Antihypertensive effects of chronic 5-hydroxytryptamine (5-HT2) receptor blockade with irindalone in the spontaneously hypertensive rat.
The present study was conducted to evaluate the antihypertensive effects of irindalone, a potent 5-HT2-receptor blocking agent with weak alpha 1-adrenoceptorblocking properties. Young spontaneously hypertensive rats (SHR) received irindalone in the food (daily intake estimated to 10 mg/kg) for 10 weeks and older SHR received irindalone subcutaneously for 2 weeks (3 mg/kg/day by osmotic pump). The indirect systolic blood pressure was measured each week (tail plethysmography) and at the end of the intervention periods the direct intraarterial blood pressure was measured in conscious rats. Subsequently a dose-response curve of pressor responses to phenylephrine was constructed in pithed rats. Chronic oral treatment with irindalone reduced the development of hypertension but influenced neither body weight nor heart weight. The subcutaneous treatment with irindalone reduced the blood pressure in relatively older SHR compared with controls. Pressor responses to phenylephrine were antagonized in rats receiving oral treatment. However, during subcutaneous treatment with irindalone the dose-response curve to phenylephrine was not influenced, suggesting that the blood pressure reduction was not directly related to a concomitant alpha 1-adrenoceptor blockade. These results demonstrate that irindalone effectively reduces the blood pressure in SHR and that no tolerance develops to its antihypertensive effects. Since the blood pressure reduction, at least following subcutaneous treatment, was not directly related to a concomitant alpha 1-blockade, it is suggested that the 5-HT2-receptor blockade may be of relevance for the antihypertensive effect.
Department of Pharmacology, University of Gothenburg, Sweden.
K
K
Gradin
T
T
Hedner
B
B
Persson
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010656:Phenylephrine / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use
D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D010656:Phenylephrine; C056634:irindalone