Richard A. Shaffer

Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice.

OBJECTIVE Recent advances in understanding the neuroendocrine pathways regulating appetite, metabolism and body weight afford an opportunity to explore further the mechanisms by which obesity influences arterial pressure. ob/ob(Lep(ob)/Lep(ob)) mice have a mutation in the ob gene and are leptin-deficient. Leptin possesses pressor actions and has been shown to increase arterial pressure when infused chronically or over-expressed transgenically. In contrast, agouti yellow obese(Ay) mice have overexpression of an agouti peptide that blocks melanocortin receptors. Stimulation of melanocortin receptors by alpha-melanocyte-stimulating hormone decreases arterial pressure. DESIGN AND METHODS This study measured arterial pressure in leptin-deficient ob/ob mice, agouti yellow obese mice and their lean controls to test the hypothesis that the effects of obesity on arterial pressure are importantly influenced by the genetic and neuroendocrine mechanisms causing the obesity. We measured arterial pressure directly in conscious ob/ob mice (n = 14), agouti yellow obese mice (n = 6) and the same number of lean littermates. RESULTS Body weight was nearly twice as high in ob/ob mice as in their lean controls, but mean arterial pressure was significantly lower in ob/ob mice (92+/-3 mmHg) compared with their lean controls (106+/-2 mmHg; P = 0.00017). In contrast, mean arterial pressure was significantly higher in agouti yellow obese mice (124+/-3 mmHg) than in their lean controls (99+/-1 mmHg; P = 0.000002) despite the fact that the agouti mice had milder obesity. CONCLUSIONS This study prompts three conclusions: (1) leptin-deficient ob/ob mice and agouti yellow obese mice have contrasting blood pressure responses to obesity, (2) obesity does not invariably increase arterial pressure in mice, and (3) the arterial pressure response to obesity may depend critically on the underlying genetic and neuroendocrine mechanisms.

Obesity-Induced Hypertension: New Concepts From the Emerging Biology of Obesity

Abstract —Obesity is associated with an increased risk of hypertension. In the past 5 years there have been dramatic advances into the genetic and neurobiological mechanisms of obesity with the discovery of leptin and novel neuropeptide pathways regulating appetite and metabolism. In this brief review, we argue that these mounting advances into the neurobiology of obesity have and will continue to provide new insights into the regulation of arterial pressure in obesity. We focus our comments on the sympathetic, vascular, and renal mechanisms of leptin and melanocortin receptor agonists and on the regulation of arterial pressure in rodent models of genetic obesity. We suggest 3 concepts. First, the effect of obesity on blood pressure may depend critically on the genetic-neurobiological mechanisms underlying the obesity. Second, obesity is not consistently associated with increased blood pressure, at least in rodent models. Third, the blood pressure response to obesity may be critically influenced by modifying alleles in the genetic background.

Neurogenic and Humoral Factors Controlling Vascular Resistance in the Spontaneously Hypertensive Rat

The mechanism of sustained hypertension in spontaneously hypertensive rats has not been elucidated. In the present investigation, vasoconstrictor responses to a variety of neurogenic and humoral interventions were studied in the perfused hindquarters of Okamoto spontaneously hypertensive rats and normotensive Wistar rats. In addition, central sympathetic electrical discharge was measured. Vasoconstrictor responses in the hindquarters to lumbar sympathetic nerve stimulation were unchanged or reduced in the spontaneously hypertensive rats, but the responses to intra-arterially administered norepinephrine and epinephrine were enhanced. Vascular responses to intra-arterially administered tyramine, angiotensin, and barium chloride were also greater in the spontaneously hypertensive rats. Vascular resistance was significantly higher in the spontaneously hypertensive rats, and this difference remained following bilateral lumbar sympathectomy. Despite elevated systemic blood pressure, integrated nerve activity at rest was not different in the spontaneously hypertensive rats. The inverse relationship between arterial blood pressure and sympathetic nerve discharge was not different between spontaneously hypertensive and control rats when pressure was either raised or lowered. Changes in efferent sympathetic discharge produced by activation of chemoreceptors (asphyxia) were somewhat less in the spontaneously hypertensive rats. The contribution of low-pressure baroreceptors (45° tilt) to activation of sympathetic vasomotor tone was not different in the spontaneously hypertensive rats despite a greater decline in systemic blood pressure during the procedure. These data demonstrate that established hypertension in the spontaneously hypertensive rat does not derive from either enhanced central adrenergic discharge or altered central integration of afferent information from peripheral sensory receptors but may result from humoral (e.g., increased reactivity to vasoconstrictors) or structural factors.

