Influence of nifedipine on pressor responses induced by different alpha-adrenoceptor agonists and angiotensin II in pithed diabetic hypertensive rats.

OBJECTIVE: Both intracellular and extracellular sources of calcium are involved in the activation of contraction in vascular smooth muscle. In the diabetic or hypertensive state, or both, changes induced in calcium handling by various types of agonists may vary considerably. METHODS: We investigated in which manner L-type calcium-channel blockade with nifedipine influences the pressor effects of the alpha 1-adrenoceptor agonists cirazoline and ST 587, the alpha 2-adrenoceptor agonist UK 14.304 and angiotensin II, all exerting a differential influence on calcium homeostasis, in pithed spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats rendered diabetic by an injection of 55 mg/kg streptozotocin. RESULTS: In diabetic WKY rats and SHR, the maximal pressor response was impaired for all agonists. The hypertensive state enhanced the maximal pressor response to all agonists. No difference was found in the nifedipine-induced depression of the pressor response to cirazoline and angiotensin II in the four groups of rats. The maximal pressor responses to ST 587 and UK 14.304 were more effectively depressed by administration of 0.3 mg/kg nifedipine both in diabetic WKY rats and in diabetic SHR than they were in their non-diabetic controls. CONCLUSIONS: Hypertension was associated with enhanced pressor response, whereas the diabetic state counteracted this effect. The pressor responses in pithed diabetic and diabetic hypertensive rats were clearly more dependent on the nifedipine-sensitive calcium influx than were those in their non-diabetic controls.

Vascular responsiveness in isolated perfused kidneys of diabetic hypertensive rats.

OBJECTIVE: The aim of this study was to investigate whether diabetes and hypertension cause additive effects in the responses to various vasoconstrictor and vasodilator agents, in isolated perfused kidneys obtained from streptozotocin (STZ)-diabetic Wistar-Kyoto (WKY) rats and from diabetic spontaneously hypertensive rats (SHR). METHODS: SHR and WKY rats were administered STZ 55 mg/kg by intravenous injection into a lateral tail vein at age 12 weeks. Eight weeks later the kidneys were isolated and perfused via the left renal artery with a physiological salt solution. Renal perfusion pressure was measured continuously. Concentration response curves were plotted for various vasoconstrictor and vasodilator agents. RESULTS: Both the diabetic and the hypertensive state were associated with an increased wet kidney weight. The contractile responses of the renal arterial system to phenylephrine (PhE), serotonin (5-HT) and angiotensin II (Ang II) in terms both of the maximal rise in perfusion pressure (mmHg) and of the sensitivity (log EC50) were the same in preparations from diabetic WKY rats and in those from normoglycaemic WKY rats. The maximal contractile responses both to PhE and to Ang II were enhanced in kidneys from SHR compared with those in kidneys from their normotensive controls, whereas simultaneously occurring diabetes impaired this sensitization. After precontraction with 3 x 10(-6) mol/l PhE both endothelium-dependent (methacholine) and endothelium-independent (sodium nitroprusside) vasodilator drugs caused the same vasodilator response in the preparations taken from the four groups of animals. CONCLUSION: In isolated perfused kidneys obtained from STZ-diabetic WKY rats and SHR, the isolated diabetic state did not influence the vasoconstriction caused by various agonists. However, the enhanced vascular reactivity in the hypertensive state was blunted by simultaneously occurring diabetes mellitus. Endothelium-dependent and -independent vasorelaxation in this model was not affected neither by the hypertensive nor by the diabetic state.

Contractile responses to various inotropic agents in isolated hearts obtained from hypertensive diabetic rats.

The profile of the contractile effects of calcium ions, the Ca(2+)-entry promoter Bay K 8644 and two alpha 1-adrenoceptor agonists (cirazoline and ST587) was studied in isolated perfused Langendorff hearts taken from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) with simultaneous diabetes. In both the hypertensive and the diabetic state the isolated hearts showed a tendency to an impaired inotropic response (increase in left ventricular pressure (LVP)) towards an increase of extracellular calcium ions. The impaired inotropic response was most pronounced in hearts of rats with simultaneous diabetes and hypertension. The Ca(2+)-influx promoter Bay K 8644 did not influence the maximally developed LVP in (diabetic) SHR and WKY preparations. The inotropic responses to both cirazoline and ST587 were increased in hearts from diabetic WKY and diabetic SHR, when compared with those from control WKY and SHR. Hypertension, however, blunted the inotropic response to ST587 but not that to cirazoline when compared to hearts from control WKY or diabetic WKY. The present study indicates that the combination of hypertension and diabetes leads to progressive cardiac deterioration, likely to be the result of important changes in calcium homeostasis.

Influence of the low thyroid state in diabetes mellitus on cardiac function and inotropic responsiveness to alpha 1-adrenoceptor stimulation: comparison with the role of hypothyroidism alone.

