hatton

Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2

The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2 (refs 4,5). These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2−/− mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2−/− mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2−/− mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2–/– mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2−/− mice following Ucn, but Crhr2−/− mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2−/− mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2−/− mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.

3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone

Thyroxine (T4) is the predominant form of thyroid hormone (TH). Hyperthyroidism, a condition associated with excess TH, is characterized by increases in metabolic rate, core body temperature and cardiac performance. In target tissues, T4 is enzymatically deiodinated to 3,5,3′-triiodothyronine (T3), a high-affinity ligand for the nuclear TH receptors TRα and TRβ, whose activation controls normal vertebrate development and physiology. T3-modulated transcription of target genes via activation of TRα and TRβ is a slow process, the effects of which manifest over hours and days. Although rapidly occurring effects of TH have been documented, the molecules that mediate these non-genomic effects remain obscure. Here we report the discovery of 3-iodothyronamine (T1AM), a naturally occurring derivative of TH that in vitro is a potent agonist of the G protein–coupled trace amine receptor TAR1. Administering T1AM in vivo induces profound hypothermia and bradycardia within minutes. T1AM treatment also rapidly reduces cardiac output in an ex vivo working heart preparation. These results suggest the existence of a new signaling pathway, stimulation of which leads to rapid physiological and behavioral consequences that are opposite those associated with excess TH.

Dietary calcium and blood pressure in experimental models of hypertension. A review.

More than 80 studies have reported lowered blood pressure after dietary calcium enrichment in experimental models of hypertension. The evidence presented here suggests that dietary calcium may act concurrently through a number of physiological mechanisms to influence blood pressure. The importance of any given mechanism may vary depending on the experimental model under consideration. Supplemental dietary calcium is associated with reduced membrane permeability, increased Ca(2+)-ATPase and Na,K-ATPase, and reduced intracellular calcium. These results suggest that supplemental calcium may limit calcium influx into the cell and improve the ability of the VSMC to extrude calcium. This could be a direct effect of calcium on the VSMC or an indirect effect mediated hormonally. The calcium-regulating hormones have all been found to have vasoactive properties and therefore may influence blood pressure. Furthermore, CGRP and the proposed parathyroid hypertensive factor are both vasoactive substances that are responsive to dietary calcium. Therefore, diet-induced variations in calcium-regulating hormones may influence blood pressure. Modulation of the sympathetic nervous system is another important way that dietary calcium can influence blood pressure. There is evidence of altered norepinephrine levels in the hypothalamus as a consequence of manipulations of dietary calcium as well as changes in central sympathetic nervous system outflow. Dietary calcium has also been shown to specifically modify alpha 1-adrenergic receptor activity in the periphery. In some experimental models of hypertension, dietary calcium may alter blood pressure by changing the metabolism of other electrolytes. For example, the ability of calcium to prevent sodium chloride-induced elevations in blood pressure may be attributed to natriuresis. However, natriuresis does not account for all of the interactive effects of calcium and sodium chloride on blood pressure. Sodium chloride-induced hypertension may be due in part to calcium wasting and subsequent elevation of calcium-regulating hormones. Chloride is an important mediator of this effect because it appears that sodium does not cause calcium wasting when it is not combined with chloride. More attention to the central nervous system effects of dietary calcium is needed. Not only can calcium itself influence neural function, but many of the calcium-regulating hormones appear to affect the central nervous system. The influence of calcium and calcium-regulating hormones on central nervous system activity may have important implications for blood pressure regulation and also may extend to other aspects of physiology and behavior.

Symptoms of Postpartum Depression and Breastfeeding

Despite important health benefits, the presence of depressive symptoms may decrease the prevalence of breastfeeding. The current study assessed the relationship between depressive symptoms and breastfeeding at 6 and 12 weeks postpartum. Participants were recruited from a cohort completing a clinical trial of calcium for prevention of preeclampsia. At 6 weeks postpartum, the Edinburgh Postnatal Depression Scale (EPDS) was completed by mail. At 12 weeks postpartum, the EPDS was completed at an outpatient visit. There was an inverse relationship between depressive symptoms and breastfeeding at 6 weeks postpartum (P < .001) but not at 12 weeks. This relationship persisted even after controlling for prior history of depression, increased life stress, and current psychoactive medication. The results suggest that depressive symptoms early in the postpartum period may lower the prevalence of breastfeeding.