VASCULAR REACTIVITY IN EXPERIMENTAL DIABETES MELLITUS.

Vascular reactivity was examined in vessels of the perfused hindquarters of alloxan diabetic and control rats. A significant increase was noted in responsiveness of the diabetic animals to intra-arterial injection of epinephrine, norepinephrine, and synthetic angiotensin. No difference was observed in the vasoconstrictor effects of lumbar sympathetic nerve stimulation or intra-arterial administration of tyramine. Results obtained in diabetic animals were compared with those in animals treated with reserpine. It was found that the reserpinized animals exhibited increased vascular responsiveness only to the catecholamines, and not to angiotensin, vasopressin, tyramine, or barium chloride. Whereas the vascular smooth muscle of diabetic rats was sensitized to epinephrine and norepinephrine, isolated atria from these animals responded normally to the catecholamines. The 24-hour urinary excretion of the catecholamines was significantly elevated in diabetic animals. The data suggest that enhanced vascular reactivity seen in diabetic rats does not result from neuropathy of the sympathetic nervous system. The possible contributions of factors including alloxan per se and body weight to development of increased vascular reactivity in diabetes were considered, but the mechanism for the increase in vascular responsiveness remains unidentified.

Contribution of the sympathetic nervous system to vascular resistance in conscious young and adult spontaneously hypertensive rats.

SUMMARY Although evidence exists for exaggerated sympathetic nervous system activity in spontaneously hypertensive rats (SHR), there are no studies in conscious animals that directly demonstrate that this increased activity is functionally involved in the elevated vascular resistance of these animals. In our present study, 8-week-old and 13-week-old SHR and Wistar Kyoto controls (WKY) were chronically Instrumented with arterial and venous catheters and miniaturized pulsed Doppler flow probes on the renal and mesenteric arteries and lower abdominal aorta. While the rats were conscious and unrestrained, bexamethonium was administered intravenously to block sympathetic nervous system transmission. Prior to bexamethonlum, the mean arterial pressure of young SHR and WKY averaged 123 ± 5 and 109 ± 4 nun Hg respectively (p < 0.05), while adult SHR and WKY averaged 159 ± 7 and 128 ± 3 mm Hg respectively (p < 0.05). Hexamethonium produced an equivalent fall in arterial pressure of young SHR (-32%) and WKY (-30%) and adult SHR (-39%) and WKY (-41%). Vascular resistance was reduced by hexamethonium in the kidney, gut, and hindquarters, but the percent changes were not significant between SHR and WKY. These data suggest that, in both young and adult SHR, vascular resistance and arterial pressure are sustained at elevated levels by some other mechanism than aeurally-derived vasoconstrictor tone.

Use-Dependent Loss of Active Sympathetic Neurogenic Vasodilation After Nitric Oxide Synthase Inhibition in Conscious Rats: Evidence for the Presence of Preformed Stores of Nitric Oxide–Containing Factors

In this study, we examined whether air-jet stress-induced active sympathetic hindlimb vasodilation in conscious rats involves the release of preformed stores of nitric oxide-containing factors. We determined the effects of repeated episodes of air-jet stress (six episodes given 5 minutes apart) on mean arterial pressure and vascular resistances in the mesenteric bed and intact and sympathetically denervated hindlimb beds of conscious rats treated with saline or the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 25 mumol/kg IV). In saline-treated rats, air-jet stress produced alerting behavior, minor changes in blood pressure, pronounced mesenteric vaso-constriction, and immediate and marked vasodilation in the sympathetically intact hindlimb but a minor vasodilation in the sympathetically denervated hindlimb. Each air-jet stress produced virtually identical responses. In L-NAME-treated rats, the first air-jet stress produced vasodilator responses in the sympathetically intact and sympathetically denervated hindlimbs that were similar to those in the saline-treated rats. However, each subsequent air-jet stress produced progressively smaller vasodilator responses in the sympathetically intact but not the sympathetically denervated hindlimb. There was no loss of air-jet stress-induced alerting behavior or mesenteric vasoconstriction, suggesting that L-NAME did not interfere with the central processing of the air-jet or the resultant changes in autonomic nerve activity. The progressive diminution of air-jet stress-induced vasodilation in the intact hindlimb of L-NAME-treated rats may be due to the use-dependent depletion of preformed stores of nitric oxide-containing factors that cannot be replenished in the absence of nitric oxide synthesis.

