Enhanced sensitivity of diabetic hearts to alpha-adrenoceptor stimulation.

Abstract

Inotropic responses to alpha-adrenergic stimulation with methoxamine were compared in 12 normal (N) and 12 diabetic (Db) lambs. Diabetes was produced by giving alloxan monohydrate (150 mg/kg iv). Measurements of maximal rate of rise of left ventricular pressure (dP/dtmax), left ventricular end-diastolic pressure (LVEDP), coronary flow, and myocardial O2 consumption were made simultaneously in hemodynamically controlled preparations. All animals were subjected to ganglionic blockade (tetraethylammonium chloride, 100 mg) and beta1-adrenergic blockade (practolol, 4 mg/kg). Methoxamine was given in incremental doses ranging from 0.4 to 6.0 mg/kg. dP/dtmax increased progressively to 126 +/- 4% of initial values in N. However, the increase was twice as large (150 +/- 4%) in the diabetics (P less than 0.005). LVEDP fell in both groups. These changes were abolished by phentolamine (2 mg/kg). Inotropic responses to methoxamine in lambs 2 and 3 wk after induction of diabetes did not differ from those with acute (2 days) diabetes. Dose-response curves obtained by infusing Ca2+ (2-8 mg X min-1 X kg-1) were identical in N and Db. It is concluded that lamb myocardium possesses an alpha-adrenergic receptor system that is stimulated by methoxamine in a dose-dependent manner and blocked by phentolamine. Db hearts are supersensitive to alpha-receptor activation. The mechanistic basis for this latter finding has not been examined but may relate to altered receptor density or nucleotide regulation.