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Diabetes-associated alterations in resting heart rate and blood pressure have been demonstrated in clinical studies and in animal models of insulin-dependent diabetes mellitus (IDDM). These alterations may result from changes in the heart, vasculature or autonomic nervous system control. Using the streptozotocin- (STZ-) treated rat model of IDDM, the current study was designed to: (1) monitor changes in heart rate and blood pressure continually during a 10-week period in conscious unrestrained animals; and (2) determine if observed alterations in heart rate were mediated by changes in sympathetic and/or parasympathetic nervous control. Biotelemetry techniques were used. Heart rate and blood pressure were recorded 24 h a day at 10 min intervals before and after induction of diabetes. Diabetes was induced by i.v. administration of 50 mg/kg STZ. Resting autonomic nervous system tone was estimated by chronotropic responses to full-blocking doses of nadolol (5 mg/kg i.p.) and atropine (10 mg/kg i.p.). STZ-induced diabetes was associated with time-dependent reductions in heart rate and its circadian variation. Diastolic blood pressure and mean arterial pressure did not differ significantly when compared between control and STZ-treated animals; however, pulse pressure was diminished in diabetic rats. Chronotropic responses to both nadolol and atropine were blunted significantly in diabetic animals suggesting that resting levels of both vagal and sympathetic nervous tone to the heart were diminished. Heart rate in the presence of both nadolol and atropine was also decreased in diabetic rats. All effects observed following administration of STZ were reversed, at least in part, by insulin treatment. These results suggest that IDDM is associated with time-dependent reductions in resting heart rate and autonomic nervous control of cardiac function.

Experiments were designed to determine whether insulin-dependent diabetes mellitus (IDDM) alters direct chronotropic effects of adrenergic and cholinergic agonists and whether the observed changes are associated with hyperglycemia or combined hyperglycemia and ketoacidosis. Diabetes was induced by intravenous administration of 45, 50, or 65 mg/kg streptozotocin (STZ). Rats treated with 65 mg/kg STZ had higher levels of blood glucose and ketones compared with the levels of the other groups. Right atria were isolated 12 wk after administration of STZ and bathed in Krebs-Henseleit solution. Basal spontaneous pacemaker rate was diminished in preparations isolated from diabetic rats. The maximum pacemaker rate observed during exposure to isoproterenol or norepinephrine was also depressed in preparations from diabetic animals; however, the increase in rate and half-maximal effective concentration values for each agent were not affected. The sensitivity to the negative chronotropic action of acetylcholine was enhanced by IDDM, whereas the response to carbachol (a cholinergic agonist not readily metabolized by acetylcholinesterase) was not changed. No significant differences were observed when we compared preparations isolated from diabetic animals with and without ketoacidosis. In summary, these data suggest 1) that IDDM is associated with a diminished basal spontaneous pacemaker without changes in the responsiveness to adrenergic and cholinergic receptor activation and 2) that ketoacidosis does not play a role in the observed alterations.

Initial experiments were designed to determine if vasoactive concentrations of nitric oxide (NO) alter contractility in rat heart. Contractile function was monitored in left atrial and papillary muscles (30 degrees C; paced at 0.5 Hz) during cumulative addition of 3-morpholino-sydnonimine-HCl(SIN-1), an agent that releases NO. At concentrations between 10(-7) and 10(-4) M (NO concentrations of approximately 10(-8)- 3 x 10(-7) M), SIN-1 did not affect contractility in either tissue. Similarly, 10(-4) M SIN-1 did not alter the positive inotropic responses to isoproterenol or increasing extracellular [Ca+2] ([Ca+2]o). To obtain higher concentrations of NO, additional studies were conducted using authentic NO. NO-saturated stock solutions and a corresponding control solvent were adjusted to pH 1.6 with HCl. Dose-dependent effects of NO were examined by adding aliquots of the stock solutions (or control solvent) to the bathing solution. At final concentrations of 1 x 10(-5)- 5 x 10(-4) M, NO produced transient, concentration-dependent decreases in contractility that were paralleled by reductions in buffer pH. Control solvent elicited similar reductions in pHo and transient decreases in contractility; however, the negative inotropic action elicited by the NO-containing solution was approximately 20% greater than that observed in control conditions. These data demonstrate that only high concentrations of NO depress contractility in isolated rat cardiac muscle, and suggest that this effect is mediated by both acidosis and a pHo-independent mechanism.

This study was designed to determine if 4-aminopyridine, a reported inhibitor of the transient outward K+ current (Ito), alters the inotropic actions elicited via stimulation of WB4101- or chloroethylclonidine-sensitive receptors in rat myocardium. WB4101 (N-[2-(2, 6-dimethoxyphenoxy)ethyl]-2,3-dihydro-1,4-benzodioxin-2-m ethanamine) is a competitive antagonist that is selective for alpha 1A- and alpha 1C-adrenoceptors, while chloroethylclonidine is an irreversible blocker that is reported to antagonize alpha 1B-, alpha 1C-, and alpha 1D-adrenoceptor binding. Inotropic effects of the alpha 1-adrenoceptor agonist phenylephrine were examined in isolated left atrial and papillary muscle before and after addition of 4-aminopyridine, and before and after addition of 4-aminopyridine in preparations pretreated with chloroethylclonidine or WB4101. In addition, effects of phenylephrine were examined before and after treatment with staurosporine (an inhibitor of protein kinase C) in chloroethylclonidine-pretreated preparations. Phenylephrine (10 microM) elicited a sustained positive inotropic response in left atria and a triphasic inotropic action in papillary muscle (transient positive and negative inotropic components preceding a sustained positive inotropic response). 4-Aminopyridine (1.0, 1.7, 3.0 mM) reduced the sustained positive inotropic responses in the absence of antagonists and in chloroethylclonidine-pretreated preparations. However, in the presence of 10 nM WB4101, 4-aminopyridine had no effect on the remaining inotropic actions of phenylephrine. The sustained positive inotropic response to the alpha 1-agonist in chloroethylclonidine-pretreated preparations was not inhibited by 100 nM staurosporine. These data suggest that the sustained positive inotropic actions of alpha 1A-adrenoceptor stimulation in rat atrial and ventricular myocardium are mediated via non-protein kinase C-associated reductions in Ito.