Cardiovascular Responses Following Immunological Sympathectomy

Sympathetic function and cardiovascular responses were measured in rats treated at birth with an antiserum developed to the sympathetic nerve growth factor. The intact animals exhibited ptosis, miosis, and decreased excretion of norepinephrine in the urine. Electrical stimulation of the sympathetic innervation to the vessels of the perfused hindquarters failed to produce vasoconstriction or vasodilatation in any of the treated rats over a wide range of stimulus parameters. Alterations in vascular reactivity characteristic of sympathetic denervation were noted; responsiveness was increased to norepinephrine but not to other constrictor agents. Chemical stimulation of the sympathetic ganglia with 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) did not activate the postganglionic fibers but did promote the release of catecholamines from the adrenal medulla. The treated rats showed elevated resistance to flow in the hindquarters. The results of this investigation thus demonstrate that treatment with the antinerve growth factor effectively abolishes vasomotor function of the fibers of the sympathetic nervous system.

Hemodynamic effects of L-glutamate in NTS of conscious rats : a possible role of vascular nitrosyl factors

This study examined peripheral mechanisms responsible for changes in mean arterial blood pressure, heart rate, and renal, mesenteric, and hindquarter vascular resistances produced by microinjections of l-glutamate (l-Glu) into the nucleus tractus solitarii (NTS) of conscious rats. Microinjection ofl-Glu produced an initial pressor response, bradycardia, and vasoconstriction in each vascular bed. Subsequent hindquarter vasodilation was observed. After prazosin was administered, l-Glu produced initial hypotension that was probably due to reduced cardiac output. This hypotension was followed by hindquarter vasodilation. Inhibition of nitric oxide synthesis did not affect the initial hypotension or bradycardia in rats treated with prazosin, but the first microinjection of l-Glu after administration of prazosin and N G-nitro-l-arginine methyl ester (l-NAME) produced significantly greater hindquarter vasodilation than after administration of prazosin alone. Second and third microinjections ofl-Glu produced significantly smaller hindquarter vasodilation. We conclude that 1) hemodynamic effects produced by microinjection of l-Glu into the NTS of conscious rats involves activation of the sympathetic nervous system and 2) release of preformed nitrosyl factors may mediate vasodilation in the hindquarter vascular bed.This study examined peripheral mechanisms responsible for changes in mean arterial blood pressure, heart rate, and renal, mesenteric, and hindquarter vascular resistances produced by microinjections of L-glutamate (L-Glu) into the nucleus tractus solitarii (NTS) of conscious rats. Microinjection of L-Glu produced an initial pressor response, bradycardia, and vasoconstriction in each vascular bed. Subsequent hindquarter vasodilation was observed. After prazosin was administered, L-Glu produced initial hypotension that was probably due to reduced cardiac output. This hypotension was followed by hindquarter vasodilation. Inhibition of nitric oxide synthesis did not affect the initial hypotension or bradycardia in rats treated with prazosin, but the first microinjection of L-Glu after administration of prazosin and NG-nitro-L-arginine methyl ester (L-NAME) produced significantly greater hindquarter vasodilation than after administration of prazosin alone. Second and third microinjections of L-Glu produced significantly smaller hindquarter vasodilation. We conclude that 1) hemodynamic effects produced by microinjection of L-Glu into the NTS of conscious rats involves activation of the sympathetic nervous system and 2) release of preformed nitrosyl factors may mediate vasodilation in the hindquarter vascular bed.