Prevention of salt-induced hypertension by an analog of gamma-melanocyte-stimulating hormone in the rat.

BACKGROUND: Rats with suppression of pituitary intermediate lobe (IL) function by treatment with the dopaminergic agonist bromocriptine develop salt-sensitive hypertension accompanied by a deficiency of gamma-melanocyte-stimulating hormone (gamma-MSH). METHODS: To study the time course, and establish the causal role, of gamma-MSH deficiency in the development of salt-sensitive hypertension, we instrumented 12 male Sprague-Dawley rats with radiotelemetry transmitters to record intraaortic mean arterial pressure (MAP). One week later, they were placed on a high-sodium diet (8% NaCl, HSD) and received daily intraperitoneal injections of bromocriptine (5 mg/kg). The rats were also implanted with micro-osmotic pumps to deliver either a stable analog of gamma-MSH ([Nle3, D-Phe6]-gamma-MSH, NDP-gamma-MSH) at 12 pmol/h or normal saline vehicle. RESULTS: In vehicle-treated rats on the HSD and receiving bromocriptine injections, MAP rose so that it was significantly greater than that in NDP-gamma-MSH-treated animals by Day 4, and reached a stable plateau of approximately 135 mm Hg between Days 7 and 14. After Day 14, bromocriptine injections were stopped, and MAP in vehicle-infused rats fell progressively despite continued ingestion of the HSD, so that by Day 18, MAP was no longer different from NDP-gamma-MSH-infused animals. The MAP in the latter group did not vary significantly from the control level of 101+/-4 mm Hg throughout the 21 days of the experiment. CONCLUSIONS: These results indicate that gamma-MSH deficiency is a consequence of the bromocriptine treatment responsible for the salt-sensitive hypertension, and these results also identify the time course during which this hypertension develops.

Hemodynamic responses elicited by gamma2-MSH or blood replacement in hemorrhaged rats.

BACKGROUND: Systemic injections of compounds such as gamma(2)-melanocyte-stimulating hormone (gamma(2)-MSH), which increase sympathetic neurogenic vasoconstriction, may be beneficial in treating hemorrhage-induced hypotension. METHODS: This study characterized (1) the hemodynamic responses elicited by systemic injections of gamma(2)-MSH in pentobarbital-anesthetized hemorrhaged rats, and (2) the hemodynamic responses elicited by the replacement of withdrawn blood in these rats. RESULTS: Controlled hemorrhage (4.8 +/- 0.3 mL/rat at 1.5 mL/min) resulted in a pronounced and sustained fall in mean arterial blood pressure (MAP). The fall in MAP was associated with a reduction in heart rate (HR) and hindquarter (HQR) vascular resistance but no changes in mesenteric (MR) or renal (RR) vascular resistances. Systemic injections of gamma(2)-MSH (10-40 microg/kg, i.v.) produced dose-dependent increases in HR, MAP, and vascular resistances of 20 to 60 s in duration in the hemorrhaged rats. In contrast, injection of the withdrawn blood produced an immediate and sustained increase in MAP, which was associated with a pronounced vasodilation in the hindquarter bed but no changes in MR or RR. CONCLUSIONS: These findings suggest that although gamma(2)-MSH elicits pressor and vasoconstrictor responses in hemorrhaged rats, the bolus injection of this peptide may not in itself be an effective strategy for the sustained restoration of MAP in these rats. Moreover, although blood replacement effectively restores MAP via increases in cardiac output rather than total peripheral resistance, it appears that this manipulation produces an active vasodilation in the hindquarter bed. The possibility that this vasodilation involves a sympathetic neurogenic vasodilator system, which innervates the hindlimb vascular bed but not mesenteric or renal vascular beds, will be discussed.