Chronic nitric oxide inhibition with l-NAME: effects on autonomic control of the cardiovascular system

To determine whether increased sympathetic activity contributes to the hypertension induced by chronic exposure to moderate nitric oxide synthase (NOS) inhibition, various indexes of autonomic function were measured in rats given the NOS inhibitor N G-nitro-l-arginine methyl ester (l-NAME, 10 mg/100 ml, ≅16 mg ⋅ kg-1 ⋅ day-1) in the drinking water. One week of treatment raised blood pressure (139 ± 3 vs. 106 ± 1 mmHg; P < 0.01) and lowered heart rate (319 ± 4 vs. 379 ± 6 beats/min, P < 0.01).l-NAME had no effect on cardiac sympathetic tone, but elevated cardiac parasympathetic tone (-73 ± 4 vs. -56 ± 7 beats/min; P< 0.05). Depressor responses to ganglionic blockade were greater inl-NAME-treated rats (-50 ± 5 vs. -34 ± 5 mmHg; P < 0.05), whereas resting plasma, renal, and adrenal catecholamine values did not differ between groups. Treated rats also showed evidence of reduced baroreflex sympathetic stimulation of heart rate during hypotension and reduced parasympathetic activation during hypertension. Together, these data provide only very limited, indirect evidence that sympathetic stimulation contributes to the hypertension associated with moderate NOS inhibition.To determine whether increased sympathetic activity contributes to the hypertension induced by chronic exposure to moderate nitric oxide synthase (NOS) inhibition, various indexes of autonomic function were measured in rats given the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/100 ml, approximately equal to 16 mg.kg-1.day-1) in the drinking water. One week of treatment raised blood pressure (139 +/- 3 vs. 106 +/- 1 mmHg; P < 0.01) and lowered heart rate (319 +/- 4 vs. 379 +/- 6 beats/min, P < 0.01). L-NAME had no effect on cardiac sympathetic tone, but elevated cardiac parasympathetic tone (-73 +/- 4 vs. -56 +/- 7 beats/min; P < 0.05). Depressor responses to ganglionic blockade were greater in L-NAME-treated rats (-50 +/- 5 vs. -34 +/- 5 mmHg; P < 0.05), whereas resting plasma, renal, and adrenal catecholamine values did not differ between groups. Treated rats also showed evidence of reduced baroreflex sympathetic stimulation of heart rate during hypotension and reduced parasympathetic activation during hypertension. Together, these data provide only very limited, indirect evidence that sympathetic stimulation contributes to the hypertension associated with moderate NOS inhibition.

Factors affecting blood pressure responses to diet: The vanguard study

To study physiologic factors affecting the blood pressure (BP) response to nonpharmacologic maneuvers, fasting blood glucose, insulin, lipid and mineral levels, urinary mineral excretion, and the calcium regulating hormones parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D (1,25 (OH)2D) were measured in 71 unmedicated hypertensive (26 hypertensive only [HT], 45 hypertensive hyperlipidemic [HTHL]), and 87 normotensive hyperlipidemic (NTHL) control subjects before and during a 10-week multicenter, randomized controlled trial comparing a prepared meal plan (CCNW) with a self-selected diet (SSD) based on nutritionist counseling. Blood pressure fell to a greater extent in hypertensive versus normotensive subjects (-8+/-1/-5+/-1 v -2+/-1/-2+/-1 mm Hg, P < .0001/P < .0001), and on CCNW versus SSD diets (delta systolic BP [SBP]/delta diastolic BP [DBP], P = .033/P = .002). Diet-induced weight change was the strongest correlate of changes in BP (SBP: r = 0.360, P < .0001; DBP: r = 0.414, P < .0001), which, on multivariate analysis for deltaSBP, could partly be accounted for by diet-induced changes in fasting glucose (r = 0.215, P = .009) and cholesterol (r = 0.219, P = .006) levels. Independently of weight, diet-induced changes in SBP also were significantly related to concomitant changes in urinary excretion of potassium (r = -0.285, P = .001), magnesium (r = -0.254, P = .003), and calcium relative to sodium (r = -0.200, P = .021), but not to sodium per se; and to changes in serum potassium (r = -0.249, P = .002), phosphorus (r = -0.279, P = .001), PTH (r = 0.288, P = .0006), and 1,25 D (r = 0.202, P = .017). We conclude that the ability of diet to lower BP successfully may result from the additive contributions of multiple components. Independently of weight loss and the associated changes in circulating glucose and cholesterol, BP is influenced by the increasing provision of minerals such as potassium, magnesium, and calcium, perhaps by virtue of their suppressive effects on circulating vasoactive calcium regulating hormones.