The hypothyroid state accompanying diabetes mellitus has been suggested to be partly responsible for the diabetes-induced metabolic, hemodynamic, and pharmacological cardiovascular changes. We assessed the effectivity of streptozotocin (STZ) to induce diabetes mellitus and a hypothyroid state. Furthermore, we investigated the influence of diabetes and hypothyrodism on cardiac function and the inotropic responsiveness to the alpha 1-adrenoceptor agonist cirazoline in isolated perfused hearts. Fasted or nonfasted Wistar rats were made diabetic with STZ 20, 40 or 60 mg/kg intravenously (i.v.). Another group was made hypothyroid by addition of 6-n-propyl-2-thiouracil (PTU) to their drinking water. Rats receiving PTU became hypothyroid, whereas rats receiving STZ became simultaneously diabetic and hypothyroid. Basal functional parameters obtained in isolated perfused hearts were not influenced by diabetes, whereas maximal contractility was reduced in hearts obtained from hypothyroid animals. Cardiac inotropic responses to cirazoline were increased in diabetic rats, whereas responses in hypothyroid rats were not different from those in hearts obtained from control animals. Although diabetes mellitus and hypothyroidism are associated with various similar metabolic and haemodynamic parameters, the increased inotropic response to alpha 1-adrenoceptor stimulation as observed in isolated perfused hearts of diabetic rats cannot be explained by the decrease in serum thyroxine levels.

Opposite influences of hypertension and diabetes mellitus on pressor responses induced by different alpha-adrenoceptor agonists and angiotensin II in pithed rats.

Hypertension is often present in the diabetic individual and it is known to aggravate the vascular complications associated with diabetes. The pressor responses to two alpha 1-adrenoceptor agonists (ST587 and cirazoline), two alpha 2-adrenoceptor agonists (azepexole dihydrochloride (B-HT933) and UK14.304) and angiotensin II were investigated in pithed spontaneously hypertensive rats (SHR) and in pithed normotensive Wistar Kyoto rats (WKY) made diabetic by a single i.v. injection (55 mg/kg) of streptozotocin (STZ). Two months after diabetes was induced, the effect of the agonists on basal diastolic blood pressure (DBP) was determined. In pithed diabetic WKY and SHR, the maximal pressor response was impaired for all agonists. The dose response curves were shifted to the right when compared with their non-diabetic controls. The hypertensive state enhanced the maximal pressor response to all agonists compared with non-hypertensive animals. Additional diabetes blunted this increase in the effects of ST587, B-HT933 and angiotensin II, but not in those of cirazoline and UK14.304. Hypertension caused a leftward shift of the dose response curve for ST587 when compared with the non-hypertensive state. However, this effect was not observed when diabetes was present as well. In conclusion, hypertension resulted in an enhanced pressor effect, possibly caused by vascular hypertrophy, whereas the diabetic state counteracted this effect.

Beta-andrenoceptors in the hearts of diabetic-hypertensive rats: radioligand binding and functional experiments.

Myocardial beta-adrenoceptors and inotropic responses to beta-adrenoceptor agonists were studied in isolated hearts obtained from diabetic and/or hypertensive rats. Streptozotocin diabetic Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), as well as normoglycaemic SHR-stroke prone rats were used. At the age of 18-20 weeks, beta-adrenoceptor density was assessed in the left ventricle and isolated hearts were perfused according to Langendorff. Concentration response curves were made for dobutamine, salbutamol and the adenylyl cyclase activator forskolin. In both SHR and SHR-SP preparations a blunted inotropic response to beta-adrenoceptor stimulation was observed, although responses to forskolin and beta-adrenoceptor density and affinity were not different from those in normotensive hearts. In hearts taken from diabetic WKY and SHR, a decrease in beta-adrenoceptor density was observed, but no parallel blunted response to beta-adrenoceptor stimulation occurred. Moreover, the absolute (and percentual) inotropic responses to dobutamine and forskolin were increased in hearts from diabetic SHR when compared to their hypertensive normoglycaemic controls. These results suggest an impaired activity of the stimulatory G-protein in hearts obtained from hypertensive rats, whereas the simultaneous occurrence of hypertension and diabetes may result in a compensatory increase in activity of the adenylyl cyclase activated pathway.

Hypertensive diabetic rats in pharmacological studies.

Since hypertensive disease and diabetes frequently occur simultaneously there exists a requirement for animal models where both pathological entities are combined. The streptozotocin (STZ)-spontaneously hypertensive rat (STZ-SHR) and the obese Zucker rat are examples of animal models where hypertension and diabetes occur simultaneously. STZ-SHRs develop a hyperglycaemic syndrome, associated with other biochemical and morphological changes that to some extent approach insulin-dependent diabetes mellitus (type 1 diabetes) combined with hypertension. The obese (Fa/?) Zucker rat is characterized by the simultaneous occurrence of obesity, hyperglycaemia, hyperinsulinaemia, hyperlipidaemia and moderate hypertension. As such it approaches the patient with non-insulin-dependent diabetes mellitus (type 2 diabetes) who is simultaneously hypertensive. Lean (fa/fa) Zucker rats are suitable controls with respect to the obese animals. Both animal models (STZ-SHRs and obese Zucker rats) were characterized with respect to their biochemical, morphometric and haemodynamic properties. Both models were examined in particular with respect to the pharmacological characteristics of their cardiovascular system, as discussed in the present survey.