Purpose: In a previous study, the authors found that recession of an extraocular muscle resulted in atrophy of both the recessed muscle and its antagonist. To determine if atrophy, caused by weakening of an extraocular muscle, results in changes in developed tension in the antagonist, the authors studied force development of the cat lateral rectus muscle after adductor weakening., Methods: Tenotomy of the left inferior, medial, and superior rectus muscles was performed in 18 cats. At 3, 6, and 12 weeks after surgery, the right (control) and left lateral rectus muscles were exposed through a lateral orbitotomy and were attached to isometric force transducers. Length-tension curves were obtained by direct muscle stimulation using bipolar contact electrodes at 0.1 Hz and 50% suprathreshold stimulus intensity. In addition, peak tetanic tension was measured at the optimal resting tension using a 5-second stimulus train at 200 Hz. Pooled data from the operative and control muscles at each postoperative interval were compared., Results: Three weeks after adductor weakening, a 28% decrease in maximal single-twitch tension was seen in the left lateral rectus muscle when compared with controls. This difference disappeared at 6 weeks. No statistically significant changes in peak tetanic tension occurred at any time interval after surgery., Conclusions: Adductor weakening results in a transient decrease in single-twitch tension in the antagonist lateral rectus muscle in the cat.

Experiments in right atria isolated from adult male rats were designed to determine which of the alpha 1-adrenergic receptor (alpha 1-AR) subtypes are involved in the positive chronotropic effect of phenylephrine, an alpha 1-AR agonist. Chloroethylclonidine (CEC), an irreversible alpha 1b-, alpha 1c-, and alpha 1d-AR antagonist, did not alter the efficacy or potency of phenylephrine; however, CEC did elicit a concentration-dependent negative chronotropic effect and reduce the absolute maximum spontaneous rate observed in the presence of phenylephrine. WB4101, a competitive alpha 1a- and alpha 1c-AR-selective antagonist, did not alter basal spontaneous rate or the efficacy of phenylephrine, but it did produce a significant rightward shift of the phenylephrine concentration-response curve. Phenoxybenzamine, an irreversible nonselective alpha-AR antagonist, elicited a concentration-dependent negative chronotropic effect, a significant rightward shift of the phenylephrine concentration-response curve, and a reduction in the efficacy of phenylephrine. The chronotropic action of the beta-adrenergic agonist isoproterenol was not affected by CEC, WB4101, or phenoxybenzamine. These data suggest that the positive chronotropic effect of alpha 1-adrenergic agonists in rat right atria is mediated via stimulation of alpha 1a-ARs.

This study was designed to determine if nitric oxide (NO) has direct effects on heart rate or if it is involved in the chronotropic actions of adrenergic or cholinergic stimulation. Right atria were isolated from hearts of adult male rats, bathed in Krebs-Henseleit buffer (37 degrees C), and used to monitor spontaneous rate. For comparison, ring segments of thoracic aorta were also suspended in the Krebs-Henseleit solution and used to examine vascular actions of various agents. The dose-dependent chronotropic effects of acetylcholine (10(-7)-10(-3) M) and norepinephrine (10(-8)-3 x 10(-4) M) in right atria were not affected by pretreatment with 10(-4) M N-nitro-L-arginine or 10(-3) M N-nitro-L-arginine-methyl ester, inhibitors of L-arginine-derived NO production. SIN-1 (3-morpholino-sydnonimine), an agent which releases NO in aqueous solution, elicited a dose-dependent (0.3-100 microM) vasorelaxation in aortic preparations constricted with 60 mM KCl; the ED50 value for this effect was increased by pretreatment with methylene blue (10 microM) and LY-83,583 (6-(phenylamino)-5,8- quinolinedione; 1 and 3 microM), compounds which inhibit NO-induced stimulation of guanylate cyclase. SIN-1 produced a negative chronotropic effect in right atria; however, this action was not observed at concentrations less than 300 microM and was not antagonized by methylene blue or LY-83,583. 8-Bromo cyclic GMP produced a dose-dependent (10-3000 microM) decrease in KCl-induced tension in aortic rings. In right atria, 8-bromo cyclic GMP elicited a positive chronotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have shown that streptozotocin (STZ) induced diabetes in rats is associated with a decrease in the spontaneous rate of isolated right atria. Present experiments were designed to determine whether this model of insulin-dependent diabetes mellitus alters the chronotropic actions of cesium (Cs+). Right atrial preparations were isolated from STZ-treated and diluent-treated control rats, and bathed in Krebs-Henseleit buffer at 37 degrees C; dose-dependent (0.2-10 mM) effects of Cs+ were examined by cumulative addition. Preparations isolated from diabetic rats had a slower beating rate before exposure to Cs+, and the negative chronotropic response to this cation was diminished in these tissues. In fact, at concentrations between 2 and 10 mM Cs+, spontaneous rate did not differ between the diabetic and control groups. These data suggest that the hyperpolarization-activated current, I(f), may play a role in the slower spontaneous pacemaker rate observed in right atria isolated from STZ-induced diabetic rats.