Chronic alcohol consumption lowers blood pressure but enhances vascular contractility in Wistar rats

Objective: To determine the effect of chronic alcohol consumption upon blood pressure, blood pressure reactivity and vascular contractility in Wistar rats. Design: Wistar rats were fed a liquid diet containing 36% ethanol; control rats were pair fed. Methods: Rats were maintained on diets for 18 weeks. Indirect systolic blood pressure was measured weekly. Catheters were implanted for assessment of direct arterial pressure and blood pressure reactivity to norepinephrine, angiotensin II and ethanol injections. In a subgroup of rats, contractility of isolated mesenteric resistance vessels was measured. Results: In comparison with simultaneously pair-fed controls, ethanol-treated rats developed significantly lower blood pressure within 3 weeks of exposure to alcohol; this continued throughout the study. Despite the reduction in blood pressure, in vitro assessment of vascular contractility in mesenteric resistance vessels indicated that ethanol consumption significantly enhanced vascular contractility to norepinephrine and attenuated the vasodepressive effects of ethanol. Measurement of blood pressure reactivity to infused pressor agents showed no difference between controls and ethanol-treated rats in response to norepinephrine but a significantly attenuated pressor response to angiotensin II was observed in ethanol-treated rats. Conclusions: The blood pressure results contrast with reports of elevated blood pressure in Wistar rats given ethanol in drinking water. This disparity may be due to nutritional factors. Increased vascular contractility combined with hypotension suggests that cardiovascular regulatory systems offset the direct effects of ethanol upon the vasculature. This view is reinforced by the lack of difference between groups in blood pressure reactivity to norepinephrine. The attenuated angiotensin II responses in the ethanol-treated rats suggests altered levels of circulating angiotensin II in this group.

Gestational calcium supplementation and blood pressure in the offspring

BACKGROUND The current study examined the relationship between calcium supplementation during pregnancy and blood pressure (BP) in the mother and offspring at 3 months and at 2 years postpartum. METHODS Nulliparous pregnant women were assigned to either receive 2 g of calcium or placebo daily beginning between weeks 13 to 21 of gestation and continuing until delivery. Blood pressure was measured in children and their mothers at 3 months (n = 260) and (n = 57) at 2 years postpartum. Systolic BP was measured in the infants using a sphygmomanometer with ultrasonic amplification. For the toddlers, three supine BP measurements were taken from the right arm using a Critikon automated sphygmomanometer just after measurement of left ventricular wall thickness. RESULTS Systolic BP in the calcium-supplemented infants was 2.2 mm Hg lower than in the placebo group (P >.05). At 2 years of age, systolic BP was 4.8 mm Hg lower in the calcium supplemented group (P <.05), whereas diastolic BP was 3 mm Hg lower (P >.05). There was no difference in left ventricular mass index between groups, although there was a significant correlation between systolic BP and wall thickness (P <.05). Maternal BP was positively correlated with circulating 1,25(OH)(2)D3 (P <.001) but did not differ between calcium groups at 3 months postpartum. CONCLUSIONS The data on BP in the children are in agreement with previous studies and argue strongly for additional research into the effects of prenatal calcium supplementation on BP regulation in the offspring.

Baroreceptor involvement in classically conditioned heart rate responses of restrained rats

A group (N = 8) of restrained, baroreceptor denervated rats and a sham-operated-control group (n = 8) received discriminated classical conditioning consisting of 30 reinforced trials in which a CS+ was paired with an electric shock US and 30 non-reinforced trials in which a different CS (CS-) was presented alone. The control group displayed a decelerative heart rate CR and a biphasic pressor-depressor blood pressure CR. The denervated group failed to show a heart rate CR but did show a pressor-only blood pressure CR. The URs of the denervated group consisted of a major depressor change in blood pressure and a slight tachycardia whereas the URs of the control group consisted of a slight pressor response and tachycardia. The results indicated that centrally initiated activity in the efferent vagal pathways mediating the decelerative HR CR in rats may be blocked by the absence of normal afferent baroreceptor neural discharge. An integrating role of baroreceptor input was also suggested for the URs.

Stress-induced hypertension in the borderline hypertensive rat: Stimulus duration

Blood pressure and circulating catecholamines were evaluated in borderline hypertensive rats (BHR) that were exposed to daily sessions of either short (20 min) or long (120 min) duration air-jet stimulation. Indirect measures of systolic blood pressure indicated that within 2 weeks both experimental groups developed stress-induced hypertension in comparison to home cage controls. Animals exposed to 120 min stress sessions had significantly higher systolic blood pressure relative to the 20 min group. However, direct measures of blood pressure taken after 5 weeks of daily stress did not reveal any differences between the stress groups. Daily measurements indicated that acute changes in blood pressure during stress were modest and transient, suggesting little contribution to the chronic elevation in blood pressure observed as a consequence of stress. Circulating catecholamines were significantly increased by the stressor. Epinephrine returned to baseline within 60 min, although norepinephrine remained elevated throughout the 120 min session. The results indicate that increasing the duration of daily air jet stimulation did not impact the development of stress-induced hypertension over the 5-week measurement period.