Absence of hypertension despite chronic marked elevations in plasma norepinephrine in conscious dogs.

Abstract

SUMMARY To better define the mechanisms of blood pressure control in states of catecholamine excess, we infused norepinephrine for 28 days using subcutaneously implanted osmotic pumps in dogs previously instrumented for monitoring left ventricular dynamics and cardiac output. Plasma norepinephrine rose from 238 ± 27 to 4346 ± 952 pg/ml at 21 days, while epinephrine and dopamine levels did not change. Heart rate fell from 85 ± 4 to 63 ± 6 beats/min, while arterial pressure was unchanged from baseline. Total peripheral resistance rose 0.011 ± 0.003 mm Hg/ml/min from a control value of 0.029 ± 0.002 mm Hg/ml/min, and cardiac output decreased 1093 ± 292 ml/min from a baseline level of 3575 ± 156 ml/min. Since stroke volume did not change, the maintenance of arterial pressure is related to decreases in cardiac output secondary to bradycardia. Buffering mechanisms are responsible for maintenance of systemic arterial pressure because hexamethonium and atropine caused hypertension. Although left ventricular end-diastolic pressure, end-diastolic diameter, shortening, rate of change of pressure, velocity of myocardial shortening, cardiac work, stroke work, and the double product did not change significantly during the study, postmortem examination demonstrated biventricular hypertrophy. Thus, despite markedly elevated catecholamine levels and no elevation of systemic arterial pressure, myocardial hypertrophy developed. These studies lend support to the hypothesis that norepinephrine may be a direct myocardial tropic hormone and suggest that intense activation of reflex buffering mechanisms maintains blood pressure in the normal range during chronic catecholamine infusion. (Hypertension 9: 582-590, 1987) KEY WORDS • bradycardia • hypertension • hypertrophy • catecholamines • total peripheral resistance • atropine E LEVATIONS in catecholamine levels may be associated with a number of disease states, including mitral valve prolapse (MVP), 1 -2 chronic myocardial failure, 3 " 6 and pheochromocytoma. 7 These disease states may be characterized by sustained or episodic hypertension, myocardial dysfunction, and cardiomyopathy.Recently, it has been noted that certain patients with MVP, chronic myocardial failure, or pheochromocytoma have dysautonomia, manifested by abnormalities in heart rate or blood pressure response (or both) to orthostatic change or exercise. 8 " 12 Some investigations of patients with MVP having dysautonomia are consistent with evidence of hyperadrenergic states and some with simultaneous hypervagatonia. 9 -13 Significant elevations in serum catecholamine levels have been observed in a group of symptomatic patients with MVP 1 ' l4 ; these results have been confirmed by other workers. 2 ' 8> l5 Patients with chronic myocardial failure, regardless of etiology, have elevated plasma norepinephrine (NE) levels. 16 In addition, defects in baroreceptor reflex-mediated vasoconstrictor responses have been noted in dogs 17 and in patients 18 -19 with marked myocardial dysfunction.Several studies, summarized by Ec...

Role of intact cardiac nerves and reflex mechanisms in desensitization to catecholamines in conscious dogs.

“…However, an excellent agreement has been reported between the radioenzymatic method and high-performance liquid chromatography, which measures NE specifically (31). In a previous, similar study (32) plasma levels of catecholamine were measured with high performance liquid chromatography as well as by the radioenzymatic method, and the plasma levels of NE were demonstrated to be similar to ours.…”

Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor.

“…In 10 animals 2 ml saline was placed in the pump, while in 16 animals NE was placed in the pump to infuse at a rate of 0.5 gg/kg per min over a 2-wk period. A second pump was implanted 10 d to 2 wk after the first pump so that the duration ofthe chronically high NE levels was 3-4 wk (4). Plasma NE samples were drawn from the chronically implanted aortic catheter and levels were assayed weekly in animals with NE pumps to assure sustained high levels of NE.…”

Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

“…a 1 -Adrenergic Receptor-Mediated Hypertrophy in Animal Models. Early studies in mice, cats, and dogs showed that long-term catecholamine infusion in various species and at doses that do not increase blood pressure produces cardiac hypertrophy in vivo, which is "physiological," in that cardiac function is normal or improved and there is no fibrosis (Laks et al, 1973;King et al, 1987;Marino et al, 1991;Patel et al, 1991;Stewart et al, 1992;Vecchione et al, 2002). Whereas these studies suggest clearly that activation of ARs induces cardiac hypertrophy directly, which was debated at the time, the lack of subtype-specific AR pharmacologic agents limits mechanistic insight.…”